JEFFCOATE’S PRINCIPLES OF GYNAECOLOGY
JEFFCOATE’S PRINCIPLES OF GYNAECOLOGY Seventh International Edition
Revised and updated from the sixth edition by
Pratap Kumar
MD FICOG
Prof. and Head, Department of Obstetrics and Gynaecology Kasturba Medical College, Manipal, Karnataka (India)
Narendra Malhotra
MD FICOG
Consultant and Director MNMH (P) Ltd., Agra Apollo Pankaj Hospital (P) Ltd., Agra (India) President, Federation of Obstetric and Gynaecological Societies of India-2008
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1957 1987 2001 2008
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Preface to the Seventh International Edition
We both, Dr Prof Pratap Kumar and Dr Narendra Malhotra feel very honoured for being asked to revise the best textbook on gynaecology by Sir Norman Jeffcoate. In the rapidly advancing age of technology and rapidly changing trends in management, diagnosis, drugs and procedures, it is of paramount importance to update books and manuals periodically. This book was earlier updated and edited by Dr Neerja Bhatla in the year 2001, an International Edition (Sixth edition), but soon the publishers felt the need for revising it within a span of five years. Prof Norman had expressed in 1974 that he had endeavoured to preserve his personal approach. We have added many new chapters and rewritten a few chapters all together trying to maintain Sir Jeffcoate’s style. We have retained the description of Professor Jeffcoate’s original case discussions, photographs and pictures. We hope that the undergraduate and the postgraduate students will appreciate our efforts to update this “Bible” of Gynaecology. Pratap Kumar Narendra Malhotra 2008
Preface to the Fifth Edition
It was inevitable that following Professor Sir Norman Jeffcoate’s retirement there would be pressure to continue to publish the Principles of Gynaecology. In the last revision in 1974 Sir Norman emphasised that he had endeavoured to preserve his personal approach, bearing in mind the objectives and principles outlined in the preface to the First Edition. In addition, some of Sir Norman’s comments in the preface to his Fourth Edition are included to emphasize the guidelines the present author has taken in an attempt to maintain the format of the Principles of Gynaecology. Much of the material presented is retained from the last edition, since it also reflects the gynaecological training of the author under Professor Jeffcoate in Liverpool. The views expressed are therefore personal ones from a pupil of Sir Norman Jeffcoate against the background of all the information available. Once given, the views expressed mean that references are excluded for the special reasons given in the preface to the First Edition. In the process of being taught obstetrics and gynaecology by Sir Norman, one was encouraged to consider all the facts about a case, to come to a conclusion and to be able to justify it. Even though a critical approach to each case was expected, we were never allowed to forget that we were dealing with a woman, mother or child with a personal problem. Indeed, Professor Jeffcoate’s personal approach was such that in a clinic with many students and postgraduates present, it was obvious that as far as the patient was concerned Sir Norman was the only person there. I have never been able to achieve the same effect, but I hope that my efforts in revising this book will be acceptable to an outstanding teacher, guide and friend. If so, then I am sure it will benefit all those who read it. Victor Tindall 1986
Extracts from the Preface to the First Edition
The book is meant to add to rather than replace clinical and tutorial instruction, so those matters which can best be taught beside the patient, or which are easy for any student to learn and understand from other sources, receive little attention. In planning the text I recalled those subjects which I myself found (and still do find) difficult to master, or on which I had to search far and long for information, and gave them disproportionate emphasis. This and other considerations resulted in a disregard for the relative importance - as judged by their clinical frequency -of different conditions. Indeed, the reader will find that quite rare conditions are mentioned, illustrated or described at length; and that all manner of asides - even some with an obstetrical flavour — creep in. This is partly because they are of special interest to me but mainly because they appeared to offer scope for presenting an attitude of mind; for discouraging loose thinking and empiricism; for inculcating a scientifically and ethically honest outlook; for emphasising the Art as well as the Science of gynaecology. I have not played safe by stating only generally accepted views, nor have I played fair by giving the differing views of various authorities. Instead, after weighing the evidence, I have attempted to reach a conclusion which satisfies me as being as rational as present knowledge allows. Without intended disrespect, mention by name of authors and workers has been avoided as a rule; references clutter up the text, destroy continuity and are hardly ever used properly. On the other hand, I have not hesitated to give my own views and have, at times, been more dogmatic than clinical experience ever really justifies. I have even gone so far as to enunciate ideas which in many respects are conjectural if not fanciful. I do not expect these all to be accepted; if they are I shall be disappointed because their object is to provoke trains of thought and discussion. In offering this book to fellow students I remember with affection and gratitude W Blair-Bell, one of the great gynaecologists of this century. He not only taught me gynaecology and a particular approach to it, he taught me to think and to write. He, more than anyone else, provided me with the stimulus and the opportunity to obtain the experience which has led to this work. Norman Jeffcoate 1957
Acknowledgements
A mammoth project like revising Sir Norman Jeffcoate’s Principles of Gynaecology requires lots of help from colleagues. We are grateful to all those who have helped us to do this mammoth job. Special appreciation and thanks are to: 1. Thank you doctors and staff of Department of Obstetrics and Gynaecology, Kasturba Medical College, Manipal, Karnataka. 2. Thank you junior doctors of MNMH (P) Ltd. and Apollo Pankaj Hospital (P) Ltd, Agra. 3. Our special thanks to the following, who have given valuable suggestions in various chapters: Prof Barun Sarkar, Prof Arun Nagrath, Dr Richa Singh, Dr Anju Sharma, Dr Alka Saraswat, Dr Jaideep Malhotra, Dr Anupam Gupta and Dr Neharikaa of Agra, Dr Sunder Rajan (Pondicherry), Dr Kavita Singh (Jabalpur), Dr Col R Puri (Jalandhar), Dr Sakshi Tomar (PGI Lucknow), Dr Maninder Ahuja (Faridabad). 4. Special thanks to Dr Pranay Shah of Mumbai for contributing Chapter on Laparoscopy and Dr Richa Saxena for editing the manuscript. We both are thankful to our families for bearing with us and sharing family time for work like this. Thank you Vidya, Dr Prabha Malhotra, Dr Jaideep Malhotra, Deepali, Deepika, Dr RM Malhotra, Kehsav and Neharikaa. We hope that our efforts will be appreciated.
Contents
1. A Clinical Approach to Gynaecology ................................................................................................................ 1 2. Anatomy ............................................................................................................................................................... 21 3. Ovarian Functions ............................................................................................................................................... 56 4. Menstruation and Other Cyclical Phenomena .............................................................................................. 79 5. Clinical Aspects of Menstruation and Ovulation ......................................................................................... 88 6. Puberty and Adolescent Gynaecology .......................................................................................................... 111 7. Conception ......................................................................................................................................................... 120 8. Spontaneous Abortions (Including Recurrent Loss) .................................................................................. 131 9. Ectopic Pregnancy ............................................................................................................................................. 142 10. Gestational Trophoblastic Disease ................................................................................................................ 160 11. Breast Function and its Disorders .................................................................................................................. 174 12. Development of the Urogenital System ....................................................................................................... 189 13. Malformations and Maldevelopments of the Genital Tract ..................................................................... 196 14. Sex Determination, Asexuality and Intersexuality ..................................................................................... 219 15. Injuries ................................................................................................................................................................ 251 16. Pelvic Organ Prolapse ...................................................................................................................................... 275 17. Other Displacements of the Uterus ............................................................................................................... 293 18. Torsion of Pelvic Organs ................................................................................................................................. 304 19. Infections Including STD ................................................................................................................................ 308 20. Infections as They Affect Individual Organs .............................................................................................. 333 21. Genital Tuberculosis ........................................................................................................................................ 361 22. Endometriosis and Allied States .................................................................................................................... 365 23. Polycystic Ovary Syndrome ............................................................................................................................ 384 24. Hirsutism ............................................................................................................................................................ 394 25. Epithelial Abnormalities of the Genital Tract ............................................................................................. 400
Jeffcoate’s Principles of Gynaecology 26. Genital Cancers ................................................................................................................................................. 427 27. Tumours of the Vulva ...................................................................................................................................... 440 28. Tumours of the Vagina .................................................................................................................................... 456 29. Tumours of the Cervix Uteri ........................................................................................................................... 464 30. Tumours of the Corpus Uteri .......................................................................................................................... 487 31. Tumours of the Fallopian Tubes .................................................................................................................... 517 32. Tumours of the Pelvic Ligaments .................................................................................................................. 521 33. Tumours of the Ovary ...................................................................................................................................... 524 34. Chemotherapy in Gynaecological Malignancies ........................................................................................ 561 35. Radiotherapy in Gynaecological Malignancies .......................................................................................... 568 36. Immunotherapy in Obstetrics and Gynaecology ........................................................................................ 573 37. Amenorrhoea, Hypomenorrhoea and Oligomenorrhoea .......................................................................... 579 38. Abnormal and Excessive Uterine Bleeding .................................................................................................. 598 39. Dysmenorrhoea ................................................................................................................................................. 617 40. Premenstrual Syndrome and Other Menstrual Phenomena ..................................................................... 627 41. Hormone Therapy in Gynaecology ............................................................................................................... 637 42. Vaginal Discharge ............................................................................................................................................. 656 43. Pruritus Vulvae and Vulvodynia ................................................................................................................... 662 44. Low Backache and Chronic Pelvic Pain ........................................................................................................ 676 45. Problems of Sex and Marriage ....................................................................................................................... 681 46. Infertility and Assisted Reproductive Technology .................................................................................... 699 47. Instruments and Gynaecological Procedures .............................................................................................. 731 48. Ultrasonography in Gynaecology .................................................................................................................. 741 49. Endoscopic Surgery in Gynaecology ............................................................................................................. 767 50. Contraception .................................................................................................................................................... 784 51. Sterilisation and Termination of Pregnancy ................................................................................................ 824 52. Urinary Problems .............................................................................................................................................. 839 53. Menopause ......................................................................................................................................................... 862 54. Hysterectomy and its Aftermath .................................................................................................................... 884 55. Conditions of the Lower Intestinal Tract ..................................................................................................... 890 56. Preoperative and Postoperative Management: Postoperative Complications ....................................... 899 57. Nutrition in Women from Adolescence to Menopause ............................................................................. 925 58. Exercise and Physiotherapy in Gynaecology ............................................................................................... 946 Index ..................................................................................................................................................................... 953
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CHAPTER
A Clinical Approach to Gynaecology
Psychosomatic and Sociological Aspects of Gynaecology Clinical Methods Special Tests and Accessory Aids to Diagnosis
“Mulier est hominis confusio,Madame, the sentence of this Latin is, ‘Woman is mannes joye and all his bits’.” - CHAUCER
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Gynaecology (from the Greek gyne, woman, and logos, discourse) is the study of woman but usage restricts it mainly to the study of the female organs of reproduction and their diseases. This is convenient although the dividing line between gynaecology and other branches of medicine is ill defined, and varies from time to time and from clinic to clinic according to advances in knowledge, to custom and to local working conditions. At one time, the breasts were wholly within the domain of the gynaecologist but now the general surgeon deals with certain breast disorders, and the gynaecologist and obstetrician with the others. The genital tract is so closely linked, embryologically and anatomically, with the urinary tract and the large bowel that certain conditions of the urethra, bladder and rectum come to a greater or lesser extent within the province of the gynaecologist. The whole endocrine system is concerned with the control of genital functions while the psyche and sex are inseparable. It may be added that, according to definition, obstetrics (the study of childbirth and its disorders) is merely one aspect of gynaecology and, in practice, the two cannot properly be separated. These points merely serve to emphasise that it is impossible to consider the reproductive system except in relation to the remainder of the body, and that it is necessary to interpret gynaecology in the widest sense. Woman is more than just a container for a uterus and ovaries. The development of the highly specialised gynaecological surgeon improves operative technique but may also engender a narrow and harmful outlook. Such a specialist can become a craftsman first and a doctor second. The woman who seeks advice for discomforts related to the genital organs is not usually in need of an operation: her need is understanding understanding the woman as a whole - her outlook, her achievements and failures, her domestic and social, as well as sexual, problems. The care of the whole woman will be threatened by the development of subspecialties such as gynaecological endocrinology, foetal medicine, gynaecological oncology and gynaecological urology, unless proper basic training in obstetrics and gynaecology remains a prerequisite to subspecialisation. These developments are justified only in a few centres, to promote growth of knowledge and expertise; otherwise they deprive the woman of the person she can look to for help at any time, one whom she knows has a personal interest in, and responsibility for, her welfare.
Jeffcoate’s Principles of Gynaecology Although covering all aspects of the physiology of the female genital tract, gynaecology is basically a clinical discipline and gynaecologists need to be primarily clinicians. PSYCHOSOMATIC AND SOCIOLOGICAL ASPECTS OF GYNAECOLOGY Environment can cause or aggravate physical and mental ill health; the psyche influences the develop-ment of organic disease in all parts of the body; illness begets anxiety and this in turn begets illness; the reactions of doctor, relatives and friends to illness can determine recovery or chronic invalidism. These are not new discoveries but are as old as the practice of medicine. Psychosomatic medicine and social medicine are merely new names for old arts which are practised almost automatically by the good doctor and which find an important place in gynaecology. Thus, menstruation can be inhibited for many months by a subconscious need to attract attention, by a desire for pregnancy and by a change in occupation or in living conditions. On the other hand, menstruation may be precipitated by excitement and can become regularly excessive in response to nervous tension and domestic disharmony. A woman may develop pelvic symptoms to escape the advances of her husband. Painful menstruation, painful coitus and the like frequently have fear, resentment or guilt over genital functions as their basis - inculcated possibly by impressions and experiences gained during childhood. Obesity is much more likely to be a manifestation of an anxiety state or bad habit than evidence of endocrine disturbance. Many women, when worried, find solace in eating and drinking; if they are sleepless, they have longer hours in which to solace themselves. A woman faced with unwanted responsibilities, or with any distasteful situation, may try to escape by blaming her genital organs about which there remains an air of mystery which secures for her the sympathy of other women and of the oversolicitous husband. A gynaecologist must be a psychologist although not necessarily a trained psychiatrist. If the part played by emotional and environmental factors in pelvic disease is recognised, only experience and wisdom are required to elicit them. The majority of women are unconscious of these factors in their illness and, when made aware of them by sympathetic explanation, encouragement and tact, can adjust themselves to ensure a cure. There are a few, however, who deliberately set out to deceive and
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go to such lengths to achieve their objective that they are not easily found out. Take for example the following rare case: A married woman aged 30 years, with two children, complained of recurrent and persistent vaginal bleeding which failed to respond to several lines of treatment. Ultimately her uterus was removed, whereupon the bleeding continued and was found to be coming from vaginal ulcers which refused to heal even when repeatedly excised. It was then proved that she deliberately injured the vagina to make it bleed. Rather than confining psychosomatic gynaecology to a single chapter, the aim in this book is to include it wherever it belongs, in the hope of placing it in its proper context. If the psychological aspects of gynaecology suffered from neglect in the past there is now some danger of their being exaggerated. In clinical practice it should be made a rule never to diagnose neurosis or a psychogenic basis for symptoms until organic disease is excluded for certain. CLINICAL METHODS The handling and examination of the patient can only be properly taught and learned in the consulting room (office) and at the bedside, and there is more than one way of doing them well. A systematic account of clinical methods is as wearisome to the writer as it is unprofitable to the reader. In this chapter, it is proposed to comment only on certain general principles and to offer suggestions for overcoming common difficulties. The diagnosis of the cause of the patient’s complaints depends on a process of detection. Some clues are worthless and misleading, others are small but important. The good diagnostician is one who quickly realises what is significant and what is not, one who will not dismiss evidence, bizarre though it may appear, if it does not fit in with preconceived ideas. Clinical intuition is no more than the capacity to take intelligent notice (sometimes almost subconsciously) of small points (Flow chart 1.1). History It is essential for the physician to communicate with a patient in a manner that allows her to continue to seek appropriate medical attention.It is necessary that a doctor listens to a patient completely and if there is a good ear to listen the diagnosis will be made easy. Not only the words used, but also the patterns of speech, the manner
A Clinical Approach to Gynaecology
Flow chart 1.1: An approach to a case with gynaecological problems
in which the words are delivered, even body language and eye contact, are important aspects of the patient– physician interaction. The most important evidence is always provided by the history which the patient or her relatives can give-if allowed to do so. The diagnosis can nearly always be made or reduced to one of two or three possibilities based on the history, without any physical examination. Indeed, it can often be made by telephone. Physical signs are less reliable and should mainly be used as confirmatory evidence. It is good practice never to examine the patient without having a provisional diagnosis in mind. The previous medical history, family history and the account of symptoms as given by the woman can be boring, but scrupulous attention to them saves time,
trouble, special investigations and mistakes. She appreciates the opportunity to tell her story and, amongst irrelevances, invariably gives vital clues. Moreover, many irrelevances can be avoided by skilful guidance and by the occasional leading question. A garrulous old woman aged 80 years was admitted to hospital as an emergency case with the history of a sudden onset of lower abdominal pain following a fall on getting out of bed. A few leading questions did not reveal typical features of any of the ordinary abdominal crises and, as the physical signs were not remarkable, she was kept under observation for 10 days during which time her discomfort subsided. She then appeared well and was prepared for discharge home. On the day the patient was due to leave hospital, as a final check, she was referred for the opinion of a gynaecologist. She was then, for the first time, allowed to tell her own story, from which it became clear that the sequence of events was (1) pain, (2) getting out of bed, (3) faintness causing her to fall, (4) unconsciousness on the floor for a few minutes, (5) residual abdominal pain and tenderness. All that remained necessary was to recognise a faint bruise around the umbilicus as ‘Cullen’s sign’, and the picture of intraperitoneal haemorrhage was sufficiently complete to justify laparotomy. This revealed the cause to be a small and previously non-palpable sarcoma in the fundus of the uterus. Successful interrogation requires an inquisitive outlook. Why has this woman come to see me today and not 6 months ago? Why has she not had children during 3 years of marriage? What was the illness which confined her to bed for 3 months in childhood and what were its symptoms and treatment? At what time in pregnancy did the two abortions occur? How long did she breastfeed the last baby? Did she suffer fever after any of the pregnancies? How old is her husband? Is she an only child? Have her aunts got hairy faces? What operation was carried out 5 years ago? What were her symptoms at the time and what was she told? Has she a home of her own? Does she go out to work and who looks after the children while she does? Why is she worrying about a trivial symptom or is it her mother worrying on her behalf? Is she afraid of cancer or of a sexually transmitted disease? History taking also requires tact, for it is concerned with details of what some women regard as highly embarrassing topics. It calls for privacy, kindness, courtesy and a deferment of the more personal questions
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Jeffcoate’s Principles of Gynaecology until confidence is established. Previous illness and confinements are usually safe grounds, although caution is necessary if a baby has been lost. A woman may find it easier to talk about menstruation than about discharge, while marital and domestic problems should come last. A matter-of-fact and coldly scientific attitude is the one most likely to encourage the patient to discuss intimate matters without embarrassment. Attention to dress, avoidance of jokes, formal behaviour and concentration on the patient and her problems are especially important to maintain the right atmosphere in a teaching clinic. Importance should be given to the Patient–Physician Relationship. One needs to listen more and talk less. Encourage the pursuit of topics important to patients. It is necessary to realise that one should minimise controlling speech habits such as interrupting, issuing commands, and lecturing. Care should be taken to understand discomfort of certain issues and become aware of discomfort in an interview, recognise when it originates in an attempt by the physician to take control, and redirect that attempt. The confidence one gives by assuring patients that they have the opportunity to discuss their problem fully is very important. Sometimes all that is necessary is to be there as a compassionate human being. If clinical findings or confirmatory testing strongly suggest a serious condition (e.g., malignancy), the gravity and urgency of this situation must be conveyed in a manner that does not unduly alarm or frighten the individual. Honest answers should be provided to any specific questions the patient may want to discuss. Often during the course of examination, some fact of which the patient is ashamed comes to light. Perhaps she is pregnant, or has been pregnant, or has had a sexually transmitted disease. Such confidential disclosures are to be received impassively and naturally, without sign of approval or disapproval, and the patient should not see that any record is made of them. SYMPTOMS Trivial Symptoms Whenever the symptom appears inadequate or atypical, suspect that it is a cloak for another worry. The recently married woman who complains of longstanding dysmenorrhoea is probably suffering from painful coitus. The woman without children after several years of
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marriage is often complaining of infertility whatever other symptoms she presents. Vague pains or insignificant discharge may denote cancer phobia. Pain
Exact Site and Radiation Ovarian and tubal pain is felt low in the abdomen, usually immediately above the inguinal ligament. Pain of uterine origin is diffuse and hypogastric in site, often referred to the inner aspects of the thighs but not extending below the knees. Backache of pelvic origin is in the midline, never higher than SI. It is not accompanied by local tenderness. It is easy to ask the patient to indicate the site of pain but failure to do so is common.
Nature of Onset and Duration These again are elementary matters, the neglect of which leads to errors. The pain present for 10 years can hardly be attributed to an event that occurred two years ago. The cervical laceration sustained during childbirth, or a retroversion following pregnancy, cannot be responsible for backache which commenced during the pregnancy. The patient should have a clear recollection of the circumstances under which a sudden onset of pain occurred.
Character A pain which the patient describes as ‘burning’ or ‘throbbing’ rarely has an organic basis. ‘Excruciating’ is also an adjective which raises doubts as to the genuineness of the discomfort.
Intensity This is best measured by the effect of the pain on sleep and work. If it does not cause wakefulness it is either caused by a lesion which is relieved by rest or is of little consequence. Severe pain is almost always reflected in the patient’s manner and demeanour. The woman of healthy appearance who describes her agony with a smile, and whose attention is easily distracted from it, is overstating her case.
Relationships In the patient complaining of pain, the clinician should try and establish its relationship to the following:
A Clinical Approach to Gynaecology • Menstruation: Women may try to link discomfort with menstruation and persuade themselves, if not the observer, that an association exists. There is always a lowering of pain threshold before and during menstruation so that even toothache feels worse at that time. Nearly every condition affecting the lower part of the body exhibits a premenstrual exacerbation, e.g. irritable bowel syndrome, sacroiliac and lumbosacral strain. Care is therefore necessary to ensure that a pain is truly associated with menstruation and, if it is, to know its exact relationship to the occurrence of the flow. • Coitus • Micturition • Defecation • Eating • Posture and movement: Recognition of the relationship with exercise and rest prevents many types of backache being attributed to a pelvic lesion. In fact, a backache which worsens by the evening is most often the result of strain imposed by a lax protuberant abdominal wall and the consequent compensatory lumbar lordosis. Menstrual Function
Menarche and Standard Menstrual Habit It is necessary to know the age of the menarche and the cycle which is normal for the particular individual. Knowledge of the latter provides a standard with which to compare symptoms. Women are often treated for ‘heavy periods’ without it being recognised that their menstrual function has never changed.
Menstrual Symptoms Patients unwittingly mislead themselves and the observer about the cycle. They say they menstruate ‘twice a month’ when periods begin on the second and twentyeighth day of the same month (that is, a 26-day cycle). They say they menstruate every 3 weeks when they mean that they are free from bleeding for 3 weeks (Fig. 1.1). Many keep no record of the dates of menstruation. When there is no urgency, ask the patient to keep a menstrual calendar for 3 months; she is often surprised at the regularity which this reveals. The amount of bleeding can be judged by the number of sanitary pads or tampons used, by interference with work or other pursuits, and by the presence of anaemia. In difficult and doubtful cases, the woman should be kept under observation throughout a certain period. Abnormal menstrual cycles deserve close analysis. It is not enough to know whether the loss is profuse or slight; its exact duration and periodicity must be determined.
Last Menstrual Period Knowledge of the date of the first day of the last menstrual period (and in many cases the date of the preceding one) is vital from the standpoints of diagnosis and treatment. The woman may say she does not know, or may use some vague expression such as ‘2 weeks ago’ but, with encouragement and help, can nearly always calculate the exact day. One of the reasons for knowing this is that every woman between the ages of 15 and 50 years should be regarded as being pregnant until proved otherwise. Failure to relate symptoms to the time in the menstrual
Fig. 1.1: Examples of misinterpretation of the menstrual cycle: (A) This represents a normal situation in which bleeding occurs for 5 days every 28 days, (B) A normal cycle with a short loss at the time of ovulation, described by the patient as menstruation every 2 weeks, (C) An essentially normal cycle (7/26) described by the patient as having two periods in one month or bleeding every 19 days
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Jeffcoate’s Principles of Gynaecology cycle explains why ovulation pain, corpus luteum haematoma, ectopic pregnancy and endometriosis are misdiagnosed as appendicitis. When there is dysmenorrhoea (painful menses) the history should be in more details as follows: As there are two types of Dysmenorrhoea (spasmodic and congestive) a careful history is needed to differentiate the same. Spasmodic or the Primary dysmenorrhoea has no obvious cause and is seen on the Day 1 or 2 of the menstruation, whereas congestive or the secondary dysmenorrhoea is due to some pathology in the gynaecological organs and the pain may be either premenstrual, menstrual or post-menstrual in nature. When a girl or a woman gets the secondary type (congestive) of dysmenorrhoea it is necessary to ask whether the pain is relieved on menstruation and if so the reason may be pelvic inflammatory disease (PID), whereas if the pain is more after menstruation it is usually due to endometriosis (ectopic menstruation). Menstrual type of dysmenorrhoea is usually due to fibroid of uterus (benign tumours of uterus) or adenomyosis (ectopic endometrium in the myometrium). Triple dysmenorrhoea (premenstrual, menstrual and post menstrual) is typical of endometriosis.
Associated Symptoms In condition like endometriosis a girl or woman may have all of the following symptoms or none of them or some of them. It is important to remember the 5 ‘D’s: • Dysmenorrhoea • Disorders of menstruation • Dysparunia (painful coitus) • Dyschezia (pain during passing stools) • Dull aching pain abdomen (due to distortion of anatomy) And Infertility will be the additional problem in cases of endometriosis. PHYSICAL EXAMINATION General A full general examination is as important in gynaecology as in any other branch of medicine and more important than in some others. Note the general appearance and behaviour of the patient. Does she show evidence of anaemia, dehydration, wasting, increasing
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weight or hirsutism? The neck may reveal enlargement of the thyroid gland or of lymph nodes. Disease of the heart and lungs must be excluded and in certain conditions chest radiography may be required. Examination of the mouth, hands, arms, legs and feet may precede or follow examination of the abdomen. Breasts While examining the heart and lungs, the breasts can be inspected to assess their development, and to exclude those changes indicative of early pregnancy without the patient realising that pregnancy is suspected. This is particularly true for the young unmarried girl. In all women and especially in those aged 30 years and more, the breasts should be palpated routinely to exclude tumour formation. Galactorrhoea should be looked for in women who are infertile and in those who have oligomenorrhoea. Abdomen It is necessary to understand that by a proper examination with the patient being comfortable, we will be able to get the right findings which will give the path to the right diagnosis. With the patient in the supine position, an attempt should be made to have the patient relax as much as possible. Her head should be leaned back and supported gently by a pillow so that she does not tense her abdominal muscles. The abdomen should be inspected for signs of an intra-abdominal mass, organomegaly, or distention that would, for example, suggest ascites or intestinal obstruction. Initial palpation of the abdomen is performed to evaluate the size and configuration of the liver, spleen, and other abdominal contents. Evidence of fullness or mass effect should be noted. This is particularly important in evaluating patients who may have a pelvic mass and in determining the extent of omental involvement, for example, with metastatic ovarian cancer. A fullness in the upper abdomen could be consistent with an “omental cake.” All quadrants should be carefully palpated for any evidence of mass, firmness, irregularity, or distention. A systematic approach should be used (e.g., clockwise, starting in the right upper quadrant). Percussion should be used to measure the dimensions of the liver. The patient should be asked to inhale and exhale during palpation of the edge of the liver.
A Clinical Approach to Gynaecology Omission to carry out an abdominal examination before a pelvic one results in many errors. The following are some points deserving emphasis: • No one is, or should be, better than the gynaecologist at palpation, for she/he is dependent on a highly developed and regularly used sense of touch for work in the antenatal clinic and in the delivery room, and for pelvic examination in general. • The lighter the palpation and the more the hand is kept on the flat, the easier it is to define tumours. • Every tumour in the lower abdomen should be suspected as being a full bladder and this condition can sometimes only be excluded for certain by passing a catheter. Otherwise, the commonest mass is a pregnant uterus. • Percussion of the abdomen can be even more valuable than palpation in the diagnosis of tumour, in distinguishing it from ascites and in deciding whether it is intraperitoneal or retroperitoneal. Except when a loop of bowel is adherent, all tumours arising from the pelvic organs are uniformly dull to percussion. A retroperitoneal tumour (including one of renal origin) almost always has one or more loops of bowel in front which show by resonance (Fig. 1.2).
Pseudocyesis and phantom tumours provide no problem to the doctor who percusses. Whenever an abdominal tumour is found, examine especially for ascites and enlargement of the liver. Examination of a Mass Per Abdomen
Inspection Note the abdomen for the shape or distension, dilated Veins.
On Palpation Note the size, shape, consistency, margins, mobility, unilateral or bilateral. It is important to differentiate between ovarian tumours (benign) from fibroid uterus. When a suprapubic mass is palpable, it is necessary to find out whether we could put our hands below the lower border or not. This is called as getting below the mass. If so the diagnosis is a benign ovarian tumour since the mass is pushed up because of the long pedicle an ovarian tumour has. If we cannot get below the lower border then the diagnosis is usually fibroid of uterus and the mass is described as ‘arising from the pelvis’. However if the problem is of malignant ovarian tumour then
Fig. 1.2: Percussion of the abdomen in the diagnosis of tumours. Dullness is indicated by shaded areas, resonance is shown in white, (A) An ovarian or uterine tumour, (B) Ascites, (C) A retroperitoneal tumour, a large hydronephrosis, for example
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Jeffcoate’s Principles of Gynaecology because of the spread of the disease the mass will be of variegated consistency, margins not clear, fixed or restricted mobility, and there may be presence of ascitis too. However all the malignant tumours do not have ascitis as only epithelial ovarian malignancy produces ascitis. Percussion: Fluid thrill and shifting dullness should be tested for to rule out ascitis. Pelvic Examination Pelvic examination is the last part of a gynaecological examination, its main purpose being to confirm a diagnosis already made or suspected from the history and symptoms. It should be repeated from time to time when an illness is long lasting, for the situation may change. One of the common traps is illustrated by the following case. A young single woman was attended on and off for many years by an excellent general practitioner because she had irregular and infrequent periods. At the original assessment no disease was found, so she was properly treated on general lines and assured that her symptom was of no consequence. At the age of 23 years she was still menstruating every 3-4 months and had become anxious to know if her fertility would be affected in the event of her marrying. Without further examination the doctor assumed that the problem was the same as it had always been. At the gynaecological clinic, it was singularly easy to reassure the young woman about her fertility because she was already 14 weeks’ pregnant.
Prerequisites • Presence of a third party, preferably a female nurse or relative, if the examiner is a male. • Consent of the patient or, if she is young and unmarried, of her parent or guardian. In the case of a specialist gynaecologist, it is generally accepted that the patient’s attendance implies consent to a pelvic examination. • The patient’s bladder must be empty. • The rectum and pelvic colon too should preferably be empty. If loaded, it may be wise to ask the patient to return after the bowel has been cleared by a laxative. • A good light which is well situated.
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Vaginal Examination Vaginal examination is usually more informative than rectal examination and is possible in most women. If the patient is virginal, the opening in the hymen may be wide enough to allow a one-finger or narrow speculum examination without pain or injury, especially if she is in the habit of using a tampon to control the menstrual discharge. A decision about attempting a vaginal examination in any case must be based on a previous assessment of the circumstances and the likely reaction of a given patient. In this connection, it is necessary to recognise the customs and religious beliefs in different countries. In the East and Middle East, for example, vaginal examination of the unmarried woman is generally never attempted for it may prejudice her prospects of marriage. Unless a bride can prove her virginity by an intact and unstretched hymen, the marriage may be annulled. For such reasons, it is not unknown for parents to refuse to allow their daughters to be treated for imperforate hymen causing haematocolpos. Whenever a tentative approach makes it clear that the patient is averse to the examination and that she is unlikely to cooperate, there should be no attempt at persuasion. If rectal examination coupled with ultrasonography does not supply all the necessary information, vaginal examination under anaesthesia is indicated. Each part of the genital tract should be examined in logical sequence - vulva, vagina, cervix, body of uterus, adnexa, pouch of Douglas. Gloves and instruments, if not disposable, should be sterilised by autoclaving before reuse. Washing and boiling offer inadequate protection against the real risk of transferring Trichomonas, Candida, Chlamydia, HIV and other organisms from one woman to another. All instruments should be dipped in bleach solution before autoclaving in order to kill HIV. The lubricant should be non-greasy. A water-soluble jelly is the best and, failing that, cetrimide solution. Antiseptic creams often cause local reactions and lanolin is difficult to remove. Any discharge or lubricant left on the vulva at the end of the examination should be swabbed away for the patient’s comfort. Inspection should precede palpation. Inspection of the vulva, vagina and cervix includes testing for prolapse. Speculum examination of the vagina and cervix should usually precede bimanual examination for the following
A Clinical Approach to Gynaecology reasons: vaginal discharge can be seen and removed for examination before it is contaminated with the lubricant; the cellular debris from the cervix and uterus is undisturbed and can be obtained for cytological study; and bimanual examination may make some lesions of the vagina and cervix bleed. Inspection thereafter is difficult, if not impossible. Although it is not easy to choose the right-sized speculum until the capacity of the vagina is judged by palpation, this difficulty can usually be overcome by careful appraisal of the introitus. A Sims’ or bivalve speculum (Fig. 1.3) should not be inserted with its blade in line with the cleft of the vulva and then rotated in the vagina. These instruments are designed for direct application after separation of the labia with the fingers of the opposite hand. The vagina is, in any case, wider from side to side than from front to back. For palpation, first insert one finger into the vagina; insert the second finger only when the patient relaxes the muscles around the vagina and when it is clear that a two-finger examination is possible without causing pain. Avoid the sensitive vestibule and urethral orifice and remember that the vagina slopes upwards and backwards. Insert and withdraw fingers slowly. The secret of bimanual examination is to use the abdominal hand more than the vaginal fingers. It is the former which must bring the various organs within comfortable reach. The beginner always thinks that shortness of the fingers accounts for inaptitude whereas it is failure to use the abdominal hand correctly. To feel the uterus, the vaginal fingers should move the cervix as far backwards as possible to rotate the fundus
downwards and forwards. The abdominal hand is then placed just below the umbilicus (not suprapubically) and gradually moved lower until the fundus is caught and pressed against the fingers in the anterior fornix. The uterus which is not felt is lying above and behind the abdominal hand. The points to be determined in regard to the cervix and the uterus are the size, shape, position, mobility, consistency and tenderness caused by pressure or movement. The normal uterus is tender when squeezed between the two hands. The position and direction of the cervix are the guides to the body of the uterus; for this reason, mere inspection of the cervix usually indicates whether the uterus is anteverted or retroverted.
How do we describe the size of a uterus? A bulky uterus (corresponding to 6 weeks pregnant size) is just bigger than normal. When the uterus is filling all the fornices it is corresponding to 12 weeks pregnant size uterus. When the fornices are not full the size can be less than 12 weeks size. In between the size could be between 8 to 10 weeks size. The following points are noted: Size of the uterus, anteverted or retroverted, mobile uterus, restricted mobility or fixed uterus. The adnexa is palpated for any masses or tenderness. If there is a mass felt its relation to the uterus is noted like whether the mass is felt separate to the uterus or is it felt continuous with the uterus. When the mass is felt separate to the uterus the origin of the mass is from the adnexa or broad ligament like the ovarian mass, broad ligament masses; whereas if the mass is continuous with the uterus it is arising from the uterus like a fibroid of the uterus. However in conditions like Endometriosis and Pelvic inflammatory diseases the adnexa may have a mass which is fixed and tender.
Rectal Examination
Fig. 1.3: The speculum is introduced directly in the transverse axis of the vagina (see text)
Rectal examination too can be assisted by placing the other hand on the lower abdomen to make it a bimanual procedure. Palpation of the cervix, uterus and adnexa is more difficult than by the vaginal route, and pressure on the cervix through the rectal wall nearly always causes pain. Rectal examination is useful when vaginal examination is impossible and has a special place in the pelvic investigation of babies and children, especially if ultrasound is not possible. It is also a useful adjunct to
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Jeffcoate’s Principles of Gynaecology vaginal examination and is the best approach for feeling the uterosacral ligaments, pouch of Douglas and the outer parts of the broad ligaments; it is, therefore used for assessing the extent of a growth arising in the cervix.
Combined Rectal and Vaginal Palpation It is extremely helpful to insert the index finger into the vagina and the middle finger into the rectum. This combined method has a special value in determining whether a lesion is situated within the bowel or between the bowel and the genital tract.
The Findings The student new to gynaecology is often depressed at being unable to palpate the uterus and adnexa. It should be explained that it usually takes one month’s work in a clinic before one can expect to feel the uterus bimanually in a reasonably cooperative unanaesthetised patient. In the more difficult case the uterus can be felt only if the patient is anaesthetised, and not always even then. The expert gynaecologist who confidently states that the uterus is normal in all respects sometimes does so without actually defining it. If honest, he or she will admit that often the findings are deduced by noting the position and mobility of the cervix, and by knowing that the uterus would be felt if it were enlarged. Normal tubes are never palpable, even in the anaesthetised patient. Palpation of the ovaries is largely a matter of chance but if they are not felt, the gynaecologist can be reasonably certain they are not enlarged. It may be added that even an expert at bimanual examination remains expert only so long as he or she is in regular practice; even one month’s holiday reduces one’s skill in the following week. A swelling which lies posterior to the vagina is nearly always caused by the rectal contents. A swelling in the left side of the pelvis should be regarded as originating in the bowel until proved to the contrary.
The Position of the Patient for Pelvic Examination There are several possible examination positions and all have a place in practice. Each has certain merits and strict adherence to one position is limiting. Full dorsal position (Figs 1.4 and 1.8A): This is the most commonly employed position. It is the best for inspection of the vulva and for bimanual palpation of the uterus
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Fig 1.4: Bimanual examination in the full dorsal position. Keeping the knees covered makes the patient feel less exposed
Fig. 1.5: Sims’ semi-prone position
and adnexa. It is not as good as the lateral position for inspecting the vaginal walls. Moreover, it can be embarrassing for the patient, especially in a teaching clinic. To maintain this position, nothing more than a firm couch is necessary, the examiner standing on the right side. The woman feels much less exposed if the thighs and knees are kept partly covered. Some gynaecologists prefer a short couch with foot rests, and they then stand directly in front of the patient. Sims’semi-prone position (Fig. 1.5): This position was devised by Marion Sims for operations on vesicovaginal fistulas. Used in conjunction with Sims’ speculum it is good for inspecting the anterior vaginal wall and cervix because, when the introitus is opened, the vagina balloons with air. The patient finds this position least
A Clinical Approach to Gynaecology embarrassing but movement is limited by the position of the left arm, and the abdomen is not easily accessible to the examiner’s left hand. It is therefore rarely used, especially nowadays with the availablity of sophisticated operating tables.
Modified Sims’or Lateral Position (Fig. 1.6) Here the patient keeps her left arm in front and she lies more on her side. It causes little embarrassment and allows good inspection of the anus, perineum, posterior parts of the vulva, vagina and cervix. It may be used for demonstrating prolapse during coughing and straining, and for minor operations on the cervix of the unanaesthetised woman. Bimanual examination is possible but is generally not as satisfactory as in the dorsal position.
dorsal position. This allows inspection of the introitus, testing for prolapse, inspection of vagina and cervix and the taking of swabs and smears. After speculum examination, first one and then two fingers are inserted into the vagina and bimanual examination is conducted. Combined rectal and vaginal examination is done when required. How to Get the Patient to Relax
This allows the vagina to balloon with air, encourages the intestines to fall away from the pelvis and is ideal for visualising the cervix and anterior vaginal wall. The patient finds it objectionable, however, so it is rarely used. It was previously used for certain operations, such as the insertion of radium or caesium, repair of a vesicovaginal fistula and culdoscopy. Bearing in mind the advantages and disadvantages, I make it a practice to examine the patient in the full
Satisfactory pelvic examination depends on the cooperation of the patient; this in turn depends on the personality of the medical attendant, the gentle but firm laying of hands and a calculated gradual but confident approach. The examiner who does not hurt the patient learns most, even if he does not reach the furthest. Despite care over these points, through nervousness, modesty and fear, some women find it difficult to relax the muscles of the abdomen and pelvic floor to allow bimanual examination. In these circumstances it is generally advised that the patient should flex the thighs on the abdomen and breathe deeply through the mouth, a procedure which is not always effective. The best way to obtain relaxation of the abdominal muscles in the dorsal position is for the patient to arch her back (without assistance from attendants) and to support herself on her shoulders and feet (Fig. 1.8B). Strong action of the extensor muscles of the trunk ensures complete and automatic relaxation of the flexors. This method also helps with the insertion of a bivalve speculum in the dorsal position. More over, in this position the pelvis rotates to bring the uterus nearer to
Fig. 1.6: Lateral position
Fig. 1.7: Lithotomy position
Lithotomy Position (Fig. 1.7) This is usually used for vaginal operations and for examination under anaesthesia.
Knee-Chest Position
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Jeffcoate’s Principles of Gynaecology the abdominal wall. Relaxation of the levators and other muscles around the vagina is secured by the patient deliberately abducting the thighs or by bearing down as in defaecation.
necessarily the complete answer. They should be used to fill in the gaps which remain after clinical assessment of the case. Cytology: Vaginal, Cervical, Uterine, Peritoneal
SPECIAL TESTS AND ACCESSORY AIDS TO DIAGNOSIS
See Chapter 26.
Ancillary Services
Colposcopy and Colpomicroscopy
With the ever-increasing number of laboratory tests and other investigations, the paramount value of ordinary clinical methods of diagnosis is in danger of being overlooked by the patient as well as by the medical attendant. It is easier to fill in a request form for blood analysis or radiography than it is to take a full history. More reliance is placed on the shadow than on the substance, and on a laboratory report than on a clinical appraisal of the patient. Because the report is typewritten, many fail to recognise that it is no more than an opinion, and sometimes the opinion of a relatively inexperienced technician. It is useful, but often not any more than the opinion of the doctor at the bedside. Information about hormones can be obtained at much less expense and trouble by noticing their effect on the patient’s own genital tract. The biochemist, pathologist and radiologist are members of a team and each can contribute valuable evidence towards the solution of the problem but not
See Chapter 25. Examination Under Anaesthesia This is a valuable weapon when pelvic examination is difficult or impossible. Examination under anaesthesia is not the answer to all problems; it is frequently less satisfactory than examination without anaesthesia, can be frankly misleading and in certain conditions, e.g. ectopic pregnancy, is dangerous. Its great disadvantage is that the all-important sign of tenderness is lost. Whenever this examination is carried out, anaesthesia must be suficient to ensure complete relaxation of the abdominal muscles. To obtain the maximum information, the examination should generally include measurement of the cavity of the uterus and endometrial sampling. Hysteroscopy may sometimes give additional information (see below). ENDOMETRIAL SAMPLING PROCEDURES Endometrial Biopsy: Out-patient (Office) Curettage The term endometrial biopsy is, by custom, applied to the incomplete diagnostic curettage carried out on the
Figs 1.8A and B: (A) Bimanual examination with the patient in the full dorsal position, (B) The attitude which the patient should adopt when examination is difficult. Use of the extensor muscles of the trunk ensures relaxation of the abdominal muscles; abduction of the thighs encourages relaxation of the pelvic floor. Tilting of the pelvis brings the pelvic organs within easier access of the abdominal hand
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A Clinical Approach to Gynaecology unanaesthetised woman. By means of a narrow biopsy curette, one or two strips of endometrium are obtained for histological study. This method is only used to determine the reactions of the endometrium to ovarian stimulation, or the presence of infective pathology, e.g. tuberculosis. Endometrial Aspiration Endometrial aspiration is an extension of the biopsy. It allows more thorough evaluation and can be used to diagnose or exclude certain types of endometrial disease as an out-patient procedure, e.g. hyperplasia and tuberculosis, to determine the response of the endometrium to endogenous hormones and thereby assess ovarian function including ovulation. A special narrow cannula curette (Vabra) is inserted into the uterus and the endometrial tissue is extracted by electric suction. A 4 mm Karman-type cannula to which is attached a 20 ml syringe can be used instead with similar results. Suction is maintained for two minutes. This detaches the endometrium, following which the curette is gently rotated in all directions and the endometrium sucked out. Endometrial aspiration is essentially a diagnostic procedure and any material obtained by it must always be submitted to histological, and often to bacteriological, examination. Its indications are definite and it should never be carried out without a clear reason and for want of something better to do. Since dilatation of the cervix is not required, no anaesthesia, or at most local infiltration of the paracervical nerve plexuses, is necessary and the patient feels little discomfort. This procedure is now used instead of endometrial biopsy or curettage, except in select cases where curettage is done for therapeutic indications. Endometrial aspiration coupled with endocervical curettage can be used instead of fractional curettage in women with postmenopausal bleeding to diagnose malignancy in the uterus or endocervix. While a positive result is conclusive, a negative result could be falsely negative and such cases may require curettage or hysteroscopy. Curettage Curettage may also be used to remove products of conception from the uterus, intrauterine polyps from the uterus or to discover disease of the endometrium. Sometimes curettage may be therapeutic as in the case of dysfunctional uterine bleeding and prolonged
menstrual flow consequent to the irregular shedding of the endometrium. In fractional curettage, the endocervical canal is curetted first and the sample set aside for histopathological examination. Next, the sound is passed gently into the uterine cavity to assess the direction and length, the cervix dilated gradually and the uterine body curetted thoroughly. The entire specimen from the body of the uterus forms the second sample. Fractional curettage is used for the diagnosis and localisation of malignancy in the uterine corpus or cervix. All curettage procedures require some form of anaesthesia. They also carry a higher risk of complications such as perforation and injury to the cervical os and, therefore, aspiration procedures are generally preferred. Culdocentesis and Culdotomy Culdocentesis is a procedure where in the needle is put through the posterior fornix into the pouch of Douglas and Culdotomy is a procedure where a transverse incision is put in the posterior fornix. However, culdocentesis was done for diagnosis of ruptured ectopic pregnancy or pelvic abscess but is no more done as there are better diagnostic modalities. Colpotomy is rarely done in cases of pelvic absecess drainage. Tubal Patency Tests The commonly used tests are: (a) Hysterosalpinogram (b) Sonosalpingogram and (c) Laparoscopy chromotubation. The passage of carbon dioxide through the uterus and tubes was used to determine tubal patency in cases of infertility. As a diagnostic procedure, its results are so unreliable that it has been abandoned in most clinics where other methods for testing tubal patency are available. (See also Chapter on Infertility). Hysterosalpingography Radiography of the interior of the uterus and tubes is especially useful in the diagnosis of tubal obstruction including hydrosalpinx, peritubal and intrapelvic adhesions, malformation of the uterus, small intracavitary tumours causing dysmenorrhoea and menorrhagia, and a defective internal cervical os causing abortion or premature labour.
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Jeffcoate’s Principles of Gynaecology Hysterosalpingography is valuable in the diagnosis of tubal disease such as tuberculosis. However, in the presence of active disease, it can lead to dissemination or activation of the disease and prove dangerous. Ultrasonography Ultrasonography or sonar (sound navigation and ranging) was originally used to detect submarines by means of ultrasonic echo sounding. Highly sophisticated apparatus working on this principle is now the most valuable diagnostic tool in a wide range of obstetrical and gynaecological conditions. Ultra-sound waves of very high frequency (3.5-5 MHz) generated by passing electric current through a piezoelectric crystal are passed through the abdo-minal wall which has been smeared with jelly to secure acoustic coupling. Solid tissues reflect the ultrasound beam while liquids allow it to pass through. The echoes, which are reflected back to the crystal, are converted to electrical energy. The images thus vary according to the character of the tissues encountered by the entering beam. By photographic recording of the echoes, a picture of the tumour or tissue under study is obtained. ‘Real-time’ imaging allows one to see the scanned object in motion by processing numerous pictures like a movie. The higher the wavelength used, the less the depth of penetration. Ultrasound permits the diagnosis of pregnancy (and of multiple pregnancy) and can determine its viability by the sixth to the eighth week. It can also identify the placental site and detect foetal abnormalities. In gynaecology, it distinguishes between ascites and abdominal tumours, and between uterine leiomyomas, ovarian cysts (benign or malignant) and other masses such as pyosalpinx. The interactivity of ultrasound makes it an extension of clinical examination. Probe palpation can be used to assess tenderness, movement and compressibility. Ultrasound is a reliable and acceptable method of distinguishing between hydatidiform mole and normal pregnancy (Figs 1.9A and B). It is routinely used in the management of infertility to detect the ripening graafian follicle, for confirmation of ovulation and for ovum pickup in cases of in vitro fertilisation. Ultrasound-guided biopsies and cyst aspiration can also be done. TRANSVAGINAL SONOGRAPHY Transvaginal sonography (TVS) is a valuable adjunct in gynaecology (Fig. 1.10). The TVS probe generates waves
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of a higher frequency, i.e. 5.5-7.5 MHz. The closer the probe is to the area which has to be scanned, the higher is the frequency required and the less the attenuation. TVS allows higher resolution imaging of pelvic structures, especially to assess endometrial thickness, follicle size and evaluation of adnexal masses. Thus, it is preferable to abdominal ultrasound in monitoring the induction of ovulation, diagnosis of ectopic pregnancy, distinguishing benign ovarian tumours from malignant ones, in evaluating endometrial lesions and assessing myometrial invasion by endometrial cancer. A major advantage is that it does not require a full bladder. However, its disadvantages are an initial lack of observer orientation to the anatomy and a depth of view limited to about 70 mm. Instillation of saline through a Foley catheter into the endometrial cavity (sonohysterosalpingography or saline infusion sonography) permits the assessment of tubal patency by transvaginal ultrasound - the fluid is seen passing through the tubes and collecting in the pouch of Douglas. It also permits the delineation of endometrial polyps. TRANSRECTAL SONOGRAPHY The transrectal probe is of particular benefit in the evaluation of cervical lesions and the assessment of parametrial extension of cervical cancers. It is also useful in patients with vaginal stenosis in whom the TVS probe cannot be inserted. COLOUR DOPPLER Another application of ultrasonics is the Doppler device which detects movement — for example, the flow of blood, and translates it into sound (Fig. 1.11). Strictly speaking, Doppler is not ultrasound because it usually falls within the audible range. The Doppler principle uses the shift in frequency of the sound wave, as the source moves relative to the observer to determine its velocity. Using this principle, it requires relatively simple apparatus to detect foetal heart action by the tenth week of pregnancy, and this can be of great help to the clinician. More sophisticated apparatus is able to quantitate blood flow through vessels, e.g. uterine artery, umbilical artery, foetal aorta, carotid and cerebral arteries and is important in managing cases of intrauterine growth restriction and pre-eclampsia. In gynaecology, it is used to diagnose the occurrence of deep venous thrombosis in the lower limbs.
A Clinical Approach to Gynaecology
Figs 1.9A and B: (A) This ultrasonic scan shows the typical molar tissue filling the uterus and below and to the lower right there is a theca lutein cyst, (B) This shows a normal foetus in its sac with the + mark indicating the crown-rump length of an 11-12-week foetus
Fig. 1.10: Transvaginal sonogram with a 7.0 MHz probe showing the uterus in longitudinal section with a central endometrial echo
Fig. 1.11: Uterine and adnexal (pelvic) arteriovenous malformation: the extensive colour signal is seen on axial power doppler imaging (courtesy. Dr Manpreet S. Gulati)
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Jeffcoate’s Principles of Gynaecology The Doppler gate is superimposed on a real-time scan that allows the target to be pinpointed. Commonly used indices of pulsatility in Doppler ultrasound are: • S-D ratio: It is the ratio of peak systolic to end-diastolic Doppler shift frequencies • Resistance index (Pourcelot index): It is the difference of maximum and minimum Doppler shifts divided by the maximum • Pulsatility index: It is the difference between maximum and minimum values divided by mean values of the waveform. This value is independent of the Doppler angle, that is, the angle between the ultrasound beam and the axis of the blood vessel. Transvaginal colour Doppler blood flow studies are useful in predicting whether tumours are benign or malignant. Malignant cell growth is accompanied by neovascularisation and angiogenesis. These vessels are thin-walled and therefore have a low impedance. Thus, benign ovarian cystic tumours may be avascular or relatively avascular and record moderate velocity and high-resistance flow with a resistance index (RI) of about 0.525. The RI falls to 0.322-0.255 in malignant ovarian tumours due to high-velocity and low-resistance blood flow, while the pulsatility index (PI) is 40 IU/L are consistent with complete cessation of ovarian function. Ovarian function can wax and wane over several years, and levels can fluctuate accordingly. Therefore, women with amenorrhoea and FSH >40 IU/L may resume menstruating for a short time in the future and occasionally may achieve pregnancy. Luteinizing Hormone In clinical practice evaluation of luteinizing hormone (LH) levels appears to be of somewhat less value than other hormone assessments during the menopausal transition. In a normally menstruating woman the LH is usually less than 10 IU/L and it is elevated in a PCOS woman. Prior to menopause, LH levels are usually in the range of 5 to 20 IU/L. However it is necessary to check both LH and FSH in women, especially young patients, with apparent loss of ovarian function. OVULATION Ovulation and the Menopause It is generally asserted that menstruation is frequently anovular during 5-10 years before the menopause and this is put forward as an explanation of lowered fertility after the age of 40 years. One of the few reported investigations into this matter showed that in women
Clinical Aspects of Menstruation and Ovulation aged 40-45 years, 75 per cent of cycles were ovular, and that in women aged more than 46 years, 60 per cent of cycles were ovular. Ovulation certainly continues sporadically if not regularly up to the time of the menopause and sometimes after wards. In England and Wales, prior to liberalisation of the abortion laws, 20-30 (1 in 28000) births each year occurred amongst women aged 50 years and over; in the USA, 1 in 20000 babies born had mothers aged 50 years or more. Most of the women who conceive late in life are still menstruating but there are reliable reports of conception occurring several months up to 11 years after the assumed menopause. In view of this, women should be advised not to discontinue contraceptive precautions until 2 years after the last menstrual period. After this time the risk is so slight as to be negligible. Spontaneous ovulation has been demonstrated, and pregnancies recorded, in women aged 52 years. The Editor of the Guinness Book of Records was convinced of the authenticity of reports of babies being born to women aged 54 or 55 years (in Britain, 1956); and 57½ years (in USA, 1956). (With assisted reproduction technology, a woman aged 63 years has now given birth to a child). Many women have the idea that there is an increased likelihood of conception at the change of life. This is not true; however, women may become careless about contraception as the menopause approaches. Ovulation and Lactation See chapter 11. Diagnosis of Ovulation It is sometimes clinically important to be able to determine if and when a woman is ovulating, and to distinguish between ovular and anovular menstruation. The following methods are available. Analysis of Symptoms
Cyclical Bleeding The occurrence of regular normal menstrual losses is strong presumptive evidence of monthly ovulation.
significance allows them to determine the approximate time of their ovulation.
Ovulation Bleeding or Discharge (Mittelblüt) Some women experience a slight loss of blood or of mucus tinged with blood at the time of ovulation. This may be associated with ovulation pain although each can occur independently. Those women who do not have obvious bleeding may notice an increase in the natural discharges. Occult ovulation bleeding, or the presence of glucose in the secretions (a postovulation phenomenon), can be detected if tampons or paper strips impregnated with appropriate chemicals are inserted into the vagina daily.
Premenstrual Mastalgia Premenstrual pain and tenderness in the breasts is in some way related to corpus luteum action, so its occurrence is fairly reliable evidence that ovulation has occurred during that particular cycle. Temperature Changes The body temperature is raised by progesterone and is therefore higher during the luteal phase of the cycle and also during pregnancy. During the later part of the menstrual flow and during the follicular phase the temperature is relatively low. Ovulation is sometimes preceded by a low peak and is generally followed by a rise. However, a monophasic tempera-ture chart does not always mean that ovulation has not occurred. The rise may occur suddenly within 24 hours or gradually over 4 days. After this the temperature remains 0.2-0.5°C higher than in the follicular phase until the onset of the next period (Fig. 5.1). This biphasic chart is evidence of ovular as opposed to anovular menstruation, and the thermal shift is a fairly accurate indication of the time of ovulation. For this test to be of value it is essential for the temperature to be recorded daily under standard conditions, before rising from bed in the morning and before eating or drinking. The drawbacks of this test are its poor correlation with hormone levels and the inconvenience to the patient.
Ovulation Pain (Mittelschmerz) Many women feel some discomfort in the hypogastrium, or in one or other iliac fossa, for 12-24 hours just before or just after ovulation. An awareness of its
Endometrial Changes The time of ovulation cannot be determined accurately by histological changes in the endometrium, but the fact
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Fig. 5.1: The biphasic basal temperature chart typical of an ovular menstrual cycle. If pregnancy occurs the temperature remains at a relatively high level
that it has occurred previously can be deduced by recognising secretory activity in the glands during the week preceding, or at the onset of, menstruation. Such activity is highly reliable evidence of corpus luteum formation. Endometrial biopsy or aspiration for this purpose can be carried out on the unanaesthetised patient without causing more than slight momentary discomfort. It is important that it is the surface endometrium and not the unresponsive basal layer which is examined. Changes in Cervical Mucus The different effects of oestrogen and progesterone on the physicochemical properties of cervical mucus are utilized in the fern test. Mucus is collected on cotton wool, spread thickly on a glass slide and allowed to dry. The fern pattern (Fig. 5.2) is seen under a low-power microscope from the sixth to the twenty-second day of
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Fig. 5.2: The fern test. Crystallisation of cervical mucus on a glass slide to produce the pattern of a fern leaf (arborisation). This phenomenon reflects an oestrogen influence and does not occur when progesterone is dominant
Clinical Aspects of Menstruation and Ovulation the cycle after which it is non-existent. A failure to demonstrate ferning during the premenstrual week, after a positive finding earlier in the same cycle, denotes a dominant progesterone influence and suggests that ovulation has occurred. In performing this test it is essential to prepare the glass slide by washing it in distilled water. The electrolytes in tap water prevent the crystallisation of mucus, and so does contamination of the mucus with blood or semen. Vaginal Smears Provided that there is no complicating pathology to confuse the picture, the daily examination of vaginal smears from the lateral vaginal wall by an expert will pinpoint ovulation quite well. The superficial cells increase in number towards mid-cycle and the number of intermediate cells declines gradually. A single smear taken in the second half of the cycle shows reliably whether a corpus luteum has formed. The intermediate cells now predominate. They have basophilic cytoplasm and large, pale, vesicular nuclei. The number of polymorphs increases. At menstruation, there is considerable debris with red and white blood cells and histiocytes. Hormone Assays Ovulation can be reliably confirmed by an estimation of the mid-luteal phase plasma progesterone level, i.e. 5-8 days after ovulation. A minimum of 6.5 ng/ ml is taken to indicate ovulation. Prediction of ovulation is possible by detection of the preovulatory LH surge which precedes follicle rupture by 34-36 hours. Radioreceptor assays can estimate the levels of LH in plasma and urine within 2 hours of collecting the sample. Various kits utilise erythrocytes coated with anti-LH antibody; their different rates of sedimentation in the presence or absence of LH gives an effective measure of the levels of LH, to enable the initiation of the surge to be detected rapidly. This demands repeated sampling to time the initial rise in LH which is related to the follicle rupturing some 36 hours later. This information is helpful in relation to the timing of artificial insemination or the timing of oocyte collection. The study of daily oestrogen and progesterone levels is only likely to be undertaken in women in whom ovulation is being induced with gonadotrophins.
Ultrasound The modern real-time ultrasonic apparatus has been used to describe ovarian and follicular characteristics throughout spontaneous and stimulated ovulatory cycles. It thus allows criteria to be set by which abnormal and possibly inadequate cycles may be identified prior to follicular rupture. This is helpful in the induction and confirmation of ovulation, artificial insemination and in vitro fertilisation. The wide range of follicular size of the dominant follicle still makes it impossible to predict the precise time of ovulation. Once ovulation has occurred the follicle appears as a smaller, irregular cyst which progressively decreases in size over the next few days. Internal echoes are seen within the follicle. Occasionally the follicle disappears completely. Sometimes, fluid is seen in the pouch of Douglas. Direct Observation Recent ovulation can be diagnosed by the finding of an active corpus luteum on inspecting the ovary during laparoscopy or laparotomy. Ovarian Dysfunction Ovarian dysfunction is classified into seven main groups (WHO 1976). Group I. Hypothalamic-pituitary failure, e.g. anorexia nervosa, Kallman’s syndrome, Sheehan’s syndrome. Group II. Hypothalamic-pituitary dysfunction, e.g. polycystic ovarian syndrome (PCOS), congenital adrenal hyperplasia (CAH), adrenal tumours, androgenproducing ovarian tumours. Group III. Ovarian failure, e.g. Turner syndrome, pure gonadal dysgenesis, Swyer syndrome, autoimmune disorders, infection (e.g. mumps), radiotherapy or chemotherapy. Group IV. Congenital or acquired genital tract disorders, e.g. imperforate hymen, Mayer-Rokitansky-KüsterHauser syndrome, Asherman’s syndrome. Group V. Hyperprolactinaemia with a space-occupying lesion (SOL) in the hypothalamic—pituitary region, e.g. pituitary adenoma. Group VI. Hyperprolactinaemia without an SOL in the hypothalamic-pituitary region, e.g. hypothyroidism, chronic renal failure, drug-induced.
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Jeffcoate’s Principles of Gynaecology Group VII. Amenorrhoea with an SOL in the hypothalamic-pituitary region with normal or low PRL, e.g. craniopharyngioma. Treatment The detailed treatment of all groups is discussed in the respective sections. Groups I and II are treated by induction of ovulation (see below) if they desire pregnancy. Group III patients will not respond to induction of ovulation but can be considered for oocyte donation. The management of group IV patients is discussed in Chapter 13. Groups V and VI are treated with dopamine agonists but may require induction of ovulation as well. Group VII need neurosurgery. Treatment of the Cause When general diseases such as diabetes, thyroid dysfunction, tuberculosis and anorexia nervosa are the basis of anovulation, treatment should be directed to cure these. Nevertheless, in resistant cases of anorexia nervosa, ovulation can be induced by gonadotrophin therapy. The Induction of Ovulation The induction of ovulation in clinical practice is only indicated when the object is to give a woman, infertile by reason of anovulation, a chance to conceive. It is not justified in the treatment of amenorrhoea alone. Moreover, no method can succeed unless the ovaries contain oocytes. This means that it is pointless to attempt to induce ovulation in the postmenopausal woman or one suffering from streak gonads. Elevated serum gonadotrophin levels coupled with lack of withdrawal bleeding on progesterone challenge indicate ovarian failure. Before treatment is planned it is necessary not only to be reasonably certain that ova are available for stimulation but to exclude the presence of all other possible bars to conception, male and female. This having been done, the methods whereby ovulation may be induced are as follows. Their results are always difficult to compute because of the possibility of ovulation occurring spontaneously irrespective of treatment.
Clomiphene This substance is an analogue of the synthetic nonoestrogen chlorotrianisene, distantly related to
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diethyl stilboestrol (DES). The usual commercial preparations comprise a mixture of the cis and trans isomers of clomiphene citrate, now redesignated zuclomiphene and enclomiphene citrate, the former being the mainly active principle. Taken by mouth, they are rapidly absorbed and are metabolised in the liver. Although mildly oestrogenic in some animals, clomiphene acts mainly as an anti-oestrogen in the human being. It competes with natural oestrogens for receptors on the specific oestrogen binding proteins and blocks their inhibitory action on the hypothalamicpituitary system. The overall effect of clomiphene is therefore to bring about a release of gonadotrophins. An upsurge in the plasma level of FSH and LH is demonstrable after clomiphene administration. It is also suggested that clomiphene may potentiate ovarian sensitivity to gonadotrophins. It follows that if clomiphene is to effect ovulation, the hypothalamic-pituitary system must be intact and capable of function. It is useless, for example, in cases of Sheehan’s syndrome. Some degree of ovarian activity also seems essential so, before clomiphene therapy is applied, it is necessary to establish, directly or indirectly, that the patient is producing a certain amount of endogenous gonadotrophins and oestrogens. The best results are seen when the level of the former is low and that of the latter is high. Some of the best indications for clomiphene therapy are the polycystic ovary syndrome and the Chiari-Frommel syndrome, amenorrhoea and anovulation following the use of oral contraceptives, and infrequent ovulation and menstruation. Clomiphene is a powerful drug and should not be given empirically. It is strongly contraindicated in the presence of impaired liver function. It is teratogenic when given in large doses to animals, so pregnancy should be excluded for certain before it is used. The initial course of treatment consists of 50 mg clomiphene daily given orally for 5 days. This can be commenced at any time in the amenorrhoeic woman but, for the woman who has regular anovular menstruation, the starting point is usually the fifth day of the menstrual cycle. (In IVF programmes, treatment is started from the second day to recruit more follicles). The treatment is monitored by daily charting of basal temperature and serum oestradiol levels or ultrasound for confirmation of ovulation, if practical. If it is successful, ovulation occurs 7-12 days after the last day of treatment and coitus should be timed accordingly. If it fails, further courses
Clinical Aspects of Menstruation and Ovulation of treatment can be related to the periods or at 30-day intervals in amenorrhoeic women if regular menses are not re-established. It is reasonable to increase the dose, if there is no evidence of ovulation or untoward reactions, to 100 mg or even 150 mg. If there are large cysts during observation of the follicular growth then the persistence of the cyst should be evaluated on Day 2 of menses since the next cycle of CC can be started only if there are no cysts. In general, no more than 150 mg of clomiphene is given in one day. Moreover, if the ovaries do not respond to six courses of treatment it is useless to give any more, and it may be dangerous to do so. Although the possible ill-effects of long-term treatment are unknown, there are stray reports of an increased likelihood of ovarian cancer in women who had received ovulation induction with clomiphene for prolonged periods. Women vary in their sensitivity to clomiphene and even small doses sometimes overstimulate the ovaries to make them the seat of pain, enlargement, cystic change, haemorrhage and multiple ovulation. Other, side-effects include hot flushes (which occur in 10 per cent of cases and which coincide with peak releases of LH), nausea and vomiting, headaches, visual disturbances, alopecia (rare) and galactorrhoea (rare). Such patients can often be successfully treated with 25 mg daily for 5 days, or sometimes even for 3 days. In well-selected cases clomiphene induces ovulation in 70 per cent but conception does not always result. This may mean that the evidence for ovulation is not always reliable and may reflect pseudo-ovulation or luteinisation of an unruptured follicle due to clomipheneinduced inhibition of prostaglandin synthesis. Another possibility is that the anti-oestrogenic action of clomiphene makes the cervical mucus unreceptive to spermatozoa. Pregnancy occurs in 40-50 per cent of women following treatment and, even though the dosage is carefully controlled, 5-10 per cent of the conceptions are multiple. Some patients with hyperinsulinaemia will not respond to clomiphene and there is emerging evidence that correction of the hyperinsulinaemia with metformin 500 mg tds will effect ovulation. If an ovulatory response is not seen in three months, clomiphene is re-started in addition, beginning at the lowest doses. Metformin should not be administered to women with compromised renal function.
Tamoxifen This is a triphenylethylene compound which has antioestrogenic properties, probably because it competes with oestrogen for binding sites in target organs. It is an alternative to clomiphene and used for the same type of case. The usual dose is 10 mg twice daily on the second, third, fourth, fifth and sixth days of the menstrual calendar. The dose may be increased, if there is no evidence of ovulation, to 20 mg twice daily and, if there is no response, up to a maximum of 40 mg twice daily. In women who are not menstruating, subsequent courses are recommended at 45 day intervals. If the patient responds with menstruation, the next course of treatment starts on the second day of the period. It is often a matter of personal choice as to whether one uses tamoxifen or clomiphene. Since some women respond to one of these drugs and not the other, it is not unusual for the alternative preparation to be given after a 3-4 month gap following six unsuccessful courses (the maximum recommended). There appears to be a rebound phenomenon with each preparation, for some women conceive shortly after completing a course. Patients on tamoxifen should be monitored as for clomiphene.
Corticosteroids In congenital adrenal hyperplasia regular treatment with small doses of cortisone or allied products usually corrects the ovarian function. The same is true for Addison’s disease (adrenal cortical failure), the occult form of which is characterised by anovular, although often regular, menstruation. Without such clear indications for it, however, corticosteroid therapy is not of any value. Dexamethasone has been added to clomiphene in women with hirsutism and high DHEAS levels. Daily administration of 0.5 mg at bedtime blunts the ACTH peak.
Gonadotrophins When ovulation is arrested because of a failure in the production of gonadotrophins by the hypothalamicpituitary system, the logical treatment is to administer these hormones. They may also be tried when the more simple clomiphene therapy fails to produce ovulation. Indeed, except when pituitary failure is clearly established, the above methods should be applied before
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Jeffcoate’s Principles of Gynaecology resorting to gonadotrophin therapy. Induction of ovulation with gonadotrophins has also been accomplished in hypophysectomised hypogonadotrophic women. All patients considered for gonadotrophin therapy will have been screened to exclude causes of amenorrhoea and anovulation treatable by other means. It is important that, if gonadotrophin therapy is considered appropriate, both husband and wife appreciate what is involved and are aware that treatment is costly and dangerous, and that success cannot be guaranteed. In most centres the number of treatments will be limited; we usually restrict it to six successful ovulations; ideally these should be confirmed biochemically. Gonadotrophin therapy should only be given in centres where appropriate facilities are available to monitor each treatment cycle in detail. Extreme caution is required when anovulation is associated with cystic ovaries, because of the high risk of an excessive ovarian response. Since each treatment schedule has to be tailored to suit each individual patient, and modified according to daily responses, it is a matter for experts in the field. Several preparations of gonadotrophins are available. The oldest is human menopausal gonadotrophin (hMG) extracted from the urine of postmenopausal women with 75 IU each of FSH and LH per ampoule; purified urinary FSH , and recombinant FSH which can be administered subcutaneously are also available. If day 3 LH levels are low, hMG is a better choice, whereas if LH is high, pure FSH is a better choice. Human chorionic gonadotrophin (hCG), recombinant hCG and recombinant LH are also available. Follicle stimulation is achieved by daily administration of gonadotrophin for 7-14 days. It is customary to start with 75 IU (one ampoule) daily from day 2 and assess the response by ultrasound, preferably vaginal, to assess the number and size of the follicles. Circulating oestradiol is periodically assessed, if possible. On the seventh day, further dose assessment is done depending on the response and the same dose is continued or it is stepped up. In the step-down method, the initial dose is higher (2-3 ampoules per day) and is reduced to one ampoule after the initial recruitment of follicles, thus mimicking the normal FSH changes. Patients with polycystic ovaries are at greater risk of hyperstimulation and need earlier monitoring and lower doses.
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Once the follicle has reached a size of 18-20 mm, the endometrium is showing the characteristic triple line and thickness of 9-10 mm, and the serum oestradiol level is 1000-1500 pg/ml, an ovulatory stimulus is given, either by 5000-10,000 units of hCG or 0.1 mg of triptorelin. The former mimics the LH surge and the latter stimulates it. The patient is advised to have intercourse regularly on that day and the next two days. Even when the optimum dosage has been determined, stringent monitoring of every course of treatment is essential because ovarian sensitivity varies from time to time and the activity of the ampoules of the commercial hormone prepara-tion is not constant. Moreover, ovulation sometimes occurs without hCG being given, this being explained by the fact that preparations of hMG contain variable amounts of LH. The postovulation phase is also monitored since it helps to determine a subsequent dose of FSH, should further treatments be required. Ovulation results more frequently than does conception, but overall the pregnancy rate should be at least 50 per cent with good selection and has been reported to be as high as 90 per cent in group I patients. The multiple pregnancy rate is about 20 per cent, with multiples over two forming 2-5 per cent. Despite all precautions, there is clinical evidence of ovarian hyperstimulation in not less than 2-5 per cent of treatment cycles. Ovarian hyperstimulation syndrome: The ovarian hyperstimulation syndrome (OHSS) is an iatrogenic condition. It has a varied spectrum but is usually manifested by ovarian pain, haemorrhage, enlargement and cystic change (Fig. 5.3). Haemorrhage in particular can give rise to an ‘acute abdomen’ and to unnecessary laparotomy. Any discomfort, with or without fainting, is most likely to commence 2-4 days after the administration of hCG; it increases for 7 days and wanes during the next 7 days. The patient should be warned accordingly. Another possible side-effect is a painful reaction and swelling in the tissues at the injection sites. When treatment has been less well controlled there have been cases of serious complications and a few fatalities have been recorded. In these, and probably as a result of a high level of ovarian steroids in circulation affecting the vascular tree, electrolyte levels and renal function, there have developed hypovolaemia, renal failure, a shift of protein from the plasma to the peritoneal, pleural and rarely the pericardial cavities with
Clinical Aspects of Menstruation and Ovulation
Fig. 5.3: Gross enlargement of the ovaries complicating treatment with human gonadotrophins and resulting in a tumour arising out of the pelvis and extending as high as the umbilicus. This developed 7 days after the giving of hCG preceded by FSH. The patient conceived during this cycle of treatment and the enlargement of the ovaries subsided only very gradually during the first 3-4 months of pregnancy
consequent ascites and hydrothorax (pseudo-Meigs’ syndrome), and venous thromboembolism. Massive intraperitoneal haemorrhage from the ovaries is also described. Adult respiratory distress syndrome (ARDS) is a rare but life-threatening complication which can lead to cardiac arrest. Based on clinical, laboratory and ultrasonographic findings OHSS is subdivided into mild, moderate and severe classes. If the ovaries are less than 8 cm in diameter and the patient complains of abdominal bloatedness, heaviness, tension or swelling with mild pain, the case is categorised as mild. In moderate OHSS, the ovaries are 8-12 cm in diametre, ascites may be detected on ultrasound, all symptoms are more severe and may be accompanied by nausea and vomiting. In severe OHSS, the ovaries are > 12 cm in diametre, there is clinical ascites, sometimes hydrothorax. Laboratory assessment reveals haemoconcentration, hypoproteinaemia and electrolyte disturbance. There is hypovolaemic perfusion. Management aims to provide symptomatic relief and prevent complications. In mild OHSS, outpatient management may suffice and the condition resolves with the onset of menstruation. Paracetamol and opiates are safe but NSAIDs should be avoided as they interfere with the dispersion of the cumulus oophorus and ovum release. Anti-emetics, adequate fluid intake orally or parenterally and discontinuation of hCG with changeover to progestogen are important ancillary measures. In moderate OHSS the cysts take 2-4 weeks to resolve, but in conception cycles they may take longer. Elastic stockings reduce the risk of thromboembolism.
The treatment of severe OHSS is to admit the patient and put her on bed rest with strict intake-output charting, frequent monitoring of vitals and daily weight record. The haematocrit, blood urea, serum creatinine, electrolytes, serum proteins with albumin-globulin ratio, coagulation studies and electrocardiogram are monitored serially. Plasma expanders, human albumin and electrolyte supplements are administered to restore the plasma volume and correct the electrolyte imbalance. Removal of the fluid from the pleural and peritoneal cavities may be required if life-threatening ARDS develops. Heparinisation is indicated in severely haemoconcentrated patients to prevent arterial and venous thromboses. Termination of pregnancy or surgery for haemorrhage or rupture of the cysts is rarely required. The incidence of OHSS can be reduced by careful monitoring of serum oestradiol and serial ultrasonography. If serum oestradiol levels are high or there are a large number of maturing follicles, hCG is withheld and the cycle is cancelled; or, if facilities permit, the oocytes are collected for cryopreservation. These patients are asked to weigh themselves daily. If weight gain is >5 kg or any of the other symptoms develop, they must come to the hospital. Using GnRH agonists instead of hCG for ovulation induction reduces the incidence of OHSS. All CC cycles must be monitored by sonography for response or hyperstimulation.
Clomiphene and Gonadotrophins When clomiphene alone fails to produce ovulation, it is supplemented with hCG 5000-10000 IU which mimics the LH surge. The combination of clomiphene with FSH and LH decreases the requirement of gonadotrophins and therefore the cost of therapy. Clomiphene administration is begun on the second or third day of the cycle with 100 mg daily for 5 days and then 2 ampoules of gonadotrophins are administered daily or on alternate days with monitoring as described above. If the response is not seen with 100 mg CC it is ideal to add Gonadotropins to CC for few days (CC 100 mg Day 2-6 plus add Gn 75 IU from Day 7 to 10 for better response or give only Gn.
Bromocriptine Although this drug does not specifically induce ovulation, it is the drug of choice for those women with amenorrhoea and/or infertility associated with
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Jeffcoate’s Principles of Gynaecology hyperprolactinaemia. A raised level of prolactin is thought to cause anovulation by a central and/or peripheral effect at the hypothalamic level by inhibiting the release of GnRH and hence FSH and LH, and peripherally by antagonising the effects of LH and FSH on the gonadal ovulatory processes. The drug may also be used for those women who have normal prolactin levels but who have not ovulated with courses of clomiphene or tamoxifen, before considering using gonadotrophins for inducing ovulation. In most instances, irrespective of the final dosage, the optimum response with the minimum of side effects is best achieved by the gradual intro-duction of bromocriptine. It is recommended that the tablets should be taken with food, starting with one tablet (2.5 mg) at bedtime, increasing after 5-7 days to two tablets. The dose may then be increased by a further tablet 5-7 days later until the a dose of 2.5 mg three times daily is reached. In infertile patients without an elevated serum prolactin level, the usual dosage is 2.5 mg twice daily. The lowest effective dose should be the objective of treatment in women with normal prolactin levels to avoid suppressing the prolactin level too much, since this would impair luteal function. Therefore, during the regular assessments the prolactin levels should be checked, since the duration of treatment will usually last 6-9 months if pregnancy does not occur. Bromocriptine should be discontinued if pregnancy occurs, although there is no evidence of any teratogenic effects.
Hypothalamic Releasing Factors (GnRH) When the anterior pituitary gland is intact and capable of function, for example, when anovulation follows inhibition of the hypothalamus, it would appear appropriate to administer releasing factors instead of gonadotrophins. There are problems in administering GnRH because it has a very brief half-life and has to be given continuously in a pulsatile fashion by portable infusion pumps. This method is effective in women with hypothalamic amenorrhoea who do not have menstrual bleeding following a progestin challenge because of deficiency of endogenous GnRH. It is also effective in women with hyperprolactinaemia who cannot tolerate bromocriptine. The pump has to be worn constantly. Drug administration may be intravenous or subcutaneous, doses being 5 mg and 20 mg per bolus, respectively every 90 minutes with the dose being increased in 5 mg
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increments if required. Intravenous adminis-tration requires heparinisation. After ovulation, the pump may be continued or alternatively hCG 2000 IU is given intramuscularly every 3 days for luteal support. The pregnancy rate after 6 cycles is 80 per cent; with polycystic ovaries it is 30-40 per cent. The incidence of multiple pregnancy is low. In spite of its physiological action and advantages, the pump has not been accepted well by patients and is not available in many countries.
GnRH Agonists and GnRH Antagonists Women with elevated basal levels of LH, e.g. women with PCOS have a poorer response to hMG treatment and a higher rate of abortion. In such women GnRH agonists are administered to convert these patients to a hypogonadotrophic state. GnRH agonists desensitise and downregulate pituitary GnRH receptors. Thus endogenous hormone production is shut off. Removal of the premature LH release improves the pregnancy rate, decreases the abortion rate and may even decrease the risk of ovarian hyperstimulation. Administration of GnRH agonists causes an initial stimulatory response, the ‘flare’, which results in enlarged follicular cysts if the agonist is administered in the follicular phase or to anovolutary women. To obviate this problem, treatment is started in the mid-luteal phase of the previous cycle. The agonists are administered subcutaneously (e.g. leuprorelin 500 μg bd or 3.75 mg im) or intranasally (e.g. nafarelin 200 μg bd). Complete downregulation takes 7-10 days if started in the midluteal phase and about 3 weeks if started in the follicular phase. At this time patients develop menopausal-like symptoms but these disappear once hMG is started. Following downregulation, hMG administration is started (Fig. 5.4). Higher doses of gonadotrophins are usually required following GnRH therapy which implies increased cost of therapy. The agonist is administered daily throughout the duration of gonadotrophin treatment until hCG is administered. Luteal support with hCG or progesterone is essential to compensate for the suppresed endogenous LH level. False-positive pregnancy tests can result from the luteal phase administration of hCG. High LH levels have a negative role in IVF, so reduction in bioactive LH levels in the serum is desirable,
Clinical Aspects of Menstruation and Ovulation
Fig. 5.4: Showing long protocol of GnRH-agonists
Fig. 5.5: Showing protocol with antagonists
particularly in the light of evidence associating raised LH levels in the follicular phase with adverse reproductive outcomes: • Reduced fertilisation and pregnancy rates. • Increased spontaneous abortion rate. Most specialist infertility clinics attempt to minimise premature LH surges using pituitary down-regulation. To achieve this, gonadotrophin-releasing hormone agonists (GnRH-a) were introduced into IVF superovulation regimens in the late 1980s and have become established as a component of standard regimens in most centres worldwide. The inclusion of GnRH-a in ovarian stimulation protocols for assisted reproduction technologies (ART) has resulted in significant improvements in outcome: • Cycle cancellation rates have decreased. • Clinical pregnancy rates have increased. In fact, before GnRH-a became available, approximately 20 per cent of stimulated cycles within an IVF program were cancelled due to premature LH surges. By using the GnRH-a to prevent LH surges via gonadotrope GnRH receptor (GnRH-R) downregulation and desensitisation, this percentage decreased to about 2 per cent, and concomitantly, the IVF and pregnancy rates (PR) per cycle initiated were increased. Several treatment schedules currently are in use (long, short, or ultrashort protocol): the long protocol, in which the GnRH-a is begun in the luteal phase of the
cycle preceding the treatment (stimulation) cycle and down-regulation occurs before the start of the gonadotrophin-stimulation treatment phase, is generally the most effective regimen and is presently the most frequently used protocol. However, it has some disadvantages, such as hypoestrogenic side effects and an increase in the number of ampoules of FSH or hMG required for adequate stimulation. Low doses of the native peptide delivered in a pulsatile manner to mimic that found in the hypothalamic portal vessels restore fertility in hypogonadal patients, and are also effective in treating cryptorchidism and delayed puberty. Administration of high doses of GnRH or agonist analogues causes desensitisation of the gonadotrope gland with consequent decline in gonadal gametogenesis and steroid and peptide hormone synthesis. This phenomenon finds extensive therapeutic application in clinical medicine in a wide spectrum of diseases and in IVF to avoid LH increase. In addition, GnRH analogues could be used as new generation male and female contraceptives in conjunction with steroid hormone replacement. GnRH-antagonists (GnRH-ant) inhibit the reproductive system through competition with endogenous GnRH for the receptor and, in view of their rapid effects, are being increasingly used for the above mentioned applications. GnRH antagonists are started midcycle to suppress LH. Hence the dose of gonadotrophins are reduced. GnRH antagonists causes immediate suppression of LH (Fig. 5.5).
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Surgical Procedures Wedge resection of the ovaries was earlier practiced in patients with polycystic ovaries who did not respond to medical induction of ovulation. Removal of stromal tissue resulted in decreased androgen and inhibin levels with a consequent rise in FSH levels and subsequent ovulation. Most centres have now replaced wedge resection with laparoscopic procedures. The procedure is reserved for those women where an adequate trial of medical induction has been unsuccessful. The ovaries are ‘drilled’ using cautery, diathermy or laser through the laparoscope. Multiple punctures are used, varying from 4 to 20 per ovary, following which there is spontaneous ovulation or at least an increased sensitivity to clomiphene. However adhesions may develop in about 10-15 per cent of cases. Severe haemorrhage may occur. Excessive tissue destruction has also been reported to result in premature ovarian failure, so current trials are evaluating the place of lesser punctures which may even be restricted to one ovary. The effect is temporary. Better results have been reported with cautery than with laser. Suppression of Ovulation The causes and means of suppression of ovulation are as follows.
Disease Ovulation is suppressed by psychoses and neuroses; by diseases affecting the hypothalamus, pituitary, ovary, thyroid, pancreas and adrenals; by metabolic disorders, including starvation and obesity; and by debilitating diseases of many kinds. In these circums-tances, ovarian failure is usually accompanied by amenorrhoea or oligomenorrhoea.
ovulation in susceptible women. They probably act via the hypothalamus, through prolactin. Some chemotherapeutic drugs, notably mustard-type alkylating agents and busulfan may cause permanent anovulation. Other drugs which have been implicated include the vinca alkaloids, bleomycin, cytosine arabinoside and hydroxyurea. Electroconvulsive therapy can have a similar effect.
Irradiation It is possible to suppress ovulation temporarily or permanently by exposing the pituitary gland or the ovaries to ionising radiations.
Oestrogens and Progestogens Ethinyloestradiol, 0.05-0.1 mg, administered daily from the fifth day of the cycle onwards, prevents ovulation by inhibiting the production of gonadotrophins. This is evidenced by the fact that it eliminates the normal midcycle upsurge of gonadotrophins in the plasma and urine. Progestogens given alone do not usually suppress ovulation. It is the oestrogen content of the combined oestrogen-progestogen oral contraceptives which mainly determines their anti-ovulatory effect.
Androgens Any androgen given in a sufficient dose inhibits ovulation, mainly by direct inhibition of the ovarian follicles.
Danazol This drug has antigonadotrophic effects that suppress the mid-cycle surge of gonadotrophins. Most women become amenorrhoeic within 6-8 weeks of treatment.
Drugs and Other Therapeutic Agents Certain drugs, notably chlorpromazine and its derivatives, and possibly reserpine, can sometimes arrest
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Analogues of Hypothalamic Releasing Factors Ovulation can be inhibited by GnRH agonist treatment.
6
CHAPTER
Puberty and Adolescent Gynaecology
Puberty and Adolescence
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PUBERTY AND ADOLESCENCE Definition and Description Adolescence (Latin: adolescere = to grow) is the period of life during which the carefree child becomes the responsible adult. The period varies in duration from one individual to another and is difficult to define. A modern description of the adolescent is the ‘teenager’. Puberty (Latin: pubertas — adulthood) is the state of becoming functionally capable of procreation. This is usually accepted as occurring at the age of 12 years in girls and 14 years in boys, but full reproductive capacity is not usually attained until later. Puberty is characterised by physical sexual differentiation and by the onset of activity of the sex organs (see Fig. 6.1 and Table 6.1). Puberty is really the first part of adolescence, the remainder being concerned with the mental and emotional adaptation to sexual function and with the development of full maturity. The menarche (Greek: month + origin) is the onset of menstruation and is merely one manifestation of puberty. During childhood the anterior pituitary is concerned mostly with physical growth. It is capable of gonadotrophic activity but is inhibited by the hypothalamus until the higher centres of the brain are more mature. At puberty, as a result of the increased secretion of releasing factors by the hypothalamus, and the increased responsiveness of the pituitary gland to these factors, all activities are increased. This is manifested by a sudden spurt in stature just before or after the menarche (GH effect); by enlargement of the thyroid (TSH effect); by increased adrenal cortical activity (ACTH effect); by skin pigmentation (MSH effect); and by the onset of ovarian activity (gonadotrophin effect). The cyclical production of gonadotrophins and oestrogens in amounts approaching those found in the adult is often demonstrable by the age of 10 years. The secretion of oestrogen by the ovaries and of androgens by the adrenals induces epiphyseal closure, and skeletal growth then ceases. Nevertheless, some sexual differentiation occurs in childhood. The nipples are rather more obvious in the female than the male by the age of 3 years, and there is a tendency to plumpness and roundness of the limbs at 6-8 years. The pelvis widens between the ages of 7 and 11 years. Definite signs of puberty are usually present by
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Fig. 6.1: Development of the female breast
Table 6.1: Tanner staging of development of secondary sex characteristics
Stage
Breast
Pubic hair
1. 2.
Elevation of papilla Elevation of breast and papilla as a small mound, increased areolar diametre (median age 9.8 years) Further enlargement without separation of breast and areola (median age 11.2 years) Secondary mound of areola and papilla above breast (see Fig. 6.1) (median age 12.1 years) Recession of areola to contour of breast (median age 14.6 years)
No pubic hair (prepubertal) Sparse, long pigmented hair mainly along labia majora (median age 10.5 years)
3. 4.
5.
Dark, coarse, curled hair sparsely spread over mons (median age 11.4 years) Adult-type, abundant hair, but limited to the mons (median age 12.0 years) Adult type spread in quantity and distribution (median age 13.6 years)
Reproduced with permission from Speroff L. et al., Clinical Gynaecologic Endocrinology and Infertility (ed. Mitchell C), Lippincott Williams and Wilkins, 1999.
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Puberty and Adolescent Gynaecology the age of 9 or 10 years when the breasts develop a ‘bud’ (thelarche, Fig. 6.2A), and soon afterwards they become generally enlarged. By this time hair begins to grow on the body, appearing first on the mons veneris (adrenarche). Meanwhile body contours change by the deposition of fat, the growth spurt occurs and there is some evidence of skin pigmentation, notably on the vulva but sometimes around the eyes, mouth and nipples, and on the abdominal wall in the form of a linea nigra. Some development of the breasts and pubic hair usually precedes the onset of menstruation, the average interval being 2 years. Axillary hair appears later, often after the menarche. Hence, the adolescence starts with thelarche (development of breast buds), followed by pubarche (development of pubic hair), adrenarche (development of axillar hair) and menarche (the first menstruation) (Flow chart 6.1). The first menstrual period usually occurs between the ages of 10 and 16 years, the average being 13.5 years in India, 13.0 years in Western Europe and 12.5 years in North America. The age of the menarche varies to some extent with family, race, social class, family size, birth Flow chart 6.1: Phases of female development
order, environment, diet and general health, but not with climate. Menstruation tends to occur earlier in the higher social classes and in urban surroundings; this probably reflects general health. The age of the menarche, and of maturity in general, is falling. Among Caucasian races at least, girls of 14 and 15 years are now as physically and sexually developed as their mothers were at the age of 16 years. In England and Wales, Western and Northern Europe and in North America the mean age of the menarche dropped from 17 to 13 years during the 100 years up to 1960, decreasing at the rate of 4 months every 10 years. Similar trends were, and are being, seen in all countries and are variously credited to better nutrition, freedom from disease and increased outbreeding which provides hybrid vigour. However, after 1965 (in girls born from 1946 onwards), the menarchal age ceased to fall in Britain, North America and Western Europe and is now static at the levels indicated above. Whether this is a temporary or permanent stabilisation remains to be seen. During the 2 years before the menarche the development of the genital tract proceeds apace. The menstrual flow itself is often preceded by mucoid vaginal discharge, and by periodic hypogastric pain caused possibly by uterine contractions. Rarely ovulation and even conception can precede the menarche. The phase of active physical growth makes the girl temporarily lanky and awkward in her movements. Thereafter, the figure becomes fuller and feminine and the shrill voice of the child changes to the slightly deeper and more melodious tone of the adult. Girls reach peak height velocity early in puberty before menarche. As a consequence, they have limited growth potential after menarche whereas, boys reach peak height velocity about 2 years later than girls. Boys grow an average of 28 cm during the growth spurt, in comparison to a mean of 25 cm for girls. The control of this is connected to the hormonal control of the pubertal growth spurt. Growth hormone, insulin-like growth factor 1 (IGF-1), and gonadal steroids play major roles. During puberty the long bones in the body lengthen, and the epiphyses ultimately close. The bone or skeletal age of any individual can be estimated closely by comparing X-rays documenting the development of bones in the nondominant hand (most commonly), knee, or elbow to standards of maturation for the normal population. Another practical clinical approach to predicting adult height uses midparental height. Several changes in body composition also occur during pubertal
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Jeffcoate’s Principles of Gynaecology development. The changes in body contour in girls, with accumulation of fat at the thighs, hips, and buttocks, occur during the pubertal growth spurt. Voice and other changes also are associated with the changes in body composition During puberty and adolescence the psychological changes are profound. The happy-go-lucky tomboy changes into a self-conscious girl who is interested in her appearance, may be moody and secretive, and is often imaginative and curious. She begins to feel that she is grown up, finds it more difficult to obey orders, and looks for independence. Her confidante becomes another girl rather than her mother. The sex urge becomes manifest and is often homosexual at first being evidenced by an unreasonable ‘passion’ for a particular older girl or woman. This phase is usually followed, sooner or later, by heterosexual impulses and activities. Temporary enlargement of the thyroid at puberty has already been mentioned. Acne of the face and back is often a nuisance for 1 or 2 years after the menarche; it is mainly the result of increased androgen secretion by the adrenal which is also manifested by an increased excretion of 17-ketosteroids in the urine. Indeed, many of the manifestations of puberty (for example, the growth of pubic and axillary hair) are the result of adrenal rather than of ovarian activity. Vasomotor instability is revealed by a tendency to blush at the slightest provocation. Management of Adolescence; Sex Education The problem of adolescence is that the girl regards herself as grown up and adult whereas physical and emotional maturity are not achieved until several years after the menarche. The management of the adolescent is difficult and is directed to ensuring that a balanced adult emerges from the testing period. The girl should not be teased or ridiculed but her move towards independence respected and controlled within limits. Affection and trust should take the place of orders. She should be encouraged to be continually occupied in either work or healthy recreation within the limits of her physical strength. Above all, her parents must be ready to accept and even encourage the disappearance of childhood ties and dependence. Failure to do so means that their daughter will never adequately fulfil her intended roles as a wife and a mother. It should be recognised that some girls are extremely embarrassed by changes in figure, especially by the development of the breasts, which they may attempt to hide by adopting a round-shouldered posture. Such girls are sensitive to
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comment and are helped by the provision of loose-fitting upper garments. On the other hand, there are many early ‘teenagers’ who worry because their bust development seems to them late or poor, and who accept the menarche and its accompaniments with pride. These are the ones who have been well primed in what to expect. The onset of menstruation in a girl who is uninformed arouses emotions of fear and shame, and can give her a psychological shock from which she never fully recovers. Failure of the adolescent to realise the implications and potential dangers of sex can lead to tragedy. Sex education should come naturally and piecemeal throughout childhood. Even infants are curious about their genitalia and their curiosity should be satisfied. Children inevitably ask questions and these should be answered simply but truthfully as they arise. Indeed, sex instruction should be merely part of the general education of the child, acquired from day to day in the course of family conversation, and becoming more detailed with the passing of time. In today’s world, the very real risks of unwanted teenage pregnancy and sexually transmitted diseases cannot be ignored. The progressively decreasing age of menarche has resulted in the first, the increasing permissiveness of society in the second. Today’s adolescent needs to be armed with sufficient information to be protected against the hazards of HIV infection, in addition to other reproductive tract infections and to avoid the psychological and physical consequences of unwanted illegitimate pregnancy. Abnormalities of Puberty and Adolescence
Obesity Adolescence is sometimes accompanied by a rapid increase in weight and the development of ‘puppy fat’. This can be associated with the formation of striae on the breasts, flanks, buttocks and upper arms which are reddish-purple at first but later fade to silver. The cause is a weakening of the elastic tissue by an increased production of adrenal corticoids together with stretching of the skin by subcutaneous fat. Some of these girls may have an underlying problem such as hypothyroidism or polycystic ovaries. Obesity in children and adolescents, irrespective of the underlying metabolic processes of the individual, is nearly always associated with overeating, or with eating predominantly carbohydrates. This is true
Puberty and Adolescent Gynaecology no matter what the protesting parent may say. Adolescent obesity of a minor degree tends to disappear by the age of 20 years if the appetite is reasonably curbed. Obesity of a gross degree, however, requires strict dietetic control (1000 kcal in 24 hours), lest it persist and progress to prejudice the girl’s future menstrual and reproductive functions, as well as her health in general. There may be variation in the age of menarche and the obesity of the girl. Typically, the age of menarche is earlier than average in children with moderate obesity (up to 30% above normal weight for age), whereas delayed menarche is common in those with severe malnutrition. Early in puberty, there is increased sensitivity of LH to GnRH. Gonadotropins are always secreted in an episodic or pulsatile fashion, even before puberty, the pulsatile secretion of gonadotropins is more easily documented as puberty progresses and basal levels increase. Appearance of the axillary and pubic hair is because of increased adrenal androgen secretion. Progressive increases in circulating levels of the major adrenal androgens, dehydroepiandrosterone (DHEA)
and its sulfate (DHEAS) accelerate at 7 to 8 years of age, and continue until 13 to 15 years of age. The accelerated increases in adrenal androgens begin about 2 years before the increases in gonadotropin and gonadal sex steroid secretion. Estrone, which is secreted in part by the ovaries and arises in part from extraglandular conversion of estradiol and androstenedione, also increases early in puberty but plateaus by midpuberty. Thus, the ratio of estrone to estradiol decreases throughout puberty, and this indicates that ovarian production of estradiol becomes increasingly important and peripheral conversion of androgens to estrone becomes less important during maturation.
Menstrual Disorders See below and Chapters 37 and 38.
Delayed Puberty The term delayed puberty is used when secondary sex characters do not develop and when menstruation does not begin before the age of 16 years (Figs 6.2A and B). If this arbitrary figure is accepted, one in every 100 girls
Figs 6.2A and B: Delayed puberty. Girl, aged 17 years, complaining of primary amenorrhoea. (A) Breast development has commenced and is characterised by the areolar bud ordinarily seen in a girl aged 9-12 years. Axillary hair has not yet appeared, (B) The labia majora are poorly developed and pubic hair is scanty. Investigation, which did not include sex chromosome analysis, revealed no abnormality and no treatment was given. Maturation proceeded spontaneously and menstruation commenced 2 years later
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Jeffcoate’s Principles of Gynaecology who subsequently prove to be normal and fertile has delayed puberty. Delayed puberty could be defined as girls who fail to develop any secondary sex characteristics by age 13, have not had menarche by age 16, or have not attained menarche 5 or more years since the onset of pubertal development. The causes and management of delayed puberty are those of primary amenorrhoea (see Chapter 37).
Constitutional In 80 per cent of cases no organic abnormality is found and the precocity appears to be merely an individual characteristic (Figs 6.3A and B). Hypothalamic, pituitary, adrenal and ovarian functions mature early and regular
Precocious Puberty Precocious puberty is defined as the onset of menstruation, accompanied by other evidence of puberty such as the development of breasts and pubic hair before the age of 8 years, taking mean ±2 standard deviations as encompassing the normal range. Physical development is also precocious in some cases but epiphyseal closure is likely to occur early so the individual may ultimately be short in stature. Mental development may be retarded or advanced and precocious girls commonly show abnormal electroencephalographic patterns. However, reproductive life is normal and menopause also occurs normally. Classification of Female Precocious Puberty I.
II.
III.
Complete isosexual precocity (true precocious puberty: gonadotropin dependent) A. Idiopathic B. CNS lesions: Hamartomas, Craniopharyngioma, etc C. Primary hypothyroidism D. Post-treatment for CAH Incomplete isosexual precocity (GnRH independent) A. Isolated precocious thelarche B. Isolated precocious menarche C. Estrogen-secreting tumours of the ovary or adrenals in girls D. Ovarian cysts E. McCune-Albright syndrome F. Peutz-Jeghers syndrome G. Iatrogenic (Isolated virilisation) A. Isolated precocious adrenarche B. Congenital adrenal hyperplasia C. Androgen-secreting ovarian or adrenal neoplasm D. Iatrogenic.
Causes Precocious puberty may be GnRH- and gonado-trophindependent or may be GnRH-independent being caused by the peripheral secretion of sex steroids.
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Figs 6.3A and B: Precocious puberty. Child, aged 3 years 11 months, who had been menstruating for 18 months. The breasts, pubic hair and the vulva are well developed. No abnormality was found on investigation and the precocity was labelled ‘constitutional’, but the after history of this case is unknown so a lesion in the hypothalamic-pituitary system is not excluded (see text)
Puberty and Adolescent Gynaecology menstruation can occur even at the age of 2 or 3 years. Gonadotrophins and gonadal hormones are excreted in adult quantities. Thus these are cases of GnRHdependent or true precocious puberty. A baby aged only 9 months (bone age = 5 years) has been recorded as suffering from constitutionally precocious puberty. In many cases, however, subsequent development reveals a previously unrecognised lesion in the hypothalamuspituitary region. Thus, an oft-quoted example of constitutional precocity is Lina Medina of Peru who not only had an early menarche but was delivered of a child at the age of 5 years 8 months. In fact, follow-up studies some years later showed that this girl suffered from Albright syndrome. One form of constitutional precocity runs in families and usually occurs around 8 years of age. In these patients the normal sequence of pubertal events described above may not be followed. Sexual precocity has been seen in a few cases of primary hypothyroidism, perhaps by stimulation of FSH receptors by the increased levels of TSH. These patients have galactorrhoea in addition to other clinical features. Though uncommon, this should be excluded in all cases of true isosexual precocity. In any case constitutional precocity is a diagnosis of exclusion and it may take many years for lesions to manifest.
lait spots) (Figs 6.4A to C). The hypothalamus and pituitary are disturbed by sclerotic overgrowth at the base of the skull.
Oestrogenic Tumours of the Ovary Precocious puberty is seen in patients with oestrogenproducing ovarian tumours such as granulosa and theca cell tumours. However malignant teratomas, ovarian cysts and cystadenomas have also been reported as causes of precocious puberty. Menstruation is not regular in time or duration and is not accompanied by ovulation. The breasts are enlarged but there is little body hair because adrenal function is not mature. The excretion of oestrogens is high and that of gonadotrophins low, although exceptions to this rule have been reported.
Disease in the Regions of the Midbrain, Hypothalamus and Pituitary A variety of lesions in the regions of the midbrain, hypothalamus and pituitary which result in precocious puberty are as follows: • Congenital defects, e.g. hamartoma, hydrocephalus, craniopharyngioma • Tumours, e.g. astrocytoma, glioma, neurofibroma, ependymoma and suprasellar tumours • Non-tumour conditions, e.g. encephalitis, meningitis, von Recklinghausen’s disease, Albright syndrome • Cranial trauma and abnormal skull development due to rickets. The pathophysiology is unclear but most lesions are associated with increased intracranial pressure and are located in the region of the hypothalamus. This stimulates the output of hypothalamic releasing factors and/or gonadotrophins. One example is the McCuneAlbright syndrome in which early puberty is associated with polyostotic fibrous dysplasia, fractures of bones and patchy yellow-brown pigmentation of the skin (café au
Figs 6.4A to C: Precocious puberty as part of Albright syndrome. Girl, aged 7 years, with well-developed breasts and vulva who had been menstruating for 2 years. She had suffered many fractures and both legs were in plaster at the time of photography. The patchy yellow-brown pigmentation is a typical feature (see text)
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Adrenal Cortical Tumours The precocity in these cases may be isosexual but is usually heterosexual; females show precocious virilism.
Androgenic Tumours of Ovary Gonadoblastomas and lipoid cell tumours are associated with heterosexual precocity.
Ectopic Gonadotrophin Production This is very rarely seen in hepatoblastoma, dysgerminoma and choriocarcinoma which secrete hCG. Management Children presenting with vaginal bleeding before the age of 8 years should be examined for evidence of secondary sex characters. If these are not present, the bleeding is
probably not menstrual and a local organic cause in the uterus or vagina should be looked for (Figs 6.5A and B). If secondary sex characters are present, then examination and special investigations should be done to exclude an intracranial, ovarian or adrenal lesion. The demonstration of pubertal or abnormal levels of plasma gonadotrophins in the plasma indicates that the anterior pituitary is showing precocious activity. Measurements of serum oestradiol, progesterone, 17-hydroxyprogesterone, testosterone and dehydroepiandrosterone sulphate (DHEAS), as indicated by the history and physical findings, along with basal FSH and LH levels are helpful. Any abnormality on neurological examination, head CT scan or MRI suggests a cerebral cause. Then management depends on whether is its gonadotropin dependent (in which case it is almost
Figs 6.5A and B: Alleged precocious puberty. Child, aged 7 years, who had bled vaginally on two occasions. There is no development of the breasts, pubic hair or vulva and this indicates that the bleeding was not menstrual or the result of hormone stimulation. It was decided that it was caused by local interference of some kind and it did not recur. A normal menstrual cycle, accompanied by physical maturation, began 6 years later. At a later stage in life this patient was seen again and was then found to have a uterus didelphys and septate vagina. So the bleeding in childhood was probably caused by injury to the lower border of the septum inflicted by the patient herself. The photograph of the vulva shows what looks like a prominent clitoris. This is usual in childhood and is explained by poor development of the labia
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Puberty and Adolescent Gynaecology invariably of central origin) or gonadotropin independent (of peripheral origin). The evaluation of precocious puberty is as follows: The first test should be the measurement of basal gonadotropin levels. Thyroid function should also be evaluated to rule out primary hypothyroidism as the cause of precocious development. High levels of LH (which really may be human chorionic gonadotropin detected because of crossreactivity with LH in immunoassays) suggest a gonadotropin-producing neoplasm, most often a pinealoma (ectopic germinoma). Increased oestradiol levels suggest an oestrogensecreting neoplasm, probably of ovarian origin. Increased testosterone levels suggest an androgenproducing neoplasm of the ovary or the adrenal gland. Such neoplasms may be palpable on abdominal or rectal examination. Increased 17α-hydroxyprogesterone levels are diagnostic of 21-hydroxylase deficiency (i.e., congenital adrenal hyperplasia [CAH]). Dehydroepiandrosterone sulfate levels are elevated in various forms of CAH as well. Bone age should always be assessed in evaluating an individual with sexual precocity. Then management with GnRH agonist therapy initially increases circulating gonadotropin and oestradiol concentrations for short periods of time. Chronic therapy is associated with suppression of pulsatile gonadotropin secretion and a blockade to the LH response of endogenous GnRH. Suppression is best monitored with GnRH challenge tests. Additionally, measurement of serum oestradiol (if elevated on prior analysis), height, bone age, and assessment of secondary sexual characteristics may be helpful. Evaluation of ovarian morphology and uterine size by pelvic ultrasonography may, in some cases, provide additional evidence of such suppression.The various effect like cessation of menses, regression in physical pubertal signs (i.e., breast size and pubic hair), and a diminution of uterine and ovarian size usually occur within the first six months of therapy.
If these are normal, it is most likely to be idiopathic sexual precocity. If a feminising adrenal tumour is suspected (with elevated serum DHEAS and oestradiol and low gonadotrophins), abdominal and pelvic ultrasound or MRI can be done. Ovarian tumours are also associated with elevated oestradiol and low gonadotrophins and can be detected by imaging. Skeletal survey for bone age shows accelerated maturation (breast development with bone age 11 and menarche with bone age 13). Virilising ovarian tumours may result in elevated serum DHEAS or androstenedione levels. Ovarian and adrenal tumours should be surgically resected. Precocious puberty with delayed bone age suggests primary hypothyroidism. Serum TSH is increased, serum T4 is low, galactorrhoea may be present along with increased serum prolactin. Serum gonadotrophins are in the pubertal range. The sella may be widened on imaging. All values return to normal with treatment. Patients with Albright syndrome may have a very variable presentation and sometimes a technetium-99 bone scan may be necessary to demonstrate areas of fibrous dysplasia in the bones. The management of true precocious puberty requires attention to maximising height, arresting further maturation and attentuating precocious features. In the past, medroxyprogesterone acetate, cyproterone acetate and danazol were used with some success. The use of GnRH analogues has significantly improved the results of treatment. These can be administered subcutaneously or intranasally, daily or in long-acting depot forms. The last are obviously the most preferred. The goal of therapy is to maintain the serum oestradiol level below 10 pg/ml. Treatment has to be continued till pubertal and chronological ages match. The final bone height is increased depending on how early treatment is instituted. Prolonged observation is required to detect evidence of underlying disease in the pituitary, ovary or adrenal gland which may appear later. Parents should be warned to guard the precocious child from possible sexual assault.
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7
CHAPTER
Conception
Fertilisation of the Ovum Early Development of the Ovum Implantation of the Ovum into the Uterus Formation of Foetus and Membranes Hormonal Control of Early Pregnancy
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FERTILISATION OF THE OVUM Pregnancy results when the liberated ripe ovum is fertilised by a spermatozoon. The opportunity for their meeting is provided by the deposition of semen in the upper vagina and on the external os during coitus. Even if spermatozoa are only deposited on the vulva they can sometimes make their way up the vagina to the cervix. This explains the occasional pregnancy in apparent virgins and also failures of coitus interruptus as a method of contraception. Semen consists of mature spermatozoa (and a variable number of immature forms) suspended in a creamy viscous fluid secreted by the seminal vesicles and prostate. When spermatozoa leave the testis they have undergone the first maturation division with reduction of the number of chromosomes from 46 to 23. But they are neither fully mature nor capable of fertilisation. It takes them about 72 days from initiation of spermatogenesis to reach the caudal end of the epididymis and they do not become motile until they mix with seminal fluid immediately before ejaculation. It has long been said that spermatozoa are not stored in the seminal vesicles, but they must be because they appear in seminal fluid for 2-3 months after division of the vasa as in vasectomy. Seminal fluid becomes clear and watery within 30 minutes of ejaculation; this liquefaction being brought about by prostatic secretion. The fluid contains fructose, the amount of which decreases rapidly after ejaculation as the spermatozoa use it for a source of energy. Once deposited in the vagina, spermatozoa find themselves in a hostile acid medium from which they must escape quickly if they are to survive. Seminal fluid itself is alkaline with a pH of 7.05-7.41, rising to 7.5-8.0 on standing in vitro. When mixed with vaginal secretion the pH of the seminal pool is 6.2, and may be only 5.5 if the alkaline contributions from the cervix and from Bartholin’s glands are limited. All spermatozoa remaining in the vagina for 2 hours or longer are killed, and it is probable that only those which can enter the alkaline cervical canal within a few minutes retain their fertilising power. They enter the cervix under their own powers
Conception of propulsion, being directed by chemotaxis (acid repels and alkali attracts). They invade the mucus plug in the cervical canal which, at the time of ovulation, is arranged to form micro-channels to allow easier penetration. Once through the cervix, spermatozoa ascend rapidly; so rapidly that it is believed that they are moved by contractions of the uterus and tubes in addition to their own power. These contractions may be stimulated by prostaglandins present in semen. The chief function of its flagellum may be to allow the spermatozoon to penetrate the corona radiata and the capsule of the ovum. The time taken for spermatozoa to travel from the vagina to the tubes may be as short as 5 minutes. Many are lost on the way, the semen being expelled from the introitus, the sperm digested by vaginal enzymes or phagocytosed by the epithelial cells of the genital tract. Those that reach the tube travel against the cilial current and some find their way into the peritoneal cavity (Fig. 7.1). Of an average of 200-300 million
spermatozoa deposited in the vagina, fewer than 200 finally reach the egg. Until they enter the female genital tract, spermatozoa do not possess the capacity to penetrate the zona pellucida and to fertilise the ovum. ‘Capacitation’ is only acquired after they have been in the cervix, uterus and tubes for 2-4 hours. The seminal plasma factors coating the surface are removed and the surface charge modified when the capacitated sperm interact with the follicular fluid, the sperm head undergoes the acrosome reaction, allowing the release of several enzymes including hyaluronidase, corona-dispersing enzymes and acrosin. The sperm motility also increases remarkably. All these changes are critical for zona penetration. In vitro, the acrosome reaction can be induced by human follicular fluid and the zona pellucida proteins of the oocyte. In vitro capacitation can be brought about in a culture medium which is a balanced salt solution containing lactate, pyruvate and glucose for energy and
Fig. 7.1: Diagrammatic representation of ovulation, maturation of the ovum and fertilisation
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Jeffcoate’s Principles of Gynaecology albumin. This is used in assisted reproduction technology. An ovum leaves the ovary having already undergone the first maturation (reduction) division and is picked up by the fimbria of the fallopian tube. In the ampulla of the tube, the gamete, still enclosed by the corona radiata, is approached by numerous spermatozoa some of which probably have the function of softening or preparing the envelope of the ovum by releasing hyaluronidase. Ultimately, a single spermatozoon penetrates the ovum and then loses its tail and body. The pronucleus, contained in its head, does not actually fuse with the pronucleus of the ovum. As they complete their second maturation divisions, each gamete contributes its chromosomes to form a single nucleus containing 46 chromosomes. Thereafter, the fertilised ovum begins a
Fig. 7.2: Maturation and fertilisation of the ovum while still surrounded by the corona radiata. These events take place in the tube and are illustrated as follows. (1) Prior to ovulation the first (reduction) division has taken place to give rise to a polar body shown as a black dot to the side of the ovum itself. (2) The second division occurs, or is completed, after the spermatozoon penetrates the ovum; the polar body also divides so that the ultimate result is three polar bodies. (3) The male and female pronuclei approach each other to contribute chromosomes which link together to form one nucleus; the pronucleus of the spermatozoon is smaller than that of the ovum but, for clarity, is here shown of similar size. (4) Fusion almost complete. (5) The first division after fertilisation to produce a 2-cell ovum
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series of cell divisions but, for the first 7 days, does not increase in overall size (Figs 7.2 and 7.3). How long can human spermatozoa survive in the female genital tract? It is true that spermatozoa have been found to retain motility in the cervical canal and uterus for 5-7 days, and have been found in the tube 60 hours after coitus, but this does not mean that they have the power to fertilise. Indeed, the evidence shows that spermatozoa do not retain this property for longer than 48 hours, and probably not for longer than 24 hours, after being implanted in the vagina. The ripe ovum can survive in a fertilisable form for only 24 hours, and probably only for 8-12 hours after it leaves the ovary. Conception is therefore extremely unlikely unless coitus takes place during the 2 days before, or immediately after, ovulation. This is the basis for the fertile period of each monthly cycle. If ovulation always occurred on the fourteenth day of the cycle, conception could only result from coitus on the twelfth, thirteenth, fourteenth and fifteenth days. In fact, there is some
Fig. 7.3: The development of the fertilised ovum during the first 7 days. (1) Morula stage. (2) Blastocyst stage. During this process, and to permit its transport along the tube, the ovum does not increase in size much. The diametre of the blastocyst is only 0.13 mm, that of the ovum immediately after ferilisation being 0.1 mm. The zona pellucida persists until the blastocyst embeds in the endometrium
Conception variability in the time of ovulation so allowance is made for this and the fertile period in a woman with a 28-day cycle occupies the seventh to nineteenth days. The other days in the cycle constitute the safe period but it should be recognised that it is relatively rather than absolutely safe. Indeed, pregnancy is recorded following coitus on any day of the cycle, even during menstruation, but this is rare and is explained by some unusual irregularity in the time of ovulation rather than by longevity on the part of spermatozoa. EARLY DEVELOPMENT OF THE OVUM The first division of the ovum into two cells occurs within 24-30 hours of fertilisation and thereafter each cell divides again and again to form a morula, a clump of cells 0.13 mm in diametre, by the third or fourth day (Fig. 7.3, 7.12 to 7.17). The morula, still covered by the zona pellucida, next becomes cystic as a result of fluid being either secreted by its own cells or absorbed from the genital tract (Figs 7.3 and 7.4). It is moved along the fallopian tube by the cilial current and by peristalsis, being nourished temporarily by the cells of the corona radiata and by the secretions of the endosalpinx. In approximately 4 days it reaches the uterine cavity where it lies free for another 2 or 3 days during which it is
supported by the secretions of progestational endometrium. This blastocyst, present by the seventh day, consists of a single layer of cells surrounding the contained fluid, with a collection of cells forming a solid area on the inner aspect of the wall at one point. This is the inner cell mass from which the foetus is formed. The cyst wall of flattened cells is the trophoblast which soon becomes differentiated into two layers: an inner one of cuboidal cells — the cytotrophoblast; and an outer one the syncytiotrophoblast (Figs 7.4 and 7.5). The latter consists of irregular masses of protoplasm with multiple nuclei and few cell walls. It is probably developed from the cytotrophoblast and its formation from this source is continued throughout pregnancy. The function of the trophoblast is to attach the ovum to the wall of the uterus and thereafter to nourish it. IMPLANTATION OF THE OVUM INTO THE UTERUS About the seventh day the blastocyst adheres itself to the wall of the uterus, normally in the upper part for which it has a special predilection, and then burrows into the endometrium (invasion). At this time it loses its covering, the zona pellucida. The site of entry is quickly sealed (Figs 7.1 and 7.6). The invasive power is provided
Fig. 7.4: The development of the early embryo and its membranes
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Fig. 7.6: A16-day ovum with differentiation into amniotic sac, yolk sac and embryonic plate. It is surrounded by loose extraembryonic mesoderm and the whole is covered with trophoblast burrowing into the endometrium. This was found as a result of curettage carried out on the twenty-eighth day of a 28-day cycle. (By permission of the Editor of JAnat and Professor R.G.Harrison)
Fig. 7.5: First trimester placental villi. The villous stroma is immature and contains blood vessels in which nucleated foetal erythrocytes can be seen. The trophoblast around the villi forms an outer syncytiotrophoblastic layer and an inner layer of cytotrophoblast. (Photomicrograph x600)
by enzymes of the syncytium and related proteins, e.g. implantation-initiating factor, fibronectin and blastokinin, and the endometrium, already sensitised by progesterone, reacts by a strong decidual change. Decidual reaction is also seen to a limited extent on the pelvic peritoneum and on the surface of the ovary. Decidual reaction is also sometimes seen in cervical tissues, including cervical polypi. Occasionally the peritoneal reaction is excessive and causes the condition of deciduosis peritonei. In this, greyish-white nodules of decidua, 2-10 mm in diametre, are found scattered on the surface of the uterus, tubes, ovaries, broad ligaments, mesocolon, omentum and even the diaphragm. These can bleed, sometimes quite seriously, to cause haemoperitoneum. So far as the uterus is concerned, decidual reaction is protective in that it controls the degree of penetration by the chorion and prevents the erosion of large blood vessels. Nevertheless, fine capillaries of the endometrium are opened and the blood leaks out to form pools and lakes around the ovum. The trophoblastic epithelium acts as an intermediary or as a semipermeable membrane.
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To facilitate the interchange of carbon dioxide during the early stages of trophoblastic development, the endometrium is rich in carbonic anhydrase. This forms as a result of a progesterone influence and is probably vital to successful implantation. The altered endometrium lying deep to the implanted ovum is the decidua basalis, and that which shields it from the uterine cavity is the decidua capsularis. The lining of the remainder of the uterus is the decidua vera (Figs 7.7 and 7.8). The decidua vera and decidua capsularis fuse by 12 weeks of gestation, obliterating the uterine cavity.
Fig. 7.7: An early conceptus, with foetal limb buds just showing, embedded in the endometrium. The small cyst near the head of the foetus is probably the yolk sac. The edge of a leiomyoma appears to the left of the pregnancy sac (see Fig. 30.13)
Conception
Figs 7.8A to C: The formation of the placenta and membranes, (A) At 4 weeks, (B) At 6-8 weeks, (C) At 12 weeks
Thus there is no access to the tubes from the cervix after this time and no possibility of ascending infection. FORMATION OF FOETUS AND MEMBRANES As the cells of the inner cell mass proliferate, a fluidfilled space appears in their midst on the side adjacent to the trophoblast; this is the amniotic cavity and its lining cells become the amnion (Fig. 7.4). A second cyst lined by a single layer of flattened cells appears on the other aspect of the inner cell mass: this is the yolk sac, a primitive structure in the human being (Figs 7.6 and 7.9). These two cavities are separated from each other by a double layer of cells. Between these two layers the mesoderm develops (probably from the amniotic layer), and grows out to form the body stalk or umbilical cord. The amniotic cavity and yolk sac are present by the seventh day. A reticulum of mesenchyme appears in the blastocyst and condenses to line the trophoblast on its inner aspect. There is now a flat plate between the amnion and the yolk sac comprising three layers - amniotic cells which become ectoderm; the intermediate mesoderm; and yolk sac cells or endoderm. It is from these primary layers that the whole foetus develops. The process of development is one in which the plate folds on itself in two dimensions (Fig. 7.4) so that ultimately a part of the yolk sac is included by the engulfing mesoderm and ectoderm. The
Fig. 7.9: A higher-power view of the inner cell mass of the ovum illustrated in Fig. 7.8. This shows the amniotic cavity above and the yolk sac below. Between the two is the embryonic plate consisting of the three primary layers of ectoderm, mesoderm and endoderm from above downwards. (By permission of the Editor of JAnat and Professor R.G. Harrison)
resulting tube-like structure stretching from end to end becomes the primitive gut and cloaca. This at first communicates with the remains of the yolk sac (vitelline duct) now lying in the body stalk. The allantois, also found in the body stalk, is a diverticulum from the primitive gut.
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Jeffcoate’s Principles of Gynaecology The neural canal forms from an invagination of ectoderm; the mesoderm gives rise to the primitive muscles, blood vessels, bones and all structures intervening between the ectoderm and endoderm. All the essential structures of the body are present in primitive but recognisable form by the sixth week. Meanwhile, the trophoblast has developed villous projections on its outer aspect to give it the appearance of a fluffy ball (Fig. 7.10). Mesenchyme invades each villus as a central core. When the trophoblast receives its inner layer of mesoderm it becomes known as chorion and its projections become chorionic villi. The situation can be summarised thus: Cytotrophoblast + syncytiotrophoblast = trophoblast; trophoblast + mesoderm = chorion. Chorionic villi are well formed by the fourteenth day. By the twenty-first day, blood vessels have developed from the mesoderm and are found in the foetus itself, in the body stalk and in the core of each villus to form a continuous circulation. The chorionic villi are thus bathed in maternal blood and oxygen. Foodstuffs and foetal waste products are exchanged between this and the foetal blood in the vessels of each villus. The villi are at first present on all aspects of the blastocyst. As the ovum grows, the decidua capsularis bulges into the uterine cavity and the chorionic villi within it atrophy on the side adjacent to the uterine cavity and persist on the side adjacent to the uterine wall. The part of the chorion still covered with villi is rough and shaggy - the chorion frondosum; the part devoid of villi is smooth - the chorion laeve. The villi of the chorion frondosum grow and invade the decidua basalis. With further development the chorion frondosum becomes more and more clearly demarcated and restricted to one
Fig. 7.10: A 3-4-week-old embryo in its amniotic sac, surrounded by chorionic villi
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area, giving rise to the placenta. This is connected to the foetus by the umbilical cord, the umbilical vessels linking up those of the chorionic villi with those of the foetus. While the foetus develops and the remains of the yolk sac shrivel, the amniotic cavity grows apace until it completely fills the original blastocyst (Fig. 7.4). It comes into close contact with the chorion and adheres to it lightly; it covers the umbilical cord and is continuous with the skin of the foetus at the umbilicus. The foetus is suspended in amniotic fluid; around this are the membranes which consist of an inner glistening thin but tough amnion (Fig. 7.11) and an outer thicker but more friable chorion. When the ovum fills the uterine cavity the decidua capsularis comes in contact and fuses with the decidua vera lining the opposite pole of the uterus (Fig. 7.8c). The arrangement of the membranes and the placentalfoetal relationships then remain essentially unchanged until the end of pregnancy. As pregnancy progresses, trophoblastic cells continually break away and migrate into the decidua and myometrium; others enter the blood-stream from which they are sieved by the lungs. These are normal and harmless happenings but the decidual reaction to these ‘wandering cells’, sometimes labelled syncytial endometritis, can be mistaken for choriocarcinoma by the histologist. Yet others break away and collect at the
Fig. 7.11: A 5-6-week-old embryo in its amniotic sac. Much of the chorion has been lost. This specimen was found lying free in the peritoneal cavity at operation for tubal pregnancy
Conception
Fig. 7.12: Mature Oocyte
Fig. 7.14: Embryonic development rating (EDR)
Fig. 7.13: Successful fertilisation
Fig. 7.15: Pronuclear assessment
Fig. 7.16: Different stages of early development from pronuclei to blastocyst stage
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Fig. 7.17: Stages of development
internal os. Transcervical mucus plug aspiration prior to 12 weeks’ gestation is a potential technique for firsttrimester prenatal diagnosis of aneuploidies, trisomies, etc. which may be less invasive than chorion villus sampling which is done between 9 and 11 weeks for foetal chromosomal disorders but carries the risk of abortion, preterm labour, premature rupture of membranes and foetal limb reduction defects.
production at about this time, the corpus luteum temporarily becomes cystic and its activity begins to wane by the tenth week. It shows evidence of colloidal degeneration by the sixteenth week but remains a recognisable structure throughout pregnancy. In the puerperium and after abortion, it occasionally undergoes calcification, but is ultimately absorbed.
HORMONAL CONTROL OF EARLY PREGNANCY
The placenta produces a wide range of hormones in the syncytiotrophoblast, of which some are clinically different from the comparable maternal hormone. The steroid hormones oestrogen and progestogen cannot be produced by the placenta alone because the necessary enzymes are absent. However, the foetal and maternal adrenals produce the precursors for the placental synthesis of the hormones. As a consequence of the shared biosynthesis of oestrogens by the foetal adrenal and the placenta, the concept of the foetoplacental unit was developed. The placenta transforms foetal adrenal dehydroepiandrosterone sulphate (DHEAS) to oestrogen using a placental sulphatase enzyme. The synthesis of DHEAS is regulated during early pregnancy by hCG and thereafter by foetal ACTH. The placenta synthesises progesterone from maternal and foetal cholesterol throughout pregnancy so that the maternal levels increase steadily during pregnancy.
The fertilised ovum is embedded in the endometrium on about the twenty-first or twenty-second day of the menstrual cycle and by that time is beginning to secrete small amounts of human chorionic gonado-trophin (hCG) which is luteinising and luteotrophic. This prevents the degeneration of the corpus luteum which continues to maintain the progestational endometrium; amenorrhoea and anovulation result. The Corpus Luteum of Pregnancy The corpus luteum not only persists but continues to enlarge slightly up to the sixtieth day of pregnancy when it may measure 3 cm in diametre. Individual cells are three to four times larger than those of the corpus luteum of menstruation. Soon after the sixtieth day, and presumably because of the dramatic fall in hCG
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Placental Hormones, Enzymes and Proteins
Conception Only the large protein hormones, hCG and human placental lactogen (hPL) will be discussed in this section, as the roles of the other hormones are largely unknown or speculative. Since the early 1970s, several new proteins of placental origin have been discovered in the maternal circulation and are called placental associated plasma proteins (PAPP). Their concentration increases as pregnancy progresses; rather like hPL. So far no definite physiological functions have been attributed to these proteins. Gonadotrophins Chorionic gonadotrophins, although glycoproteins, differ chemically from pituitary gonadotrophins, but act similarly and have both a follicle stimulating and luteinising action. The latter, however, is dominant. As soon as the ovum is implanted in the endometrium, the production and excretion of hCG rises rapidly from approximately 100 IU/L in the maternal serum at the time of the expected menses to a maximum of approximately 100,000 IU/L at the sixtieth day of pregnancy; thereafter they fall to a fairly constant low level. The purpose of hCG in circulation in early pregnancy is mainly concerned with maintaining the corpus luteum. Some of the suggested biological functions of hCG include stimulation of placental progesterone production, inhibition of maternal—foetal graft rejection, stimulation of the foetal adrenal and production of DHEAS and stimulation of the foetal gonads, in particular the production of testosterone by the testis. Human Placental Lactogen (HPL) This hormone, also known as chorionic somatomammotrophin (hCS), is also secreted by the syncytiotrophoblast. It is demonstrable in the plasma by the sixth week of pregnancy and rises to a maximum in the third trimester of pregnancy to disappear quickly after delivery. It is a protein hormone with immunological and certain biological similarities to growth hormone (GH). As its alternative name implies, it is growthpromoting, but is less than one-twentieth as effective as GH, and is lactogenic, although this has only been proved in other animal species. Its action is weak compared with pituitary prolactin. The hormone participates, directly or indirectly, in a number of metabolic processes. It has been suggested that it may function as a metabolic regulatory, albeit a
fine one, in the mother to ensure that the nutritional requirements of the foetus are met. In the mother, hPL induces insulin resistance and carbohydrate intolerance. It mobilises lipids as free fatty acids. Thus it ensures an adequate supply of fuels to the foetus between maternal meals. Alterations in the levels of hPL have been used in early pregnancy to assess viability in cases of threatened abortion, and in late pregnancy as an indication of placental function. However, biophysical techniques are more reliably predictive and sensitive for assessing foetal well-being. Progesterone The activity of the corpus luteum of pregnancy explains the slight rise in the level of progesterone in the blood during the first few days or weeks following conception. The placenta, however, soon takes over responsibility for producing progesterone in ever-increasing amounts until term or near term. The daily production of progesterone in late pregnancy is about 250 mg with blood levels of 100-200 ng/ml. Progesterone helps prepare and maintain the endometrium to permit implantation. It may have a role in suppressing maternal immunological response to foetal antigens, thus preventing maternal rejection. It reduces myometrial contractility. It also serves as the substrate for some of the foetal adrenal gland production of gluco- and mineralocorticoids. The increased progesterone levels have an effect on the kidneys since progesterone competes with aldosterone for renal receptor sites. The sodium balance in pregnancy reflects, to some extent, the increased aldosterone and progesterone levels. The secretion of progesterone by the human placenta explains why, in women, the corpus luteum is not important to the maintenance of pregnancy in contrast to other animals. In the human being both ovaries, including the corpus luteum, can be removed in the first trimester without abortion taking place in 50 per cent of cases. There are reports of the human corpus luteum having been removed as early as the twenty-third day of the menstrual cycle (presumed ninth day of pregnancy) without untoward effect. Nevertheless, if it is removed within the first 4 weeks (6 weeks’ amenorrhoea), abortion usually occurs within 80 hours. This is the basis for the use of the antiprogestogen RU 486 (mifepristone) for medical induction of abortion in the early first trimester.
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Oestrogens These hormones are produced in ever-increasing quantities from the beginning to the end of pregnancy. The corpus luteum makes a contribution in the first few weeks but the main source, as described above, is the placenta. This secretes oestradiol, oestrone and oestriol. Oestrone and oestradiol levels increase to about 100 times the non-pregnant levels, but oestriol excretion is increased about 1000 times. Although oestriol is a weak oestrogen, its high concentrations compensate and the biological effect is equivalent to oestradiol. If the foetus is removed and the placenta remains in situ, as in some cases of abdominal pregnancy, the level of oestriol falls considerably. This level is also low if foetal adrenal function is defective as it is with anencephaly. The level
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of unconjugated oestriol along with levels of maternal serum alfa-fetoprotein and maternal serum hCG form the triple test which is used antenatally to screen for foetal aneuploidy. Here, unconjugated oestriol and AFP levels are low whereas the hCG level is raised. Most of the oestrogens found in the blood and urine are in a biologically inactive form, being conjugated with glucuronic acid. Only about 8-10 per cent of maternal serum oestradiol is unconjugated. The role of oestrogens in pregnancy is not clearly defined, although there is hardly an organ or tissue which is not, directly or indirectly, affected to some extent during pregnancy. The hypertrophy and hyperplasia of the uterine muscle and development of the breast tissue are obvious target-organ effects but much still remains unknown.
8
CHAPTER
Spontaneous Abortions (Including Recurrent Loss)
Spontaneous Abortion Pathology Clinical Varieties Recurrent Early Pregnancy Loss
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The definition of abortion is the termination of pregnancy by any means before the foetus is sufficiently developed to survive. In the United States this definition is confined to the termination of pregnancy before 20 weeks based upon the date of the first day of the last normal menses. Another commonly used definition is the delivery of a foetus-neonate that weighs less than 500 g. SPONTANEOUS ABORTION When abortion occurs without medical or mechanical means to empty the uterus, it is referred to as spontaneous. Another widely used term is miscarriage. PATHOLOGY Haemorrhage into the decidua basalis and necrotic changes in the tissues adjacent to the bleeding usually accompany abortion. The ovum becomes detached, and this stimulates uterine contractions that result in expulsion. When the sac is opened, fluid is commonly found surrounding a small macerated foetus, or alternatively there may be no visible foetus in the sac, the so-called blighted ovum. Blood or carneous mole is an ovum that is surrounded by a capsule of clotted blood. The capsule is of varying thickness, with degenerated chorionic villi scattered through it. The small, fluid-containing cavity within appears compressed and distorted by thick walls of old blood clot. The incidence of spontaneous abortion is about 15 per cent of all pregnancies. More than 80 per cent of abortions occur in the first 12 weeks, and the rate decreases rapidly thereafter. Chromosomal anomalies cause at least half of these early abortions, and their incidence likewise decreases thereafter. 1. Chromosomal abnormalities: Cause at least 50 per cent of early abortions e.g. trisomy, monsomy X (XO) and triploidy (Fig. 8.1). 2. Blighted ovum (anembryonic gestational sac): Where there is no visible foetal tissues in the sac. 3. Maternal infections: e.g. listeria monocytogenes, mycoplasma hominis, ureaplasma urealyticum, cytomegalovirus and toxoplasma gondii which causes
Jeffcoate’s Principles of Gynaecology
Fig. 8.1: USG picture of YS and embryo
4. 5.
6.
7. 8. 9.
10. 11.
abortion if there is acute infection early in pregnancy. Acute fever for whatever the cause can induce abortion. Trauma: External to the abdomen or during abdominal or pelvic operations. Endocrine causes: a. Progesterone deficiency (causes abortion between 8-12 weeks). b. Diabetes mellitus. c. Hyperthyroidism. Drugs and environmental causes: e.g. quinine, ergots, severe purgatives, tobacco, alcohol, arsenic, lead, formaldehyde, benzene and radiation. Maternal anoxia and malnutrition. Overdistension of the uterus: e.g. acute hydramnios. Immunological causes: a. Systemic lupus erythematosus. b. Antiphospholipid antibodies that are directed against platelets and vascular endothelium leading to thrombosis, placental destruction and abortion. c. Histocompatibility between the mother and father and in turn the foetus. It is assumed that histoincompatibility particularly in human leucocyte antigen (HLA- DR locus) is essential for stimulation of the immune system to produce blocking factors which prevent rejection of the foetus. Ageing sperm or ovum. Uterine defects: e.g. Septum, Asherman’s syndrome (intrauterine adhesions) and submucous myomas.
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12. Nervous, psychological conditions and over fatigue. 13. Idiopathic. Autosomal trisomy is the most frequently identified chromosomal anomaly associated with first-trimester abortions. Trisomies can be the result of an isolated nondisjunction, maternal or paternal balanced translocation, or balanced chromosomal inversion. Balanced structural chromosomal rearrangements are present in 2 to 3 per cent of couples with a history of recurrent abortions. Translocations may be identified in either parent. Balanced chromosomal inversions may also be identified in couples with recurrent abortions. Trisomies for all autosomes except chromosome number 1 have been identified in abortuses, but autosomes 13, 16, 18, 21, and 22 are most common. Monosomy X (45, X) is the next most common chromosomal abnormality and is compatible with liveborn females (Turner syndrome). Triploidy is often associated with hydropic placental degeneration. Incomplete hydatidiform moles may have foetal development that is triploid or trisomic for chromosome number 16. Foetuses associated with these frequently abort early, and the few carried longer are all grossly malformed. Advanced maternal and paternal age are not associated with this abnormality. Tetraploid abortuses are rarely live born and are most often aborted very early in gestation. Chromosomal structural abnormalities are unusual causes of abortion and have been identified only since the development of banding techniques. Some of these infants are live born with balanced translocations and can be normal. Autosomal monosomy is extremely rare and is incompatible with life. Sex chromosomal polysomy (47,XXX or 47,XXY) is unusual in abortus material but is commonly seen in live births. In women with genetic problem can be offered chorion villi sampling (Fig. 8.2). Euploid Abortion: Three fourths of aneuploid abortions are before 8 weeks, while euploid abortions peaked at about 13 weeks. The following causes are possibilities: 1. A genetic abnormality such as an isolated mutation or polygenic factors. Approximately 0.5 per cent of live births have chromosomal abnormalities, while at least 2 per cent of live births have diseases associated with a single-gene mutation or a polygenic mechanism of inheritance.
Spontaneous Abortions (Including Recurrent Loss)
d.
e.
f. g. h. Fig. 8.2: Chorionic villi in spontaneous abortion
2. Various maternal factors. a. Infections: Some chronic infections have been implicated in causing abortion. There is no evidence in humans that either Listeria monocytogenes, Brucella or Chlamydia trachomatis produce abortions. Herpes simplex, however, has been associated with an increased incidence of abortion following genital infection in early pregnancy. The association of Mycoplasma hominis and Ureaplasma urealyticum in abortion was suggested by few. However, there was no evidence of spontaneous abortion with genital mycoplasma. b. Endocrine abnormalities: There does not appear to be an increased incidence of abortion associated with clinical hypothyroidism. Diabetes Mellitus who are insulin dependent have a higher incidence of spontaneous abortion and major congenital malformations. c. Progesterone deficiency: Insufficient progesterone secretion by the corpus luteum or placenta has been associated with an increased incidence of abortion. It has been suggested that abnormal levels of one or more hormones might help to forecast abortion. Unfortunately, reduced levels of these hormones are usually the consequence
i. j.
k.
l.
rather than the cause. Luteal phase deficiency is uncommon. There is no conclusive evidence that dietary deficiency of any one nutrient or moderate deficiency of all nutrients is an important cause of abortion. The nausea and vomiting that develop rather commonly during early pregnancy, and any inanition so induced, are rarely followed by spontaneous abortion. Drug use and environmental factors: Different agents has been reported, but not confirmed, to be associated with an increased incidence of abortion. However this is not proved. Smoking: This has been associated with an increased risk for euploidic abortion. Alcohol: Both spontaneous abortion and foetal anomalies may result from frequent alcohol use during the first 8 weeks of pregnancy. Caffeine: Coffee consumption at greater than four cups per day appears to slightly increase the risk of abortion. This may be due to paraxanthine (a caffeine metabolite) levels of which are associated with a significant two-fold risk of spontaneous abortion. However moderate consumption of caffeine is unlikely to be associated with spontaneous abortion. Radiation: In sufficient doses, radiation is a recognised abortifacient. Environmental toxins: In most instances, there is little information to indicate any specific environmental agent; however, there is evidence that arsenic, lead, formaldehyde, benzene, and ethylene oxide may cause abortion. Immunological factors: Much attention has been focused on the immune system as important in recurrent pregnancy loss. Two primary pathophysiological models that have evolved are the autoimmune theory (immunity against self) and the alloimmune theory (immunity against another person). Autoimmune factors: It has been determined from compiled studies that approximately 15 per cent of over 1000 recurrent pregnancy loss patients have recognised autoimmune factors. The most significant antibodies have specificity against negatively charged phospholipids and are most commonly detected by testing for lupus anticoagulant (LAC) and anticardiolipin antibody (ACA).
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m.
n.
• • •
o.
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The lupus anticoagulant is an immunoglobulin (IgG, IgM, or both) that interferes with one or more of the phospholipid-dependent tests of in vitro coagulation. The term is a misnomer because it is associated with clinically important increases in thromboembolic events. Importantly, the lupus anticoagulant is most often diagnosed in patients who do not meet the diagnostic criteria for lupus. Antiphospholipid antibodies are acquired antibodies targeted against a phospholipid. They can be of the IgG, IgA, or IgM isotope. The mechanism of pregnancy loss in these women is thought to involve placental thrombosis and infarction. Investigators have proposed various treatments for the antiphospholipid antibody syndrome, including low-dose aspirin, prednisone, heparin, and intravenous immunoglobulin. These treatments are thought to counteract the adverse action of antibodies by affecting both the immune and coagulation systems. Alloimmune factors: A number of women with recurrent pregnancy loss have been diagnosed as having an alloimmune cause. They have received a variety of therapies targeted at stimulating maternal immune tolerance of foetal material. Diagnosis of an alloimmune factor has centered on several tests: Maternal and paternal HLA comparison. Assessment of maternal serum for the presence of cytotoxic antibodies to paternal leukocytes. Maternal serum testing for blocking factors for maternal-paternal mixed lymphocyte reactions. In essence, those couples determined to have significant HLA-type homology, or in which the women were found to have minimal antipaternal antibodies, were judged to represent an alloimmune disorder. This view is doubtful. Inherited thrombophilia: There have been numerous reports of an association of spontaneous abortions and inherited thrombophilias. It has been found to have increased incidence of activated protein C resistance and factor V Leiden mutation. Some reported that elevated serum homocysteine levels were also a risk factor. The optimal treatment for the various thrombophilias during pregnancy is unclear, but heparin
(including low molecular weight heparin) appears to be efficacious for the treatment of antithrombin III deficiency as well as protein C and S deficiency. Aspirin plus heparin seems to be efficacious for treatment of factor V Leiden mutation and antiphospholipid syndrome. p. Aging gametes: Some researchers found an increased incidence of abortion relative to successful pregnancies when insemination occurred 4 days before or 3 days after the time of shift in basal body temperature. They concluded, therefore, that aging of the gametes within the female genital tract before fertilisation increased the chance of abortion. q. Uterine defects and acquired uterine defects: Large and multiple uterine leiomyomas usually do not cause abortion. Uterine synechiae (Asherman syndrome) are caused by destruction of large areas of endometrium by curettage. This in turn results in amenorrhea and recurrent abortions believed to be due to insufficient endometrium to support implantation. r. Defects: These defects are the consequence of abnormal mullerian duct formation or fusion; Some types, such as uterine septa, may be associated with abortions. s. Incompetent cervix: The term incompetent cervix is applied to a discrete obstetrical entity. It is characterised by painless cervical dilatation in the second trimester or perhaps early in the third trimester, with prolapse and ballooning of membranes into the vagina, followed by rupture of membranes and expulsion of an immature foetus. Unless effectively treated, this sequence tends to repeat in each pregnancy. Numerous methods have been described in nonpregnant women to make the diagnosis, usually by documenting a more widely dilated internal cervical os than is normal. Methods have included hysterography, pull-through techniques of inflated catheter balloons, and acceptance without resistance at the internal os of specifically sized cervical dilators. It is not recommended to do the tests inbetween pregnancies. During pregnancy, attempts have been made with moderate success to predict premature cervical dilation using ultrasonic techniques. Ultrasound is useful in identifying women with subtle changes in the cervix who would benefit from urgent cerclage.
Spontaneous Abortions (Including Recurrent Loss) There is little doubt that ultrasound, especially transvaginal sonography (TVS), is a useful adjunct for the diagnosis of cervical shortening or funneling of the internal os and in the early detection of cervical incompetence. Endovaginal sonography has been shown to be a reproducible and safe method to assess cervical length objectively when compared to digital examination or abdominal or perineal ultrasound. Earlier studies used transabdominal ultrasound. This technique required a full bladder to visualise the cervix, which often falsely elongated the apparent cervical length introducing an unpredictable effect on measurement. The Transvaginal sonography (TVS) has become the gold standard. Ultrasound images of the cervix in pregnancy have demonstrated that cervical effacement begins at the internal cervical os and proceeds distally through a process called funneling. This process is usually established prior to dilatation of the external cervical os and can begin as early as 16-24 weeks in patients who eventually deliver preterm. Zilanti et al described the appearance of cervical effacement as seen by TVS as progression of the letters T,Y,V and U to denote the relationship of the lower uterine segment to the axis of the cervical canal. The mean cervical length is 35-40 mm from the 14-22 weeks and falls to approximately 35 mm between 24-28 weeks and 30 mm after 32 weeks. The cervical length from 22–32 weeks gestation displays a normal bellshaped distribution, with the 50th percentile approaching approximately 35 mm and the 10th and 90th percentile at 25 mm and 45 mm respectively. Hence a cervix below 25 mm at mid pregnancy is suggestive of short cervix. A good evidence in the literature shows that inflammation contributes to preterm labour and it is shown that a short cervix predisposes to inflammation. A cervix less than 15 mm has very high incidence of preterm labour. Insertion of cervical suture may not substantially reduce the risk of prematurity. However, when diagnosed along with aggressive preterm tocolysis, antibiotics etc will help in a good number of those women otherwise would have delivered preterm. Hence TVS has a good positive predictive and negative predictive value for preterm labour and therefore could be used as a screening method in pregnancy. 3. Paternal factors: Little is known about paternal factors in the genesis of spontaneous abortion. Certainly, chromosomal translocations in sperm can lead to
abortion. DNA abnormalities may be contributory in these cases and it may be worth assessing this. Mechanism of Abortion a. Up to 8 weeks: The gestational sac tends to be expelled complete and the decidua is shed thereafter. b. From 8-12 weeks: The decidua capsularis ruptures and the embryo is expelled either entire or after rupture of the amnion. c. After 12 weeks: The placenta is completely formed and the process of abortion is like a miniature labour. It is more common for the foetus to be expelled but for the placenta to be retained due to firmer attachment to the uterine wall (Figs 8.3 and 8.4). CLINICAL VARIETIES
Threatened Abortion Clinical picture: Symptoms and signs of pregnancy coincide with its duration. Vaginal bleeding slight or mild, bright red in colour originating from the choriodecidual interface. Pain is absent or slight. Cervix is closed. Pregnancy test is positive. Ultrasonography shows a living foetus. Prognosis: With or without treatment if the foetus is normal in chromosomes the chances of pregnancy continuation is 85 per cent. Treatment: Rest in bed until one week after stoppage of bleeding. No intercourse as it may disturb pregnancy by the mechanical effect and the effect of semen prostaglandins on the uterus. Sedatives can be used if the patient is anxious. Progestogens and its role is controversial. However, low plasma progesterone level is an indication of pregnancy failure. Progestogens may cause retention of the dead ovum leads to missed abortion. Gonadotrophins (hCG) may be of benefit in cases of luteal phase deficiency which is once again not proved.
Inevitable Abortion Clinical picture: Symptoms and signs of pregnancy coincide with its duration.Vaginal bleeding is excessive and may be accompanied with clots. Pain is colicky felt in the suprapubic region radiating to the back. The internal os of the cervix is dilated and products of conception may be felt through it.
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Jeffcoate’s Principles of Gynaecology Rupture of membranes between 12-28 weeks is a sign of the inevitability of abortion. Treatment: Any attempt to maintain pregnancy is useless. Resuscitation and ergometrine 0.5 mg is given by IM or IV route to induce tetanic uterine contraction and stop bleeding. I. If pregnancy is less than 12 weeks: Termination is done by vaginal evacuation and curettage or suction evacuation under general anaesthesia. II. If pregnancy is more than 12 weeks: • Oxytocin is given by intravenous drip to expel the uterine contents. • If the placenta is retained it is removed under general anaesthesia. Cervical abortion: is a variety of inevitable abortion in which the products of conception has been separated from the uterine cavity but retained in the cervical canal causing its distension. Clinical Picture • The patient complains of considerable bleeding and severe lower abdominal pain referred to the back. • On examination, the products of conception is felt through the dilated cervix.
Fig. 8.3: Proposed mechanisms of foetal loss
Treatment: Under anaesthesia, the cervix is dilated, contents is removed and cavity is curetted to remove the decidua.
Incomplete Abortion Retention of a part of the products of conception inside the uterus. It may be the whole or part of the placenta which is retained. Clinical picture: The patient usually noticed the passage of a part of the conception products. Bleeding is continuous. On examination, the uterus is less than the period of amenorrhoea but still large in size. The cervix is opened and retained contents may be felt through it. Ultrasonography: shows the retained contents. Treatment: Complete the process by evacuation.
Complete Abortion
Fig. 8.4: Threatened abortions
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• All products of conception have been expelled from the uterus. • Clinical picture: The bleeding is slight and gradually diminishes. The pain ceases.
Spontaneous Abortions (Including Recurrent Loss) • The cervix is closed. The uterus is slightly larger than normal. • Ultrasound: shows empty cavity.
Missed Abortion Retention of dead products of conception for 4 weeks or more. Carneous mole is a special variety of missed abortion in which the dead ovum in early pregnancy is surrounded by clotted blood. Clinical picture Symptoms: Symptoms of threatened abortion may or may not be developed. Regression of pregnancy symptoms as nausea, vomiting and breast symptoms. The abdomen does not increase and may even decrease in size. The foetal movements are not felt or ceases if previously present. Milk secretion may start particularly in second trimester abortion because of the decline in oestrogens secretion that were normally blocking the action of prolactin on the breasts. A dark brown vaginal discharge may occur (prune juice discharge). Signs: The uterus fails to grow or even decreases in size and becomes firmer. The cervix is closed. Investigations: Pregnancy test becomes negative within two weeks from the ovum death, but it may remain positive for a longer period due to persistent living chorionic villi. Ultrasound shows either a collapsed gestational sac, absent foetal heart movement or foetal movement (Fig. 8.5).
Fig. 8.5: Foetal cardiac activity
Evacuation is carried out as following: If the uterine size is less than 12 weeks’ gestation: vaginal or suction evacuation is done. If the uterine size is more than 12 weeks’ gestation : evacuation can be done by : a. Prostaglandins: given intravaginally (PGE2), intravenously, intra-or extra- amniotic (PGF2α). b. Oxytocin infusion. c. Combination: starting with prostaglandin and completed with oxytocin. d. Hysterotomy: is not done in modern methods of evacuation.
Septic Abortion It is any type of abortion, usually criminal abortion, complicated by infection.
Complications: Disseminated intravascular coagulation (DIC) may occur if the dead conceptus is retained for more than 4 weeks and superadded infection.
Microbiology: E. Coli, bacteroids, anaerobic streptococci, clostridia, streptococci and staphylococci are among the most causative organisms.
Treatment: The dead conceptus is expelled spontaneously in the majority of cases. Evacuation of the uterus is indicated in the following conditions: spontaneous expulsion does not occur within four weeks. However, in clinical practice one does not wait for too long as there is an increased psychological feelings in the woman and her relatives. Hence the same may be evacuated either medically or surgically depending on the size of the uterus.The other indications to interfere is that when there is bleeding or infection or DIC.
Clinical picture General examination: • Pyrexia and tachycardia. • Rigors suggest bacteraemia. • A subnormal temperature with tachycardia is ominous and mostly seen with gas forming organisms. • Malaise, sweating, headache, and joint pain. • Jaundice and/or haematuria is an ominous sign, indicating haemolysis due to chemicals used in
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Jeffcoate’s Principles of Gynaecology criminal abortion or haemolytic infection as clostridium welchii. Abdominal examination • Suprapubic pain and tenderness. • Abdominal rigidity and distension indicates peritonitis. Local examination • Offensive vaginal discharge. Minimal inoffensive vaginal discharge is often associated with severe cases. Uterus is tender, products of conception may be felt, local trauma may be detected. Fullness and tenderness of Douglas pouch indicates pelvic abscess which will be associated with diarrhoea. Complications Endotoxic (septic) shock may develop with its serious sequels as acute renal failure and DIC. Treatment • Isolate the patient. Bed rest. • An intravenous line is established for therapy. In case of shock a central venous pressure (CVP) line when needed to aid in the control of fluid and blood transfusion is added. • Observation for vital signs: pulse, temperature and blood pressure as well as fluid intake and urinary output. A cervico-vaginal swab is taken for culture (aerobic and anaerobic) and sensitivity, • Antibiotic therapy: Ampicillin or cephalosporin (as a broad spectrum) + gentamycin (for gram -ve organisms) + metronidazole (for anaerobic infection) are given by intravenous route while awaiting the results of the bacteriological culture. Another regimen to cover the different causative organism is clindamycin + gentamycin. • Fluid therapy: e.g. glucose 5 per cent normal saline and/or lactated ringer solutions can be given as long as there is no manifestations of acute renal failure particularly the urinary output is more than 30 ml/ hour. • Blood transfusion: is given if CVP is low (normal: 8-12 cm water). It is of importance also to correct anaemia coagulation defects and infection. • Anti-gas gangrene (in Cl.welchii) and antitetanic serum (in Cl. tetani). • Oxytocin infusion: To control bleeding and enhances expulsion of the retained products.
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• Surgical evacuation of the uterus can be done after 6 hours of commencing IV therapy but may be earlier in case of severe bleeding or deteriorating condition in spite of the previous therapy. • Hysterectomy may be needed in endotoxic shock not responding to treatment particularly due to gas gangrene (Cl. welchii). RECURRENT EARLY PREGNANCY LOSS Recurrent miscarriage (RM) is traditionally defined as three or more consecutive miscarriages occurring before 20 weeks of pregnancy. Majority of RM cases following investigations are classified as idiopathic, that is, no identifiable cause in either partner, it is generally accepted that within the idiopathic group there is considerable heterogeneity and it is unlikely that one single pathological mechanism can be attributed to their RM history. Aetiology (Fig. 8.6)
Coagulation Investigations Acquired maternal thrombophilia is a well-recognized cause of RM. All women with a history of three or more early pregnancy losses, that is, before 10 weeks, or 1 or more unexplained deathsat 10 weeks of a morphologically normal foetus, or 1 or more premature births at 34 weeks with severe pre-eclampsia or placental insufficiency, should be offered a testing for lupus anticoagulant (LAC) and anticardiolipin antibodies
Fig. 8.6: Aetiology
Spontaneous Abortions (Including Recurrent Loss) (ACA), known collectively as antiphospholipid antibodies (APA), to exclude an antiphospholipid syndrome (APS). More recently, an increased incidence of early and recurrent foetal loss has also been suggested in women with inherited thrombophilia, including Factor V Leiden deficiency, activated protein C
resistance, prothrombin G20210A and protein S deficiency. Other coagulation abnormalities, including impaired fibrinolytic activity, factor XII deficiency and reduced activated partial thromboplastin time have also been reported to be associated with RM, but the corresponding epidemiological data are limited.
Figs 8.7A to G: Genetic anomalies in embryo
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Jeffcoate’s Principles of Gynaecology
Endocrinologic Investigations Early epidemiological data have shown an association between RM and hypothyroidism or diabetes mellitus. Although current evidence indicates that treated hypothyroidism and well controlled diabetes are not associated with RM, it is better to rule out the same with a TSH levels and blood sugars for diabetes mellitus. Obesity certainly has a wider impact on women’s health, and several studies have shown that the association between polycystic ovary syndrome (PCOS) and RM could be secondary to the association between obesity and miscarriage.
Immunologic Investigations An excessive maternal immune response against paternal antigens resulting in abnormal immune cells and cytokine production has and is thought to be one of the causes of RM but no definitive data has been found.
Parental Cytogenetic Investigation The incidence of structural chromosome abnormalities, usually a balanced translocation is increased in couples with RM. A high resolution 11-14 weeks scan can pick up many markers of genetic anomalies (Figs 8.7A to G).
Fig. 8.8A: 3D ultrasound septate
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Cytogenetic studies in the abortus: The risk of live born trisomy following an aneuploidy in a sporadic early pregnancy failure is around 2 per cent. By contrast, chromosomal analyses of the products of conception in couples with RM indicate that a normal conceptus karyotype in a previous pregnancy is a predictor of subsequent miscarriage since chromosomal abnormalities in recurrent early pregnancy loss is not seen. Uterine anomalies: Using 3D ultrasound, it has been reported that women with a subseptate uterus have a higher incidence of first trimester loss, whereas women with an arcuate uterus have a greater proportion of second trimester loss and preterm delivery. However uterine anomalies per say does not contribute to increased incidence of RM (Figs 8.8A and B). Other investigations: High level of homocysteine (hyperhomocysteinaemia) can be associated with RM. Among the genetic causes of this condition, a common one is polymorphism at position 677 in the methyl tetrahydrofolate reductase (MTHFR) gene, which in the homozygous form leads to a thermolabile enzyme variant. Within this context, low plasma folate levels have been associated with an increased risk of first trimester miscarriage. Infections: Toxoplasmosis, Rubella, cytomegalovirus, herpes (TORCH) screen is of limited value in the investigation of RM.
Fig. 8.8B: Hysteroscopy showing septum
Spontaneous Abortions (Including Recurrent Loss) Management: Aspirin and/or heparins have become routine treatment for women with APS and inherited thrombophilias and a history of RM, on the basis of limited evidence. There seems to be a considerable medical use of progestogens and there is currently insufficient information to allow recommendations regarding optimal dose, route and timing of progesterone supplementation. A recent systematic review found no
evidence to support the routine use of progesterone in the first trimester to prevent miscarriage. The use of intravenous immunoglobulin (IVIG), antiTNF, glucocorticoids or cellular therapies in order to prevent or reduce an ‘excessive immune response remains controversial. A small number of non-randomised studies have reported that psychological support, that is, tender loving care (TLC) in early pregnancy, decreases miscarriage rates in women with unexplained RM.
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9
Ectopic Pregnancy
CHAPTER
Tubal Pregnancy Ovarian Pregnancy Cornual Pregnancy Cervical Pregnancy Abdominal Pregnancy Intraligamentary Pregnancy
144 155 156 157 157 159
Definition An ectopic pregnancy is one in which the fertilised ovum becomes implanted in a site other than the normal uterine cavity. Although extrauterine pregnancy is often used as a synonymous term, it is different in that it does not include certain rare types such as pregnancy in the rudimentary horn of a bicornuate uterus. Ectopic pregnancy is the consequence of an abnormal implantation of the blastocyst. Frequency Ectopic pregnancy is seen in about 2 per cent of all pregnancies in USA, 3-4 per cent worldwide incidence. In some studies the incidence reported is as high as 16 ectopic pregnancy for 1000. The incidence of ectopic pregnancy has risen in the past 20 years due to various reasons like predisposing factors and also better diagnostic techniques. Ectopic pregnancy is the leading cause of maternal mortality in USA (10-15%). Sites of Ectopic Pregnancy Any pregnancy occurring outside the uterine cavity is labelled as ectopic pregnancy. The possible sites can be classified according to above downwards and according to frequency. Above downwards 1. Abdominal cavity 2. Ovary 3. Fallopian tubes 4. Broad ligament 5. Rudimentary horn of uterus 6. Cervix
Ectopic Pregnancy
Frequency 1. Fallopian tubes 95-98 per cent 2. Uterine cornu 2-2.5 per cent 3. Ovary, cervix and abdominal cavity 6 cm in diametre. In these women the chance of subsequent choriocarcinoma maybe 10 per cent. Older women are also at a higher risk of developing persistent tumour. Clinical Features The symptoms and signs of complete hydatidiform mole are at first those of early pregnancy but, with the development of the mole, the general reactions are exaggerated. Excessive vomiting is common, the patient loses weight, and she feels and looks ill. Pre-eclampsia
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develops in approximately one-third of the cases and earlier than usual. Its appearance is directly related to the weight of the mole, and this suggests that excessive trophoblastic activity is the primary cause of the preeclampsia. Strangely, eclamptic convulsions rarely supervene. The symptom which most often calls attention to the abnormality is recurrent uterine bleeding and brown discharge. The initial diagnosis is therefore likely to be threatened abortion and, in approximately 50 per cent of cases, the mole is not suspected until it is expelled in part or whole, or the patient undergoes ultrasonography to check for foetal viability. Abortion almost always takes place sooner or later. Heavy and prolonged vaginal bleeding superimposed on pre-existing malnutrition leads to anaemia in half these women. The possibility of hydatidiform mole should be considered whenever the symptoms of threatened abortion do not subside quickly or when they recur, and especially if the patient is reacting badly to the pregnancy. The physical signs are as follows: • The uterus is too large for the period of amenorrhoea. This sign is present in only 50 per cent of cases; sometimes the uterus is smaller than normal, especially if the mole dies. • The uterus is doughy in consistency and does not contract. • Foetal parts are not felt. • Foetal movement and heart sounds are absent. • The passage of vesicles in the uterine discharge is conclusive evidence but rarely occurs until abortion is imminent. • Bilateral ovarian enlargement is palpable in 25-50 per cent of cases. A rare but fascinating development is thyro-toxicosis. Although several investigators speculated that a unique thyroid stimulating hormone (TSH) is synthesised by trophoblastic tissue, there is evidence that hCG itself may cause hyperthyroidism. Human chorionic gonadotrophin has an alpha subunit identical to that of TSH and therefore has an inherent capacity to stimulate the thyroid. The thyrotoxicosis disappears dramatically when the mole is removed, but may be severe enough to require treatment with β-adrenergic blockers before operation or the patient can have a thyroid storm. In patients with partial hydatidiform mole, the clinical picture is not so dramatic. Of the clinical features described above, only vaginal bleeding is usually seen,
Gestational Trophoblastic Disease the remaining features being seen in less than 4 per cent of cases. The general presentation is that of incomplete or missed abortion. Now-a-days, many more cases are being diagnosed by ultrasound. Diagnosis When the clinical features are suggestive, the following tests can be applied.
Ultrasound Ultrasonography is the diagnostic method of choice because of its reliability, sensitivity and safety. The diffuse hydropic swelling of the chorionic villi produces a characteristic ‘snow-storm’ appearance throughout the uterine cavity (Fig. 10.6). No gestation sac or foetus can be identified. A similar picture can, however, sometimes be seen in cases of degenerated leiomyomas or adenomyomatous polyp. In the case of a partial mole, focal cystic spaces are seen in the placental tissues and the transverse diametre of the gestation sac is increased.
Human Chorionic Gonadotrophin The serum level of β-hCG is markedly elevated. The condition most likely to be confused with hydatidi-form mole is multiple pregnancy. This, in the early months, is not infrequently manifested by threatened abortion, an unusually large uterus, vomiting and elevated β-hCG levels. Consequently, hCG estimations cannot be depended upon alone for absolute diagnosis of hydatidiform mole, although they usually add strong supporting evidence. Since accurate dating of the pregnancy is necessary for assessment of the level of hCG, ultrasonic examination is essential, and will also prove the diagnosis. The two modalities are thus complementary to each other. Serum β-hCG level is important in the follow-up. Dangers These are severe haemorrhages, with or without an associated coagulation disorder, at some stage of the expulsion of the mole; infection; perforation or rupture of the uterine wall by the invading chorion or by attempts to remove it; and simultaneous or subsequent development of choriocarcinoma. The risk of malignant change averages 5 per cent. If, however, there is proper supervision of all affected women, with the administration of
cytotoxic drugs when indicated (see below), the risk is small. Treatment If the mole is spontaneously expelled from the uterus, the immediate treatment is the same as for inevitable abortion. If none of the mole is expelled when the diagnosis is made, the uterus must be emptied as soon as possible. Suction curettage is done with a wide-bore cannula, even if the uterus is 20 weeks or more. Blood should be crossmatched and kept available if necessary and an intravenous lifeline should be in place. Accumulated old blood and fresh blood in the lower part of the uterus may gush out at first, but continued suction will remove the mole and control the bleeding. After the uterus is evacuated, a gentle sharp curettage of the uterus should be carried out. It is now recommended that an oxytocin drip should be started only after evacuation is complete to decrease the risk of trophoblastic embolisation. Rhnegative women should receive Rh immune globulin as trophoblast cells express the RhD factor. A check ultrasound is done after one week to see the completeness of the evacuation. Suction curettage is the preferred method of evacuation, regardless of uterine size, for patients who desire to preserve fertility. It involves the following steps: 1. Oxytocin infusion—This procedure is required to keep the uterus contracted so that the bleeding is less during the procedure of evacuation. 2. Cervical dilation—Usually the cervical dilatation is not required as the cervix is very soft and easily permits the use of the suction canulae. 3. Suction curettage— Passage of the uterine sound is avoided as this may cause perforation of the uterus sometimes. Within a few minutes of commencing suction curettage, the uterus may decrease dramatically in size, and the bleeding is generally well controlled. The use of a 12-mm cannula is strongly advised to facilitate evacuation. The tip of the suction canula is inserted just beyond the internal os . Deep insertion of the suction canula near the fundus may cause uterine perforation as the uterus will be very soft in this condition. If the uterus is larger than 14 weeks of gestation, one hand should be placed on top of the fundus, and the uterus should be massaged to stimulate uterine contraction and reduce the risk of perforation.
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Jeffcoate’s Principles of Gynaecology Hysterectomy may be performed with the mole in situ for women aged 40 and over who have completed their families. However inspite of hysterectomy a careful follow up is required since choriocarcinoma can still develop. The ovaries can be preserved; large theca lutein cysts can be decompressed by aspiration. In any case, these disappear spontaneously once the chorionic activity is quelled. Most medical oncologists believe in careful follow up and in the administration of cytotoxic drugs only as and when required. They point out, justifiably, that only 20 per cent of women who deliver a hydatidiform mole develop persistent tumour. There is some evidence that routine prophylactic chemotherapy can prevent the incidence and morbidity of locally invasive disease as well as metastases. A decision in any case may depend on facilities for follow up as well as on patient cooperation. There maybe a place for prophylactic chemotherapy in the management of high-risk complete molar pregnancy, especially when hormonal follow up is unavailable. Further Management The material removed from the uterus is always examined histologically but the microscopic appearance by itself is not reliable to assess the prognosis. Knowledge of the blood groups of the patient and of her husband can indicate whether she is in the category at special risk. In any case, and even if the mole has been removed by hysterectomy, regular observation of the patient is essential to detect the first sign of remaining or reawakening chorionic activity. After six ovulatory cycles which is made out by six regular cycles, the next pregnancy is allowed. However if the woman goes to persistent trophoblastic tumour the next pregnancy should be avoided for two years. Pre-eclampsia develops almost exclusively in patients with excessive uterine size and markedly elevated hCG levels. Hydatidiform mole should be considered whenever pre-eclampsia develops early in pregnancy. Hyperemesis requiring antiemetic or intravenous replacement therapy may be seen particularly in those with excessive uterine size and markedly elevated hCG levels. Severe electrolyte disturbances may develop and require treatment with parenteral fluids. Currently, less than 10 per cent of patients have hyperemesis. Irregular uterine bleeding and amenorrhoea can both signify the development of
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persistent disease. The persistence or development of cystic ovaries can also suggest continued chorionic activity. The most reliable method of follow-up is by serum β-hCG assay. Prominent theca lutein ovarian cysts (6 cm in diametre) develop in about one-half of patients with a complete mole. Theca lutein ovarian cysts result from high serum hCG levels, which cause ovarian hyperstimulation. Ultrasonography can accurately document their presence and size. After molar evacuation, theca lutein cysts normally regress spontaneously within 2 to 4 months. Prominent theca lutein cysts may cause symptoms of marked pelvic pressure, and they may be decompressed by laparoscopic or ultrasonographically directed aspiration. If acute pelvic pain develops, laparoscopy should be performed to assess possible cystic torsion or rupture.
Gonadotrophin Assays Serum β-hCG levels are assayed every week after molar evacuation till 3 consecutive levels are found to be normal. Thereafter the assays are done at monthly intervals until they are normal for 6 consecutive months. Serum hCG levels remain high for a longer time after evacuation of a mole than after a normal pregnancy. The average time to achieve the first normal hCG level after evacuation is about 9 weeks. If, after a phase of normal hCG titres, the patient is found to have high levels, the occurrence of a new conception must be excluded before it is assumed that she has developed choriocarcinoma. For this, and other reasons, it is important at the outset to warn the woman against conceiving again within 12 months of having a hydatidiform mole. In this respect, however, care is necessary over the method of contraception advised. An intrauterine contraceptive device (IUCD) is inadvisable because it may cause uterine bleeding to raise the fear of choriocarcinoma. Insertion of an IUCD before normalisation of hCG levels also carries the risk of perforation. If the patient does not desire surgical sterilisation, the choice is to use either oral contraceptives or barrier methods. Previously the combined oestrogen-progestogen pills were avoided as it was feared that they would increase the risk of postmolar trophoblastic diseases. However, these fears have not been substantiated and the combined pills are actually preferred because they provide reliable contraception. Progestogen-only pills, however, are
Gestational Trophoblastic Disease liable to produce irregular bleeding and should not be used. In subsequent pregnancies, because of the slight chance of choriocarcinoma developing, it is always advisable to confirm normal development by an ultrasound in the first trimester. The placenta or products of conception should be sent for histological review on delivery and the hCG level checked 6 weeks after pregnancy to rule out trophoblastic neoplasia. Contraception Patients are encouraged to use effective contraception during the entire interval of hCG follow-up. Because of the potential risk of uterine perforation, intrauterine devices should not be inserted until the patient achieves a normal hCG level. If the patient does not desire surgical sterilisation, the choice is to use either oral contraceptives or barrier methods. It was reported earlier that there was increased incidence of persistent trophoblastic tumours when oral contraceptives were used for contraception following evacuation of Hydatidiform mole. But it appears that oral contraceptives may be used safely after molar evacuation during the entire interval of hormonal follow-up.
Indications for Chemotherapy after Hydatidiform Mole The risk following the evacuation of a hydatidiform mole, is principally that of developing persistent trophoblastic tumour. The principles of all follow-up programmes must be to ensure that all patients who require chemotherapy should receive it at the time it is effective; and it is not given to those patients who do not need it. If this cannot be done, prophylactic chemotherapy is justified. Some of the factors which influence attendants to use chemotherapy have already been mentioned, namely, the age, parity, and mode of evacuation, as well as the geographical variations. Criteria for treatment are as follows: High levels of hCG more than 4 weeks postevacuation; progressively increasing levels of hCG at any time postevacuation; any detectable level of hCG not showing a tendency to disappear 4-6 months postpartum; and evidence of metastases with any level of hCG. After one molar pregnancy, the risk of having molar disease in a future gestation is about 1 per cent.
Persistent Trophoblastic Tumour The serum hCG level is measured weekly after each course of chemotherapy, and the hCG regression curve serves as the primary basis for determining the need for additional treatment. If the patient’s response to the first treatment was adequate and a second course of MTXFA is required the dosage of MTX is unaltered. An adequate response is defined as a fall in the hCG level by 1 log after a course of chemotherapy. If the response to two consecutive courses of MTX-FA is inadequate, the patient is considered to be resistant to MTX, and ActD is promptly substituted. If the hCG levels do not decline by 1 log after treatment with Act-D, the patient also is considered resistant to Act-D as a single agent. She must then be treated intensively with combination chemotherapy to achieve remission. The EMA-CO (Etoposide, Methotrexate, Actinomycin, Cyclophosphamide, Oncovin) regimen is generally well tolerated, and treatment seldom has to be suspended because of toxicity. The EMA-CO regimen is the preferred primary treatment in patients with metastasis and a high-risk prognostic score. Therefore, for any subsequent pregnancy, it seems prudent to undertake the following approach: 1. Perform pelvic ultrasonographic examination during the first trimester to confirm normal gestational development. 2. Obtain a thorough histologic review of the placenta or products of conception. 3. Obtain an hCG measurement 6 weeks after completion of the pregnancy to exclude occult trophoblastic neoplasia. Pregnancies after persistent GTT patients with GTT who are treated successfully with chemotherapy can expect normal reproduction in the future. PERSISTENT GESTATIONAL TROPHOBLASTIC TUMOUR This is generally classified as non-metastatic and metastatic disease. Non-metastatic Disease Non-metastatic locally invasive gestational trophoblastic tumour (GTT) develops in about 15 per cent of patients after molar evacuation, though it may
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Jeffcoate’s Principles of Gynaecology infrequently develop after other gestations. The patients present with irregular vaginal bleeding. On examination, the uterus may show subinvolution and may be asymmetrical in its contour. Theca lutein cysts may be present. Serum β-hCG levels are persistently elevated. Perforation of the tumour through the myo-metrium may cause intraperitoneal haemorrhage. If a vessel is eroded, massive vaginal bleeding may occur. The necrotic tumour tissue is a focus for infection.
Placental Site Trophoblastic Tumour This is an uncommon, monomorphic trophoblastic tumour comprised principally of cytotrophoblast. The lesion may be microscopic in size or form a soft, brown, partly haemorrhagic mass which protrudes into the uterine cavity and infiltrates the myometrium. The placental site trophoblastic tumour shows a range of behaviour from benign, with a capacity for spontaneous regression, to a highly malignant form which proves resistant to cytotoxic chemotherapy. It differs from choriocarcinoma in that it produces relatively little hCG and hPL in relation to the size of the tumour. When diagnosed it is essential to follow-up patients with serum β-hCG levels. Typically it occurs in the reproductive years and the patient presents with amenorrhoea and uterine enlargement. Most of the sensitive radioimmunoassays for pregnancy will be positive and a clinical diagnosis of missed abortion is likely to be made. Curettage can lead to uterine perforation because the tumour penetrates deeply into the myometrium. These tumours are best treated by hysterectomy if still localised to the uterus. Conservative surgery with excision of the tumour has been described in sporadic cases where preservation of fertility is desired. Metastatic Disease
Incidence Choriocarcinoma is rare; it has a geographical distribution similar to that of hydatidiform mole, and occurs in the same type of women. In Britain and North America, choriocarcinoma arises only once for every 50,000-70,000 pregnancies. In the Far East and in Central Africa, the incidence is one case for every 5000-6000 pregnancies, those women affected being mostly relatively old, of high parity and in poor physical
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condition. The Middle East holds an intermediate position. The growth may commence, in its full malignant form, during pregnancy but more commonly arises afterwards from remaining islets of trophoblastic tissue. Nevertheless, small foci and microscopic areas of choriocarcinoma in otherwise normal term placenta are described. These give no clinical evidence of their presence and it seems possible that many small growths of this type are missed. Some may be delivered with the placenta and give no more trouble; others may be the origin of the choriocarcinoma which follows normal pregnancy. When choriocarcinoma develops during normal pregnancy, metastases may rarely be found in the baby. These are mostly in the liver, indicating a bloodstream spread. In fact, choriocarcinoma accounts for about half the cases of metastatic disease in the foetus. The interval between pregnancy, molar or other-wise, and the development of overt choriocarcinoma may be as long as 5 years or more, although it is usually less than 2 years. Extraordinary cases have been reported. In one, choriocarcinoma appeared 12 years after hysterectomy for a mole. In another, ‘ectopic choriocarcinoma’ developed in the lungs 20 years after the last pregnancy and 8 years after hysterectomy. In 50 per cent of cases the condition is preceded by hydatidiform mole. In 25 per cent it follows abortion or ectopic pregnancy, and in the remaining 25 per cent, delivery of a normal foetus. A normal pregnancy intervening between a mole and the development of choriocarcinoma is recorded.
Pathology The primary growth, which is a tumour of embry-onic chorion, is usually in the uterine wall, but may be in the cervix or vagina, or in the tube or broad ligament following ectopic pregnancy. The tumour is soft, necrotic and haemorrhagic so it appears plum-coloured to the naked eye (Fig. 10.6). Its invasive character is usually obvious and quite often there are multiple and apparently entirely separate primary nodules in the cavity and wall of the uterus. Although the degree of malignancy varies, it is usually high and the growth spreads early by local extension into the broad ligaments and paracolpos, and by the bloodstream to the lungs, (80%), vagina (30%), pelvis (20%), brain (10%) and liver (10%).
Gestational Trophoblastic Disease 10.5). Occasionally the hCG level is low, possibly because the tumour is encapsulated, possibly because it is mainly composed of non-secretory elements. There may be mole and foetus co-existing (Fig. 10.6). Choriocarcinomas also secrete hPL but the amount is variable; it has been suggested that it varies inversely with the degree of malignancy.
Clinical Features
On section, the tumour shows cyto- and syncytiotrophoblastic cells in varying numbers, actively proliferating and assuming bizarre forms; also mononucleated and multinucleated giant cells (Figs 10.7 and 10.8). When syncytial tissue predominates, the growth is sometimes called a s y n c y t i a l k n o t — a distinction of little practical importance. Chorionic villi are characteristically absent. A choriocarcinoma is functional and usually secretes hCG in large quantities. This causes luteinisation (with or without cyst formation) of the patient’s ovaries (Fig.
The leading symptom is irregular uterine haemor-rhage, coming on sooner or later after the expulsion of a mole or a normal pregnancy. The haemorrhage is characteristically intermittent but alarmingly heavy while it lasts. Such bleeding is arterial and can arise either from a nodule in the vagina or from one in the uterus. For the former, the treatment has been by suture; for the latter, an emergency hysterectomy may be necessary to control bleeding into the vagina or into the peritoneal cavity. As the condition advances, an offensive vaginal discharge develops and cachexia with pyrexia supervenes. Often, the disease presents by way of its metastases. Thus, the occurrence of a haemothorax, a complaint of dyspnoea or haemoptysis, or the appearance of neurological signs and symptoms such as headaches, visual disturbances or focal neurological deficits can be the first evidence of choriocarcinoma. Chest radiography, revealing ‘cannon balls’ or a ‘snow storm’ appearance in the lungs may give the lead, as may a finding of acute pulmonary hypertension or pleural effusion. Solitary lesions appearing in the lungs or brain many years after
Fig. 10.7: Choriocarcinoma. The actively proliferating pleomorphic cells are derived from both layers of the trophoblast
Fig. 10.8: A higher-power view of choriocarcinoma, showing mainly syncytial cells
Fig. 10.6: USG showing mole and foetus
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Jeffcoate’s Principles of Gynaecology the causal pregnancy are often misdiagnosed. Hepatic metastases may stretch the hepatic capsule and present as epigastric or right upper quadrant pain. Such patients may also present as an acute emergency with massive intraperitoneal bleeding following hepatic rupture. On pelvic examination, vaginal metastases may be seen; these are characteristically suburethral or in the fornices and bleed briskly if biopsied. The uterus often feels enlarged and cystic ovaries are sometimes palpable.
scan of the chest can show micrometastases or lesions located behind the heart shadow in patients with a normal chest X-ray. If there are pulmonary metastases, brain metastases must be ruled out, but in the absence of pulmonary metastases, brain metastases never occur. Pelvic ultrasonography may help to identify patients with large tumour bulk in and around the uterus and determine whether hysterectomy is indicated. Baseline complete blood count, hepatic, thyroid and renal function tests are part of the pretreatment investigation.
Staging Gestational trophoblastic tumour can be staged according to the FIGO system (Table 10.1).
Diagnosis The diagnosis is usually made or confirmed by the finding of high levels of serum β-hCG. Biopsy is contraindicated to prove any metastasis as it would lead to profuse bleeding. It should be noted, however, that the growth does not always abut on to the uterine cavity so that curettage usually gives negative findings. Another fact to be remembered is that in one-third of the cases of metastatic choriocarcinoma there is no evidence of disease in the uterus. Curettage of uterus also is not needed as tissue diagnosis is not important. In fact curettage also may cause torrential bleed. A high index of suspicion is required for the diagnosis of metastatic disease. This differential diagnosis must be kept in mind when any woman who has ever been pregnant presents with pulmonary, neurological or hepatic symptoms as described above. The work-up includes a chest X-ray, a CT scan of the chest in some cases, an ultrasonogram or CT scan of the abdomen and pelvis, CT scan of the head and CSF hCG if required. CT Table 10.1: Staging of gestational trophoblastic disease Stage I Stage II
Stage III Stage IV
Disease confined to uterus Gestational trophoblastic disease (GTD) extending outside uterus but limited to genital structures (adnexa, vagina, broad ligament) GTD extending to lungs with or without known genital tract involvement All other metastatic sites
All stages subdivided as (a) No risk factors; (b) One risk factor; (c) Two risk factors Risk factors: 1. hCG >100 000 mlU/ml 2. Duration of disease >6 months from termination of antecedent pregnancy.
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Treatment
Chemotherapy Chemotherapy is indicated in all cases of choriocarcinoma, alone or in conjunction with surgery. It is essential that all those treating these cases have available an accurate, reliable and sensitive method of determining hCG for the diagnosis, monitoring of therapy, and follow-up. They must be familiar with all the possible drugs, their mode of delivery and particularly their toxicity and how to control it. These are vital for optimal results and hence the advantage of referral of patients to special centres if possible and practical. Several factors affect the prognosis and response to therapy apart from age, parity and blood groups (Table 10.2). The number and size of metastases will obviously influence the response, but the site is also important. Tumours involving the brain, liver and gastrointestinal tract have a poor response. The duration of the disease from the pregnancy, or the onset of symptoms associated with a pregnancy also influence the outcome. The critical time interval appears to be 4 months, since after that period of time the patient is less likely to respond to chemotherapy. The level of hCG prior to starting treatment is of major importance in predicting the response to therapy. Patients with serum hCG levels above 100,000 IU/litre have a poor response. If the diagnosis is made early, and with limited disease, even if metastases are present, patients have a good prognosis; but those patients who are treated late, have extensive disease and a high hCG output have a bad prognosis. It has also been noted that patients with metastatic disease following a term pregnancy fare less well than those following abortion or hydatidiform mole. Finally, those patients who are referred for treatment following previous chemotherapy or inadequate chemotherapy, as might be expected, fare badly.
Gestational Trophoblastic Disease
Table 10.2: Scoring system based on prognostic factors
Prognostic factors Age (years) Antecedent pregnancy Interval* hCG(IU/L) ABO groups (female X male) Largest tumour, including uterine tumour Site of metastases
Score 0
1
12 >105
Gastrointestinal tract, liver 4-8 single drug
Brain >8 2 or more
The total score for a patient is obtained by adding the individual scores for each prognostic factor. Total score: 8 = high risk. * Interval time (in months) between end of antecedent pregnancy and start of chemotherapy.
Prior to commencing treatment, patients are graded according to their risk factors so that the optimal course of chemotherapy can be given (Table 10.2). The grading is either low-risk (good prognosis), or high-risk (poor prognosis). In some centres, there is a third grade in between these called medium-risk. Since there are wellknown side-effects of all the drugs used, a careful check is made before a course of treatment is commenced or continued. The principal adverse effects are on the bone marrow, the liver and kidney, so regular checks are made on white cell count, platelets, liver function and blood urea. The systemic effects as far as the patient herself is concerned are stomatitis, skin rash, alopecia, gastrointestinal disturbances and conjunctivitis, which are treated symptomatically. They rarely influence the decision about continuing drug therapy. Any life-threatening toxicity must be treated vigorously. In non-metastatic and in low-risk metastatic GTT, single-agent chemotherapy is recommended. The drug of choice for single-agent chemotherapy is methotrexate given intramuscularly, 50 mg (35 mg/m2) on alternate days for four doses, with 6 mg of folinic acid given in the days between the four doses. An alternative singleagent drug is actinomycin D, 10-13 ng/kg per day, intravenously, for 5 days. The serum hCG is measured weekly after each course and if the level is found to be progressively declining, no further chemotherapy is given.
If the titre rises or plateaus at an elevated level after two courses, or if the hCG level does not undergo one log fall within 18 days after completing the first course, a second course is given in the same dosage and monitored similarly, until there is a negative β-hCG subunit assay. Once this level is reached, treatment is stopped or one further course given. This regimen is used for low-risk (good prognosis) cases which constitute the majority of the cases at risk on the two-grade system. Patients with medium- and high-risk factors or those who have failed to respond to single-agent chemotherapy are given combination chemotherapy. The same criteria as mentioned above are used for changing a particular combination of drugs. Several regimens have been tried. Triple therapy with methotrexate, actinomycin D and cyclophosphamide (MAC) may be useful in cases with failed single-agent therapy but has remission rates of only 50 per cent in patients with metastases and a high-risk prognostic score. The EMA-CO regime (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) is used in patients with metastatic GTT and a high-risk score. When a patient fails to respond to multi-agent therapy, her chances of cure are poor. Intra-thecal methotrexate is administered for the treatment of CNS metastases. A diagnosis of remission is not made until three consecutive weekly negative β-hCG subunit assays are obtained. After remission, two additional courses of
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Jeffcoate’s Principles of Gynaecology chemotherapy are given to reduce the risk of relapse. Follow-up is usually carried out with monthly hCG estimations for 2 years for stage I through III and for 2 years for stage IV disease. In general, less than 1 per cent of those who have been in remission for a year ever require further treatment. Cure is usually said to have occurred after a period of 5 years in remission. After two years in remission, patients who had retained their reproductive capacity may embark on another pregnancy if they wish. Surgery If investigations failed to reveal evidence of extension of the growth outside the uterus, it was once the practice to proceed with immediate total hysterec-tomy. It still has a place in selected Stage I cases in whom future fertility is not desired or those who are resistant to chemotherapy. It is also indicated in patients with placental site trophoblastic tumour which is usually resistant to chemotherapy. Combined with chemotherapy, some gynaecologists favour this operation even when secondary deposits are known to exist in Stage II and III. They do so on the grounds that it is best to remove as much growth, primary or secondary, as is possible to give ‘host response’ and cytotoxic drugs the optimum effectiveness. In some it may be required to control uterine bleeding. In all cases there should be joint consultation, with either the medical oncologist or a specialised centre, regarding the management of each case. The fact that a proportion of cases (10-40% reported) in which hysterectomy is carried out reveal no evidence of choriocarcinoma on histological examination suggests that investigations carried out before surgery should indicate that the uterus is involved. Whenever hysterectomy is carried out, the ovaries should be conserved. It is illogical to do otherwise. If the growth is confined to the uterus there is no point in removing the adnexa; if it has already entered the bloodstream it is equally useless. Metastases to the ovary are also rare, and these are usually easily identified at operation. Rarely, a young woman who wishes to retain her fertility does not respond to either single-agent or combination chemotherapy. In such patients, local uterine resection has been attempted after defining the exact site of the resistant tumour by MRI or arteriography.
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Under the heading of surgery it is necessary to mention the occasional need for the excision of isolated nodules in the vagina and lungs when these persist after chemotherapy. Vaginal metastases may bleed profusely and may require wide local excision or arteriographic embolisation of the hypogastric arteries. Thoracotomy for excision of resistant disease should be supplemented with postoperative chemotherapy. Similarly, hepatic resection or arterial embolisation for hepatic lesions and craniotomy for cerebral resection may be required for localised metastatic disease or for control of bleeding. Radiotherapy Radiotherapy is not an appropriate mode of treat-ment for pelvic lesions as it will interfere with the delivery of optimal chemotherapy. Whole brain irradiation is sometimes used in conjunction with chemotherapy for localised cerebral metastases to reduce the risk of haemorrhage. Intensive combination chemotherapy supplemented with intrathecal methotrexate has shown similar results.
Results The advent of chemotherapy improved survival rates dramatically, although the results of this, like those of surgery, depend on how early the disease is recognised and treated. If the tumour is confined to the uterus (or pelvis) and there is no evidence of metastatic disease, it is claimed that the cure rate is 90-97 per cent. When the disease is metastatic, then the remission rate is still high if it is considered to be in the group of good prognosis as judged by the pretreatment assessment. Some workers have reported very similar results to low-risk patients without evidence of metastatic spread. For patients with metastatic disease and poor risk, the remission rate is 75-90 per cent. The best results are obtained amongst those cases discovered as a result of routine serial assays of hCG in women who have had a hydatidiform mole; treatment can then often be started before the disease; is clinically evident. There is a place for surgery in cases treated with chemotherapy and it is possible that it may give the best results.
Gestational Trophoblastic Disease Contraception is essential during treatment and the period of hCG follow-up and is recommended as described above for hydatidiform mole. There is no real evidence that successfully treated trophoblastic disease is associated with subfertility or foetal wastage. There does not appear to be any increase in abortions, congenital abnormalities, perinatal loss or neonatal morbidity. The explanation suggested is that the period of contraception allows all mature ova affected by chemotherapy to be eliminated, whilst the resting oocytes are not affected by the drugs. The treatment of gestational trophoblastic tumours has been one of the chemotherapy success stories since
the first patient of metastatic choriocarcinoma was cured in 1956. Nevertheless, there still remains the problem of treating patients where it is impossible to arrange for the necessary detailed hCG follow-up facilities, which are vital, or those individuals who are unlikely to return for their follow-up visits. Under these circumstances prophylactic therapy has a place. Even where all facilities are available and the patient cooperates, there is the problem of those who do not respond to therapy. With improvements in chemotherapy these are now very few in number and even these will hopefully be resolved in the foreseeable future.
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11
CHAPTER
Breast Function and its Disorders
Breast Development Developmental Anomalies of Breast Changes in Pregnancy and Lactation Breast Feeding and Lactation Suppression of Lactation Drugs and Lactation
174 176 177 178 179 179
Endocrine Disorders (Galactorrhoea and Breast Atrophy) Screening for Breast Diseases Benign Breast Diseases Carcinoma Breast
179 183 186 188
BREAST DEVELOPMENT The female breasts (mammary glands) develop rapidly between the age group 1020 years. The adolescent breast development takes place according to sexual maturity rating and the breast bud development is the first sign of puberty in girls at around eight years of age. Embryologically the breasts (mammary glands) develop on the mammary line/ ridge which is a thickened ectoderm from axilla to inguinal region. On this mammary line the ectoderm thickens as a mass of epidermal cells and projects into the dermis in the pectoral region and this forms the mammary glands on both sides. About 15 to 20 outgrowths arise from this thickened epidermal mass and grow into the dermis to get surrounded by fat, vascular and connective tissue. The distal part of these outgrowths forms secretary elements and proximal part cannulates to form lactiferous ducts. All the ducts open into a pit which becomes elevated to form nipple. The breast lobes develop at puberty in response to endocrine stimulation (Figs 11.1 and 11.2). Stages of Breast Development at Puberty At birth the breast is a simple system of ducts without alveoli. By 9-10 years female breasts begin to enlarge, first the area around nipples enlarges.
Fig. 11.1: Areolar bud (Patient on oestrogen therapy)
Breast Function and its Disorders P3 Increase in size of palpable breast tissue and areolae. Increased dark pubic hair on mons veneris and of axillary hair and characteristic body odour. P4 Further increase in breast size and areola which protrudes above breast level. Adult sexual hair but limited to pubes. Acne and menarche may occur. P5 Adult breast and areolae. Adult amount and distribution of pubic hair with extension to upper thigh. Menarche occurs. Fig. 11.2: Chiari-Frommel syndrome
• The ducts and acini develop in the next 3-4 years. • By menarche there is fat deposition and breasts become prominent and round. • Further enlargment of breasts occurs till 18 years of age. • Prepubertal development is mainly due to oestrogens from ovary and also due to growth hormone and adrenal corticoids. • The hormones which are required by a non-lactating breast to grow are oestrogens, progesterone, growth hormone, insulin, cortisol, thyroxine and prolactin. • The receptors in mammary glands (cytoplasm of mammary epithelium) depend on prolactin and these receptors respond to oestrogen. Adequate fat deposition is also needed for normal breast development and this adipose tissue provides a loose matrix for glandular and ductal expansion under hormonal stimulation. • The morphological changes in breasts at puberty are described by Tanner in five stages (P1 – P5) (Fig. 11.3). Tanner’s Staging
Endocrine Control of Female Breast The mature breasts undergo a cycle which corresponds to the ovarian cycle. Oestrogen will stimulate ductal elements whereas oestrogen and progesterone stimulate glandular elements and increase in water content of breast. In the luteal phase there is increased epithelial activity (slight secretion) in the ducts and acini; this regresses during menstruation. The breast as a whole increases in size during a week before menstruation and this is mainly due to congestion and oedema of the connective tissue between lobules. This is manifested as premenstrual heaviness and pain and tenderness in breasts (Table 11.1). Table 11.1: Endocrine control of female breast development and function from prepubertal stage to pregnancy
Stage
Duct system
Major Hormones
Permissive Hormones
Prepubertal
None
Unknown
Adult
Oestrogen (Progesterone)
Pregnancy
Progesterone Prolactin Human placental lactogen
P1 Prepubertal (Breast bud only) P2 Early development of subareolar bud, widening of areolae, small amount of labial or axillary hairs
Insulin Thyroxine Glucocorticoids Growth hormone
Fig. 11.3: Morphological changes in breast at puberty
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Jeffcoate’s Principles of Gynaecology During pregnancy there is an active development of both ducts acini (Many acini are formed for first time). The breast enlarge and their vascularity increases. The acini secrete a small amount of glairy fluid (colostrum). The development of breast during pregnancy is endocrine hormone (oestrogen + progesterone) dependant for full preparation for Lactation is also dependant on an adequate diet, corticosteroids and prolactin (placental or pitutary) (Fig. 11.4). At menopause, as the level of sex steroid hormones decrease, the breast tissue, both glandular and stromal undergoes atrophy. The breast size will decrease and this may also contribute to psychological disturbance during menopause. Breast is also an important secondary sexual organ and it is an erogenous zone, the stimulation of which aids in orgasm. Breast give the women a female identity, hence changes in breast size and problems of breast cause a lot of psychological upset and trauma. DEVELOPMENTAL ANOMALIES OF BREAST The breast development may show various anomalies which are seen during the adolescence growth period and cause a lot of psychological trauma. The breast anomalies are classified as: 1. Congenital Anomalies 1. Absence 2. Supernumerary 3. Ectopic position (Accessory breast/Nipple) 4. Midline webbing 5. Retracted Nipples 2. Modification of Physiological response 1. Hypoplasia or Aplasia 2. Hypertrophy
Fig. 11.4: Breast enlargement in pregnancy and lactation
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3. Asymmetry 4. Painful engorgement (Neonatal or pubertal) 5. Malformation of shape 3. Faulty sexual development 1. Premature development 2. Delayed or failure of development 1. Congenital Anomalies 1. Absence a. Amastia: absence of complete breast b. Athelia: absence of nipple c. Amazia: nipple is formed but not breast tissue 2. Supernumerary a. Polymastia: multiple breast b. Polythelia: multiple nipples c. Polythelia areolaris : only multiple areolas d. Only glandular tissue 3. Ectopic position of nipple or breast (accessory breast and nipples) 4. Symmastia: Midline webbing between breasts Congenital breast anomalies should be indentified early and mostly reassurance is needed and counselling is needed for corrective surgery in most cases. The surgeries done for such anomalies are augmentation mammoplasty, surgical removal of supernumerary breast or nipples, mammary prosthesis or glandular flap for unequal breasts. 2. Modification of Physiological response 1. Aplasia or Hypoplasia: Varying degree of under developed breasts are seen in young women and is usually due to fat and glandular tissue. The treatment for hypoplasia ranges from good diet, excercises of pectoral muscles, massage, oestrogen therapy in cases of low ovarian oestrogens and plastic surgery. 2. Hypertrophy: True hypertrophy (not adiposity) is uncommon. The cause is not known and it affects glandular tissue and not nipples. Usually bilateral and seen at puberty. These breasts may weigh as much as 6-13 kgs. These breasts will further hypertrophy during pregnancy and lactation but they do not lactate. Treatment is support or surgical reduction (subtotal mastectomy). Bromocriptine may be of some benifit during pregnancy. 3. Asymmetry: Like all other paired organs breast also will show some inequality in size (In 7% Adolescent which disappears later). Breast measurement is done with a centimetre tape from
Breast Function and its Disorders 3 O’ clock to 9 O’ clock and then from 12 O’ clock to 6 O’ clock over the nipples. The two measurements are multiplied and the figure is called “breast unit” Right breast normally tends to be slightly larger than left breast (Table 11.2). Table 11.2: Breast unit
Age
14 15 16
Rt Breast
Left Breast
Measure (cm)
Unit
Measure (cm)
Unit
19 × 13 21 × 17 22 × 18
247 357 396
18 × 14 17 × 20 18 × 21
252 340 378
The fault of asymmetry of breasts is always inherent fault in target tissue hence endocrine treatment is of no value. If the asymmetry is too much then surgery is the only answer (usually reduction of the larger breast and sometimes enlargement of the smaller). 4. Painful engorgement (Mastitis) (Neonatal or Adolescent): Breasts of male or female babies sometimes become enlarged and hard 3-4 days after birth. This is due to congestion related to the withdrawal of the influence of maternal oestrogens. A discharge may also occur from the nipple, known as “witch’s milk”. No treatment is required. Adolescent mastitis is a nodular painful enlargement of breasts in both boys and girls. It is due to an upsurge of pitutary hormones. No treatment is required. Reassurance and sometimes analgesics for symptom relief. A well fitting brassiere for breast support. 5. Malformation of shape: Usually the malformation involving inferior quadrant will present with various degree of severity. Minor malformations are high submammary sulcus, hypoplasia of inferior quadrant. Major malformations are flatness of whole inferior quadrant leading to “Funnel breast” or “Tubular breasts” also known as “nipple” breast or “snoopy” breasts. Surgical correction is the only treatment (Fig. 11.5). 3. Faulty Sexual Development 1. Premature development: where breast growth starts before the age of 8 years (Premature the larche), is due to increased organ sensitivity. This is usually self limiting.
Fig. 11.5: Tubular breast: excision of glandular tissue
If breast growth is associated with other secondary sexual characters and menstruation then it is known as “precocious puberty”. 2. Delayed or failure of development of breast: Absence of breast growth by age of 14 years is regarded abnormal. If menses is normal then it is hypoplasia due to target organ receptor. If amenorrhoea is there then the causes could be gonadal dysgenesis, pituitary hypothalamic lesion or androgen producing tumours. Complete endocrine and genetic investigations with CT skull may be required. 3. Changes in pregnancy and lactation: The mature breast is a collection of sweat glands modified during evolution to produce milk. Developed breast (mammary gland has stroma and glands which consist of fat, connective tissue, ducts and lobuloalveolar system. Breasts undergo mammogenesis during pregnancy.
Anatomic Changes a. General enlargement upto 2 to 3 times b. Increased vascularity and engorgement of superficial veins c. Brown pigmentation of areola d. Raised areas of areola: Montogomery’s tubercle e. formation of secondary areola f. Increased erectility of breasts g. Nodularity of breasts h. Secretion of a glairy fluid (colostrum) i. Pain and tenderness
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Jeffcoate’s Principles of Gynaecology Anatomic changes are more pronounced in primigravida rather than multigravida.
Physiological Changes 1. 2. 3. 4.
Mammogenesis Lactogenesis Galactokinesis Galactopoiesis The preparation of breasts (Mammogenesis) begins during pregnancy. Synthesis and secretion of milk (Lactogenesis) occurs due to high prolactin and fall in oestrogen and progesterone after delivery of placenta. The hormones responsible for mammogenesis or lactogenesis are cortisol, growth hormone, thyroxine and insulin. Galactokinesis is a centrally mediated reflex of milk let down. Galactopoiesis is maintenance of lactation and depends on frequent suckling of breast by infant. 4. Breast Feeding and Lactation Breast milk is universally recognised as the preferred nutrition for infants. Exclusive breast feeding is promoted internationally as optimum feet upto 4-6 months. Breast milk is nutritionally and immunologically superior to any substitute. The advantages of breast feeding to infant are nutrition, fat demand of baby, lactose content, protein content, vitamins and minerals, protective role against infections (due to IgA, lactoferrin, bifidus factor, unsaturated fatty acids, antibodies, lacto-peroxidase, interferons and chemotactic factor). Breast feeding also has benifits for the mother. 1. Breast feeding women return to prepartum state faster 2. Low risk of long term osteoporosis 3. Lower risk of premenopausal breast cancer 4. Inhibits ovulation hence contraceptive value. Other advantages are: a. Economic b. Benefits to community and country c. Ecologic benefits d. Psychological advantages e. Other benefits to baby: Minerals, protective role, lactoferrin, bifidus factor, unsaturated fatty acids, antibodies and non specific factors against viruses, other cellular components, development of brain and CNS.
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The Benefits of breast feeding also extend to the mother and these are: 1. Faster return to prepartum state 2. Low risk of long term osteoporosis 3. Lower risk of premenopausal breast cancers 4. Exclusive breast feeding, inhibits ovulation and hence delays return of fertility (contraceptive benefits). 5. The other benifits are economic, benfit to community and country, ecologic and psychological. The role of health care professionals is very important in initiating breast feeding in women during the first few days of hospital stay. WHO and UNICEF have also launched Baby Friendly Hospital Initiative (BFHI) in India and as a part of global effort to protect, promote and support breast feeding. Special Conditions Breast feeding can be reliably continued in various maternal health problems, except in heart failure, severe lung and kidney diseases and severe psychosis or postnatal depression. Mastitis and breast abscess do not contraindicate breast feeding. In mothers suffering from open tuberculosis, breast feeding can be continued and infant should be given prophylactic isoniazide. Breast milk is a primary form of immunisation for the infant hence in HIV and Hepatitis B infected mothers the benefits overweight the risk of transmission. Maternal malnutrition does not affect breast milk, however extreme prematurity and bilateral cleft palate may be a contraindication. Breast Diseases in Lactation The most common problem during lactation is mastitis and abscess formation. Mother may develop tender painful masses of galactoceles which can be diagnosed and cured by aspiration. Fibroadenomas may enlarge and become painful due to infarct. Breast cancer diagnosis becomes delayed if it occurs during lactation. Failure of Lactation Lactation fails if not initiated by early suckling. In 70 per cent cases lactation can be restored by counselling, good nutrition, rest and frequent suckling.
Breast Function and its Disorders If there is complete failure (aglactia) or very less breast milk, then galactogogus may be tried (chromprompazine or metoclopramide). Also it is possible to induce breast milk in non puerperal mothers.
ENDOCRINE DISORDERS (GALACTORRHOEA AND BREAST ATROPHY) Galactorrhoea About 5-10 per cent of normally menstruating women and 22 per cent of infertile women have milky discharge
SUPPRESSION OF LACTATION In some conditions breast milk needs to be suppressed in about 60-70 per cent. This can be achieved by no suckling and breast support. Drugs used for suppression are oestrogen and progesterone and androgen combination. This combination can reduce engorgement and discomfort but there is a risk of thromboembolism and rebound engorgement. Pyridoxine is a cheap and effective drug for lactation suppression. Bromocriptine is effective but has side effects. Cabergoline in a single 1 gm dose is very effective.
Table 11.4: Ratio of drug distribution in milk/plasma
Drug Type
M:P Ratio
Lipid soluble Water soluble (with MW 200) Weak acids Weak bases Actively transported drugs
+1 +1 =1 >1
Table 11.5: Drugs contraindicated in lactation • • • • •
DRUGS AND LACTATION Safety of prescribing any drug during lactation is questioned and a through knowledge of pharmacokinetics excretion in breast milk and probable hazards to infant should be kept in mind. Drug therapy beneficial to mother and not detrimental to infant is ultimate goal. Tables 11.3 to 11.8 includes safe and unsafe drugs.
Table 11.3: Factors affecting drug transfer into milk
Maternal pharmacology Drug dose, frequency and route of administration Clearance rate Plasma protein binding Metabolite profile Breast Blood flow and pH Yield capcity Ion nd other transport mechanism Milk Composition (Fat, Protein, Water) Infant Suckling time and amount/feed Feeding intervals Drug PKa Solubility characteristics in fat Protein binding characteristics, molecular weight
Antineoplastic Diazepam Lithium Phenindione Radiochemicals
Table 11.6: Drugs with limited safety in lactation Anthraquinones Barbiturates (safe in low doses) Cimetidine Indomethacin Isoniazid Methyldopa Metronidazole
Nalidixic acid Oral contraceptives (safe in low doses) Phenylbutazone Reserpine Sulphonamides Tetracycline Thiazide diuretics
Table 11.7: Probable safe drugs in lactation Alcohol Ampicillin Antihistamines Caffeine Carbamazepine Carbenicillin Cephaloridine Chlordiazepoxide Chloroquine Chlorpromazine Codeine Desipramine Dichloralphenazone Digoxin
Erythromycin Folic acid Frusemide Gentamycin Guanethidine Heparin Heroin Imipramine Iron Kanamycin Lincomycin Mefenamic acid Methylergometrine Morphine Nitrazepam
Nitrofurantion Paracetamol Penicillin Pentazocine Pethidine Phenothiazines Potassium iodide Propanthelene Quinine Salicylates Sodium fucidate Streptomycin Thyroxine Tolbutamide Warfarin
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Table 11.8: Analgesics and anti-inflammatory drugs
Drug
Quantity in Milk
MP Ratio
Adverse effects(Infant)
Comments
Aspirin Mefenamic acid Indomethacin** Morphine Phenylbutazone Pentazocine
Trace Negligible Excreted Trace Trace Not excreted
300 ng/ml
Normal Functional or tumour Very suggestive of a tumour Tumour present in 90% of cases Tumour is invariable
Diagnosis All preliminary routine mandatory investigations to include serum prolactin, thyroid and renal function tests. A serum prolactin should be done on two occassions as a mid-morning fasted, non stressed, no drugs and in follicular phase of menstrual cycle (Table 11.10).
Table of Levels Screening for pituitary tumours is done by imaging sella turcica by the various imaging modalities as shown in table 11.11.
Endocrinal tests to discriminate hypothalamic and pituitary causes. • GnRH stimulation • TRH stimulation Endocrine tests do not give any more additional value than a coned down view of sella turcica. Visual field examination is not useful as these may be altered only in very big tumours which are evident by radiological examination.
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Table 11.11: Imaging techniques of sella-turcica
Lateral coned down view of sella turcica
Computer axial tomographic scan in coronal plane with intravenous contrast (Enhancement CT Scan)
Magnetic resonance imaging (MRI)
Detects macroadenoma and craniopharyngioma Advantages Cheap and easily available Disadvantages • It is not very sensitive for small tumours as interpretation is dependent upon bony changes occurring in sella turcica secondary to tumour enlargement • In large tumours it cannot detect suprasellar extension
Uses 1 mm slices of the pituitary gland and hypothalamus. It visualises pituitary tissue and surrounding soft tissue. Therefore, it can diagnose microadenoma, suprasellar extension and empty sella syndrome
Best imaging technique for sella turcica It gives resolution of 1 mm, more sensitive than CT. Scan gives better accuracy in assessing extrasellar extension and empty sella syndrome. It has no biologic hazard Disadvantages • Very expensive • Requires lengthy period of time to obtain images
Disadvantages • High cost • Radiation exposure which is 3 rads, to eye lens it is 7 rads
Treatment Treatment depends on aetiology, stop aggravating drug, treat hypothyroidism, chest lesions and renal disease. If pituitary tumour is diagnosed, there are three options: medical, radiation or surgery. In cases of microadenoma only close surveillance in non-infertile parous women is a treatment option. Breast Atrophy Breasts are symbolic of feminity and maternal and sexuality not well formed breast and small atrophic breasts after puberty have a psychological feeling of disfigurement, loss of womanhood, social rejection or isolation. Breast atrophy or deformity is the most emotionally devastating of the physical deformities in women.
Table 11.12: Causes of small breasts
Clinical type
Causes
1. Developmental breast hypoplasia
1. Congenital 2. Iatrogenic in pre-pubertal age • Trauma • Infections • Incision • Radiation therapy Hormonal Oestrogen deficiency 1. Endogenous factors Neoplasms • Adrenal and ovarian tumours Non-neoplastic conditions • CAH* • Late onset CAH • Cushing’s syndrome • PCOD** 2. Exogenous-drug induced • Androgens and anabolic steroids • Danazol, dilantin • Minoxidil, diazoxide • Oral contraceptives Unknown viral
2. Late-onset breast atrophy a. Postpartum atrophy b. Postmenopausal atrophy c. Secondary atrophy
Classification A. Developmental breast hypoplasia (Micromastia) i. Congenital ii. Iatrogenic B. Late onset breast atrophy i. Postpartum ii. Postmenopausal iii. Secondary breast atrophy iv. Idiopathic
d. Idiopathic
*CAH — Congenital adrenal hyperplasia **PCOD — Polycystic ovarian disease
Clinical Features and Evaluation Aetiology Table 11.12.
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• Age (Adolescent, Post-pregnancy, Post-menopausal) • History (weight loss or gain)
Breast Function and its Disorders • Development (puberty/pregnancy/lactation) • Endocrine (secondary sex characters) • Breast masses • Family history of breast cancer • Psychological • Medical diseases In secondary breast atrophy: • Virilism • CAH or Cushing’s disease • Ovarian tumours
Laboratory Tests 1. 2. 3. 4. 5. 6. 7.
17 ketosteroids and hydroxy ketosteroids in urine Plasma testosterone and free testosterone Plasma androstenedione, LH, FSH, PRL Adrenal and Ovarian vein studies CAT Scan and MRI Ultrasound Laparoscopy
Management Look for underlying causes in adolescent group and treat them however to increase breast size. Mammary augmentation surgery is required. The figure 11.7 highlightes the management of small breasts.
SCREENING FOR BREAST DISEASES In the western countries breast cancer is the foremost killer. The incidence is as high as one in nine women. In India breast cancer is second to cervical cancer in incidence and mortality. To reduce mortality early detection is essential and statistics show that by screening mortality can be reduced by 25 per cent. Risk Factors Twenty per cent in 30-54 years age group and 29 per cent in women aged 55-84. Every woman is assumed at risk and must be screened. Age: At the age of 70 years a woman has 10 times more risk than 40 year old. Screening will benefit women 50-69 years most as there will be a 29 per cent reduction in mortality. Recommended screening is two yearly mammography (National cancer Institute) As the incidence of breast cancer is less than 10 per cent before 40 years these women benefit maximum by screening. Genetics (familial) Almost 5-10 per cent of breast cancer is seen to have a familial pattern over many generations. The relative risk
Fig. 11.7: Management of breast atrophy
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Jeffcoate’s Principles of Gynaecology is 1.5 to 2 with one first degree relative and 4-6 with two first degree relatives. BRCA-1 gene on the long arm of chromosome 17 and BRCA-2 on chromosome 13 and mutation p53, the tumour suppressor gene are implicated. Reproductive Factor Early menarche is a weak risk factor, relative risk of 1.2 for women with a menarche before 12 years as compared to 14 years. Chinese women have a 5 times less risk of breast cancer as compared to American women as the menarch is 17 years. Incidence is doubled in women with natural menopause occurring after 55 years. Nulliparity and delay of first child birth are also risk factors, increasing the risk by 3.5. Lactation is a weak to moderate protector. BENIGN BREAST DISEASE Women with history of benign breast disease contribute to 5 per cent of breast cancer cases. Diet/obesity/Alcohol: High fat contents in diet may influence, obesity is not a major risk factor. Alcohol consumption of even one drink per day is a moderate risk factor. Hormones and Breast Cancers: Oestrogen and very long term use of oral pills appear to increase risk but the risk drops as soon as drug is stopped. Ionising Radiation: No increase of risk in low dose exposure as low dose screening mammography. Risks increased from atomic blast exposure (Japanese women), radiation exposure for postpartum mastitis, tubercular patients undergoing multiple fluoroscopy. Screening Strategy Screening is basically done by: 1. Breast self examination (BSE) (every month) 2. Clinical examination by Physician (Annually) 3. Screening mammography (every two years) 1. BSE: Should be done every month after a menstrual period when breasts are soft (Fig. 11.8). The woman is asked to uncloth to waist and sit in front of a mirror: 1. Hands by the side 2. Hands pressed against the hips 3. Hands above the head 4. Stooping forwards
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Fig. 11.8: Routine breast self examination
The woman is taught to look for changes in size, contour, nipple retraction, elevation, visible lumps, skin changes like erythema, dimpling, ecchymosis. Breast should fall forwards on stooping. The woman should palpate after inspection in both sitting and supine position. Palpate right breast with left hand and vice versa. Teach the woman to palpate using palmar surface and areola is compressed to demonstrate nipple discharge, and then feel supraclavicular area. 2. Clinical examination by Physician: A complete and thorough history, assesment of reproductive history, counselling handing out pamphlets and reteaching BSE. The clinical examination is same as BSE but done by the physician. Screening Mammography The breast imaging can be done by ultrasound (high resolution probes) or radiologically by mammography. (Filmscreen mammography or xeromammography). For screening purpose breast mammography should be done every two years. Breast ultrasound is done by a 5-7.5 MHz transducer. The entire quadrant is scanned in sagitial and transverse planes. Both film screen and xeromammography are sensitive techniques in evaluating breast diseases.
Breast Function and its Disorders
Fig. 11.9: Breast examination by physician
Film Screen Mammography has a sensitivity of 90 per cent. It is the only method that allows reproducible and reliable detection of a prognostically relevant non palpable carcinoma. Xeromammography provides good penetration specially in dense breasts (Fig. 11.10). The procedure is dry, quick and does not need a darkroom, but only 5 per cent of mammograms are performed with xeromammography due to high dose of radiation and some technical disadvantages. Ultrasound: Today high resolution ultrasound with high frequency probes and the newest introduction of elastography (still under trial as screening for breast
Fig. 11.10: Mammogram shows diffuse increased density with no evidence of calcification. Benign breast disease
cancer) has revolutionised breast imaging ultrasound is becoming indispensable after a clinical examination. Ultrasound is quick, reliable and cheap and reproducible with patient comfort. Also almost all interventional procedures for diagnosis in breast disease are now done under ultrasound guidance (Fig. 11.11). Thermography shows thermal asymmetry and an abnormal thermography indicates • A localised abscess or inflammation • Alveolar lesions. Diaphanography is based on identifying lesions using transillumination.
Fig. 11.11: Ultrasound shows normal anatomy
185
Jeffcoate’s Principles of Gynaecology CAT Scan is of no use in evaluating breast lesions. MRI: A contrast enhanced MRI is most sensitive additional imaging modality after ultrasound and mammography (Fig. 11.13). Others: Digital Imaging and PET (Positron Emission Tomography) are being evaluated. Breast Cancer Screening Aims of screening for any cancer is to decrease the mortality and detect cancer before they become symptomatic. Mammography is the most sensitive method. Feig’s imaging protocol
Fig. 11.12: Galactography—shows normal and dilated ducts in otherwise normal mammography but H/o nipple discharge
Pneumocystography may tell us the extent of intracystic tumour. Ductography/Galactography is done by injecting radiographic dye into mammary ducts (Fig. 11.12). Abnormalities of nipple discharge like ductal ectasia, fibrocystic changes, papillomas and intraductal carcinoma can be diagnosed.
Fig. 11.13: MRI—shows normal breast, T1 and T2 weighted image
186
SN
PT Age years
Imaging
1. 2. 3. 4.
< 20 20-30 30-35 > 35
Sonography alone Sonography + Mammography Sonography + Mammography B/L views per breast mammography then sonography and MRI
BENIGN BREAST DISEASES a. b. c. a.
Mastodynia Fibrocystic disease Benign tumours Mastodynia or Mastalgia or Breast pain: can be cyclical or non-cyclical. Cyclical pain in breasts may occur related to menstrual cycle in the week preceding menstruation and is usually due to benign mammary dysplasia. Non-cyclical breast pain is more common and is usually in pre or post menopausal women. The pain is dragging or burning like pain. A mammography usually reveals coarse calcifications and ductal dilatations Pain in breasts may also be due to sclerosing adenosis, breasts cancer and Tietze’s syndrome. Breast pain is best managed by reassurance, a thorough clinical examination ultrasound and mammography. Supportive therapy helps like a good supporting Bra, low caffeine and mild anti-inflammatory drugs. Hormone therapy in form of use of Progesterone, Bromocriptine, Tamoxifen, Danazol, Gestrinone, Lisuride Maleate, LHRH analogues and thyroid hormone have been tried. Use of Evening primrose oil, Vit E and Diuretics may also help.
Breast Function and its Disorders
Table 11.13: TNM system of classification and staging Breast: Left Right Tumour Size _________ cmx _________ cmx _________ cm Lymph nodes total no
No with metastasis
Definitions:
Primary tumour (T) TX Primary tumour cannot be assessed T0 No evidence of primary tumour Tis Carcinoma in situ: Intraductal carcinoma, lobular carcinoma in situ, or Paget’s disease of the nipple with no tumour T1 Tumour 2 cm or less in greatest dimension T1a 0.5 cm or less in greatest dimension T1b More than 0.5 cm, but not more than 1 cm in greatest dimension T1c More than 1 cm but not more than 2 cm in greatest dimension T2 Tumour more than 2 cm but no more than 5 cm in greatest dimension T3 Tumour more than 5 cm in greatest dimension T4 Tumour of any site with direct extension to chest wall or skin T4a Extension to chest wall T4b Edema (including peau d’ orange) or ulceration of the skin of breast or satellite skin nodules confirmed to same breast T4c Both T4a and T4b T4d Inflammatory carcinoma Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed (e.g. previously removed or removed for pathologic study) N0 No regional lymph node metastasis N1 Metastasis to movable ipsilateral axillary lymph node(s) N2 Metastasis to ipsilateral auxillary lymph nodes that are fixed to one another or to other structures N3 Metastasis to ipsilateral internal mammary lymph node(s) Distant Metastasis (M) MX Presence of distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis (includes metastasis to ipsilateral supraclavicular lymph node(s)
Table 11.14: Management depending on stage of carcinoma
Stage
In all cases
Special staging tests
I
T1N0
CBC urinanalysis LFT, KFT X-ray chest, EKG Mammogram USG abdomen
Bone scan CT/MRI only if indicated
IIA
T1N1 T2N0
-do-
-do-
IIB
T2N1 T3N0
-do-
Bone scan selective vs. universal
IIIA
T0-T3, N2
-do-
Bone scan in all cases CT/MRI if indicated
IIIB
T4 any N any T N3
-doMammogram
-do-
IV
any Tany N M1
-doMammogram
Bone scan in all cases CT/MRI in all cases
187
Jeffcoate’s Principles of Gynaecology b. Fibrocystic disease: is common and distressing to the women as it may last for years. Fibrocystic disease is seen in one of four women with breast complaints may occur at any age. Aetiology is not clear may be hormonal disturbance, fluid retention, excessive caffeine and psychoneurosis. Breasts may have any of the numerous presentations described like small cystic feel, diffuse cystic feel, lumpy breasts etc. Risk of cancer with fibrocystic disease is poorly understood with an odd ratio of 1:8. A thorough clinical exam with mammography and FNAC should be advised. These women are best managed as per ABOG (American Board of obstetric and gynaecology) guidelines. After ruling out breast cancer the treatment is reassurance, pain killers, primrose oil, vitamin E, Danazol, bromocriptine, diuretics and pyridoxine. If no relief then progesterone therapy can be tried. The pain response and relief is charted by cardiff breast score. c. Benign Tumours of Breast: Breast lumps cause a lot of anxiety to patients and the possibility of malignancy is a challenging diagnostic dilemma. Benign tumours of breasts may be: 1. Fibroadenoma 2. Giant fibroadenoma 3. Phyllodes tumours 4. Papilloma and ductal tumours 5. Intraductal papilloma 6. Juvenile papillomatosis 7. Nipple adenoma 8. other benign tumours 9. Adenomyoepithelioma 10. Hamartoma 11. Lipoma 12. Leiomyoma These tumours are best treated by excision (Lumpectomy). Emphasis on breast self examination should be a part of education to girls. CARCINOMA BREAST Cancer Breast is the commonest cancer in women in Europe, USA and Australia and in India it is second commonest after cancer cervix. The incidence has increased and almost one million women will have cancer breast every year.
188
Risk Factors • • • •
Genetic Reproductive history Diet Hormone usage Radiation exposure
Clinical Features Usually presents as an ill-defined lump in breast associated with indrawing of nipple. Stage I: Discrete palpable lump of 2 cm or less Stage II: Discrete lump less than 5 cm with palpable ipsilateral mobile axillary lymph node Stage III: Large lump with local extension • Skin ulcer • Peaud’ orange • Satellite skin nodules • fixed chest wall • fixed ipsilateral lymph nodes Stage IV: All the above features plus • Supraclavicular lymph node • Liver enlargement • Krukenberg tumour • Ascitis • Pleural effusion • Bone pains and swelling • Headache and epileptic episodes • Chronic cough and recurrent haemoptysis Diagnosis is based on clinical examination and a thorough search should be made with all investigative modalities for extension and secondaries Staging TNM staging and classification (Table 11.13). Investigations are aimed to: 1. Confirm Diagnosis 2. Assess extent of disease 3. Predict response
Modalities and Tests 1. Ultrasound 2. Mammography 3. FNAC 4. Doppler studies 5. Bone scan 6. CAT and MRI Scans 7. Hormone receptor studies Management of breast cancers depends on the staging (Table 11.14).
12
CHAPTER
Development of the Urogenital System
The Gonad Wolffian System Müllerian Ducts Mesenteries and Ligaments
189 190 191 193
Development of the Vagina, Bladder and Urethra Development of the Vulva
194 194
The development of the three primary layers of the foetus is described in Chapter 7. By the twenty-first day (7-somite ovum) the embryo is completely covered by ectoderm, and the primitive gut (endoderm) has acquired a mesentery which attaches it to the posterior wall of the body cavity (coelom). The lining of the latter develops from mesenchyme; between it and ectoderm is the mesoderm (Figs 12.1A to D). On either side of the root of the mesentery is the intermediate cell mass of mesoderm and one part of this proliferates to form the urogenital ridge or nephrogenic cord. This extends from the cervical to the caudal region of the embryo. With the exception of the vulva, lower vagina, bladder and urethra, all the organs of the genital and urinary systems develop in these ridges. THE GONAD The mesenchymal cells of the coelom on the medial aspect of the intermediate cell mass and the underlying mesodermal cells proliferate to form a genital ridge which is apparent in the cervical and thoracic regions of the 4-5-week-old (4.5 mm crownrump [C.R.]) embryo. This elongated mass of undifferentiated cells is the sex gland anlage destined to become either the testis or the ovary. Sexual differentiation of the gonad is recognisable by the sixth week (17 mm C.R. embryo). The coelomic cells form the germinal (surface) epithelium and probably the cortex of the ovary; the underlying mesoderm gives rise to the medulla. At an early stage, connective tissue cords or septa develop to divide the undifferentiated cells into epithelial columns. These are probably mesenchymal downgrowths from the surface epithelium. In the male, the epithelial columns or primary sex cords become separated from the surface epithelium by the development of the connective tissue tunica albuginea; they subsequently differentiate to form the seminiferous tubules, Sertoli cells and the interstitial cells of the testis. In the female, the tunica albuginea does not appear at this stage, and the cords of epithelial cells break up into clumps and ultimately collect around the primordial ova to form primitive follicles. Secondary downgrowths (Pflüger’s tubules) occur later and also contribute pregranulosa cells. So, although the ovarian stroma is
Jeffcoate’s Principles of Gynaecology derived from basal mesoderm, all the granulosa and theca elements develop from coelomic epithelium. It is suggested that the differentiation of the mesenchyme cells into granulosa and theca cells is dependent on the presence of ova, each one of which acts as an organiser of the cells around it to form a primordial follicle. Oogonia become encapsulated with pregranulosa or granulosa cells by about the sixteenth to twentieth week; these cells are essential to their survival (see Fig. 3.1). The primordial germ cells - oogonia and spermatogonia - are formed at a very early stage from cells of the dorsal part of the hindgut (originally yolk sac). Having a capacity for amoeboid movement, they migrate during the first 3 weeks of foetal development, passing through the mesentery of the gut to reach the gonad. Originally a limited number, the oogonia divide rapidly to produce, according to one estimate, 600,000 oocytes at 8 weeks, and 7 million at 22 weeks. Thereafter cell division ceases and, coincident with a proliferation of stroma, many, and particularly those which have not acquired a covering
of pregranulosa cells, are destroyed. Hence, the number of primary oocytes present in the ovaries at birth is not more than 2 million, and these are in the dictyate stage of meiotic division (see pages 56 and 58). WOLFFIAN SYSTEM By the twenty-second or twenty-third day (8- or 9-somite ovum) small tubules develop in the cervical portion of each urogenital ridge, lateral to the future site of the gonad (Figs 12.1, 12.2 and 12.3). These constitute the pronephros and they acquire a duct which extends down to meet the cloaca which is the caudal extremity of the primitive gut. The pronephros is functionless and its tubules disappear almost entirely by the thirty-fifth day (10 mm C.R. embryo), their only remains in the adult female being the hydatid of Morgagni and possibly Kobelt’s tubules (Fig. 12.5). The pronephric (wolffian) duct, however, persists to serve the mesonephros - a second system of tubules which
Figs 12.1A to D: (A) Cross-section through the trunk of a 4-5-week-old embryo, showing the posterior coelomic wall with the root of the mesentery and the urogenital ridge on either side, (B) Similar cross-section through a slightly older embryo showing the left urogenital ridge and the mesentery of the gut. (C) Diagrammatic representation of (A), (D) Diagrammatic representation of (B), the right side being Jettered. Mes.-mesentery of gut; G-gonad; M-müllerian duct; W-wolffian duct; Meson.-mesonephric tubules; A-aorta; G.M.-genital mesentery; U.G.M.-urogenital mesentery; Ov-ovary
190
Development of the Urogenital System
Fig. 12.2: Diagrammatic representation of the urogenital system in a 6-week-old embryo as seen from the front. The müllerian duct is not shown
Fig. 12.3: The developing urogenital system as seen from the side
appears in the thoracic region on the twenty-ninth or thirtieth day (22-23-somite ovum). The mesonephros also quickly degenerates, disappearing almost completely by the seventh week (22 mm C.R. embryo). A few caudal tubules persist as the functional vasa efferentia and rete of the testis in the male, and as the vestigial paroophoron, epoophoron (organ of Rosenmüller) and possibly Kobelt’s tubules in the female (Figs 12.1, 12.2, 12.3, 12.4, 12.5 and 12.7). A third system of tubules, the metanephros, first appears in the caudal portion of the urogenital ridge about the thirty-fifth day and develops into the cortex and medulla of the kidney. The calyces and pelvis of the kidney, together with the ureter, have a different origin, being formed from a bud which grows up from the lower end of the wolffian duct to meet the metanephros (Figs 12.2 and 12.3). It will be noted that the kidney is at first situated at a low level in the foetal trunk. Its subsequent ‘ascent’ is more apparent than real, being mainly explained by disproportionate growth of the caudal end of the foetus. The wolffian (pronephric and subsequently mesonephric) duct runs down the posterior coelomic wall in the urogenital ridge to join the forepart of the cloaca which, when separated from the hindgut, becomes
the urogenital sinus (Figs 12.3 and 12.7A to E). The lower end of the ureter, below and in the region of the ureteric bud, ultimately opens up to form part of the urogenital sinus. In this way the openings of the wolffian duct and of the ureter become separated (Fig. 12.6). In the male, the wolffian duct persists as the vas deferens and epididymis, and is connected to the testis by the vasa efferentia and rete testis which are of mesonephric origin. The seminal vesicle is an outgrowth from the wolffian duct. In both sexes, the ureteric bud forms the ureter, the pelvis and calyces of the kidney and, by its contribution to the wall of the urogenital sinus, part of the base of the bladder and the urethra. But, in the female, the wolffian duct proper begins to degenerate at the eighth to the ninth week (33 mm C.R. embryo) and only remains in the adult as the rudimentary Gartner’s duct (Figs 2.13 and 12.5). Portions of this are found in the meso-salpinx, beside the uterus, in the cervix, in the anterolateral vaginal wall and in the region of the clitoris and urethra. MÜLLERIAN DUCTS The müllerian (paramesonephric) ducts appear between the fifth and sixth weeks (10 mm C.R. embryo), one in the outer part of each intermediate cell mass (Fig. 12.1). They
191
Jeffcoate’s Principles of Gynaecology form as buds of coelomic epithelium at the cranial end of the urogenital ridge. Each one grows down lateral to the corresponding wolffian duct until it reaches a low level. There it turns inwards and, crossing anterior to the wolffian duct, joins its fellow from the opposite side at the back of the urogenital sinus (Fig. 12.4). The Sertoli cells secrete a glycoprotein known as anti-müllerian hormone (AMH), which causes regression of the paramesonephric (müllerian) duct system in the male embryo and is the likely signal for differentiation of Leydig cells from the surrounding mesenchyme. Testosterone is produced by the Leydig cells and, with the converting enzyme 5α-reductase, dihydrotestosterone. Testosterone is responsible for evolution of the mesonephric (wolfian) duct system into the vas deferens, epididymis, ejaculatory ducts, and seminal vesicle. Dihydrotestosterone results in development of the male external genitalia and the prostate and bulbourethral glands. In the male, the action of a specific müllerian inhibiting substance liberated by the foetal testes causes the ducts to degenerate quickly, their only remnants in the adult being the uterus masculinus. In the female they persist, and their lower ends fuse to form the uterus while their separated upper parts with open ends become the fallopian tubes and the abdominal ostia. They also give off solid downgrowths to form the upper vagina.
In forming the uterus, the mullerian ducts fuse from below upwards, their adjacent walls breaking down to form a single cavity. Fusion begins at the seventh or eighth week (22 mm C.R. embryo) but is not complete until the twelfth week (55 mm C.R. embryo) of intrauterine life. The top of the uterus is at first flat, the domed fundus being a later postnatal development. Differentiation of the cervix from the body of the uterus is recognisable by the tenth week but the cervix is not clearly separated from the vagina until the twentieth week. Primitive endometrial glands are present by the sixteenth week and cervical glands by the twenty-eighth week. These later come under the influence of placental hormones so, at birth, they show evidence of some proliferation and even secretory activity which subsides during the early days of extrauterine life. At birth the uterus measures approximately 35 mm in length and weighs 2 g. It is disproportionately large because of the stimulus it has received from the maternal oestrogen. Within 2 weeks it decreases in size by onethird so that its overall length is 23 or 24 mm, two-thirds of which is made up of cervix (Fig. 2.16). Throughout infancy and childhood there is only slight growth in proportion to physical development, and the uterus of a girl of 8 or 9 years of age is essentially similar to that of a newly born child. During the 2 years preceding the menarche, the uterus suddenly grows apace so that it
Fig. 12.4: Diagrammatic representation of a later stage in the development of the wolffian and müllerian ducts
Fig. 12.5: The ultimate fate of the ducts and ligaments before and after descent of the ovary and its associated structures. H-hydatid of Morgagni; E-epoophoron; P-paroophoron
192
Development of the Urogenital System
Fig. 12.6: The stages whereby the lower part of the mesonephric (wolffian) duct is opened out to form part of the wall of the urogenital sinus. By this process the duct and its ureteric bud come to have separate openings into the sinus
doubles in length and increases 10 times in weight to approach adult dimensions and shape. At this stage, however, it is not mature and is not fully capable of reproduction. Uterine maturity, a rather nebulous property, is only attained during the following 2 or 3 years. At birth and during childhood the uterus is almost devoid of flexion and version, characteristics which only develop around the time of puberty. It is upright in the pelvis or tilted slightly backwards towards the sacral promontory. MESENTERIES AND LIGAMENTS As the gonad and wolffian systems develop, they project into the coelom until ultimately they are attached to its
Figs 12.7A to E: Diagrammatic explanation of the partition of the cloaca and the development of the vagina, (A) The early situation, hindgut and cloaca developing from endoderm. The arrow indicates a mesodermal downgrowth. (B) The urogenital sinus is forming as the urorectal septum of mesoderm (arrowed) divides the cloaca and separates the hindgut. (C) The müllerian ducts impinge on the urogenital sinus and form the müllerian tubercle. The sinovaginal bulbs develop at this site. The ureter now opens separately into the urogenital sinus, (D) The urogenital sinus above the müllerian tubercle narrows to form the urethra. The lower vagina forms from the urogenital sinus, (E) The cloacal membrane breaks down to expose the opened-up lower part of the urogenital sinus which is the vulva. The posterior part of the cloacal membrane opens to form the anus. All tissues of urogenital sinus origin are shown in heavy black in (C), (D) and (E)
193
Jeffcoate’s Principles of Gynaecology posterior wall by the urogenital mesentery (Figs 12.1 B, D); this is destined to become the broad ligament. The gonad then develops its own genital mesentery which is ultimately the mesovarium. The part of the urogenital mesentery lying outside or above the attachment of the genital mesentery contains the müllerian duct, wolffian (Gartner’s) duct and the remains of the pronephros and the meso-nephros; it is thus recognisable as the mesosalpinx. Below the gonad, the genital ridge is continued down the posterior coelomic wall and turns forwards to what will become the lower abdominal wall. It is called the genital ligament or gubernaculum and plays an important part in the ultimate descent of the gonad, especially in the male. In the female, the genital ligament is caught up by the müllerian ducts where they come together, and is thus divided into two parts. The lower part becomes the round ligament running from the cornu of the uterus to the abdominal wall. The upper part is the ovarian ligament attaching the ovary to the cornu of the uterus (Fig. 12.5). As their foetal development proceeds, the unfused portions of the müllerian ducts and the adjacent gonads descend towards the pelvis; this accounts for the fallopian tubes’ lying at right angles to the uterus and for the change in direction of the urogenital mesenteries to become the broad ligaments. The ovaries descend during the seventh to the ninth months and, at birth, are situated at the pelvic brim. DEVELOPMENT OF THE VAGINA, BLADDER AND URETHRA The cloaca is the lower end of the included yolk sac (endoderm) and, at an early stage of development, is divided into the hindgut and urogenital sinus by a downgrowth of mesoderm which forms the urorectal septum and ultimately the perineal body (Fig. 12.7). The lower ends of the fused müllerian ducts lie in close association with the posterior part of the urogenital sinus, and give rise to a solid downgrowth of tissue which invaginates the urogenital sinus to produce a prominence called the müllerian tubercle. (Fig. 12.7). There is a proliferation of urogenital sinus tissue to form the bilateral sinovaginal bulbs, also solid structures. The upper three-quarters of the vagina, and sometimes most of the vagina, is formed from the müllerian downgrowths which become canalised.
194
The lower part of the vagina develops by canalisation of the sinovaginal bulbs, a process which is not complete until the twenty-first week. Incomplete breakdown of the junction between the bulbs and the urogenital sinus proper leaves the hymeneal membrane. Although the vagina is mainly müllerian duct in origin, it is said that its epithelial lining represents an upgrowth of urogenital sinus tissue (which includes the bulbs) and that this explains why it is stratified in type. There are doubts about this explanation because clinical observations show that, when the lower half or more of the vagina fails to develop, its upper compartment is still lined by stratified squamous epithelium. A better explanation is metaplasia. The vaginal fornices are differentiated by the twentieth week. The part of the urogenital sinus immediately above the müllerian tubercle becomes narrowed to produce the urethra; the part below opens out to become the vestibule of the vulva with the urethra and vagina opening into it (Fig. 12.7D). The bladder itself is the upper part of the uro-genital sinus and at first has a diverticulum (allantois) into the body stalk. This later retrogresses, its remains being the urachus running from the fundus of the bladder to the umbilicus. DEVELOPMENT OF THE VULVA The external genitalia develop in the area bounded in front and above by the body stalk, and below and behind by the tail of the embryo (Fig. 12.8). It is not easy to recognise the sex of the external genitalia until the eleventh or twelfth week (50 mm C.R. embryo). By the fourth or fifth week, the genital tubercle is formed in front
Fig. 12.8: The sexually undifferentiated genitalia of the 4-5-week-old (10 mm) embryo
Development of the Urogenital System
Fig. 12.9: The external genitalia of the 10-12-week-old female embryo. The cloacal membrane has broken down to expose the urogenital sinus (vestibule)
by the fusion of two mesodermal thickenings. From this the genital swellings sweep backwards one on either side towards the tail; between them is the cloacal membrane
which is two-layered, ectoderm without and endoderm within. The urorectal septum of mesoderm, which grows down to separate the urogenital sinus from the hindgut, divides this membrane into urogenital and anal parts, and forms the perineal body. The genital tubercle ultimately becomes the phallus (the penis in the male and the clitoris in the female); the genital swellings develop into the scrotum in the male and the labia majora in the female. The urogenital membrane breaks down in its centre at the sixth week to expose the lower parts of the urogenital sinus which are destined to become the vestibule, urethra and lower vagina (Figs 12.7 and 12.9). Meanwhile, genital folds appear medial to the genital swellings, passing backwards from the genital tubercle, one on each side. In the male, and commencing at the tenth week, these fuse in the midline to form the floor of the penile urethra. In the female they remain separate as the labia minora. Bartholin’s glands and Skene’s tubules are developed from outgrowths of the urogenital sinus, the former being homologous to Cowper’s (bulbo-urethral) glands, and the latter to the prostate, in the male. The female urethra is homologous to the upper part of the prostatic portion of the male urethra.
195
Malformations and Maldevelopments of the Genital Tract
13
CHAPTER
Müllerian Duct Anomalies Ovary Fallopian Tube Uterus Vagina
196 209 209 209 211
Vulva Errors Arising in Connection with the Cloaca Malformations of the Urinary Tract
214 216 217
It is important to understand the connection between the urogenital system in development. The female urinary and genital tracts are closely related, not only anatomically but also embryologically. About 10 per cent of infants are born with some abnormality of the genitourinary system, and anomalies in one system are often mirrored by anomalies in another system. The early development of the genital system is similar in both sexes and the ambiguous sex is seen usually if it is connected to chromosomal abnormalities and are called as intersex conditions or hermaphroditism. Three main principles govern the practical approach to malformations of the genital tract. 1. The müllerian and wolffian ducts are so closely linked embryologically that gross malformations of the uterus and vagina are commonly associated with congenital anomalies of the kidney and ureter. 2. The development of the gonad is separate from that of the ducts. Normal and functional ovaries are therefore usually present when the vagina, uterus and fallopian tubes are absent or malformed. 3. Gross malformations such as absence of the uterus and vagina may be associated with anomalies in the sex chromosome make-up of the individual (see Chapter 14). There is also some evidence that less severe malformations, such as bicornuate uterus, can be genetically determined, the taint being passed from mother to daughter. MÜLLERIAN DUCT ANOMALIES The classification of müllerian duct anomalies is shown in Table 13.1. Absence or Incomplete Development of Both Müllerian Ducts (Class I)
Pathology Complete failure in development of the müllerian ducts results in absence of the fallopian tubes, uterus and most of the vagina (Mayer-Rokitansky-Küster-Hauser
Malformations and Maldevelopments of the Genital Tract
Table 13.1: American Society for Reproductive Medicine Classification of Müllerian Anomalies (1988)
Classification
Anomaly
Class I (Agenesis/Hypoplasia)
a. b. c. d. e. a. b. c. d.
Class II (Unicornuate)
Class III (Didelphys) Class IV (Bicornuate) Class V (Septate) Class VI (Arcuate) Class VII (DES-related)
a. b. a. b.
Vaginal Cervical Fundal Tubal Combined Communicating Non-communicating No cavity No horn Didelphys Complete Partial Complete Partial Arcuate DES-related
Reprinted by permission from the American Society for Reproductive Medicine (Fertility and Sterility 1988; Vol. 49 (6): pages 944-945)
[MRKH] syndrome). In such cases the vulva is likely to be normal and there may be a depression of variable depth representing the lower (urogenital sinus) part of the vagina. It is usual to find such a depression covered with a normal hymen (Figs 13.1, 13.3 and 13.12). The patients have a normal female karyotype. Renal ectopy and agenesis, skeletal abnor-malities, as well as cardiac anomalies are associated. A multifactorial mode of inheritance has been postulated. The MRKH syndrome has been linked with decreased galactose-1-phosphate uridyl trans-ferase activity leading to increased intrauterine galactose exposure. An association with the major histocompatibility antigen has also been reported. Poorly formed ducts of full length result in hypoplasia of the whole genital tract. Incomplete development sometimes affects the lower parts of the ducts only. Thus, well-formed abdominal ostia may be associated with hypoplasia or absence of the remainder of the tubes, of the uterus and of the vagina (Fig. 13.1). Or again, the tubes and uterus may be present and the vagina absent, rudimentary or imperforate. The converse is not usually
Fig. 13.1: Examples of malformations resulting from absence, hypoplasia or atresia of both müllerian ducts. The ovaries are usually present and functional as shown in each of the figures. (A) Complete absence of all the müllerian derivatives and also of the urogenital sinus component of the vagina. (B) As (A) but the urogenital sinus part of the vagina, with the hymen below, is normally formed; this is more common than (A). (C) Only the proximal parts of the müllerian ducts are developed so only the fimbrial extremities of the tubes are present. (D) Failure of the distal parts of the müllerian ducts to develop or to canalize. A hypoplastic uterus is therefore present but the vagina is absent. (E) As (D) but the uterus is well enough developed to menstruate with a resulting haematometra. In practice, whenever there is a functional uterus there is usually a small compartment of the upper vagina present as well (see text and Fig. 13.12). (F) Imperforate vagina with haematocolpos and haematometra. The hymen is normal and is situated below the obstructing membrane. (G) Congenital atresia of the cervix with haematometra; in this condition the vagina below is usually normal as shown here. (H) A congenital incomplete membrane or stricture in the upper vagina - ‘phimosis of the cervix’
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Jeffcoate’s Principles of Gynaecology true because the ducts grow downwards; so a wellformed uterus is rarely associated with absence of the fallopian tubes. Clinical Aspects Patients usually present between 15 and 18 years of age with primary amenorrhoea. Growth and secondary sexual characteristics are normal. Although findings on local examination are usually as described above, some patients may have a small vaginal pouch developed as a result of repeated attempts at intercourse. On rectoabdominal examination, the uterus cannot be palpated. Ultrasound confirms the absence of the uterus and demonstrates the ovaries. Occasionally, the rudimentary uterine horns can be seen. If ultrasound is inconclusive, MRI or laparoscopy is required. MRI is the ideal method for demonstrating uterine malformations. Chromosomal analysis is not usually required in these patients; however, some patients who present before puberty may require a karyotype to distinguish the condition from one of the forms of male pseudohermaphroditism. Renal anomalies are the commonest associated features seen in 40 per cent of cases, ranging from complete agenesis to malposition (usually a pelvic kidney), to subtle architectural alterations. Skeletal
abnormalities can involve the spine, limbs or ribs. These are seen in 10-15 per cent of patients. Some patients have subclinical auditory defects. Treatment is primarily by vaginoplasty and is discussed on pages 209-210. The clinical aspects are discussed under malformations of the tubes, uterus and vagina. Absence or Incomplete Development of One Müllerian Duct (Class II)
Pathology Absence of one müllerian duct results in a unicornuate uterus with only one fallopian tube (Class II). The cervix and vagina may be normal in appearance and function but they represent strictly only one half of the fully developed organs. A true unicornuate uterus is rare and is usually associated with absence or gross malformation of the renal tract on the side of the missing müllerian duct (Figs 13.2 and 13.3). Incomplete development of one müllerian duct gives rise to the more common apparent unicornuate malformation; this is distinguished by the finding of a fallopian tube and round ligament, rudimentary though they may be, on the affected side. In this condition two kidneys are usually present, although occasionally, the one on the affected side may also be hypoplastic and not show on intravenous pyelography (Figs 13.2A and B).
Figs 13.2A to C: (A) and (B) Hysterosalpingogram and intravenous pyelogram in the same woman, illustrating congenital absence of the left müllerian duct and wolffian system. A true unicornuate uterus is thus associated with absence of the kidney on the opposite side, (C) A hysterogram showing an apparent right-sided unicornuate uterus; but the presence of kidneys, indicated by the pyelogram on the same woman, proves that the uterus must be bicornuate with a hypoplastic horn on the left side not communicating with the cavity of the uterus. This was proved at laparotomy
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Fig. 13.3: The American Society for Reproductive Medicine classification of müllerian anomalies. Reprinted by permission from the American Society for Reproductive Medicine (Fertility and Sterility 1988; Vol. 49 (6): pages 944-945)
Symptoms A unicornuate uterus causes few symptoms and is usually only discovered by chance or as a result of pregnancy complications. If it happens that the patient has dysmenorrhoea, the pain is limited to the side on which the horn is present. The condition does not, as a rule, lower fertility significantly but it favours abortion and premature labour, breech presentation of the foetus and fundal insertion of the placenta. The uterus usually contracts efficiently in all stages of labour.
Diagnostic Signs The uterus which leans well to one side of the pelvis and which cannot easily be straightened should always be suspected as being unicornuate but the diagnosis can only be made for certain by inspection of the pelvic organs. Hysterosalpingographs are helpful but do not always distinguish between true and apparent unicornuate deformity (Figs 13.2 and 13.3).
Treatment No treatment is indicated for the true unicornuate uterus. The rudimentary horn of an apparent unicornuate uterus may have to be excised if it causes symptoms (see below).
shape are included, this type of malformation is extremely common and can be demonstrated in 10-15 per cent of fertile women. The different nomenclatures and classifications of the resulting deformities are confusing. Sometimes the external and internal shapes of the uterus are both affected, sometimes only one. From the standpoint of obstetrical complications the shape of the cavity is the more important.
Uterus didelphys (Class III) If the two mullerian ducts remain separate, the two halves of the uterus remain distinct and each has its own cervix (Figs 13.3, 13.5 and 13.7). Some distinguish between uterus didelphys and uterus pseudodidelphys according to the degree of separation of the two ducts and they believe that even the vulva should be duplicated in a true didelphys uterus. However, this view is not widely held. Occasionally, and especially if they are rudimentary, the horns are very widely separated and rarely may be found in the sacs of inguinal hernias.
Bicornuate Uterus (Class IV)
Imperfect Fusion of the Müllerian Ducts
In this condition only the lower parts of the ducts fuse, leaving the cornua separate (Figs 13.3, 13.4, 13.6 and 13.7). The cervix and vagina may be single or double.
Pathology
Septate and Subseptate Uterus (Class V)
Failure of fusion of the müllerian ducts occurs in varying degrees (Fig. 13.3). If minor degrees involving uterine
The uterus is outwardly normal but contains a complete or incomplete septum which reflects a failure in
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Fig. 13.4: Uterus bicornis unicollis. Both horns are equally and well developed; the resulting increased bleeding surface explains why the patient concerned always had very heavy periods which ultimately necessitated hysterectomy
Fig. 13.5: Uterus didelphys with one half of a septate vagina imperforate. This has resulted in a unilateral haematocolpos and haematometra, the diagnosis of which in life might have been missed because the patient concerned menstruated normally from the other side
Septate and Subseptate Vagina A sagittal septum with a crescentic lower edge may be present in the upper vagina or throughout its length (Fig. 13.8). It can occur alone or in conjunction with a septate or bicornuate condition of the uterus, and may have one or two cervices opening into it. This condition arises either because late fusion of the müllerian ducts gives rise to two müllerian tubercles, or because of failure of proper canalisation of the two sinovaginal bulbs. Very rarely, the septum is disposed from side to side and this is supposed to be explained by rotation of the müllerian ducts on each other.
Arcuate Uterus (Class VI) Fig. 13.6: A bicornuate uterus containing a pregnancy of 32 weeks’ duration. The broad-topped uterus with a depression between the horns is clearly visible. This condition may cause a transverse lie but, in this case, the patient delivered normally at term
This is a flat-topped uterus in which the fundal bulge has not developed after fusion of the ducts (Figs 13.3 and 13.7A and B). If only the exterior of the uterus is affected, the fundal myometrium is abnormally thin.
Deformities in Combination (Figs 13.3 and 13.5) breakdown of the walls between the two ducts (Figs 13.3 and 13.7D). The cervical canal may be single or double, and the vagina whole or septate.
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The above deformities occur in all manner of combinations. Moreover, they may be associated with atresia or underdevelopment of one or both müllerian ducts.
Malformations and Maldevelopments of the Genital Tract
Figs 13.7A to F: Certain types of müllerian duct malfusion deformity revealed by hysterosalpingography. (A), (B) Degrees of arcuate deformity, (C) A minor degree of bicornuate malformation; this type of radiograph is difficult to interpret because a similar picture can be produced by a fundal leiomyoma. (D) Septate uterus, (E) Uterus bicornis unicollis, (F) Uterus didelphys with a cannula in each cervix
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Jeffcoate’s Principles of Gynaecology that a defect in this process is a cause of these malformations. The uterus didelphys and bicornuate uterus often have unusually thick and strong round ligaments, and a tough vesicorectal fold running between each horn; it may be that these prevent the müllerian ducts coming together. Symptoms These abnormalities are relatively common but they pass unnoticed because they are often symptomless. The majority are first recognised during pregnancy, or as a result of a pregnancy mishap; this only goes to show that, excepting the condition of septate vagina, they do not as a rule lower fertility materially. Menstrual The menstrual cycle is usually normal. Fig. 13.8: Septate vagina, the septum being displayed by a fourbladed speculum. The patient concerned also had a uterus didelphys with a cervix opening on either side of the septum. She was an unmarried woman, aged 31 years, who was admitted to hospital suffering from haemorrhage from the lower border of the septum and was so exsanguinated as to require blood transfusion. The alleged cause of the haemorrhage was an attempt to insert a menstrual vaginal tampon for the first time; it may, however, have been an attempt at coitus
For example, one half of a uterus didelphys may communicate with the vagina and the other may not. Or again, one or both horns of a bicornuate uterus may be rudimentary.
DES-related Anomalies (Class VII) Several characteristic anomalies have been described in women who were exposed to diethylstilboestrol (DBS) in utero. Benign vaginal adenosis and cervical hoods, septae, collars and cockscombs are seen in a large number of cases. T-shaped uteri, wide lower segments and constriction bands have also been described. There is a high incidence of perifimbrial paratubal cysts. Vaginal clear cell adenocarcinoma is very rare. Unlike all other congenital uterine malformations, the DES uterus is not associated with an increase in renal anomalies.
Menorrhagia Menorrhagia can occur because of the larger bleeding surface offered by two well-developed uterine horns (Fig. 13.4).
Spasmodic Dysmenorrhoea This is presumably explained by the unusual arrangement of the musculature and by abnormal contractions. Unequal development of the two horns can be manifested by one-sided dysmenorrhoea.
Failure to Contain Flow Failure to control the menstrual outflow by means of a single intravaginal tampon can give a clear lead to the diagnosis of a septate vagina and uterus didelphys. Coital
Dyspareunia A vaginal septum may cause difficulty in coitus but this is often overcome without the couple realising the abnormality. One half of the vagina is then usually dilated and the septum is pushed to the side.
Bleeding Cause The müllerian ducts are ordinarily pulled together by subperitoneal fibromuscular tissue and it is suggested
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Attempts at coitus or at the insertion of a tampon sometimes cause bleeding from a vessel in the lower edge of the septum (Fig. 13.8).
Malformations and Maldevelopments of the Genital Tract
Obstetrical
Inefficient Uterine Action
Infertility
This is not often seen in the first and second stages of labour but is common in the third. Manual removal of the placenta may be necessary in cases of bicornuate, septate and subseptate uterus and the incidence of postpartum haemorrhage is increased. If the horns are completely separate, however, expulsive action is generally good. A high vaginal septum can prevent the cervix from dilating.
The only form of malfusion deformity which may lower fertility significantly is a fully septate vagina. In such circumstances, coitus may take place in the half which does not communicate with the cervix or with the better developed cervix and uterus. Even if coitus is practised sometimes on one side and sometimes on the other side of the septum, there is always a 50 per cent chance that semen is deposited in the müllerian duct which does not serve the ovary which has ovulated in that particular cycle.
Cornual Pregnancy See page 156.
Site of the Conceptus In successive pregnancies, this is not necessarily the same cavity of the ‘double’ uterus. If both horns are well developed, either may be used. When twinning occurs the foetuses sometimes have a horn each.
Sacculation of the Uterus This presents as either an organic or a functional abnormality during pregnancy. When the saccule is sited on the line of junction of the müllerian ducts it may be a manifestation of a fusion defect.
Abortion and Premature Labour These are common when the uterus is malformed because of abnormal contractions; inadequate stretching and hypertrophy to accommodate the pregnancy; poor implantation; or placentation on a septum. Uterine malformation tends to cause late, rather than early abortion, because of an associated incompetent os.
Malpresentation Malpresentation of the foetus, and the related fundal or cornual insertion of the placenta, are often explained by an abnormality in shape of the uterus. A subseptate or bicornuate deformity favours a transverse lie; a uterus didelphys or a unicornuate uterus favours a breech presentation. The finding of a transverse lie which resists version, or a history of malpresentation in several pregnancies, should always raise a suspicion of uterine malformation.
Obstructed Labour The non-pregnant horn of a uterus didelphys enlarges during pregnancy, being subjected to the same hormone influences as the pregnant horn. Sometimes it remains low in the pelvis and then constitutes a tumour which obstructs the delivery of the foetus. Labour may also be obstructed by a vaginal septum, a classical situation arising when the breech presents astride the septum. Diagnostic Signs A septate vagina and two cervices may be obvious on vaginal examination and either finding should immediately raise the possibility of a fusion defect in the uterus. On bimanual examination it may be possible to feel the two separate uterine horns or a depression in the fundus; failing that, a very suggestive sign is an impression that the uterus is unusually wide from side to side. A septate uterus cannot be diagnosed on bimanual examination but may be recognised by passing a sound, as may the more extreme malformations. Apart from laparotomy or laparoscopy (which may fail to reveal a septate uterus), the diagnosis of uterine malfusion defects is best made by hysteroscopy or hysterosalpingography (Fig. 13.7). MRI is an excellent modality for accurate diagnosis, but is more expensive and not universally available. The clinical diagnosis of septate vagina and of uterus didelphys can be extraordinarily elusive, particularly if there is unequal development of the two sides and if a septum is displaced. I recall several cases in which experts overlooked the existence of a second vagina and uterus in patients examined under anaesthesia. This resulted in dilatation of only one cervix in cases of dysmenorrhoea - without relief of the pain; delay in the diagnosis of two cases of carcinoma of the body of the uterus - only the healthy horns being curetted; local treatment of vaginitis in only one half of the vagina;
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Jeffcoate’s Principles of Gynaecology insertion of an IUCD into one horn; insertion of a dye for hysterosalpingography into only one horn with a subsequent erroneous diagnosis of unicornuate uterus; evacuation of the non-pregnant horn during therapeutic abortion; and caesarean section in two successive pregnancies for failure of the non-pregnant cervix to dilate. The overlooking of duplication due to ductal malfusion can also cause problems with intravaginal and intrauterine contraceptive devices (lUCDs). During pregnancy, a diagnosis of uterus bicornis or didelphys is made by feeling the non-pregnant horn lying to one side and a little in front of or behind the main tumour. It is frequently mistaken for a subserous leiomyoma or ovarian cyst. This error can usually be avoided by careful palpation, which reveals varying shape and consistency due to intermittent contractions in the case of the uterine horn. The shape of the pregnant horn and the lie of the foetus may also be guides (Fig. 13.6). Whenever a placenta has to be removed manually, or curettage carried out to complete an abortion, the cavity of the uterus should carefully be explored by hand, finger, sound or curette to exclude a septum or bicornuate deformity. Treatment The treatment of malfusion deformities of the müllerian ducts depends on the exact state of affairs present and on the symptoms produced. Each case requires separate consideration. Many are best left untreated. Vaginal septa are generally removed unless they are symptomless and there is no prospect of marriage and childbearing. Rudimentary uterine horns, especially those not communicating with the main cavity, often require excision. When a bicornuate or septate uterus has caused not less than three miscarriages and no pregnancy has resulted in a viable child, surgery may be indicated. Prior to surgery a thorough work-up is mandatory to exclude all other causes of recurrent abortion. In the case of bicornuate uterus, an incision is made over the uterus and the two horns are sutured together to form a single cavity (Fig. 13.9). The results depend on a careful choice of cases according to the exact anatomy as shown by hysterography. The management of pregnancy and labour after this type of operation is important. Contrary to what is sometimes said, my experience indicates that
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these scars heal well and withstand the stress of subsequent pregnancy and labour. Close monitoring is required. Caesarean section is reserved for obstetric indications; intraoperatively the scar of the previous repair can hardly be seen. However, induction of labour requires careful assessment of the case and even more careful monitoring. In such cases, there is a place for elective caesarean section. Undoubtedly there are many who would prefer to do an elective caesarean section at 38 weeks’ gestation in all cases. In the case of a septate uterus, the operation has been remarkably simplified with the advent of operative hysteroscopy. The older methods involved excision (Jones) or incision (Tompkins) of the uterine septum, followed by unification of the horns. These have now been replaced by a simple procedure wherein the septum is cut hysteroscopically by scissors, resectoscope or laser (argon, KTP or Nd-YAG) after inducing endometrial atrophy by adminis-tering a GnRH analogue for two months. The septum is relatively avascular but bleeding may occur when normal myometrium is reached. The resectoscope is therefore the most preferred method as it simultaneously coagulates the bleeders. Laser does not offer any special benefit. Laparoscopic guidance is required to confirm that the uterus is indeed septate and not bicornuate, and to determine the end-point of resection - the myometrial fibres can be seen hysteroscopically and the light can be seen transmitted through the fundus uniformly. If the diagnosis has been firmly established beforehand and the surgeon is experienced, laparoscopic control may not be required. The main complications of hysteroscopic proce-dures are uterine perforation and fluid overload. Healing of the septal areas occurs in two months and they are covered by endometrium. Prophylaxis against intrauterine adhesion formation by the use of oestrogens, intrauterine Foley balloon catheters or IUCDs is not required. These patients do not face any additional risk in subsequent labours. Duplication and Diverticula of Müllerian Ducts If the müllerian ducts are duplicated, a true double uterus with four fallopian tubes can result but this is a condition of extreme rarity. More common are diverticula of the ducts which give rise to: accessory abdominal ostia of the tube; accessory tubes; diverticula of the tube; or a uterine diverticulum or accessory horn. In the last
Malformations and Maldevelopments of the Genital Tract
Figs 13.9A to F: Hysterograms illustrating uterine causes of abortion, (A) A normal uterus for comparison with the other hysterograms. Note the well-shaped fundus and the constriction at the level of the isthmus and internal os. (B) A normal fundus but a defective internal os (‘funnel cervix’) in a woman who had had repeated abortions and premature labours, (C) A funnel cervix and a minor degree of bicornuate deformity in the uterus of a woman who had had a series of premature labours, (D) A competent cervix but a bicornuate malformation in a woman who had had one abortion and one premature labour, (E) A bicornuate uterus in a patient with a history of four successive pregnancies ending in mid-trimester abortion or premature labour and stillbirth, (F) The same case as (e) after metroplasty. After this radiograph was obtained the woman conceived again and the pregnancy progressed well until the thirty-seventh week when bleeding from a placenta praevia prompted caesarean section; a live healthy baby resulted
condition, which is sometimes called a mülleroma, and is very rare, the third horn is not supplied with a fallopian tube or round ligament. If functional it can cause severe dysmenorrhoea. Incomplete Canalisation of Müllerian Ducts-congenital Gynatresia The müllerian buds have solid tips behind which canalisation takes place progressively. The müllerian and sinovaginal bulb tissues which form the vagina are also lumenless at first. Failure to canalise results in either solid organs or membranes of varying thickness obstructing the genital canal. Thus a rudimentary uterus sometimes lacks a cavity and the vagina may be represented by an uncanalised column of tissue. Atresia may affect only
one müllerian duct so that one horn of a bicornuate uterus may fail to communicate with the cervical canal, or one half of a septate vagina may be a closed cavity (Fig. 13.5). Unilateral haematocolpos, mucocolpos and pyocolpos are not common. They can give rise to difficulty in diagnosis because the retained secretions create a tumour lying beside an apparently anatomically and functionally normal genital tract. Sites
Cervical Atresia Congenital atresia of the cervix of an otherwise normal uterus or of a bicornuate uterus is rare. When it does occur, a reasonably normal vagina is invariably present. It is more common to encounter apparent cervical atresia
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Jeffcoate’s Principles of Gynaecology in association with absence of the lower vagina (Fig. 13.12).
Vaginal Atresia This occurs in various degrees and forms. The whole vagina may be represented by a solid strand of tissue which is difficult if not impossible to recognise. Whether or not this is present the condition is labelled congenital absence of the vagina. Next, the upper (46%), middle (40%) or lower (14%) zones of the vagina may be imperforate over an area 0.5-6.0 cm in depth. More frequently, the vagina is obstructed by a thinner membrane situated low in the vagina, just above the hymen. It represents a failure in breakdown of the partition between the müllerian and sinovaginal bulb contributions to the vagina. This condition of imperforate vagina is frequently misdiagnosed as the much less common imperforate hymen. However, the distinction between the two is largely academic because their effects and treatments are identical. An obstructing membrane situated across the upper vagina, just below the cervix, may be complete but usually has a laterally placed tiny opening through which menstrual discharge escapes. This state of affairs which, on examination, gives the impression of a vaginal vault without a cervix, is sometimes called phimosis of the cervix (Fig. 13.1H). A minor degree of this deformity, amounting to no more than an annular constriction of the upper vagina, is more common. Pathology Atresia of the lower genital tract has no serious ill effects if the uterus is absent or functionless. If the uterus is
present, it is unusual to see any harm arise in childhood although a collection of mucus, sometimes bloodstained, in the uterus or upper vagina (mucocolpos) is possible. This may even be present at or soon after birth, the secretions of the uterus and cervix having been stimulated by placental hormones (Figs 13.10A to C). When the uterus begins to menstruate, the fact is not recognised because the blood remains hidden behind the obstruction, a condition of cryptomenorrhoea. With each monthly discharge the vagina fills with blood which remains fluid. Some of its water content is continually being absorbed, so the material becomes inspissated. Nevertheless, the amount gradually increases and in the course of months or years distends first the vagina (haematocolpos), then the cervix and uterus (haematocervix and haematometra), and finally the tube (haematosalpinx). The altered blood tends to set up an aseptic inflammation in the tubes and this closes their outer ends and prevents or limits spill into the peritoneal cavity. If the tubes remain open, pelvic endometriosis is a possible complication. A mucocolpos or a haematocolpos can become infected to cause a pyocolpos. Atresia of the cervix has similar results but only the uterus and tubes are affected. The vagina can accommodate a large quantity of blood and, as it distends, forms a tumour which fills the pelvis and extends into the lower abdomen. The pelvic tumour displaces the fundus of the bladder upwards but not the urethrovesical junction. It causes retention of urine, not by elongating and attenuating the urethra, as is so often stated, but by interfering with the opening of the internal urethral sphincter.
Figs 13.10A to C: A mucocolpos in a newborn baby with the imperforate lower vaginal membrane bulging. This was incised when the baby was 3 days and 500 ml of mucoid fluid escaped. (By permission of Mr H.H. Francis)
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Clinical Features An incomplete vaginal membrane may cause dyspareunia, infertility or obstructed labour. Complete atresia only occasionally causes symptoms before puberty. The secondary sex characters then develop as usual but menstruation does not appear. Primary amenorrhoea, therefore, is often the complaint which brings gynatresia to light. In the case of an imperforate lower vagina or hymen, the amenorrhoea may not at first be regarded as significant by the girl or her mother, and the symptom which sometimes prompts them to take advice is acute retention of urine. This occurs 3 or 4 years after the onset of hidden menstruation and the patient is therefore generally aged 15-18 years. Retention can be preceded by a phase of bladder irritability. Often there is a history of monthly attacks of lower abdominal pain or backache with menstrual molimina. Pelvic discomfort and rectal pain are also noticed by some patients. On examination, a tumour, dull to percussion, is found in the lower abdomen. This is caused partly by an overfull bladder with hypertrophied walls. When a catheter has been passed, however, a tumour may still extend to the level of the umbilicus or higher and this consists of the distended vagina with the uterus perched on top (Figs 13.11A and B). Even in babies a mucocolpos can result in a large abdominal tumour. If the obstructing membrane is thin and situated low in the vagina it can be seen bulging at the introitus; the underlying blood
gives it a bluish colour. Rectal examination is allimportant to the diagnosis. With atresia of the upper vagina or cervix, the patient is more likely to present with attacks of severe abdominal pain occurring at monthly intervals. The tumour then consists of a distended uterus, cervix or upper vaginal compartment, or combinations of these (Fig. 13.12). It is not likely to be as large as in the case of a classical haematocolpos because the severe pain forces the patient to seek advice at an earlier stage. If the lower vagina is absent, the swelling is usually only palpable on rectal examination. Differential Diagnosis Conditions most likely to be confused are pregnancy and tuberculous peritonitis, both of which cause amenorrhoea and a lower abdominal swelling; acute or subacute appendicitis - attacks of pain; all causes of true amenorrhoea; ovarian cyst; and pelvic kidney this is common when the vagina is absent and may be mistaken for a haematometra. Ultrasound helps in the diagnosis. Treatment Once the diagnosis of cryptomenorrhoea is made, surgical treatment is urgently required since every menstrual episode further dilates the genital tract and threatens permanent impairment of reproductive function. Obstruction at the level of the cervix is least often encountered but is the most controversial. The
Figs 13.11A and B: (A) Haematocolpos resulting from an imperforate vagina producing, in a girl aged 15 years, a tumour which extends from the pelvis to the umbilicus, (B) The bulging membrane at the introitus, made dark by the underlying tarry blood
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Fig. 13.12: Variations in vaginal congenital atresia and aplasia with haematocolpos and haematometra. (A) The classical imperforate vagina with only a thin obstructing membrane at the introitus. M - membrane; H - hymen; LM - labium minus, (B) A gross deficiency of the lower vagina resulting in a thick obstruction, (C) Most of the vagina is imperforate and clinically this is usually mistaken for complete absence of the vagina with cervial atresia causing a haematocervix and haematometra. In fact, even though a haematocervix is present there is always an upper compartment of vagina if the uterus is functional. The treatment of (A) is by simple incision or excision of the membrane. This treatment, however, gives poor results for (B) and (C) because the obstruction always reforms within a few hours or days (see Fig. 13.13).
conservative approach is of uterovaginoplasty, while the radical method is to perform a hysterectomy. The decision is based on the clinical features, psychological status, approach and experience of the surgeon and, not the least, the wishes of the patient and her family. When the vagina is well developed and the uterus well formed and functional, uterovaginoplasty can be attempted by a combined abdominovaginal approach. This is a technically difficult operation in which the uterus and vagina are opened, the collected menstrual blood drained from the uterus and the posterior wall of the vagina sutured to that of the uterus. A Foley catheter is inserted through the vagina into the uterus and anchored there. The uterine body is then reconstructed and sutured to the anterior vaginal wall. The Foley catheter remains as a stent for 8-12 weeks to permit epithelialisation of the new tract. In patients with cervical atresia, restenosis may occur in 50 per cent and hysterectomy is then required. In some of these patients, severe sepsis may result and even the occasional fatality has been reported. All these patients have severe morbidity from the incapacitating pain. These features
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Fig. 13.13: Advancement of the upper compartment of the vagina in dealing with all except minor degrees of lower vaginal aplasia or atresia causing a haematocervix, as shown in Fig. 13.12 (B) and (C). In the past such vaginal deficiencies were often dealt with by creating and skin grafting a lower vagina but the results are not always good and a stricture tends to form at the junction of the artificial vagina and the true vaginal compartment above. Once the diagnosis is made there is no need even for laparotomy. Careful dissection from below leads to the collection of blood above and after this has been released the upper vagina and cervix are mobilized so freely that they can be brought down to be sutured to the introitus. (A) A path through the obstruction is dissected (D) and the vaginal compartment and the cervix containing the menstrual blood (VC and C) are freed to be advanced to a lower level as indicated by the arrows, (B) The operation is completed, VW being the vaginal wall, (C) This shows the final result; the cervix returns to its normal shape and what was an upper compartment of vagina adapts to produce a vagina of good length
prompt many gynaecologists to recommend a hysterectomy to patients with cervical atresia. However, since these are young women, the psychological sequelae of such a radical step are tremendous, hence most surgeons nowadays attempt reconstructive surgery at least once. Pregnancy has occurred in some cases after creation of a neocervix and this fact further encourages surgeons towards the conservative approach. When the outflow of menstrual blood is prevented by a thick vaginal membrane at any level, incision of the latter alone is inadequate. The raw area in the vagina always seals over rapidly within days if not hours. It is therefore essential to cover any deficiency with vaginal epithelium; this is best done by dissecting free the upper vaginal walls and ‘advancing’ them downwards to be sutured to the margins of the vagina around the lower limit of the obstruction (Fig. 13.13). Alternatively, the raw area can be covered with a skin graft, as for the creation of an
Malformations and Maldevelopments of the Genital Tract artificial vagina, but this is usually unnecessary. Pregnancy following such procedures is not very rare and is often best terminated by elective caesarean section. The treatment of the more common and typical case of haematocolpos, when the obstructing membrane is thin and low down, is simple. The membrane is merely excised (not incised) and the edges subsequently heal rapidly. However, this apparently minor operation demands great care over asepsis, as do the more complicated ones mentioned above. The vagina has been closed throughout life so it is without the protecting lactobacilli, its epithelium is poorly formed, and its reaction is alkaline or weakly acid. There is therefore little natural resistance to bacteria entering from below; indeed, the degenerated blood and debris offer a favourable medium for their growth. Postoperative salpingitis and peritonitis are therefore real hazards and, in the past, were sometimes fatal. Bilateral hydrosalpinges occur as late sequelae. The fluid which escapes after removal of the obstruction resembles liquid chocolate. It is devoid of fibrinogen and prothrombin and contains mucins (from the cervix), lactic acid (from the blood), calcium and altered blood pigments. Its amount varies from 200 ml to 2 litres or more, and it may take several days to run away. Its escape should not be hurried by the insertion of a drainage tube or by intermittent pressure over the lower abdomen, because such procedures encourage the entry of organisms. For the same reason vaginal examination should be avoided and the state of the uterus and tubes left in doubt for 1-2 months. Meanwhile the vulva is kept covered with a sterile pad and the patient is discouraged from sitting in a bath. At the end of the prescribed time, vaginal examination is carried out to see if there is any remaining evidence of haematometra or haematosalpinx. Fortunately, the uterus and tubes show enormous powers of recovery so that radical treatment such as salpingectomy and hysterectomy is rarely necessary. A high percentage of girls treated for haematocolpos later prove to be fertile. Incomplete atresia such as stricture of the upper vagina is treated by dilatation or by incision and suture on the principles of plastic surgery. Occasionally, excision of fibrous tissue and coverage of the raw area by freeing the adjacent vaginal wall is necessary. OVARY Malformations may affect one or both ovaries.
Absence or Underdevelopment Absence of the gonads is extremely rare and betokens a fundamental error in the formation of the; urogenital ridge. I have seen women with testes instead of ovaries but never one without gonadal tissue of some kind. Rudimentary ovaries which are functionless or cease to function at an early age come under the headings of streak gonads and gonadal dysgenesis and are usually associated with errors in the sex chromosome pattern. Accessory and Supernumerary Ovaries An accessory ovary on one or both sides is not uncommon but the condition as a rule is one in which a single ovary is divided into two portions which are attached to each other by fibrous tissue. Nevertheless, true supernumerary ovaries or portions of ovarian tissue have been found in the broad ligament and elsewhere; they probably account for the occasional reports of menstruation continuing, and of pregnancy occurring, after the removal of both ovaries. Failure of Descent The ovary may remain at the level of the pelvic brim or even near the lower pole of the kidney. Sometimes it is found in a hernial sac. Ovotestis See page 224. FALLOPIAN TUBE Malformations of the tube are described under müllerian duct anomalies. They include: absence in whole or part; underdevelopment; congenital atresia; excessive length; duplication; accessory tubes; diverticula; and accessory ostia. UTERUS Absence Complete absence of the uterus results when the müllerian ducts fail to develop and is often associated with an error in the sex chromosome make-up. The upper vagina is inevitably absent as well. If the fallopian tubes or their fimbriated extremities are present, they taper inwards to a transverse fold — the plica transversalis.
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Hypoplasia
Types Hypoplasia of the uterus occurs in varying degrees as the result of an error in either antenatal or postnatal development. Sometimes the organ consists of nothing more than a small nodule of solid or hollow functionless tissue, a condition often mistaken for absence of the uterus. The uterus may, however, be essentially normal in shape and structure yet have reduced dimensions. Persistence of the infantile proportions in which the cervix is long in relation to the corpus is another feature.
Causes • An inherent error in müllerian duct tissues, often associated with sex chromosome abnormality, resulting in a uterus which is incompletely formed or which is incapable of responding to the normal postnatal growth stimulus of oestrogen. • Failure of the ovaries and adrenals to supply the oestrogen stimulus to a basically normal uterus at the time of puberty. • Some disease or circumstance which destroys oestrogen or nullifies its effect on the uterus.
Clinical Features The traditional symptoms of uterine hypoplasia are primary amenorrhoea, late menarche, infrequent menstruation and infertility. All except the first are more likely to be manifestations of an underlying ovarian inactivity than of the uterine abnormality. There is no reason why smallness of the uterus per se should prevent conception or alter the ovarian cycle. Scanty menstruation (hypomenorrhoea) may be a symptom but is often found with normal-sized uteri. Some believe that the first pregnancy is more likely to abort if the uterus is hypoplastic but the evidence for this is insecure. On examination the uterus is found to be small in overall length and width, although the cervix may be relatively long. The endometrium is thin. When the complaint is secondary amenorrhoea, the finding of a small uterus means atrophy rather than hypoplasia; it is sometimes difficult, if not impossible, to distinguish between these two states.
Diagnosis The diagnosis of uterine hypoplasia is made all too frequently on a mere impression that the uterus feels
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small on bimanual examination. Indeed, uterine hypoplasia is more often a convenient label than a proven state, especially in cases of infertility where the cause is unknown. The essential criteria of uterine hypoplasia are: a subnormal menstrual cycle; a uterine cavity measurement of 6 cm or less; and an endometrium which appears unstimulated on microscopy. All must be present.
Treatment Treatment needs to be directed at the cause. The results of treatment with exogenous oestrogens are unsatisfactory for the following reasons: • If hypoplasia is the result of the uterus being unresponsive to the ovaries, oestrogens have no effect on it. • If hypoplasia is the result of an inadequate ovarian stimulus then oestrogens will promote full development of the uterus, but the effect is temporary and, unless ovarian function becomes normal in the meantime, the uterus returns to its former state when treatment is suspended. In practice, therefore, the administration of oestrogen is of more value as a diagnostic than as a therapeutic procedure. It may be added that, when the complaint is infertility, attention should be directed to establishing normal ovarian function rather than correcting the consequential uterine hypoplasia. Cochleate Uterus
Pathology In young nulliparous women, it is not uncommon to find a uterus which is cochleate or C-shaped when viewed from the side. The position of the body of the uterus is normal and the deformity arises because the cervix is angled forwards. The condition is therefore also called acute anteflexion of the cervix. (Fig. 13.14). A similar malformation in reverse can occur when the body of the uterus is directed backwards and is a common feature of congenital retroflexion of the uterus. In these states the cervix is usually longer, narrower, and more conical than normal, the corpus being well developed. Menarche is at a normal age and menstruation is free and regular. A cochleate uterus should therefore be regarded as being maldeveloped rather than underdeveloped, the site of the trouble being at the level of the internal os. The deformity nearly always disappears after pregnancy.
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Fig. 13.14: Acute anteflexion of the cervix (cochleate uterus)
Fig. 13.15: Acute anteflexion of the cervix determined clinically by apposition of the body of the uterus and of the cervix to the sides of one finger
Clinical Features A cochleate uterus rarely gives rise to symptoms and its rinding is incidental. There is a greater likelihood of spasmodic dysmenorrhoea, possibly because of disturbed uterine polarity. When both the body of the uterus and the cervix can be defined, the acute angle between them can be demonstrated by being able to feel each lying in close contact with opposite sides of one finger (Fig. 13.15).
Treatment Treatment is directed to the symptoms, if any. Conical Cervix and Pinhole os The normal cervix varies in shape and size but occasionally it is so conical, or its external os appears so small, as to warrant these descriptions. Conical cervix and pinhole os often go together and the cervix as a whole tends to be long and narrow. These diagnoses are largely a matter of fashion and personal opinion; at present they are out of fashion. Congenital Hypertrophy of Cervix This condition is developmental rather than congenital, and a malformation rather than hypertrophy. Congenital hypertrophy of the cervix is, in fact, merely a name for an unusually long cervix. The elongation affects the vaginal rather than the supravaginal cervix and the
diagnosis is only made in nulliparous women. The condition is usually symptomless. Sometimes the cervix is so long that the patient is conscious of it during straining and during coitus; this is particularly true if the vagina happens to be short. VAGINA Absence
Pathology The vagina maybe completely absent (Fig. 13.1) or, more often, the müllerian duct portion is absent and the urogenital sinus part is present as a depression of variable depth. The condition can be associated with intersexuality, but in otherwise apparently normal women the sex chromosomes are usually XX.
Clinical Features If the uterus is present and functional, an upper compartment of the vagina is invariably present, and a deep-seated haematocolpos and haematocervix develop after puberty. These cause monthly attacks of pain associated with apparent amenorrhoea. If the uterus is functionless, the complaints are primary amenorrhoea and dyspareunia or apareunia. In fact, absence of the vagina is usually diagnosed during the investigation of amenorrhoea before marriage.
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Treatment If cryptomenorrhoea is present, a plastic operation can be carried out to connect the upper vagina and uterus to the lower vagina and introitus (Fig. 13.13). In neglected cases hysterectomy may be necessary. If the aim is merely to permit coitus then it is usually advised that treatment should be deferred until 6-9 months before marriage, and that a plastic operation should only be carried out with the knowledge and consent of the partner. This attitude rarely deserves modification, even though there are young women who consider it unfair to encourage a proposal of marriage until their physical handicap has been corrected as far as possible. Several lines of treatment are available. If the lower vagina is present as a depression or pouch, then continued or repeated pressure with an obturator (or repeated attempts at coitus) over the course of several months will often stretch the vagina sufficiently to allow reasonably normal coitus. Success or failure with this method depends very much on the outlook and determination of the patient. In this respect the patient should always be told that the vagina is underdeveloped rather than absent; this encourages in her the idea that it is capable of being stretched. The same holds good if it becomes necessary to create an artificial vagina by one of the following methods.
• A space is dissected between the bladder and rectum and lined with a skin graft carried on a mould made of light plastic material or foam. Even after the graft has taken, the patient has to wear an obturator or mould for at least 6 months afterwards to prevent contracture, and may have to use it indefinitely unless coitus is practised regularly. The danger of the operation is injury to the bladder and rectum with fistula formation. Contracture of the artificial vagina is common, but, if the patient is determined to get coitus established, the result can be very satisfactory (Figs 13.16A and B). A rare late sequel to this type of operation is enterocele formation. • A more recent development has been the use of an amnion graft instead of a skin graft. The dissection is as above but the mould is covered with amnion (obtained under sterile conditions at a caesarean section delivery and kept in sterile solution until used). The mould is sutured in situ and removed after 7 days. The vagina is washed out. A new mould with amnion may be inserted for a further 5-7 days. The epithelium of the lower part of the vagina appears to grow over or into the amnion and therefore gives a more satisfactory end result than a skin graft, in my opinion. • A pouch superficial to the vestibule, and opening anteriorly, is created by suturing together a linear
Figs 13.16A and B: Artificial vaginas created surgically by dissection and skin grafting of a space between the bladder and rectum. Photographs taken one year after the operations, (A) The vulva looks normal and the vagina accommodates a good-sized obturator. This is one type of light plastic obturator which the woman inserts and wears regularly to prevent contracture. (B) A second case with the artificial vagina demonstrated by means of a Sims’ speculum
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Malformations and Maldevelopments of the Genital Tract U-shaped incision in the hairless aspects of the labia majora (Williams’ operation). This is a simple and safe procedure. Once coitus is established, it permits a gradual indentation of the vestibule to lengthen the available canal. However, the angle of the neo-vagina is not physiological. Also, if the pouch is too close to the uretha urine can collect in it. This method is sometimes used for patients with a pelvic kidney or following radical surgery. • Muscle and skin flaps have also been used for reconstruction of the vagina following radical surgery. The gracilis myocutaneous flap has a high failure rate due to vascular problems. Neuro-vascular pudendal-thigh flaps (the Singapore flap) are reported to have better blood supply and innervation. • The labia majora and minora have been used to create a satisfactory vagina but this distorts the vulvar anatomy. Labiovaginal flaps created by tissue expansion techniques have been used to overcome this problem. • Operations involving the transplantation of an isolated loop of colon into a space dissected: between the bladder and the rectum are described. They are unjustified for congenital absence of the vagina but may be used following radical cancer surgery (pelvic exenteration). • Laparoscopic techniques using an olive device which exerts traction on the pseudohymen through the abdominal wall have been used (Vuchietti’s method), but the device has not been approved by the FDA. Before any of these operations is undertaken, the presence of associated kidney malformations and impairment of renal function should be excluded. Nonsurgical Approach (Frank Procedure): The Frank technique was initially described in 1938. The goal was to increase the depth and caliber of the vagina with the use of graduated dilators, thus avoiding the need for surgical intervention. The Ingram “bicycle seat” represented a dramatic improvement in the Frank procedure. The major advantage of this racing-type bicycle seat is that it is positioned between the buttocks and is therefore in better contact with the perineum, providing direct pressure from the graduated dilator on the incompletely developed vagina. In the Franks nonsurgical method firstly, the patent is instructed to use a mirror to examine her genitalia at home, identifying the external structures and introit
dimple. Dilators of graduated sizes are used to create pressure on the vaginal dimple, beginning with a dilator approximately 1.5 cm in diametre and 2 to 3 cm in length. The same is used for 20 to 30 minutes three to four times daily. She should be seen monthly, not only for physical evaluation but also for continued encouragement and motivation; she should be made aware that consistent use of this technique will enable her to avoid surgery and will eliminate the risk of postoperative scarring and the need for painful, potentially disfiguring skin grafting. Steady progress should be readily apparent on periodic pelvic examination. Adequate vaginal caliber and depth can usually be demonstrated in 14 to 16 weeks. On occasion, the position may be difficult to manage because of the shallowness of the vaginal dimple. In these cases, the patient can begin with the lithotomy position, applying manual pressure to hold the dilator firmly in contact with the vaginal dimple until there is sufficient invagination to accommodate the bicycle technique comfortably. Some women can pedal a stationary bicycle during dilatation after several weeks of nonsurgical treatment, but this should be discontinued if there is any chafing or discomfort. The Ingram technique is successful in approximately 90 per cent of cases, and Ingram himself contended that surgery should not be considered until the patient had undergone a sufficient trial of this approach. The Franks and the Ingram technique is successful in a fair number of girls and can be considered until the patient has undergone a sufficient trial of this approach. Vaginal Hypoplasia Vaginal hypoplasia is evidenced by shortness, narrowness, shallow fornices and by thin and inactive epithelium. It is caused either by an inherent fault in the müllerian ducts or by absence of the oestrogen stimulus from the ovary. In the latter case it is always associated with uterine hypoplasia and can be overcome by oestrogen therapy. This treatment is worthwhile if the complaint is dyspareunia because, once the vagina is well formed, it does not contract back to its former state so long as coitus is continued regularly. Congenital Atresia and Stricture See page 205.
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Septate and Subseptate Vagina
Bifid Clitoris (Diphallus)
See page 200.
This is seen in association with hypoplasia of the rest of the genital tract in states of hypo-oestrogenism (for example, infantilism, streak gonads). The secondary sex characters are poorly developed as well.
The genital tubercle is formed from two mesodermal bands which grow round from the dorsal aspect of the foetus in the third week. These also provide for the musculature of the abdominal wall, the musculature of the anterior walls of the bladder and urethra, and the symphysis pubis. Failure of these bands to develop properly or to fuse results in a bifid clitoris (bifid or double penis in the male), ectopia vesicae, epispadias, a muscular defect of the lower abdominal wall, divarication of the foreparts of the labia majora, absence of the hair-bearing skin of the pubes and a split pelvis (Figs 13.18 and 13.19). The vulvar deformity is often associated with shortness of the vagina and stricture of the introitus and there is strong predisposition to uterine prolapse. For this condition, the primary object of treatment is to close the bladder wall anteriorly but it is often necessary to divert the urinary stream to ensure some sort of continence. I know of three cases in which the ureters were transplanted to the colon in childhood and in which the women remained healthy 15-20 years later. One of these women had two normal pregnancies followed by easy vaginal deliveries.
Fig. 13.17: Duplication of the vulva in a baby which died from multiple malformations 7 weeks after birth. There was a single anus and rectum but two bladders, a uterus didelphys and a ‘double’ vagina. There were only two kidneys, one grossly hydronephrotic
Fig. 13.18: Split pelvis in a woman aged 21 years suffering from ectopia vesicae and bifid clitoris. Her urinary incontinence was controlled by transplantation of the ureters into the pelvic colon at the age of 10 years. There was normal renal function and electrolyte balance 11 years later
Double Vagina (duplication) This is extremely rare, occurring in association with double vulva, double uterus, double bladder and urethra, and sometimes with supernumerary lower limbs (Fig. 13.17). The condition really represents an included twin. In most cases labelled ‘double vagina’ the vagina is single but septate. VULVA Absence, Gross Underdevelopment and Duplication These curiosities are usually only found with other malformations incompatible with life (Fig. 13.17). Hypoplasia
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Abnormalities of the Hymen The hymen may be absent, imperforate or tough. The last causes apareunia. Atresia of the Labia Minora In the young female embryo, the genital folds may fuse as they do in the male. The introitus then becomes enclosed by a membrane which represents the two labia minora, with an exit for urine anteriorly. This is a feature of congenital adrenal hyperplasia and can be caused by any virilising agent acting on the foetus before vulvar development is complete. In most cases of fused nymphae seen in children aged 1-3 years, the abnormality is the result of adhesions forming after acute vulvitis of infancy rather than an error in development. Fig. 13.19: Bifid clitoris, and divarication of the labia associated with a defect of the lower abdominal wall, ectopia vesicae and split pelvis
Hypertrophy of the Labia Minora (‘spaniel ear nymphae’)
Pathology Hypertrophy may affect one or both labia minora and does not ordinarily become obvious until puberty. It is sometimes stated that bilateral hypertrophy of the labia minora is the result of masturbation. There is no doubt that manipulation and stretching of the labia as practised by some primitive tribes can lead to their permanent gross enlargement. Nevertheless, the hypertrophy seen in civilised communities is rarely attributable to anything more than a developmental peculiarity (Fig. 13.20).
Symptoms Usually there are no symptoms but the patient may complain of a ‘tumour’ or of ‘something hanging’ from the vulva. If the labia are very long they can become chafed, oedematous and ulcerated during exercise. Such symptoms are mostly seen during adolescence when there is a tendency for leucorrhoea and uncleanliness. Fig. 13.20: Bilateral hypertrophy of the labia minora in a virgin aged 14 years. She complained of recurrent discomfort caused by abrasion so the labia were trimmed down to size by a simple plastic procedure
Hypertrophy of the Clitoris See Chapter 14.
Treatment No treatment other than reassurance and attention to hygiene is usually necessary. Talcum powder should be avoided because it cakes in the crevices. A barrier cream, or zinc and castor oil cream, can be applied before exercise. If these conservative measures fail, the size of the labia can be reduced by a simple plastic operation which gives excellent results.
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Defects in the proper partition of the cloaca into the hindgut and urogenital sinus result in: a persistent cloaca with a common opening for the bladder, vagina and bowel (this is extremely rare); a fistula between the rectum or anus and the vagina; a perineal, vestibular or vaginal anus (Fig. 13.22); or an imperforate anus. A perineal or vaginal anus is not too uncommon and is characterised by a deficiency in the perineal body and by the lower bowel opening low down on the posterior vaginal wall or at the fourchette. A vaginal anus is usually recognised in the newborn, and is distinguished from imperforate anus by the escape of meconium from the vagina. Nevertheless, it is the subject of much unnecessary and harmful surgery in children. Rarely, the anus is so narrow as to obstruct the passage of meconium. In that case a simple ‘cut back’ operation is
indicated and does not generally result in faecal incontinence in later life. Usually the opening is sufficiently large not to obstruct the bowel and, in that case, should be left alone. The baby, as it grows, develops quite a good sphincter control. In adult life, the individual suffers little or no inconvenience but, if the opening is high and the vagina gets badly contaminated, a reconstruction operation may be necessary before marriage. A high vaginal anus is exceptional and is usually associated with a failure in development of the lower rectum, the pelvic floor and the sacrum. As a rule, however, no surgery is necessary at any age. A perineal anus is only a problem during childbirth when the thin rectovaginal septum is vulnerable to trauma in the second stage of labour. A rectovaginal fistula with faecal incontinence is not an inevitable result but the risk is sufficient to justify elective caesarean section in many of these cases. If it does become necessary to transplant a vaginal or perineal anus backwards, one of the difficulties is to provide it with a sphincter. The operation may have to be preceded by temporary colostomy. An imperforate anus results when the cloacal membrane over the hindgut fails to break down or when the division of the cloaca leaves a blind lower end of the bowel. The latter can be some distance away from the ectoderm in which case surgical correction of the error
Fig. 13.21: Unequal development of the labia minora, which is a common finding. Vaginal prolapse is also present in this case
Fig. 13.22: Perineal anus. The anus is just outside the fourchette; sometimes it opens nearer to or just within the vagina
Asymmetry of the Labia Minora Like all paired organs, the labia minora are often unequal in size. One may be unusually large or small (Fig. 13.21). The condition is rarely more than of interest; often the patient is unaware of the inequality. No treatment is necessary unless the larger labium causes chafing, when its size can be reduced surgically. ERRORS ARISING IN CONNECTION WITH THE CLOACA
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Malformations and Maldevelopments of the Genital Tract can be difficult. All babies should be examined at birth to see if the anus is perforate; if it is not, operative treatment is urgent. MALFORMATIONS OF THE URINARY TRACT Some of these come within the remit of the gynaecologist and some have already been mentioned. They often occur in association with abnormalities of the uterus, vagina and vulva. Epispadias and Ectopia Vesicae See page 214. Urethral Diverticula See chapter 27. Accessory and Aberrant Ureter (and kidney) Duplication of the renal pelvis and ureter is common and arises as a result of an accessory ureteric bud from the wolffian duct (Figs 13.23A and B). The accessory ureter always links with the upper pole of the kidney
and crosses posterior to the main ureter. Its importance is that it may be injured during pelvic operations because the surgeon is usually unaware of its existence. Sometimes the ureter, but more often an accessory ureter, opens into the anterolateral wall of the uterus, the vagina, the vestibule or the urethra; the commonest site is the vestibule. It then causes incontinence of urine which is frequently mistaken for enuresis in childhood. The amount of urine which escapes can be small and intermittent so, bearing in mind that micturition is otherwise normal, the leakage may be regarded as vaginal discharge. An aberrant ureter may become infected. The diagnosis of an accessory ureter can be extremely difficult and sometimes eludes the expert for years. That part of the kidney served often has poor function, so neither it nor the ureter may be revealed by intravenous pyelography. Moreover, the opening on the vestibule or elsewhere is usually tiny and difficult to locate unless a bead of urine happens to escape at the time of examination. Treatment is by excision of the aberrant structure and of the kidney tissue which it drains.
Figs 13.23A and B: Bilateral aberrant ureters. In this case a girl, when aged 12 years, had bilateral aberrant kidneys and the upper parts of their ureters removed. She remained symptom-free until her first pregnancy at the age of 22 years when she developed what was first thought to be stress incontinence of urine. Investigation then showed that the pelvic parts of the aberrant ureters were still present; the left one entered the bladder just above the internal urethral meatus and caused no trouble. The right one opened into the urethra at a low level and is here shown as the dilated structure lying behind the bladder and upper urethra. It was removed successfully, (A) Lateral urethrocystogram with the aberrant right ureter filled from below with radio-opaque medium, (B) Anteroposterior exposure of the lower part of the right aberrant ureter
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Absence of One Kidney and Ureter This is commonly associated with absence of the müllerian duct on the same side or with gross malfusion deformities of the uterus (Fig. 13.2). Fusion of the Kidneys - Horseshoe Kidney
Pelvic Kidney
Fig. 13.24: An intravenous pyelogram showing three separate kidneys, a normal one on the right, a hydronephrotic one on the left, and one in the left side of the pelvis. The site of the last is typical for a pelvic kidney. This situation was discovered during the investigation of a girl aged 16 years complaining of primary amenorrhoea and who had the stigmata of Turner syndrome including stunted growth and webbing of the neck. She was nevertheless chromatin-positive and later menstruated normally so she did not have streak gonads. The sex chromosome pattern was not determined but was almost certainly abnormal
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Failure of the kidney to ascend results in a pelvic kidney which lies extraperitoneally, sometimes at the pelvic brim but more often below the brim in front of the sacroiliac joint (Fig. 13.24). It is more likely than a normal kidney to develop hydronephrosis and pyonephrosis. It may present merely as a pelvic tumour, palpated during vaginal examination, or obstructing labour. It is usually mistaken for an ovarian tumour and this sort of error can only be avoided by keeping the condition in mind, and by carrying out pyelography in the case of any tumour of the right size and position which is more fixed than an ovarian cyst. A pelvic kidney, or a single horseshoe kidney in the pelvis, is not uncommon in cases of vaginal agenesis. It can be mistaken for a haematometra.
14
CHAPTER
Sex Determination, Asexuality and Intersexuality
Intersex Sex Determination in the Foetus and its Anomalies Chromosomal Sex Hormonal Intersex
219 220 221 232
Psychological Sex Sex of Rearing The Management of Aberrations of Sex Present at Birth Intersex Developing After Birth
238 240 240 244
The sex of an individual is not a singular entity but is dependent on various factors. Normal sex of an individual is determined by the following factors: 1. Chromosomal sex (Genetic sex) 2. Gonadal Sex 3. Hormonal Sex (secondary sex characterstics) 4. External anatomical sex 5. Internal anatomical sex 6. Sex of rearing 7. Gender role (Societal role). Intersexuality can be defined as a condition of imperfect sexual differentiation into either male or female. It is a relative term because no human being is completely male or female. Each carries the rudiments of the sexual apparatus of the other; many men are slightly effeminate and many women slightly masculine in bearing and outlook. A man may be rather smooth skinned or fastidious about dress, and a woman may be flat-chested or have hairy legs, without its being significant. Indeed, the borderline between a normal and an abnormal degree of intersex is vague and impossible to define. Gender identity is determined by the genetic, gonadal and phenotypic sex and is influenced by social mores and environmental upbringing. Physiological Considerations Every human foetus is destined to be a female foetus. Early embryo is potentially bisexual upto 6th week of intrauterine life. Hormone influences triggered by genetic make up will cause müllerians atrophy and formation of male organs. In presence of TDF (Testes determining factor) and Y chromosome and the SRY gene on short arm of Y chromosome; the testes develops and MIF (Müllerian inhibiting factor) causes Müllerian degeneration and formation of scrotum and penis. While in XX chromosomal make up there is no MIF and this causes development of Müllerian system (vagina, uterus and fallopian tubes). INTERSEX Intersex is defined as a gross discrepancy in factors that define sex. Classification: There is an original old classification of sex and intersex.
Jeffcoate’s Principles of Gynaecology 1. 2. 3. 4. 5. 6. 1. 2.
3. 4.
Sex chromosomal intersex Autosomal intersex Gonadal intersex Hormonal intersex Psychological intersex Sex of rearing The newer classification of intersex is as follows: Deletion syndromes of Y lines (45X, 46XY) 46 XY a. Gonadal dysgenesis (Swyer’s syndrome) b. Empty pelvis: agonadia c. Enzyme deficiency i. Affecting both adrenals and testes • P-450 • 3 β-HSD • 17 α hydroxylase ii. Affecting testes • 17 α hydroxylase • 17 HSD • 5 α reductase d. Androgen insensitivity/resistance • Complete • Incomplete e. Defect in synthesis/secretion/response to AMH • Persistant müllerian duct syndrome f. Non-sex chromosome defect 46 XY true hermophrodite 46 XX true hermaphrodite 46 XX a. 46 XX sex reversal male b. Congenital adrenal hyperplasia • 21 Hydroxylase deficiency • 11 β Hydroxylase deficiency • 3 β-01-dehydrogenase deficiency c. Aromatase deficiency (placental) d. Material Androgens • Drugs • Tumours of pregnancy e. Non-sex chromosome defects.
In the past, the gross and bizarre types of physical intersex were described as examples of hermaphroditism. This word derives from the name of a bisexual Greek god, Hermaphroditos, the offspring of Hermes and Aphrodite. Although true hermaphroditism implies the possession of the reproductive function as well as the genital apparatus of both sexes, as is the case in the earthworm, human individuals found to possess both ovarian and testicular tissue are sometimes described as
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true hermaphrodites. An association of the gonads of one sex with the secondary sex organs of the other is termed pseudohermaphroditism. If the gonads are testes, the individual is said to be a male pseudohermaphrodite; if they are ovaries, the individual is a female pseudohermaphrodite. Classifications of this kind not only impose a narrow outlook on intersex, they imply that the nature of the gonad is the criterion of sex. This view is no longer medically acceptable. As will be clear from what follows, a woman is not a woman because she has ovaries; she has ovaries because she is a woman or, better still, because she is not a man. Femininity is a neuter state and masculinity is a superimposed characteristic. Destruction of the gonads of the young male embryo results in its developing a female genital apparatus. Castration after birth, especially if performed at an early age, results in a eunuch who has many female qualities. Removal of the ovaries at any stage in life, on the other hand, does not lead to masculinity. The sex of an individual cannot be judged by any one feature, not even by the number and type of sex chromosomes or the histological characters of the gonad. More important than these, both to the individual and to the community, are the secondary sex characters such as the external genitalia, breasts, voice and facial hair. Community interests are concerned when it comes to the rights of individuals to marry or partake in women’s athletics. In the first case, genital sex is all-important. In the second, chromosomal sex can be the main criterion. It is currently used to screen women competitors only in the Olympic games. Other amateur organisations now perform only physical examination. It follows that terms such as male and female pseudohermaphroditism should be abandoned in favour of the non-committal term intersexuality. SEX DETERMINATION IN THE FOETUS AND ITS ANOMALIES Of the several factors that determine sex in the foetus, none is all-powerful and decisive. The action of each can be modified by that of the others. This explains why states of physical intersex and incomplete sex, present at birth, assume so many forms and are difficult to classify. After the genetic determination of sex and triggering of formation of ovaries or testes the hormonal influence of sexual development occurs (Flow charts 14.1 and 14.2).
Sex Determination, Asexuality and Intersexuality
Flow chart 14.1: Sex determination of embryo
Flow chart 14.2: Genetic pathway
Statistically it might be expected that this mechanism would produce equal numbers of the two sexes. In fact, the sex ratio among very early embryos is said to be 160 males to 100 females. Two of the reasons postulated for this are: the uterus is more receptive to males than females; and the Y-carrying spermatozoa are either present in greater numbers in the semen or have smaller heads and greater vigour which give them an advantage in penetrating the capsule of the ovum. The sex ratio at
CHROMOSOMAL SEX Sex is primarily determined at the moment the ovum is fertilised, by the type of sex chromosome supplied by the spermatozoon. The chromosomal pattern, even the sex chromosomal pattern, varies in different animals but the nucleus of every cell of the human body normally carries 46 chromosomes arranged in 23 pairs. One of these pairs, the sex chromosomes, is mainly concerned with sex; the remaining 22 pairs are designated autosomes (Figs 14.1 and 14.2). In the female the two sex chromosomes are similar -XX, the upper arms of the X being much shorter than the lower. In the male they are dissimilar - XY, the Y being a much smaller structure than the X and having very short upper arms (Fig. 14.1). As a result of reduction division, the mature ovum carries 22 separate autosomes and one X sex chromosome. Mature spermatozoa, however, carry either an X or a Y chromosome and are therefore of two types. If one type fertilizes the ovum, it contributes an X chromosome to result in a female zygote whose karyotype is expressed as 46,XX; if the other is operative the outcome is a male with the karyotype of 46,XY.
Fig. 14.1: The 23 pairs of chromosomes in the normal human male, numbered according to an internationally agreed system. The chromosomes are obtained from cultures of lymphocytes or fibroblasts and identified from a metaphase spread using special stains (in this case G banding using Giemsa stain plus trypsin)
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Fig. 14.2: The normal distribution of autosomes (A) and sex chromosomes (SC) before and after reduction division of the ovum and spermatozoon, and after fertilisation
birth, however, is only 106 boys for every 100 girls. The suggested explanations for this apparent discrepancy are: the estimate of the number of male zygotes quoted above is incorrect, and this may well be if they are based on nuclear chromatin studies; and male embryos have a special susceptibility to death in utero at an early stage in development. Throughout their length, all chromosomes carry genes at specified points - gene loci - each one of which is known as an allele. These are paired, as are the chromosomes. The X and Y chromosomes carry paired genes as do the two X chromosomes in the female. This pairing is essential for the genes to have an overt effect and if only one of a pair of chromosomes carries a particular gene its influence is usually recessive, except in the case of certain genes associated with malignancies, e.g. p53, BRCA and the retinoblastoma gene. In addition to being concerned with sex, the sex chromosomes also have loci for genes that determine other characteristics of the individual. The X chromosome, for example, has at least 100 markers for features such as colour vision and the enzymes of red blood corpuscles. This explains why colour blindness and several inherited diseases are sex linked. Errors in Sex Chromosome Division and Distribution During cell division the chromosomes normally split longitudinally, one half of each going to each of two daughter cells. When cleavage does not take place, the
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Fig. 14.3: Non-disjunction of the sex chromosomes of the ovum at the time of reduction division. After fertilisation the possible combinations of sex chromosomes are XXX (triple X syndrome); XO (gonadal dysgenesis or Turner syndrome); XXY (primary microorchidism or Klinefelter syndrome); and YO which has never been found clinically and may be incompatible with life of the embryo. Although probably much less common, non-disjunction can affect the spermatozoon instead of the ovum, the possible results after fertilization being XXY and XO patterns
phenomenon is termed non-disjunction; this is not uncommon, especially during the first meiotic (reduction) division leading to the formation of a mature ovum or spermatozoon. The result is an oocyte which may contain either two X chromosomes or no sex chromosome at all, and a spermatozoon with either XY or no sex chromosomes. When fertilisation takes place, the outcomes that are possible are zygotes whose chromosome make-up is 45, XO, 45, YO, 47,XXX and 47,XXY. An embryo with a chromosome pattern of 45,YO has never been found. This, it is assumed, is because such an arrangement is incompatible with the life of a cell or an early embryo (Fig. 14.3). During mitotic division of the fertilised ovum, errors in the distribution of the chromosomes, even if their original complement is normal, can still occur. Nondisjunction is again possible or, if cleavage takes place, all the resulting products can pass to one daughter nucleus to give it a 48,XXXX or 48,XXYY complement. This is known as duplication. Sometimes in the course of cell division, all or part of a chromosome may be lost (by anaphase lag, depletion or fragmentation). One or two of the arms of an X, for example, may disappear or, on the other hand, become displaced and link with an autosome (translocation). Even translocation of part of a Y to an X chromosome, the socalled X—Y interchange, is described. Another possibility is for chromosomes to divide across their centrosomes
Sex Determination, Asexuality and Intersexuality differentiation and reproductive function (Fig. 14.10). The possible combinations are endless. A few examples are 46,XX/ 45,XO; 46,XY/45,XO; 46,XX/46,Xx; 46,XX/ 45,Xf (f meaning a fragment); and 46,XY/47,XXY. The effects on the genital apparatus and phenotype depend on the relative numbers of the different types of cells, that is, on which cell line is dominant, and on their tissue distribution. Thus, if the primitive gonad is predominantly 45,XO it is not likely to develop or function even though most other tissues in the body are 46,XX; if it is 46,XY it will become a testis despite the fact that elsewhere the dominant cell line is 45,XO. The earlier in embryogenesis that any of the abnormalities in the sex chromosome pattern arise, the more widespread and serious is their effect. Three to four per 1000 live babies are born with clearly recognisable sex chromosome aberrations. This, however, understates the incidence since many affected foetuses, especially those with XO patterns, are aborted. Chimaerism and Dispermy
Fig. 14.4: This diagram illustrates the abnormal division of chromosomes, across their centrosomes instead of longitudinally, to produce isochromosomes
instead of longitudinally to produce isochromosomes (Fig. 14.4). Examples of end results of this happening are longarmed X and short-armed X isochromosomes. Errors of these kinds, affecting only one or two cells at a very early stage of segmentation of the ovum, are reproduced in their offspring and the final outcome is two or more cell lines in the fetus. These can be found throughout the whole body or each may be localized or dominant in particular tissues. This phenomenon is called mosaicism and the affected individual a mosaic. How far mosaicism is present in all men and women is unknown but, in minor degrees, it may be universal. Mosaicism of a gross degree is not uncommonly found in men and women suffering from aberrations in sex
The one type of mosaicism which is difficult to understand is the rare combination of XY/XX. This is said to arise under two circumstances. If binovular twins of different sexes have placentas with vascular connections, their bloods intermingle to result in each having leucocytes some of which are XY and some XX. This is the condition of chimaerism. When a singleton foetus shows XY/XX mosaicism, the probability is that the ovum was fertilised by at least two spermatozoa (dispermy), one carrying an X and one a Y chromosome. Double fertilisation of a two-nucleated ovum and fusion of two zygotes are also postulated happenings. Sex Chromatin Pattern The number of X chromosomes in the nuclei of various cells can be judged roughly by the sex chromatin pattern. This can be studied in all tissues but clinically those most readily available for examination are the epithelial cells (obtained by buccal smear or skin biopsy) and leucocytes. When more than one X chromosome is present, the nucleus has an additional deposit of chromatin. In epithelial cells this is disposed eccentrically and is called the Barr body after its discoverer (Fig. 14.5). In neutrophils it appears as a ‘drum stick’ appendage to one of the lobes of the nucleus. This chromatin mass is found whenever two or more X chromosomes are present in the nucleus
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Fig. 14.5: The nuclei of two epithelial cells whose cytoplasm has been removed. Each contains the darkly staining peripheral deposit of nuclear material (the Barr body), which denotes that they are chromatin-positive. This is a feature of nuclei carrying two or more X chromosomes, the satellite chromatin being the inactivated X
and irrespective of the Y complement. A cell which carries it is said to be chromatin-positive; one which does not is chromatin-negative. So the normal female cell (46,XX) is chromatin-positive, and the normal male cell (46,XY) is chromatin-negative. A cell with only one X chromosome (45,XO) is chromatin-negative; one with 47,XXY is chromatin-positive. One with 47,XXX or 48,XXXY chromosomes is strongly positive since the eccentric masses vary in size or number according to the X complement. This is because only one of the X chromosomes normally plays an active role in the nuclear direction of cell function. The extra chromatin mass represents the X chromosome(s) which is discarded or inactivated, and this happens from about the twelfth day of intrauterine life onwards. This process of inactivation is called ‘lyonisation’ of the X chromosome after its discoverer, Dr Lyon. The X chromosome which is lyonised may have come originally from either gamete. So, in women, it may be presumed on statistical grounds that the nuclei of half the tissue cells are motivated by an X chromosome of paternal origin and half by one of maternal origin. In men, the active X chromosome is always a maternal one. The Barr body first appears in trophoblast cells at about the twelfth day, and in the tissues of the foetus itself by the eighteenth day. The percentage of cells in which the Barr body is recognised microscopically varies with the preparation and the observer. A figure between 15 and 50 per cent is accepted for epithelial cells in the female; for leucocytes it may be only 20 per cent. The situation is further complicated in mosaics. Today, chromosomal culture is widely available and karyotyping has become the method of choice. Tissue cultures of leucocytes or skin epithelial cells are prepared by the addition of a mitogenic agent, i.e. phytohaemag-
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glutinin. They are subsequently arrested at the metaphase by the addition of colchicine. A number of banding techniques are used to stain and identify the separate chromosomes. Of these, G-banding is the commonest. DNA probes prepared for individual chromosomes or for chromosomal regions can be used to identify particular chromosome arrangements or an abnormal number of chromosomes. The Chromosomal Sex Drive The Y chromosome gives the all-powerful and positive drive towards sex differentiation and, in particular, determines the nature of the gonad. The testisdetermining gene, the sex-determining region Y (SRY), is located on the distal short arm of the Y. It is a singlecopy gene expressed only at the time of development of the testicular cords, which is instrumental in the expression of the testis-determining factor (TDF). The foetal testes produce the anti-müllerian hormone (AMH) and testosterone. The development of an ovary depends not so much on an XX chromosome complement but on the absence of the Y and the consequent absence of AMH. A few isolated cases of individuals without a Y sex chromosome yet possessing testes are described (the XX male). The finding is explained by an X-Y interchange which results in fertilisation of the ovum by an X spermatozoon carrying the TDF gene on the SRY to give rise to an XXY individual. In such a case, lyonisation of the X to leave the X Y active might result in the development of testes. Conversely, XY females are described in whom the absence of the TDF results in the development of an XY female. These sex-reversal disorders are seen in approximately 1 in 20000 births. The Y chromosome is also a positive masculinising force in other ways. Irrespective of the total sex chromosome complement, the presence of a Y usually means that the general physical characters of an individual (phenotype) are male. TDF may also play a role in spermatogenesis in the adult. Ovotestis When the chromosomal direction to the gonad is confused, as it may be in certain states of mosaicism, a possible result is the development of both testicular and ovarian tissue, these being either separate (Fig. 14.14) or in the form of an ovotestis (Figs 14.6A and B). This is the condition of so-called true hermaphroditism. Affected
Sex Determination, Asexuality and Intersexuality
Fig. 14.6: A condition of ovotestis in a child aged 3 weeks who, despite the male appearance of the external genitalia, was registered as female. At operation for bilateral inguinal hernias she was found to have a normal uterus and tubes, and gonads in the position of ovaries. Sex-chromatin positive, the chromosome pattern was not determined but was assumed to be XX at the time; mosaicism now seems possible (Miss Isabella Forshall’s case), (A) External genitalia showing enlargement of the phallus and hypospadias; the presence or absence of a vagina was not determined, (B) Section of one of the gonads showing two ova to the left of the field and, in other areas, groups of Sertoli cells attempting to form testicular tubules
Figs 14.7A and B: Turner syndrome with presumed streak gonads. The patient, aged 17 years, complained of primary amenorrhoea. Height 130 cm. Chromatin-negative; sex chromosome complement not determined. Note the short wide neck, barrel-shaped trunk, increased carrying angle, deformities of the toes and the absence of secondary sex characters
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Fig. 14.8: Turner syndrome. Girl aged 7 showing webbing of the neck and exaggerated epicanthic folds. She also had a congenital abnormality of the heart. Buccal smears chromatin-negative. Sex chromosomes 45,XO
individuals may be phenotypically male or female. If the former, they often have gynaecomastia in later life, and if the latter they often manifest virilism. The chromosome patterns in true hermaphrodites, as judged from cultures of epithelial cells and leucocytes, are said to be 60 per cent 46,XX, 20 per cent 46,XY and 20 per cent mosaics and chimaeras. It nevertheless seems likely that the testicular tissue cells must always have some part of a Y component. Indeed, if both gonads contain dominant 46,XY cell lines, individuals with a 46,XY/46,XX karyotype may possess normal testes and be completely masculine. Streak Gonads, Gonadal Aplasia and Hypoplasia When the chromosomal drive to the gonad is weak, hypoplasia of the gonad is likely. Thus, if the Y chromosome is defective, the result may be undescended or poorly developed testes. When the Y is absent, the result is usually the formation of an ovary but only if two complete X chromosomes are present. So, individuals with a 45,XO complement usually show failure of gonadal development - streak gonads. The condition of streak gonad is often referred to as gonadal dysgenesis (ovarian agenesis in the past) but this term strictly means any disturbance in the development of the gonad. Gonadal agenesis or aplasia are preferable
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Fig. 14.9: The ‘streak’ gonad (white arrow), formerly regarded as typical of Turner syndrome but now known to be a possible result of a variety of sex chromosome aberrations. This photograph was taken at laparotomy on a girl aged 17 years complaining of primary amenorrhoea and absence of secondary sex characters. The vagina, uterus and tubes were present in an infantile state. The patient was 165 cm in height and showed none of the stigmata of Turner syndrome. The sex chromosomes, in leucocytes, skin and gonadal tissue, were XY and the buccal smear chromatin-negative
names despite the chosen descriptive label. For the gonad concerned is represented by nothing more than a strand of white undifferentiated connective or stromal tissue lying on the back of the broad ligament, the internal genitalia being always female (Fig. 14.9). The embryological history of the streak gonad is as follows. Initially primordial germ cells appear in the genital ridge in the normal way but, although some may persist up to the fourteenth week of intrauterine life, they all die quickly. They are therefore unable to organise or maintain other tissue elements in the gonad, which becomes little more than fibrous tissue. Very occasionally the picture is incomplete and a few ova are found in the ovary at birth but these disappear in childhood or adolescence. SEX CHROMOSOMAL INTERSEX Turner Syndrome (First described in 1957 by Henry Turner) This is the classical syndrome associated with streak gonads, and the underlying error is a karyotype of 45,
Sex Determination, Asexuality and Intersexuality XO or a mosaic containing this cell line. The primary cause is non-disjunction of the sex chromosomes as described on page 222, the single X chromosome being maternal in origin in 75-79 per cent of cases. Many of the 45, XO embryos are aborted but those that are not become malformed and, in addition to having streak gonads, present the features of Turner syndrome at and after birth. Being without a Y chromosome, all affected individuals appear female and their incidence is 0.2 per 1000 live girl babies. The diagnosis can often be made in infancy, being prompted by somatic defects listed below: Characteristic 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
16. 17. 18. 19. 20.
21.
22. 23.
Short slender female less than 5 ft. (150 cm) Height span ratio altered Secondary sexual ratio altered Breast Bo or B1 (tanner classification) Body hairs absent Shield chest, webbing of neck, cubitus valgus (90% show skeletal abnormality) Cardiovascular abnormalities (aortic stenosis, coarctation of aorta 30-40%) Urinary abnormalities (50-60%) Mental retardation (15%) External genitalia poorly developed. Uterus and tubes-hypoplastic Internal gonads-agenetic or dysgenetic Chromosomal pattern 45XO Case of chromosomal deletion Extra X chromosome in females usually does not affect physical development or fertility. Absence of sex chromosome is serious. Primary ovarian failure Germ cells are present in the embryonic gonads but usually disappear or are severely depleted at birth. Mosaicism in 45X patients may occur (46XX/45XO) Colour blindness and multiple navi on skin Autoimmune disorders such as Hashimoto’s thyroiditis, Addison’s disease and vitiligo are common In newborn babies with Turner’s these may be chronic nuchal oedema as well as other stigmata of the nuchal cystic hygroma syndrome. Newborns may have life threatening effusions in serous cavities. Abnormality of lymphatic system may sometimes cause gross swelling of the legs in the child or adult.
Other Syndromes and Karyotypes Associated with Streak Gonads The genes which protect against the physical malformations of Turner syndrome are carried on the short arms of two matching chromosomes - XX or XY; those which protect against streak gonads are on the long arms. If only the short arms of an X or Y are missing, the effect can be to produce some or all of the stigmata of Turner syndrome without failure of gonadal and genital development in either a male or female direction. Conversely, if the short arms of a second X, or Y, are present, even in fragmentary form, the woman with streak gonads may be of normal height and free from other physical extragenital defects. This can happen when the karyotype is 46,XXf and 46,XX/45,XO. Incidentally, the possibility of a mosaic background, and sometimes even an XX one, explains why 20 per cent of women showing a fairly typical Turner syndrome have chromatin-positive buccal smears, hence the importance of doing a complete karyotype if possible. For the above reasons, streak gonads can be found when the karyotype is 46,XY or 45,XO/46,XY; in such cases the patients tend to be tall and eunuchoid in build. The genitalia are always female but the ‘woman’ may develop a degree of virilism by way of slight enlargement of the phallus and hirsutism. It comes about therefore that all variants between a typical Turner syndrome and something approaching a normal male or female phenotype can accompany streak gonads, although the genital tract is essentially female. In Noonan syndrome (male Turner syndrome), streak gonads go with a 46,XY karyotype. The somatic defects resemble many of those of Turner syndrome but the characteristic cardiac lesion is stenosis of the pulmonary valve. Those affected are also likely to have mental retardation and develop autoimmune thyroiditis. These patients are fertile and the trait is transmitted as an autosomal dominant one with variable expression. The situation is further complicated by the fact that 46,XX/45,XO mosaicism can, rarely, result in a functional ovary on one side and a streak gonad on the other and thus a menstruating woman with the physical stigmata of Turner syndrome. Rarely, such women can have a pregnancy also, but there is a high risk of congenital abnormalities in the offspring, including Down syndrome, spina bifida and congenital heart disease, so prenatal testing is mandatory. More commonly, a streak gonad on one side is accompanied by a testis (in the
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Figs 14.10A to F: Unilateral streak gonad and unilateral cryptorchidism. An apparent girl of unusual facial beauty, aged 16 years, complaining of primary amenorrhoea and deepening of the voice. Height 155 cm; chromosomes 45,XO/46,XY/47,XYY. The vagina, uterus and tubes were present, with a testis on the back of the left broad ligament and a streak gonad on the right, (A) Axillary hair present, breasts undeveloped.The ‘cleft’ chin was the only masculine feature of the facies. (B) The left gonad as seen at laparotomy is typical of an undescended testis. (C) Pubic hair normal; the thighs are slightly hairy but this apart there was no hirsutism. (D) An enlarged phallus obscuring an otherwise female introitus. (E) The appearance of the vulva after removal of the phallus (today we would prefer clitoroplasty to cliotoridectomy). (F) Breasts beginning to develop as a result of oestrogen therapy instituted after removal of the gonads. This treatment also induced cyclical uterine bleeding
position of the ovary) on the other (Figs 14.10A to F). The background for this is mosaicism such as 46,XY/ 45,XO. Again, the ducts are almost invariably müllerian. Streak and dysgenetic gonads have a high potential for neoplasia if the owner’s karyotype contains a Y
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chromosome. In such cases, the risk of a tumour, such as a disgerminoma or gonadoblastoma, developing in later life is put at 20-30 per cent. Unless a Y chromosome is in the background, however, streak gonads carry a negligible risk in this respect.
Sex Determination, Asexuality and Intersexuality
Triple X Syndrome (47,XXX) One per 1000-1200 women have a 47,XXX chromosome make-up, this being mostly the result of non-disjunction during oogenesis (Fig. 14.3) i.e. X sperm fertilising XX ovum. These were originally described as super females which they are not, for they are likely to suffer from oligomenorrhoea, secondary amenorrhoea, infertility, genital tract hypoplasia and premature menopause. Other features of the triple-X syndrome are low intelligence, sometimes gross mental deficiency or psychosis, and often abnormal EEG patterns and presence of two Barr bodies. Nevertheless, the majority of women with a 47,XXX karyotype appear to be normal in every way and are fertile. Moreover, the taint is not transmitted to their offspring, the extra X being lost during oogenesis, even though there is a theoritical risk of XXX or XXY. Primary Micro-orchidism: Klinefelter Syndrome (47,XXY) The 47,XXY karyotype is found only with a male phenotype, its incidence being 1.5-2.0 per 1000 men. It is correctly known as “seminiferous tubule dysgenesis”. It usually results from non-disjunction, the additional X chromosome being maternal in 60 per cent of cases (Fig. 14.3). The typical effect is the Klinefelter syndrome which
combines a tall eunuchoid figure with testicular and genital hypoplasia (Figs 14.11A and B). Slender male with female distribution of fat. The testes are very small and may or may not be descended. Their embryological history is rather similar to that of the streak gonad. Germ cells are present in the genital ridge in the embryo but disappear early in foetal life. After birth, the tubules are aplastic and functionless so sterility is the rule. The secretion of gonadotrophins is sometimes increased. Gynaecomastia develops in the adult in 15 per cent of cases, and there is a much increased risk of carcinoma of the breast in later life. The Klinefelter syndrome is also characterised by mental defects, antisocial behaviour (psychopathic behaviour) and abnormal EEG patterns. So the incidence of the 47,XXY karyotype, if not of the syndrome, amongst inmates of prisons and of institutions dealing with psychiatric disorders is as high as 1-10 per cent. External genitalia are hypoplastic, phallus small or normal with undescended testes, usually subfertile or infertile but not impotent. Testicular biopsy shows hylanised seminiferous tubules and hyperplastic leydig cells. Pituitary hormones normal (FSH, LH), adrenal MKS normal and testosterone reduced. The above is the classical picture, which is also seen with mosaics such as 47,XXY/46,XY. Men with an XXY complement in their chromosome make-up can be
Figs 14.11A and B: Klinefelter syndrome. Man aged 28 years, married but infertile and complaining of gynaecomastia. Chromosomes 47,XXY. (Professor Sir Cyril Clarke’s case) (A) An apparently normal male but tall. The scrotum is small and contains very hypoplastic testes. (B) Slight enlargement of the breasts
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Jeffcoate’s Principles of Gynaecology completely normal, physically and mentally, and may even have superior intelligence and drive. Moreover, they can be fertile and produce normal 46,XY and 46,XX offspring, the additional X being lost during the maturation of spermatozoa. The YY Syndrome As a result of errors in nuclear division, such as duplication in the zygote, there are men with two or more Y chromosomes and with karyotypes such as 47,XYY, 48,XYYY and 48,XXYY, and mosaic patterns containing these. Such men often suffer from the ‘YY’ syndrome which is characterised by excessive tallness, aggressive and antisocial behaviour, and criminal tendencies with or without mental subnormality. Their genital development and fertility are usually normal. The possible aberrations of sex chromosome numbers and types, and their combinations in mosaics are endless, but their effects are always in line with the principles stated above. Thus, a 48,XXXY individual is likely to present as Klinefelter syndrome, as are the mosaics in which the 47,XXY cell line is dominant. A woman with a 48,XXXX karyotype is likely to have the clinical features of the triple-X syndrome.
genes on the autosomes (Fig. 14.12). These, which are mainly masculinising, can modify the chromosomal urge towards sex differentiation, especially if it is weak or if they are strong. Autosomal genetic masculising influences in an otherwise normal female probably account for ‘constitutional’ hirsutism (Fig. 14.13). So it is not surprising that this common syndrome shows a strong familial and inherited tendency. An autosomal genetic influence, operating at an early stage in embryonic development, can also modify the development of the genital tracts, if not the gonad. Thus, malfusion deformities of the uterus, and hypospadias in the male, are sometimes familial. The polycystic ovary syndrome is also known to have a familial tendency. AUTOSOMAL INTERSEX Constitutional Hirsutism There is normal development. Gonads are ovaries and are normal, ovulation is present. Because of presence of certain genes on autosomes there may be excessive response of hair follicles to androgens resulting in hirsutism.
Other Genetic Influences Although relatively weak as compared with those on the sex chromosomes, there are also sex-influencing
Fig. 14.12: Diagrammatic representation of factors determining sex in utero. These are sex chromosomes, genes on autosomes, organiser influences of the gonad directly on the ducts, and hormones of the foetus. Their sites of operation are indicated by arrows
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Fig. 14.13: Hirsutism of constitutional origin. A woman aged 24 years complaining of gross hairiness of the legs, arms, back and face. Yet she menstruated regularly and had well-developed breasts. All hormone assays gave normal findings
Sex Determination, Asexuality and Intersexuality
Testicular Feminsing Syndrome The chromosomal sex is XY, the patient is phenotypically female. The gonads are testes. The testes actually secrete oestrogens and cause female secondary sexual characters. Characteristics are: 1. Phenotypic female 2. Female distribution of fat and female voice 3. Good breast development 4. No body hair (hairless female) except scalp 5. External genitalia female but infantile 6. Vagina absent or blind pouch but normal vulva 7. Internal gonads usually undescended testes 8. Uterus and tubes absent (due to MIF from testes) 9. There is an enzymatic block in testicular epithelium so testosterone is not converted to active dihydrotestosterone. 10. There is insensitivity of end organs to androgens (hair follicles, vocal cords and phallus). 11. Treatment is gonadectomy as risk of malignancy is 4% and vaginoplasty for sexual function 12. This syndrome shows a familial tendency, the trait being transmitted maternally. 13. Plasma levels of testosterone and other androgens are above normal range for male due to increased LH. There is associated increase in testicular oestradiol and also there is peripheral conversion of androgens to oestradiol. 14. Incomplete syndrome (Reifenstein syndrome) are also described as partial androgen insensitivity. Management depends on degree of ambiguous genitalia and sex of rearing some men of Reifenstein syndrome may respond to high doses of testosterone for those assigned as females. The treatment is gonadectomy, vaginoplasty and HRT. 15. A third form of androgen insensitivity is 5α reductase deficiency. Testosterone is not converted to dihydrotestosterone (DHT) at target tissues. GONADAL INTERSEX Gonadal intersex is of three types: 1. True hermaphroditism 2. Male hermaphroditism 3. Female hermaphroditism 1. True hermaphroditism
a. Mostly are 46 XX with chromatin positive but may be 46 XY b. Gonads are both ovaries and testes either ovary one side and testes other side or ovotestes on both sides. c. Phenotypic growth is feminine d. External genitalia may be ambiguous: perioclitoris or incomplete labioscrotal folds e. Familial cases are autosomal recessive, autosomal dominant is rare. 2. Male Hermaphroditism a. Chromatin negative i.e. 46 XY b. External genitalia are masculine but there is presence of müllarian tissue c. Normal development, normal puberty and fertility d. Usually detected during hernia surgery. When müllerian tissue is present (lack of MIF) e. Condition is rare. 3. Female hermaphroditism a. Relatively common b. External genitalia show perioclitoris, incomplete fusion of labioscrotal folds, single urogenital opening c. Gonads are usually testes, have normal testicular tissue but no spermatogenesis d. Testes fail to have proper influence through morphogenetic hormone, hence reared as females. The Organising Power of the Gonad Irrespective of chromosomal and genetic drives, sex differentiation in utero is partly controlled by the organising power of the gonad. The development of the gonad itself is dependent on the presence of the primitive germ cells which determine whether the gonadal mesoderm shall differentiate into granulosa cells or testicular tubules. Without these germ cells, as in Turner syndrome, the gonad remains asexual. The gonad inturn controls the persistence or degeneration of the müllerian and wolffian ducts but, in this respect, it is the testis which is all-important. Unless functional testicular tissue is present in the foetus, the müllerian ducts invariably persist to give rise to a female genital tract, irrespective of the sex chromosome complement. This is because the foetal testis secretes AMH, which is a polypeptide produced by the Sertoli cells.
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Jeffcoate’s Principles of Gynaecology When half the genital tract is male and half female, it is the presence of a testis rather than the absence of an ovary which accounts for the vas and epididymis on that side. Moreover, it is the absence of the testis rather than the presence of the ovary on the other side which allows the corresponding müllerian duct to persist and the wolffian duct to atrophy (Fig. 14.14). Occasionally, a fertile man, with either one or both testes normal, is found to house a complete uterus and fallopian tubes. The explanation of this is that during early foetal life, his testes failed to produce AMH, even though they functioned properly after birth (Fig. 14.15). HORMONAL INTERSEX The steroid hormones cross the placenta and it is somewhat surprising that the large amounts of oestrogen and progesterone in circulation during pregnancy do not influence sex differentiation in the foetus. If, however, the mother suffers from an androgenic tumour of the ovary (e.g. luteoma, androblastoma, mucinous cystadenoma or Kruken-burg’s tumours), adrenal (e.g. adenoma), or if she takes exogenous androgens, the genitalia of the female foetus become virilised. The degree and type of virilisation depend on the timing and strength of the hormone influence but, since there is no müllerian inhibitor, the tubes, uterus and vagina develop normally. The effects are seen only in the external genitalia and consist of enlargement of the clitoris, with or without fusion of the labia minora as seen in congenital adrenal hyperplasia (see below). To produce gross deformity the androgenic impulse must be applied before the fourteenth week. Progesterone is weakly androgenic and synthetic progestogens, especially ethisterone and norethisterone, can, when given to the mother, sometimes virilise the female foetus. It is remarkable how few girl babies have been reported to have had masculinised external genitalia considering the large numbers of mothers who, in the past, were treated with progestogens for threatened and recurrent abortion. In explanation it is suggested that virilisation only occurs when the metabolism of the mother or her foetus is such as to convert progestogens to androgens. Sex differentiation of the external genitalia is normally strongly directed by the hormones which the foetal adrenals and gonads produce. The androgenic influence is especially important. The adrenal cortex of the foetus
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Fig. 14.14: Influence of the gonad on development of the genital ducts. An adult African man with a normal phallus (P) and scrotum but only the left testis (T) descended. Within the abdomen and behind the bladder (B) is a right-sided unicornuate uterus (U) with a tube and ovary (O). The ovary contains a recent corpus luteum. It is the absence of a testis on the right side which explains the persistence of the müllerian duct on that side. The buccal smears were chromatin-positive but the chromosomal pattern was not determined. It might have been 46,XX/46,XY. This case of socalled true hermaphroditism was in the care of the late Dr N.de la Harpe of Pretoria
Fig. 14.15: A uterus and fallopian tube, the former containing histologically typical endometrium, removed from the hernial sac of a man aged 31 years and the father of 2 children. The gonad in the specimen is a hypoplastic testis with its vas in the position of Gärtner’s duct. This man had a normal testis (and a fallopian tube) on the other side and good function of this testis was shown by semen analysis (Mr Donald Young’s case)
Sex Determination, Asexuality and Intersexuality is active by the twelfth to sixteenth week and an abnormality in its function can cause a state of intersex (Flow chart 14.3).
Flow chart 14.3: Hormonal pathway
Congenital Adrenal Hyperplasia This is a familial disease transmitted by a recessive gene. If any couple has had one affected child, a subsequent baby has a 1 in 4 chance of having the same disability (Figs 14.16A to F). The cause of the disease is an inherent enzymatic error in the adrenal cortex, which is unable to complete the normal biosynthesis whereby progesterone is converted through hydroxyprogesterone to cortisol. There are several levels at which arrest can occur, with consequent variations in the effects. The most common enzymatic defects are those of 21-hydroxylase, 11 β-hydroxylase and 3 β-hydroxysteroid dehydrogenase. Typically, however, the metabolic chain is broken at the hydroxyprogesterone stage, i.e. 21-hydroxylase deficiency (Figs 14.17A and B). The resulting deficiency of corticoids means that the output of ACTH by the pituitary is not controlled. The excessive production of ACTH causes bilateral adrenal hyperplasia and an increased secretion of nearly all adrenal cortical
hormones. These include androgens so, in the female foetus, sex differentiation of the external genitalia is disturbed. The ovaries, tubes, uterus and vagina are basically unaffected because their development is not subservient to androgens but the vulva and introitus are affected. The genital folds fuse in an attempt to form a penile urethra instead of labia minora, and the phallus enlarges so the infant at birth appears to be a male with hypospadias (Fig. 14.16C). Distinction between the two conditions, at one time difficult, is now easy. Girls
Figs 14.16A to F: Sisters each exhibiting congenital adrenal hyperplasia. Another child of the same parents had been born earlier and registered as a male. It died when 6 weeks old from ‘wasting’; so it was probably affected and died from electrolyte imbalance, (A) The older girl aged 4½ years, physically and sexually precocious. Axillary and pubic hair present and voice breaking. Excretion of 17 ketosteroids = 25 mg/24 hours, (B) Younger child aged 2½ years and also precocious. 17-ketosteroid excretion = 15 mg/24 hours, (C) The external genitalia were identical in appearance and this shows the finding in the child aged 2½ years. The uterus, tubes and ovaries were normal in both, (D) The external genitalia at the age of 10 years; the catheter is inserted for the purposes of a vaginogram. (E) The external genitalia 3 months after a reconstruction operation at the age of 10 years, (F) Breast development, previously absent, after 1 year’s treatment with prednisolone. Regular menstruation had also resulted from this treatment. Both girls responded equally well
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Figs 14.17A and B: (A) Normal relations between the hypothalamic-pituitary system and the adrenal cortex. Corticosteroids are synthesized in the adrenal from pregnenolone and these in turn control the secretion of ACTH by the pituitary. A balance is thus maintained, (B) The relations between the hypothalamic-pituitary system and the adrenal cortex in congenital adrenal hyperplasia. Synthesis of corticoids by the adrenal is blocked, usually at the hydroxyprogesterone link in the chain. The excretion product of this substance, pregnanetriol, therefore appears in large amounts in the urine and liquor amnii. Absence of the corticoid inhibitory effect on the hypothalamus and pituitary allows an excessive output of ACTH and consequent overstimulation of the adrenal cortex. The result is increased blood levels and secretion of androgens and sometimes other products, and a rise in the urinary excretion of 17-ketosteroids
suffering from congenital adrenal hyperplasia are always sex chromatin-positive, and have a 46,XX chromosome pattern. The serum levels of 17-hydroxyprogesterone (17 OHP) are elevated. (Correspondingly, urine levels of 17ketosteroids and of pregnanetriol are also elevated). The anatomy can be confirmed by instilling a radio-opaque medium into what appears to be the urethra to demonstrate the presence of the vagina within (Figs 14.18A and B).
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After birth the fundamental metabolic upset continues, so the excessive adrenal cortical function causes physical and sexual precocity which, in the female child, is of the virile pattern (Figs 14.16A to F). Pubic and axillary hair appear, and the voice deepens by the age of 2-4 years. Affected children at first grow quickly but the epiphyses of their long bones close at the age of 8 or 9 years. They thus first outstrip and later lag behind their contemporaries in height. The ovaries, although
Sex Determination, Asexuality and Intersexuality
Figs 14.18A and B: Congenital adrenal hyperplasia. Vaginograms obtained by running in radio-opaque fluid through a catheter inserted as in Fig. 14.16(D), the head of the patient being slightly lowered, (A) In this case the fluid not only filled the obscured vagina but ran into the uterus and even into the peritoneal cavity. Girl aged 11 years, (B) Here the fluid entered both the urethra and the vagina to produce a cystogram superimposed on a vaginogram. Girl aged 8 years
normally formed, do not function; the uterus remains infantile and fails to menstruate; hirsutism becomes a problem. As the years go by masculinity becomes so intense that, in the days when effective treatment was impossible, many sufferers from the congenital adrenal hyperplasia (CAH) found it easier to live as men. In the more severe forms of the disease, salt-wasting and shock may also be present at birth. Very mild, nonclassical disease may present only at puberty. When male foetuses suffer from congenital adrenal hyperplasia, their precocious masculinity is accentuated to produce the ‘infant Hercules’. Provided that the diagnosis is made early, postnatal development can be corrected. Cord blood can be assayed for 17 OHP levels and is the basis for some neonatal screening programmes. It requires only a relatively small dose of one of the corticosteroid preparations, determined by clinical trial and con-trolled by periodic assays, to inhibit the ACTH output and to allow the function of the reticular layer of the adrenal cortex to return to normal. Treatment has to be continued throughout life but, if properly regulated, is not likely to involve the risks of adrenal suppression. The adrenals are not made inactive; their function is merely reduced to normal.
The abnormality of the vulva can readily be corrected by plastic surgery (Figs 14.16 and 14.19). Exposure of the vagina can be deferred until puberty but, to avoid a psychological reaction, the large phallus should be removed before the age of 5 years. Early diagnosis and treatment are important, otherwise voice changes, persistent hirsutism and premature closure of epiphyses leave permanent stigmata. With steroid therapy, ovarian and uterine functions become normal and fertility is possible. The disorder is transmitted to the offspring as a monogenic autosomal recessive trait. Psychological counselling is required both for the parents and the child. Deficiency of 11 β-hydroxylase is the hypertensive form of CAH. The levels of 11-deoxycorticosterone are raised as a result of the enzyme deficiency and since this has salt-retaining properties, hypertension ensues, although aldosterone levels are reduced. Elevated levels of androstenedione can result in ambiguous genitalia. Diagnosis is made by measuring elevated levels of urinary 17-hydroxycorticosteroids and of serum androstenedione. Treatment is as described above. Deficiency of 3 β-hydroxysteroid dehydrogenase is a rare form of CAH. The block in steroidogenesis occurs very early in the pathway leading to decreased synthesis of gluco- and mineralocorticoids, androgen and
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Figs 14.19A to F: Correction of the deformity of the external genitalia in congenital adrenal hyperplasia. (A) The normal development of the vulva, vagina and urethra at the fourth month (after Hamilton, Boyd and Mossman). (1) urethra; (2) vagina; (3) vestibule forming from the urogenital sinus; (4) clitoris; (5) site of cloacal (urogenital) membrane, (B) The deformity in the adrenogenital syndrome represents essentially a fusion of the genital folds to form a perineal membrane which obscures the introitus and vagina, (C) The occluding membrane demonstrated, (D) Incision of the membrane reveals the urethra and vagina, (E) Removal of the enlarged clitoris, (F) The ultimate result; compare with Fig. 14.16(E)
oestrogens. A severe salt-losing state ensues which results in electrolyte upsets in the newly born baby. Unless recognised and treated, these cause vomiting, wasting and death within a few days or weeks. The possibility of an abnormal electrolyte balance should always be investigated before any operation on a child suffering from the adrenogenital syndrome. Dehydroepiandrostenedione (DHEA) is the androgen most elevated and it causes mild virilisation. Treatment of the salt-losing crisis involves correction of the electrolyte imbalance and replacement with prednisolone, dexamethasone or desoxycorticosterone acetate. The majority of cases require fludrocortisone 0.1-0.2 mg/day in addition to prednisolone or dexamethasone.
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In one of Professor Jeffcoate’s cases, the finding of excessive amounts of 17-ketosteroids and preg-nanetriol in the liquor amnii, contributed by foetal urine, allowed the diagnosis to be made before birth (Fig. 14.20). This original observation has since been confirmed by others. Antenatal screening is indicated when the mother has previously had an affected child. In 21-hydroxylase deficiency, levels of 17 OHP, 21-deoxycortisol and androstenedione in the amniotic fluid are elevated. With 11 β-hydroxylase deficiency, 11-deoxycorticosterone is elevated. However, these measurements of amniotic fluid steroids have now been replaced by direct mutational analysis which can detect even mild deficiencies - chorion villus biopsy samples are evaluated
Sex Determination, Asexuality and Intersexuality
Fig. 14.20: The virilised external genitalia of a newborn female suffering from congenital adrenal hyperplasia. This condition was diagnosed before birth because the mother, known to be at special risk of having such a child, was subjected to amniocentesis. Examination of the liquor showed it to contain unusually large amounts of pregnanetriol and of 17-ketosteroids (the latter being less significant). These substances were contributed by the foetal urine. This was the first case in which the diagnosis of any form of foetal metabolic error was made before birth, the possibility having come to mind when it was realised that, since the foetus normally urinates in utero, its urine can be examined (via the liquor) before birth. It was this case which led to all subsequent developments in this field
by DNA probes. Therapy with 1.5 mg dexamethasone per day is started at 4-5 weeks’ gestation in all women whose foetuses are at risk of 21-hydroxylase deficiency and continued once the deficiency is proved. This prevents the development of ambiguous genitalia in female foetuses and may also have some effect on the foetal brain with regard to gender identity.
Other Causes of Hormonal Intersex a. Use of androgenic progesterone in pregnancy (intrauterine adrenogential syndrome) b. Pituitary basophilic adenoma c. Virilising tumours of ovary. Combinations of Chromosomal, Genetic and Gonadal Causes of Intersex From the foregoing, it is evident that states of intersex often have a complicated aetiology with several
Figs 14.21A to C: The testicular feminisation syndrome. A girl aged 18 years complaining of primary amenorrhoea although her breasts had developed well since she was 12 years old. Interests and outlook feminine; chromosome pattern 46,XY. Undescended testes were removed and there was no sign of tubes or uterus at operation. Following operation the girl did not experience any reactions and the output of oestrogens in the urine remained virtually unchanged, within the male range. She married one year later and had normal heterosexual libido and coitus, (A) A very attractive female figure with a well-developed bust and a smooth hairless skin, (B) Feminine external genitalia although the pubes and vulva are characteristically almost devoid of hair. The vagina is of good length although it must represent a urogenital sinus component only, (C) Section of one of the gonads, showing inactive seminiferous tubules and large islands of interstitial (Leydig) cells
background factors operating. Thus, the testicular feminisation and congenital adrenogenital syndromes, although mediated by hormone influences, are basically genetic in origin and are strongly familial. The same is true of the not-uncommon conditions in which men have breasts, partly feminised genitalia, and personalities. A good example is penile hypospadias in an otherwise masculine individual with a 46,XY karyotype. It is reckoned that 75 per cent of men suffering from hypospadias have an inherited taint of some kind (Figs 14.22A and B and 14.27). This deformity, however, is
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Figs 14.22A and B: (A) Two siblings, aged 2 and 4 years respectively, reared as girls. The older one had already been operated on for bilateral hernias, and testes had been returned to the abdominal cavity from the inguinal canals. External genitalia identical. Chromosomal sex = XY in both cases. The height scale is in feet. The younger child was treated by removal of undescended testes, this being justified by the appearance of the external genitalia. (B) The external genitalia of the younger child. A very poorly developed phallus is associated with gross hypospadias and the split scrotum looks like labia majora except for strong evidence of a dartos muscle
not only familial but is often associated with cryptorchidism, the testes being hypoplastic. Is it testicular hypoplasia which results in non-descent or vice versa? And is the hypospadias the result of a failure in androgen secretion or of an inherent genetic defect in the target organ? Again, the male phallus may be underdeveloped and the scrotum split despite the presence of apparently normal testes (Figs 14.23A and B). A urogenital sinus component of vagina may or may not be present in association with testes, usually un-descended (Figs 14.21A to C and 14.24). This may be determined by sex chromosomal, genetic or hormonal factors with considerable interplay. Similar considerations apply to the development of postpubertal feminism in the male (for example, gynaecomastia) and of virilism in the female (for example, hirsutism). When these conditions go with an apparently normal sex chromosome make-up, an underlying factor may be weak or strong masculising genes on autosomes, unrecognised mosaicism or some fault in the Y chromosome of a 46,XY individual. Hypospadias is sometimes related to deletion of one
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small portion of the Y chromosome. As methodology becomes more refined more errors of this kind may come to light. PSYCHOLOGICAL SEX Many men and women psychologically dominated towards sexual inversion, a persistence of childhood tendency. a. Effeminate behaviour b. Speech c. Dress d. Sexual inclination Transvestism a. Male and female type b. Male type more common i.e. a male likes to wear female clothes and does not think he is a male. Transsexuality The person starts believing that he or she belongs to opposite sex i.e. mind trapped in wrong body.
Sex Determination, Asexuality and Intersexuality
Figs 14.23A and B: (A) The external genitalia of a child aged 9 months and registered as a girl. A poorly developed hypospadic penis is associated with a split scrotum. The presence of the gonads in the ‘labia’ strongly suggests that they are testes and this was confirmed by biopsy. Sex chromatin pattern negative; chromosome analysis not available at the time. Because the poor development of the phallus would have made life as a male inadequate, the penis and both testes were removed and the child continued to be regarded as a girl and developed well as such. (B) The same patient at the age of 14 years, attractive and feminine physically and psychologically; the bust has now been developed by giving oestrogens
Figs 14.24A to C: Cryptorchidism in a registered female, a common form of intersex. The patient concerned, aged 21 years, had been brought up as a girl but had never menstruated or developed a bust. Although not very muscular she became an outstanding ‘woman’ athlete. Slight facial hirsutism and voice change were noticed at the age of 20 years; the phallus had been enlarged as long as she could remember. Buccal smears were chromatin positive but the chromosome complement was not determined. The presence of testes almost certainly means the presence of a Y in the karyotype so XXY or a mosaic are possibilities, (A) The findings at laparotomy; testes present on each side of the pelvis and these have suppressed the persistence of any müllerian duct tissue, (B) The external genitalia appear female except for the large phallus; behind the urethral meatus is a vagina 3 cm in depth and this must represent the urogenital sinus component only, (C) Good development of the breasts resulting from 3 months’ treatment with oestrogen. Before this treatment, and in view of the weak masculinity and the woman’s strong desire to remain female, the gonads and the phallus were removed. This patient, as so often in cases of intersex, had had an operation for bilateral inguinal hernias in childhood. Oestrogen therapy caused a recurrence of the hernia on one side; this is a recognised reaction in these cases
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SEX OF REARING There are many males and females, brought up by their parents in the mistaken identity. They, over the years, acquire habits and mental inclinations of the opposite sex to such a degree as to pass as members of wrong sex. THE MANAGEMENT OF ABERRATIONS OF SEX PRESENT AT BIRTH Diagnosis The earlier in life that errors in sex differentiation are recognised and treated, the better are the prospects for the individual to find a satisfactory place in society. In examining every newborn it is important to look not only for skeletal and visceral deformities (which may give an immediate lead to a diagnosis of Turner syndrome) but for anomalies of the external genitalia. It is easy to be deceived by casual examination of these. The appea-
Fig. 14.25: The external genitalia of a child aged 3 months and registered as female. Her sex was questioned, however, because of the prominent phallus. Buccal smears were reported as being chromatin-negative and intersex associated with cryptorchidism seemed possible. It was decided to await further developments and, when the child was 1 year old the genitalia appeared normally female. At that time the chromatin sex was reported positive and the conclusion was that no abnormality existed. Slight enlargement or prominence of the clitoris is not uncommon in infancy and can be deceptive. Chromatin sexing can be unreliable, especially in recently born babies. Chromosome analysis was not available when this case was seen
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rances are not always easy to interpret and a normal clitoris is sometimes relatively large (Fig. 14.25). Evidence of dartos muscle in what seem to be labia majora suggests that they really represent a bifid scrotum. A median perineal raphe is a male characteristic. Whenever the sex is ambiguous, the chromosome pattern should be determined. Hormone assays of blood may help. At some stage, not in the newborn infant, ultrasound examination under general anaesthesia and laparoscopy may become necessary to discover the exact state of the genitalia. When as much information as possible is available and the parents of the child, or the patient if an adult, have been consulted, a decision is made as to the sex to be adopted permanently. In this, prevarication may be necessary for a short time in the case of a small infant, for not all diagnostic methods can be brought to bear at that stage. Investigations a. History • Familial • Drugs in pregnancy • Virilising symptoms in pregnancy • Operations in childhood • Amenorrhoea • Fertility if adult b. Examination • Height/span ratio (normal 1:1) • Special features e.g. cubitus valgus, webbing of neck • Secondary sexual characters • External genitalia • P/V if possible • Size of clitoris • Location of urethral meatus • Hymen • Length of vagina (blind pouch) • Masses in labia or inguinal canal • Hernia • Intelligence quotient (IQ) c. Tests 1. Sex Chromatin study • Barr body • Y fluorescence • Cyanophilic cytoplasm This can diagnose 95-98% aberrations of chromosomes.
Sex Determination, Asexuality and Intersexuality Chromatin + ve • True female hermaphroditism • Adrenal cortical hyperplasia • Mother receiving androgens Chromatin – ve • Male hermaphroditism • Testicular feminising syndrome • True hermaphroditism (very rare) 2. 17- Ketosteroids in 24 hours urine. Normal values are: Upto 10 days High 1 month 1 mg 1 year 0.5 mg 5 years 1 mg 7 years 1.5 mg 9 years 2 mg Adults 5-15 mg The values are excessively increased in adrenogenital syndrome. 17 ketosteroid can also be detected in amniotic fluid for prenatal diagnosis. 3. Adrenal stimulation/suppression tests 4. Ovarian stimulation/suppression tests 5. Vaginography/Vaginoscopy 6. Intravenous urography (IVU) 7. Gonadal biopsy 8. Laparoscopy 9. Exploratory laparotomy 10. Psychiatric evaluation Treatment of Intersex A. Principles 1. Sex of rearing should not be changed if possible 2. Careful counselling 3. It is easier to castrate a small penis or enlarged clitoris and convert to female genitalia. 4. Abnormal gonads hare a 4% risk of malignancy so should be removed. 5. Supportive hormone therapy 6. Counselling for sexual activity and fertility. B. Treatment may be 1. Medical 2. Psycological 3. Surgical Once the above decision is taken, efforts should be made to accentuate the agreed sex by surgery and by endocrine therapy. The girl suffering from CAH can be
made and kept female by a maintenance dose of adrenal corticoids and their substitutes, and by operations on the vulva. The treatment of hypospadias in an otherwise normal male is by plastic surgery. But in most cases in which there are anomalies and discrepancies, the sex of the individual is best allocated according to the secondary sex characters and especially the appearance of the external genitalia. If the hypospadiac phallus of the baby boy with undescended testes is so poorly developed that it can never be made to function sexually, the gonads and the phallus are best removed and the child then reared as a girl (Fig. 14.23). If the child with cryptorchidism and hypospadias has already been conditioned to femininity, then this management is appropriate even if the phallus is moderately well developed (Fig. 14.26). Indeed, when a condition of intersex first comes to light at or after puberty, the general rule is to mould the sexual apparatus to match the individual. The uterus and ovary found in an apparent man should be removed; similarly the testes discovered in an apparent girl. It is sometimes argued that it is unnecessary to remove undescended testes from a phenotypic girl, and that it may be undesirable in that they contribute to her hormone status. In my view their removal is generally indicated because: their hormone contribution is androgenic and, except in the case of the feminising testes syndrome, can cause hirsutism and voice changes at puberty; they may become the site of malignant disease. Even streak gonads in a patient with a Y chromosome can undergo tumour formation and it seems desirable, although probably not legally important, to remove male tissue before the individual is advised to live and marry as a woman. Psychologically, however, it is important that the nature of the gonad removed should not be revealed to the patient. A girl or woman can never accept that she can take her proper place in society if she knows that she has, or has had, a testis; it is enough for her to be told that her ovary(ies) is incompletely developed. Similarly, a man would be shattered to learn that he had had an ovary or uterus excised. In planning treatment, it is necessary to recognise that femininity is neutral and that masculinity is something positive which is superimposed. The removal of testes inevitably encourages subsequent femininity. Indeed, it is easier to make a good woman than a passable man. When testes are excised, the development of breasts and
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Figs 14.26A to D: A girl aged 12 years whose voice was beginning to deepen but without evidence of facial hirsutism. Karyotype = 46,XY, determined from cultures of skin and testicular tissue, (A) The figure is rather masculine but the breasts are beginning to enlarge; the patient’s interests and outlook were feminine, (B) The external genitalia showing a male phallus with hypospadias and dartos muscle activity in the split scrotum; the sound marks the urethra. Testes were in the inguinal canals and there was no evidence of vagina, uterus or tubes. The gonads and the phallus were removed and the patient treated with oestrogens. (C) A more feminine figure and good breast development 6 months after operation and commencement of oestrogen therapy, (D) The ‘Vulva’ 6 months after operation
feminine traits is encouraged by the administration of oestrogens at and after the normal age of puberty (Figs 14.23 and 14.26). This treatment, however, when it follows the removal of undescended testes, commonly causes inguinal hernia formation (Fig. 14.24). It is therefore important to close the inguinal canals at the time of orchidectomy. The timing of operative treatment is also important. The removal of the phallus from a ‘girl’ should, if possible, be performed before she is aware of its presence. This means before the age of 5 years, and some would say 2 years. Testes are best excised before the age of 14 years. ‘Girls’ from whom testes are removed commonly have a urogenital vagina of good dimensions and this permits satisfactory coitus and successful, if infertile, marriage. If a vagina is not present, an artificial one can be created if the circumstances justify it. Once an individual is conditioned to living as a member of one sex, he or she finds it extremely difficult to adjust to the other. So when an older child or an adult is found to have been reared contrary to the nature of the gonad or other sex characters, it is rarely wise to advise a change in sex. The result is often one of misery (Figs 14.27A to D). The only cases in which a late change in sex is ever successful are those in which the genital
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apparatus is such that, with the new sex, the individual is capable of a normal married life and preferably of reproduction too. Although converting a female to a male is technically more difficult, it has been done successfully. The phallus is fashioned out of flaps rotated down from the anterior abdominal wall and inflatable prostheses are inserted to make it functional. The Klinefelter and YY syndromes have no specific treatment. Aplastic testes cannot be stimulated to produce spermatozoa but, if the interstitial cells are also defective, replacement therapy with testosterone is indicated. The girl suffering from Turner or other syndromes associated with streak gonads can never be made fertile but, when she reaches the age of puberty, can have her secondary sex organs and characters developed by replacement therapy with oestrogens and progestogens in the form of the oral contraceptive pill, or sequential conjugated oestrogens with progestogens. Such treatment needs to be continued for 1-3 years, depending on how well the breasts develop. Subsequently, if treatment is discontinued, amenorrhoea returns, but the bust measurement does not usually go down even though the mammary gland atrophies (Fig. 3.16). In these
Sex Determination, Asexuality and Intersexuality
Figs 14.27A to D: Hypospadias and cryptorchidism in an otherwise normal male. This individual was reared as a girl and was first seen at the age of 17 years when she complained of primary amenorrhoea and hirsutism. The voice was then deep and she walked with a manly stride. Her father had had three operations for hypospadias. When the true state of affairs was elucidated, this person elected to change sex and she was re-registered as a male. He subsequently had four operations for hypospadias and married. The outcome was a failure for he proved both impotent and sterile, (A) The external genitalia. (B) Facial acne and hirsutism. (C) Individual dressed as a girl, (D) After being re-registered as a man; one month’s interval between (C) and (D)
women, marriage should be preceded by further courses of hormone replacement therapy or low-dose contraceptive pills to overcome vaginal atrophy and thus permit the establishment of coitus. However, there is a definite place for continuation of hormone replacement therapy on a long-term basis to prevent osteoporosis and other problems of oestrogen deficiency. The extragenital deformities found in Turner and allied syndromes are treated according to their nature and the degree of disability they cause. The possibilities include plastic surgery for the webbing of the neck, correction of bony deformities and cardiac surgery. Little more than advice is needed for the woman suffering from the triple-X syndrome. The ovaries are likely to be refractory but it is nevertheless reported that they can sometimes be made to ovulate by treatment with gonadotrophins. SPECIALISED TREATMENT SCHEDULES
iii. Gonadectomy must be done after puberty iv. Hauser has recommended no gonadectomy. According to him gonadectomy converts symptomless individual to menopausal individuals. According to him risk of malignancy is 10% and is so after the age 40. Male Hermaphroditism i Treatment depends on the degree of development of the phallus ii. In the presence of a well developed phallus they are reared as males. iii. In the absence of a well developed phallus, they are reared as females by excising the enlarged clitoris and a gonadectomy before puberty, i.e., before masculinisation. iv. Vaginoplasty or separation of labioscrotal folds v. Maintenance with female hormones.
Testicular Feminisation Syndrome
True Hermaphroditism
i. Reared as female ii. Gonadectomy is a must as the testes have a high chance of malignancy
i. Corrective surgery ii. Medical therapy. Corticosteroids are given to reduce the increased ACTH levels
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Jeffcoate’s Principles of Gynaecology iii. Corticosteroids are given at high doses and then tapered according to 17-KS levels iv. The dose is adjusted to the lowest level to avoid complications v. Medical therapy stops further adrenal hyperplasia and masculinisation vi. If of the salt-losing type then treatment is given with deoxycorticosterone. Turner’s Syndrome
Possibility of ovarian transplantation may impart fertility and natural endogenous hormones for phenotypic development. Principles of Surgical Therapy 1. Clitoris should be excised in infancy either total or partial. This may lead to loss of orgasm. 2. Division of perineal body can be done later on 3. Treatment of major urogenital abnormalities 4. Reconstructive surgery – Vaginoplasty 5. Ablative surgery – Gonadectomy – Phallectomy – Septum removal 6. Curative surgery – Adrenalectomy – Gonadectomy
Fig. 14.28: A male suffering from unilateral gynaecomastia of unknown cause (Mr J.M. Leggate’s case)
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INTERSEX DEVELOPING AFTER BIRTH Sex differentiation after birth is controlled by hypothalamic-pituitary, thyroid, adrenal and gonadal hormones as well as by inherent genetic forces. Any disturbances in the functions of these glands, due to a genetic taint or to acquired disease, can modify the sexual apparatus and behaviour of the otherwise normal male and female. The development of feminine traits in the male is called feminism, that of masculine traits in the female, virilism. FEMINISM Manifestations
Sex Organs Feminine features appearing after birth include failure of the testes to descend or develop, hypoplasia of the phallus and gynaecomastia. Galactorrhoea can, but usually does not, accompany gynaecomastia. Gynaecomastia can occur without genital aberrations and may be unilateral or bilateral (Figs 14.28 and 14.29).
Fig. 14.29: Gynaecomastia which developed rapidly in a man aged 50 years. The cause proved to be the application of an oestrogenic ointment for pruritus ani; only two tubes were used to produce this effect
Sex Determination, Asexuality and Intersexuality
Secondary Sex Characters Feminism is indicated by a feminine figure with poor muscular development, broad hips and narrow shoulders, a characteristic gait, a high-pitched voice, a smooth skin with a weak growth of hair on the trunk and face.
Personality and Outlook Caution is necessary in regarding these as sexual characteristics since they depend largely on fashion and custom in a particular community (see below).
Libido Heterosexual impulses may be weak or absent and the man may be impotent. Homosexuality and transsexuality are extreme examples of abnormal libido (see Chapter 45). Causes
Physiological Slight gynaecomastia (often familial) is common in pubertal and adolescent boys but disappears in 1½ years. It is caused either by increased hypothalamic-pituitary activity or by temporary hyperoestrogenism resulting from disturbed metabolism of androgens.
Genetic and Constitutional An inborn weakness of masculinising genes explains some disorders of behaviour and personality. It can also account for a weak beard, high-pitched voice and failure of the phallus to develop at puberty. This is because the sensitivity of target organs to sex hormones is determined genetically.
Psychological Many examples of effeminate behaviour and appearance have an entirely psychological basis. Transvestism and trans-sexuality are gross forms (see Chapter 45).
Androgen Deficiency Hypoplasia, injury, disease and removal of either the adrenals or the testes can cause feminism. If the testes are removed before puberty the resulting eunuch has a tall feminine figure, soft hairless skin, a high-pitched voice, and weak or absent heterosexual interests. The
effect of castration later in life is less obvious but gynaecomastia is recorded as a sequel. The undescended testis or the one damaged by orchitis usually preserves its endocrine function even though it does not produce spermatozoa.
Oestrogenism Excessive production of oestrogen is a possible explanation of the rare cases of feminism associated with adrenal cortical tumours and hyperplasia. The administration of oestrogens to the male inhibits testicular activity, suppresses sex drive and causes gynaecomastia (Fig. 14.29). Feminism is also some-times seen when the liver is damaged by disease or by malnutrition: this is because the liver is no longer able to inactivate oestrogen normally secreted by the adrenal. Gynaecomastia in association with raised blood oestrogen levels is described as a complication of refeeding after starvation, pulmonary tuberculosis, chronic renal failure, renal dialysis, psoriasis, eczema and bronchogenic carcinoma. In the case of the last, the tumour itself can secrete oestrogens, and some-times other hormones including gonadotrophins.
Diseases of the Pituitary, Hypothalamus and Midbrain; Hyperthyroidism When these cause feminism they do so by suppressing the androgen production of the adrenals and testes, or by increasing the oestrogen secretion of the adrenals.
Drugs Testosterone and other androgens, by being metabolised to oestrogens, can cause gynaecomastia in young boys. This condition is also seen following the administration of gonadotrophins for cryptorchidism, and of drugs such as reserpine and phenothiazine derivatives which act on the hypothalamus. Digitalis and methyldopa are also reported causes. Treatment This varies with the cause of feminism and its manifestation. Oestrogenic tumours can be removed, cryptorchidism and gynaecomastia may require surgery. An androgen deficiency can be made good by giving testosterone, but this hormone is of little value when the cause of feminism is constitutional, psychological or a genetically determined insensitivity of the target organs.
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Virilism
Manifestations Because of variations in the sensitivity of target organs, these can occur singly or in various combinations. This sensitivity may depend on a high or low capacity of the local tissues to convert testosterone to its active end product which mediates cell response.
Sex Organs Hypertrophy of the clitoris, and hypoplasia or atrophy of the breasts and the genital tract, are the main evidences of acquired anatomical virilism (Figs 14.30A to D). Functional virilism includes amenorrhoea, infertility and failure to lactate.
Secondary Sex Characters Virilism is indicated by coarse features, acne, a heavy angular build, well-developed muscles, broad shoulders and narrow hips with a striding gait. Exceptional athletic skill, especially in those sports which involve throwing, can betoken masculinity. Many international women athletes have been virilised females or congenital intersexes, and some have been disqualified on this account. Other signs of virilism are a prominent larynx (Adam’s apple) and a deep voice.
Hair A growth of hair over the triangle between the pubes and the umbilicus is said to be a masculine trait but occurs in approximately one-third of all women. It carries no special significance. Similarly, a slight down on the upper lip and on the arms and legs is as much a female as a male characteristic. The first is found in 25 per cent of young normal women, and in 40 per cent of those aged more than 40 years. Seventeen per cent of normal women aged 18-25 years have hair on the chest and breasts. The more important signs of virilism are hirsutism affecting the beard area and back; a heavy growth of hair on the arms and legs; eyebrows which extend over the bridge of the nose; hair in the nostrils and ears, and on the dorsal aspects of the toes; baldness of the scalp. Significant hirsutism is accompanied by thickening of the affected skin whose collagen content is increased (male features). The sweat-gland response is also masculine. So hirsutism is sometimes called cutaneous virilism.
Personality and Outlook Under this heading come a forceful manner, a weak maternal instinct, disregard for appearance and dress, and an assumption of male attire and habits. In respect of the last, it is a fashion in many communities for normal girls and women to assume what is sometimes
Figs 14.30A to D: Postnatal adrenogenital syndrome caused by an adrenal tumour. Woman aged 31 years complaining of primary amenorrhoea and hirsutism. Genitalia infantile except for enlargement of the clitoris. An adrenal cortical adenoma was found and removed; thereafter menstruation became established spontaneously in 3 months, (A) Before operation (abdomen and pubes shaved). Note the masculine figure and enlargement of the clitoris, (B) Three months after operation and without hormone therapy. The breasts are now well formed and increased modesty is indicated by the patient’s refusal to be photographed nude, (C) Before operation, showing the growth of hair on the face; the hair on the chin and upper lip had been removed with a razor, (D) Facial appearance one year after operation. The growth of hair on the face ceased only very slowly and, at the time of photography, this woman still had to shave, although infrequently
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Sex Determination, Asexuality and Intersexuality regarded as the traditional masculine role and dress, whilst their husbands and brothers adopt ‘female’ hair styles and clothing, and share with them domestic and parental duties. This move towards ‘unisex’ merely emphasises that many of the sexual differences in behaviour and outlook are the creation of society and are not inherent.
Libido Heterosexual impulses are weak or absent. The virile woman is usually asexual although likely to have platonic friendships with those of her own sex. Frankly homosexual desires and activities are sometimes regarded as virilism. Causes
Constitutional Virilism of a minor degree is usually an inherent constitutional trait (see Fig 14.13); hirsutism and a masculine build, for example, show strong familial and racial tendencies. Hirsutism by British standards is general amongst women of Mediterranean races. The Chinese, however, have little body hair. The majority of the large number of women who seek advice for facial hirsutism have no gross endocrine disturbance; their only trouble is that they have hairy parents, or parents with hairy brothers and sisters. They generally have good menstrual and reproductive functions and assessment of ovarian and adrenal function proves normal. Their problem is undue sensitivity of hair follicles to normal amounts of androgen. If the onset of hirsutism is acute, or associated with masculinisation, the androgen excess might be due to a functional tumour of the ovary or adrenal glands (see below).
Psychological Masculine trends in outlook and behaviour are often of psychological origin. For one reason or another there is a conscious or subconscious determination to suppress or deny the female sex, and this sometimes amounts to overt transvestism and trans-sexuality.
Oestrogen Deficiency Failure of the ovaries to function, or removal of the ovaries, results in genital hypoplasia or atrophy but does not lead to positive virilism.
Excessive Androgen Stimulus
The Administration of Androgens Testosterone and danazol therapy in women, unless carefully controlled, causes facial hirsutism, amenorrhoea, atrophy of the breasts and uterus, and deepening of the voice. The last is permanent, hirsutism may persist but the others disappear when treatment is suspended.
Adrenal Androgenic tumours of the adrenal cortex, which may be benign or malignant, cause a postnatal adrenogenital syndrome which is biochemically different from the congenital one. The manifestations are also different in that the genital organs are normally formed before being exposed to an excessive androgen stimulus. However, the clitoris enlarges, menstruation and follicular ripening are suppressed (Fig. 3.11), the breasts and uterus remain infantile or undergo atrophy, and there are the usual manifestations of virilism including personality changes (Figs 14.30A to D). The types of tests used in the diagnosis of virilism are to measure the concentration of some or all of the following: DHEA, DHEA sulphate (DHEAS), testosterone (free preferable to total) and androstenedione by radioimmunoassay techniques in the peripheral circulation. Adrenal tumours generally produce elevated plasma DHEAS levels which are not suppressed with high doses of dexamethasone. Methods such as IVP, ultrasonography and computerised tomography (CT scan) may demonstrate these tumours. The adrenogenital syndrome developing in; childhood (not having been present at birth) is always caused by a tumour. After puberty, however, it may be due to so-called postpubertal adrenal cortical Hyperplasia, a condition which is probably not different from constitutional virilism associated with evidence of minor changes in adrenal function. The clinical picture presented is less dramatic than that produced by an adrenal tumour from which adrenal hyperplasia is distinguished by the facts that: it does not usually suppress menstruation completely; it results in excretion levels of 17-ketosteroids (usually less than 50 mg/24 hours); and this level can be raised by giving ACTH and lowered by dexamethasone. Because of the adrenal response, severe burns and other stresses sometimes initiate hirsutism. In Cushing’s syndrome (Fig. 37.8), hirsutism and oligomenorrhoea are associated with a rapid increase in
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Jeffcoate’s Principles of Gynaecology weight, striae formation, hypertension, polycythaemia, and hyperglycaemia. These reflect a disturbance in the output of sex hormones and corticosteroids by the adrenal. The urinary excretion of 17-ketosteroids is moderately raised and that of 17-hydroxycorticoids grossly raised. Plasma cortisol levels are assayed in the late evening and after a single-dose overnight dexamethasone suppression (1 mg at 11 pm). If plasma cortisol is less than 5 μg/dl it is normal, whereas if it is greater than 10 μg/dl it is diagnostic of adrenal hyperfunction. An abnormal result can be confirmed by the 2-day low-dose dexamethasone suppression (0.5 mg 6-hourly) test. Twenty-four-hour urinary 17-hydroxysteroids and free cortisol can be assayed together. The cause is often a primary adrenal disorder. A malignant or benign tumour may be present but sometimes there appears to be nothing more than an oversensitivity of the gland to normal amounts of ACTH. The anterior pituitary may show a predominance of basophil cells (pituitary basophilism) but this is probably the result rather than the cause of the adrenal upset. Occasionally, however, the syndrome is caused by a primary hypothalamic or pituitary lesion. A true Cushing’s syndrome is quite rare. Many suspected cases prove to be nothing more than fat and slightly hairy women with oligomenorrhoea but without a demonstrable gross endocrine disturbance. This picture is sometimes labelled ‘Cushingoid’. Other conditions associated with this presentation include alcoholism, response to stress, anorexia and bulimia nervosa.
Ovary Certain rare tumours of the ovary such as the androblastoma and the hilus cell tumour are androgenic. They usually occur in young adults and cause enlargement of the clitoris, suppression of menstruation, hirsutism, acne and voice change. These features are not associated with an increase in the output of 17ketosteroids but if the serum testosterone level is above 1.5 ng/ml the possibility of an ovarian tumour should be considered. Secondary malignant deposits in the ovaries can also make these organs androgenic. The Stein-Leventhal syndrome was characterised by oligomenorrhoea, infertility, heavy build and hirsutism in association with polycystic ovaries. This condition is now recognised to be part of a spectrum of clinical manifestations, termed the polycystic ovary syndrome (PCOS) (see Chapter 37). Insulin resistance and
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hyperinsulinaemia are recognised correlates and are exacerbated in the presence of obesity. Using pelvic ultrasound, polycystic ovaries are seen in up to 20 per cent of normal women and in higher numbers in those with evidence of hyperandrogenism, e.g. acne, hirsutism and alopecia. The cause is an error in hormone biosynthesis in the ovary although an adrenal component for the hyperandrogenism is also suggested. The theca cells are increased in number and also produce an excess of androstenedione per cell. Determination of the folliclestimulating hormone (FSH) and luteinising hormone (LH) levels may help to confirm the diagnosis of polycystic ovaries. These are assayed on the second or third day of the cycle. FSH levels may be normal or slightly low whereas LH levels are raised leading to a reversal of the normal FSH:LH ratio. In fact, LH levels may be 3 to 4 times those of FSH. Serum testosterone, androstenedione (AH) and dehydroepiandrosterone sulphate (DHEAS) levels may also be increased whereas sex hormone binding globulin (SHBG) level is decreased. Ultrasound shows enlarged ovaries, with multiple cysts 6-8 mm in diameter arranged around the periphery, and stromal hyperplasia. At laparoscopy, these plump ovaries have a thickened capsule with multiple follicles.
Diseases of the Pituitary, Hypothalamus, Midbrain and Base of Skull These conditions can produce a measure of virilism by way of their effect on the adrenal or gonad. Acromegaly, for example, is characterized by angular masculine features, heavy build, amenorrhoea, voice change, loss of libido and atrophy of the breasts and uterus (Fig. 38.1). It is not infrequently mistaken for the adrenogenital syndrome. Prolactin-secreting tumours can have the same effect.
Drugs Apart from androgens, other hormones and drugs such as ACTH, progestogens, corticosteroids and anabolic agents can sometimes cause virilism. Diagnosis Successful treatment depends on finding the cause of the virilism. This can sometimes be determined by clinical methods. Vaginal examination, for example, may reveal a palpable ovarian tumour. Generally, special
Sex Determination, Asexuality and Intersexuality investigations are necessary: hormone assays — measurement of serum testosterone, sex hormonebinding globulin, FSH, LH, AH, DHEAS, 17-OHP; studies of the effects of giving adrenal cortical stimulators and depressants; electrolyte and metabolic studies, radiographs of the sella turcica; CT scanning and ultrasonography of the pelvis, and intravenous pyelography (Figs 14.31A and B); selective catheterisation of the adrenal veins for hormone assays; pelvic examination under anaesthesia and laparoscopy. Treatment
Surgical Removal of androgenic tumours of the adrenal and ovary results in reversal of all signs of masculinity except deepening of the voice (Figs 14.30A to D). The effect is not always as dramatic as might be expected in that the hirsutism subsides only slowly over the course of many months or years; the clitoris may also never revert completely to normal. Both ovarian and adrenal androgenic tumours may be malignant so the ultimate result is not always good from the stand-point of life and health. For adrenal cortical hyperplasia and for Cushing’s syndrome, partial adrenalectomy gives unsatisfactory
results. If a primary pituitary lesion can be excluded, and if the condition is sufficiently serious, total bilateral adrenalectomy followed by substitution therapy is sometimes practised. In the case of polycystic ovaries, treatment depends on whether the patient desires conception or not. For those desirous of procreation, induction of ovulation should be tried (see Chapter 5). In women who do not want conception at the time of presentation, oral contraceptive pills are the treatment of choice. Wedge resection of the ovaries, sometimes advocated in the past as treatment for PCOS, never improves hirsutism even if it is followed by cure of other symptoms. This procedure has now been replaced by laparoscopic ovarian drilling and is done only if medical induction of ovulation fails. Its effects are usually temporary.
Medical If drugs are the cause of virilism they are discon-tinued. Mild acne requires only regular washing with soap and water or with lotions containing chlorhexidine. If it does not respond, local nightly applicaiton of preparations containing benzoyl peroxide and retinoic acid is advised. For severe acne, antibiotics for at least 3 months (or longer, if necessary) are advised.
Figs 14.31A and B: Radiological demonstration of an adrenal tumour, (A) Intravenous pyelography shows distortion and downward displacement of the right kidney, (B) A retroperitoneal pneumogram in the same case outlines the tumour; this sort of investigation is not without risk and has been superceded by ultrasonography, CT scan and selective catherisation of the adrenal veins for hormone assays
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Hormonal
Oestrogen Although it is the ‘female sex hormone’, oestrogen never completely overrides an androgen effect. It is used, alone or in combination with progestogens, and is effective in decreasing adrenal and ovarian steroid production and reducing hair growth in two-thirds of hirsute patients. Combined oral contraceptive pills containing ethinyl oestradiol with desogestrel or gestodene have been found to be useful in mild hirsutism.
Medroxyprogesterone Acetate It decreases gonadotrophin-releasing hormone production (GnRH) production and gonadotrophin release and therapy decreases testosterone and oestrogen levels. It can be administered orally (20-40 mg daily in divided doses) or intramuscularly (150 mg of the depot form every 6-12 weeks) with excellent results in decreasing hair growth.
GnRH Agonists Leuprolide acetate intramuscularly every 4 weeks decreases hair growth and diameter in idiopathic hirsutism and in hirsutism with PCOS. Add-back therapy with oral contraceptives or conjugated oestrogen prevents bone loss, vasomotor symptoms and genital atrophy.
Corticosteroids Dexamethasone can be tried in cases of postpubertal adrenal cortical hyperplasia and PCOS. The rationale is an attempt to depress the output of ACTH by the pituitary. Low doses of 0.25 mg daily improve hirsutism and acne. Serum cortisol should be monitored.
Antiandrogens Cyproterone acetate: A synthetic antiandrogen drug such as cyproterone acetate, which has progestational as well as anti-androgenic and antigonadotrophic properties, can be used. It is widely used but is not always effective and hirsutism may recur after the therapy is stopped. For mild androgenic states, e.g. acne, it is given in a dose of 2 mg per day combined with ethinyl oestradiol. This serves the dual purpose of regularising the menstrual cycle as well as preventing conception during therapy as it is teratogenic. In severe cases of hirsutism with PCOS
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it is given in a dose of 50 to 100 mg from day 5 through 16; ethinyl oestradiol is given from day 5 through 26 in a dose of 30 to 50 μg. The maximum dose of cyproterone acetate is 300 mg per day. Spironolactone: This mineralocorticoid antagonist has a beneficial effect on hirsutism without serious side-effects but is ineffective for the other signs of virilism. It acts by competitive inhibition of dihydrotesto-sterone at the intracellular receptor level, suppression of testosterone biosynthesis and increase in testo-sterone catabolism. It improves hirsutism when taken in a dose of 100 mg for 6 months but side-effects include menstrual irregularity, nausea, fatigue, scalp hair loss, mastodynia and urticaria. A contraceptive must be used because of the possible risk of feminising a male foetus. Its use for the treatment of hirsutism has not been approved in the USA and UK. Flutamide: This is a nonsteroidal antiandrogen which is a weak inhibitor of testosterone biosynthesis. It can be added to oral contraceptives when patients do not show any benefit with the latter alone. It is administered in a dose of 250 mg tds. Side-effects include dry skin, hot flushes, decreased libido, breast tenderness, fatigue, nausea, dizziness and haepato-toxicity. Finasteride: This is a new follicular 5 α-reductase inhibitor currently under evaluation. It is administered in a dose of 5 mg daily. Finasteride can cross the placenta.
Cosmetic This is indicated mainly in cases of hirsutism without a definite organic cause, and these comprise the majority. It is also often a necessary supplement to more definitive treatment. If the hair growth is slight, nothing more than bleaching may be required. Otherwise, the superfluous hair is best removed by means of a depilatory wax, a razor or pumice stone. After centuries of experience, men know that shaving is the most efficient method but women are prejudiced against it, often because they have heard tell that it encourages a stronger growth of beard; this is not true. Electrolysis is painful and leaves scars. Thermolysis and laser epilation give better cosmetic results. The new chemical depilatories (destroyers of hair) are, unlike the older ones, relatively harmless to the skin and can be useful. In the form of pastes or creams they commonly contain mercaptans as the active principle as these act in the presence of an alkaline material.
15
Injuries
CHAPTER
Foreign Bodies in the Genital Tract Vaginal Burns Direct Trauma to Vulva and Vagina Defective or Deficient Perineum Complete Perineal Tear Laceration of the Cervix
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Rupture and Perforation of the Uterus Broad Ligament Haematoma Genital Tract Fistulas Acquired Atresia and Stenosis of the Genital Tract
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FOREIGN BODIES IN THE GENITAL TRACT Vagina
Types and Sources An extraordinary variety of foreign bodies may be found in the vagina. Sometimes the patient knows that the object is there but is unable to remove it by reason of its size and shape, or deliberately neglects it. More often she is unaware of its presence, having forgotten it or not knowing that it has been inserted.
Therapeutic Agents Packs and dressings of various kinds may be left in the vagina after operation or treatment. Packs or swabs are most commonly left after taking cervical biopsy. The swab used to wipe the urethral orifice, and thereafter to hold the labia apart, for the purpose of catheterization is easily overlooked and can slip into the vagina. Instruments such as supporting pessaries can be retained for many years. Among primitive peoples nuts, seeds and plant leaves are put into the vagina for supposed medicinal effect. These have even been recovered from the peritoneal cavity, having presumably reached it through the posterior fornix or through the uterus and tubes.
Contraceptive Devices These include sponges, occlusive caps, and even condoms which have slipped off without the woman’s knowledge during coitus.
Articles Inserted by the Patient or Entering Accidentally Under this heading all manner of household utensils are recorded - glass jars, serviette rings, tin cans and metal piping. Sticks can also be found sometimes
Jeffcoate’s Principles of Gynaecology embedded in the vagina. In these cases the patient is often mentally deranged or sexually perverted. Children insert toys, sweets, hairpins and the like into the vagina and do so mainly out of curiosity. Accidental inclusions such as small stones and fragments of clothing are found in baby girls.
Instruments for Inducing Abortion and Labour Laminaria tents, bougies and catheters have all been left behind. The instruments of the criminal abortion-ist are even more likely to be lost or overlooked.
Articles of Toilet and Hygiene The most important example under this heading is a forgotten menstrual tampon; douche nozzles have also been found in the vagina.
Vaginal Calculus Stone formation in the vagina is exceptional but occurs under two conditions: in an accessory ureter or a diverticulum of the urethra; or around a foreign body such as suture material or cotton wool (Fig. 15.1).
quickly lead to local infection and a stinking discharge. Perforation, abrasion, pressure necrosis and local vaginitis result in ulceration of the vaginal walls; this can involve neighbouring structures to cause urinary and faecal fistulae. Infection may spread to produce salpingitis and peritonitis. Sometimes the foreign body becomes embedded with the vaginal wall closing over it. Carcinoma of the vagina is a late sequel. In all cases the predominant symptom is an offensive discharge which is often bloodstained.
Treatment The foreign body must be removed. This may be easy although, in young children, some form of narrow lighted endoscope is required. In certain cases where the article is sharp or of unusual size and shape, or where the lower vagina has undergone senile contracture, there is considerable difficulty and general anaesthesia may be required. Once the foreign body is removed, the vaginal wall heals by itself although cleansing and antiseptic douches help to reduce the odour and to clear up the infection more quickly. Uterus
Effects The effect of any object varies with its nature and shape. Articles made of rubber are very irritant; those made of inert materials such as plastic, porcelain and man-made fibres may cause little trouble. Cotton and woollen fabrics
Fig. 15.1: A vaginal stone, 4 cm in length, passed spontaneously from a bed in the lateral wall of the vagina. It contains a nucleus of fabric material the origin of which is not easy to understand. The only operation which the woman concerned had had was laparotomy for ectopic pregnancy 23 years previously. (Mr H. H. Francis’ case)
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Types and Sources Foreign bodies may remain in the uterus after operations. Sometimes gauze packs are deliberately inserted by the surgeon and their subsequent removal overlooked. Sometimes the woman herself inserts an object with the idea of preventing or terminating pregnancy. One patient who had intractable uterine bleeding was ultimately treated by hysterectomy; a match stick, presumably inserted by the woman herself, was found in the uterus (Fig. 15.2). Rarely an IUCD may be found years after insertion. The most common forgotten IUCD is the Lippes loop which on occasion has been first detected in hysterectomy specimens (there have been instances of IUCD insertion particularly immediately postpartum without the patients knowledge. Sometimes because of sheer convenience of the device, the patient may conveniently forget the presence.
Effects Mechanical irritation of the endometrium leads to infection, ulceration and possibly to cancer. Leading
Injuries Instruments and needles broken during operation are more often lost in the tissues of the cervix or of the perineum. A perineal sinus after perineorrhaphy often has unabsorbed suture material as its root. This is rarely seen nowadays with the use of delayed absorbable sutures. VAGINAL BURNS Causes
Fig. 15.2: A match stick in the uterus of a woman, aged 32 years, treated by hysterectomy for ‘dysfunctional uterine bleeding’. She probably inserted it as a means of contraception. The patient was previously treated by curettage twice and even had abdominal hysterotomy carried out without any foreign body being found. (Mr C.H. Walsh’s case)
symptoms are menorrhagia, discharge and dysmenorrhoea.
Treatment The diagnosis usually depends on the history and investigations, such as ultrasound, hysterogram or hysteroscopy. Once the object is known to be present it can usually be removed with forceps or with a small blunt hook after dilating the cervix. Occasionally an embedded object may require hysteroscopy-guided removal. Other Organs and Tissues Sometimes an object alleged or known to have been inserted cannot be found in the vagina or uterus. Leaving aside the special problem of the displaced intrauterine contraceptive device, the likely sites for foreign bodies are the bladder, or the broad ligament and the peritoneal cavity which are entered through a tear in the vaginal fornix or in the wall of the uterus. Cystoscopy, laparoscopy, ultrasound and radiography are indicated in these circumstances. A foreign body in the female bladder can sometimes be palpated bimanually and can often be removed through the urethra using an operating cystoscope. One in the peritoneum may be retrievable by means of a laparoscope.
Vaginal burns can be caused by the following: • Douching with fluid of too high a temperature • Clumsiness and errors in using the electric cautery, diathermy, cryoprobe or laser • Chemicals. Burns result from: an idiosyncrasy on the part of the patient to antiseptics and contraceptives; in the past, douching with too strong a solution of preparations containing cresols and phenols (Fig. 15.3); or the deliberate insertion of caustics. Potassium permanganate tablets and crystals have an unwarranted reputation as abortifacients and extensive punched-out ulcers of the vagina result from their use. In Arab countries the ritual placing of rock salt into the puerperal vagina causes severe chemical burns. The object of this practice is said to be the restoration of the vagina to its nulliparous dimensions. • Radium and deep X-rays. Effects The effects vary from relatively innocuous superficial burns to extensive lesions resulting in denudation of large areas of the vaginal wall (Fig. 15.3), deep ulceration, cellulitis and fistula formation. Healing can lead to adhesions, scarring and stenosis of the vagina and adjacent cervix. Sequelae to these include haematocolpos and obstructed labour. Treatment Rest in bed is important for resolution of the inflammation; douches with warm saline solution or applications of an emulsion of acriflavine in liquid paraffin may also help. Instillations of hydrocortisone ointment offer the best means of limiting tissue reaction and fibrosis. Residual scar tissue may require dilatation or plastic surgery.
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Fig. 15.3: A piece of vaginal epithelium which sloughed following a self-administered douche of a strong antiseptic solution
DIRECT TRAUMA TO VULVA AND VAGINA Abrasions from Clothing See chapter 20. Cuts and Lacerations
Accidents Cuts and lacerations of the vulva and vagina are frequently sustained in accidents involving fractures of the pelvis or falling and sitting on sharp objects. They may also result from careless use of instruments during obstetric manoeuvres and during attempts to induce abortion. Adjacent structures such as the urethra, rectum, bladder and pouch of Douglas may also be involved. Treatment usually consists of cleansing the damaged tissues under general anaesthesia, immediate suture and the prophylactic administration of antibiotics. In certain circumstances antitetanus serum may be indicated. Where young children are concerned, surgical access to the upper vagina can be very difficult. Rupture of the posterior vaginal fornix is also reported as a consequence of an accidental forced ‘douche’ resulting from a fall during water skiing. Girls and women engaging in this sport should wear a strong vulvar protective.
Coitus Tearing of the hymen is almost inevitable with defloration and is sometimes accompanied by a small tear in
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the fourchette. These generally cause slight bleeding which ceases spontaneously. Occasionally a rather large vessel is torn and can bleed so profusely that the woman becomes exsanguinated to the extent of requiring blood transfusion. Such bleeding can ordinarily be controlled by keeping the patient recumbent and by applying direct pressure to the bleeding point. If these measures do not stop the bleeding, then ligation or suture is often necessary. Rough coitus (including rape) can result in serious tears involving the perineum, vaginal wall, bladder and rectum. These are most likely in young virgins and in old women with atrophied tissues; the subject may be drunk and insensitive at the time. Coital rupture of the vaginal vault is seen particularly after total hysterectomy and can include the pelvic peritoneum to cause shock, prolapse of intestines and peritonitis. Such injuries require immediate investigation under general anaesthesia to determine the extent of the damage; they are treated by primary repair according to the findings.
Spontaneous Rupture of the posterior fornix, or of the posthysterectomy vaginal vault, involving the peritoneum above, can also occur spontaneously, being precipitated by a violent increase in intra-abdominal pressure during straining or coughing. It happens in old women with atrophic tissues. The effects and treatment are similar to those described above.
Childbirth Some degree of laceration of the vaginal wall, perineum, vulvar skin and underlying tissues accom-panies the delivery of 70 per cent of first babies. A special and rare form of circular tear, resulting in partial avulsion of the uterus from the vagina, is termed colporrhexis. The prevention and treatment of these injuries is covered by textbooks on obstetrics. Their after effects are considered below. Haematoma of the Vulva and Vagina Haematoma formation can result from a knock or a fall but is mostly seen in connection with childbirth. In the latter circumstance it can arise spontaneously to become manifest either during labour or within a few hours or days after labour. Vulvar and vaginal varicosities are said to predispose to this lesion but they did not play a part
Injuries in any of the cases which I have seen. The source of the bleeding is usually arterial. The commonest cause of vulvovaginal haematomas is inadequate haemostasis during closure of tears and incisions. A deep-seated paravaginal haematoma can also be a complication of pudendal nerve block. A vulvar haematoma presents as a painful, tender, purple-coloured swelling but, when it lies deeper and there is no skin bruising, it can be mistaken for a Bartholin’s gland tumour. A low paravaginal haematoma tracks to the vulva, a high one can spread upwards retroperitoneally. The direction of spread is determined by whether the bleeding occurs below or above the attachment of the pelvic diaphragm to the vagina. A retroperitoneal haematoma forms a tumour which is often palpable abdominally. General systemic upset and shock out of all proportion to the blood loss are striking clinical features of most cases. I have seen several ‘near deaths’ as a consequence of inadequate suturing of obstetrical tears of the vagina. Treatment is urgent. The tumour should be incised as soon as possible, the blood clot evacuated, bleeding arrested, and the cavity obliterated by careful suturing. Only if it is impossible to secure haemostasis should packing or drainage be employed, for this leads to prolonged convalescence and much scar formation. Conservative treatment is rarely wise, and then only when the haematoma is inaccessible.
case the introitus gapes and the vaginal walls are exposed (Fig. 15.4). The weak perineal support favours the development of haemorrhoids and rectal prolapse but not of cystocele as is often supposed. The exposure of the vagina is said to increase the risk of vaginitis but in practice this does not occur. Symptoms A deficient perineum is usually symptomless and, in a minor degree, may be a physiological outcome of labour, compensating for vaginal contracture in later years. Sometimes it gives rise to a feeling of pelvic insecurity when the woman is tired by standing. The atonicity can result in loss of sensation for both partners during coitus. Another possible symptom, and one causing great embarrassment, is vaginal flatus or garrulitas vulvae. The gaping introitus allows air to enter the vagina when the woman is in certain postures (for example, kneeling); this is then noisily expelled when the posture is changed. This symptom in minor degree is noticed quite commonly for a few weeks after delivery but usually disappears as the pelvic floor recovers tone. Treatment No treatment is necessary unless symptoms are present. If they are, and they rarely are, treatment is by pelvic
DEFECTIVE OR DEFICIENT PERINEUM Pathology The tissues of the vulva, and especially of the perineum, have remarkable powers of healing and of resistance to infection. So obstetrical tears and incisions, if sutured accurately with scrupulous attention to haemostasis, usually heal readily and completely. Bilateral episiotomy, however, should never be performed; it results in ischaemia of the intervening tissue so breakdown of the suture lines is almost inevitable. A defective perineum is the end result of an unhealed (often unsutured) obstetrical tear which involves the muscles of the perineal body and the overlying skin. Sometimes the skin remains intact and the original injury consists of subcutaneous tearing and overstretching of the muscles; this leaves them slack and atonic. In either
Fig. 15.4: A defective perineum. A small rectocele is also present
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Jeffcoate’s Principles of Gynaecology floor exercises when the trouble is mainly muscular atony, and by posterior colpoperineor-rhaphy when there is gross anatomical deformity.
Incontinence of faeces usually occurs only when the motions are fluid. Treatment
COMPLETE PERINEAL TEAR
Despite the gross injury, many women remain surprisingly comfortable for many years by learning to use the levator ani muscle as a sphincter. The main problem for them is the involuntary escape of flatus.
In the long-standing case treatment need not be instituted unless the patient has symptoms. The standard repair operation consists of dissecting the vagina free from the rectum and identifying the ends of the anal sphincter. The tissues are then sutured together in the following order: rectal and anal mucosa from above downwards; anal sphincter; vaginal wall from above downwards; levatores ani muscles; superficial perineal muscles; and perineal skin. This type of operation can be carried out immediately after the injury is sustained; or from 3 to 6 months after delivery when involution is complete and the baby is weaned. Other procedures applicable to cases in which there is much loss of tissue, or in which the standard operation has failed, include: using a flap of posterior vaginal wall to fill the defect in the anterior wall of the bowel; and advancement of the anterior rectal wall to a lower level. Whichever procedure is adopted, the preoperative and postoperative care are important.
Fig. 15.5: A complete perineal tear sustained during a delivery several years previously. The puckering of the skin denotes that the anal sphincter is intact posteriorly, its torn ends being marked by a depression on either side. Through the tear in the sphincter and in the anal canal, the bowel mucosa is bulging as a red mass, here appearing dark in colour
Fig. 15.6: A complete perineal tear which has partly healed, leaving a vaginoperineal fistula, and scar tissue in place of the anterior fibres of the anal sphincter. The dimples at the sides of the fistulous opening denote the retracted ends of the torn and sphincter. (Mr K. Baker’s case)
Pathology A third-degree (complete) obstetrical tear is one which involves skin, perineal muscles, and the anal sphincter. If it does not heal in the puerperium, the ultimate deformity is as shown in Fig. 15.5. The perineal body is absent in its lower part and the vaginal epithelium is continuous with the anal mucosa at the upper end of the defect. The external anal sphincter is only present posteriorly and is indicated by wrinkling of the skin. The torn ends of the retracted sphincter are marked by a dimple on each side (Fig. 15.6). The absence of sphincteric grip is revealed by inserting a finger into the anus. Symptoms
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Injuries
LACERATION OF THE CERVIX Types and Causes
Obstetrical injuries
Fig. 15.7: A complete perineal tear, the healing attempt of which resulted only in a fibrous bridge which created an anovaginal fistula. The sound has been passed through the anus beneath the bridge
Results The results of the standard repair operation, per-formed at the right times (see above), are generally satisfactory although anatomical success does not always mean perfect sphincteric control, especially during an attack of diarrhoea.
There is always some degree of physiological tearing of the cervix during childbirth and this explains why the multiparous external os is typically a transverse slit (Fig. 15.8B). Pathological tearing of the cervix during labour is caused by: delivery by forceps, ventouse or breech extraction before the cervix is fully dilated; manual or instrumental dilatation of the cervix - accouchement force; precipitate labour, either spontaneous or as the result of the giving of oxytocic drugs; and failure of the cervix to dilate by reason of an inherent fault, scars dating from a previous operation or obstetrical injury, or disease. Cervical tears usually occur in the axis of the cervix and may be: unilateral, more commonly on the left side than on the right; bilateral; or multiple giving rise to a stellate external os (Fig. 15.8C). A lateral tear can extend so deeply as to open the base of the broad ligament, and to involve the lower uterine segment to produce an incomplete rupture of the uterus (Figs 15.8D and 15.9B).
Fig. 15.8: (A) Normal nulliparous cervix (B) Normal multiparous cervix (C) Stellate laceration (D) Lateral tear extending into vaginal fornix (E) Ectropion of the cervix (F) Erosion of the cervix
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Figs 15.9A and B: (A) A nulliparous cervix, easily seen because it is prolapsed, (B) A multiparous cervix, showing the typical scars resulting from old obstetrical tears. The tearing is three-pronged, the one on the left being deep and extending into the vaginal fornix
Fig. 15.10: The mechanism whereby the anterior lip of the cervix first becomes oedematous and then sloughs from ischaemia during labour. (By permission of the Editor, J Obstet Gynaecol Br Emp)
Fig. 15.11: The mechanism of annular detachment of the cervix during labour complicated by cervical dystocia. The foetal head fits tightly on to a thinned-out cervix and ischaemic necrosis occurs and below the pressure ring. Separation is completed by retraction of the uterus acting against the downward thrust of the presenting part. (By permission of the Editor, J Obstet Gynaecol Br Emp)
Rare obstetrical injuries include: • Detachment of a part of the cervix, usually the anterior lip which becomes imprisoned between the presenting part and the symphysis pubis (Fig. 15.10).
• Annular detachment of the vaginal portion of the cervix (Fig. 15.11); this occurs during long labours in which the external os refuses to dilate — cervical dystocia.
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Injuries • Cervicovaginal fistula formation. This results from the birth of the baby through the wall of a sacculated cervix instead of through the external os. • If a cervical stitch applied for an incompetent cervix is not removed and the patient passes in labour, the stitch may cut through or even an annular detachment of the cervix can occur. In the production of these lesions ischaemic necrosis from prolonged pressure plays a greater part than does direct trauma. These lesions are seen less often nowadays because of earlier resort to caesarean section in such cases. A characteristic tear seen in women in whom midtrimester abortion is induced with prostaglandin F2α is the bucket-handle tear. As the name suggests, part of the cervical rim is detached. This can be prevented by adequate cervical ripening.
Surgical Injuries Perforation or deep laceration of the cervix can occur during operations such as dilatation of the cervix for dysmenorrhoea, and exploration of the pregnant or recently pregnant uterus whose cervix is soft and friable. A volsellum can sometimes cause a nasty tear in the cervix which on rare occasions may even require stitching. Other surgical injuries include those deliberately inflicted such as amputation of the cervix and cone biopsy.
muscle free to act unopposed. The effect is to curl the lips of the cervix upwards and outwards to produce a condition of ectropion (Figs 15.8E and 15.12). The redlooking endocervix then becomes exposed so the condition is confused with erosion. Many ectropions are apparent rather than real, the observer being deceived by the fact that a bivalve speculum can pull open the lips of the cervix by its drag on the adjacent vaginal walls.
Distortion and Scarring of the Cervix This is seen to some extent following all injuries but is most obvious when a tear has involved the vaginal fornix and when there has been actual loss of tissue (Fig. 15.13). Clinical Features At the time of the injury and immediately afterwards no symptoms arise unless the tear opens a large blood vessel to cause haemorrhage, external or into the broad ligament; or unless it extends so high as to constitute rupture of the uterus; or the cellular tissue of the broad ligament becomes infected. Here we are mainly concerned with the condition as seen at a later date and, again, a lacerated cervix is usually symptomless. When symptoms are present they are the
Complications and after Effects
Cervical Ectropion Bilateral vertical laceration of the cervix disrupts the connective tissue and circular fibromuscular fibres, leaving the longitudinal fibres of the external cervical
Fig. 15.12: The mechanism whereby ectropion occurs, following bilateral tearing of the circular muscle fibres in the cervix. The external longitudinal muscle then retracts unopposed
Fig. 15.13: The scarred stump of the cervix remaining 4 years after spontaneous annular detachment during prolonged labour. The patient concerned complained of infertility dating from delivery. (By permission of the Editor, J Obstet Gynaecol Br Emp)
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Jeffcoate’s Principles of Gynaecology result of: an associated cervicitis and cellulitis; tearing of the internal os causing abortion and premature labour; or partial or complete destruction of the vaginal cervix causing infertility, with or without stenosis of the canal (Fig. 15.13). On examination the injury is usually obvious. As a rule it feels worse than it looks because underlying scar tissue and fixation are only appreciated by the tactile sense. Treatment Cervical lacerations recognized at the time of their occurrence are sutured immediately. If found at a later date, no treatment is indicated in the absence of symptoms. The possible lines of treatment are described in chapter 20. RUPTURE AND PERFORATION OF THE UTERUS Rupture and perforation of the uterus maybe complete or incomplete. A complete rupture involves all coats including peritoneum; an incomplete rupture leaves the peritoneum intact and generally has less serious consequences. Rupture Spontaneous rupture of the non-pregnant uterus is described as a rare complication of haematometra and pyometra due to any cause. It is more likely if the uterus is senile as well as overdistended. The non-pregnant as well as the pregnant uterus can be ruptured by an extension of a cervical tear during operative dilatation of the cervix. During pregnancy the uterus ruptures as a result of: • Severe direct violence • Weakness of the wall resulting from old scars (Fig. 15.14). The most susceptible scars are those left after classical caesarean section (including hysterotomy), after injuries sustained in previous pregnancies (for example, perforation during curettage to complete or induce abortion), after reimplantation of the fallopian tubes, and after plastic operations on bicornuate uteri. • Weakness of the wall due to abnormal invasion of the trophoblast (placenta increta). • Abnormal thinning of the wall as found in sacculations, diverticula and rudimentary horns.
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Fig. 15.14: Spontaneous rupture of the uterus at the thirty-sixth week of pregnancy. The rupture occurred at the site of the scar of a previous classical caesarean section, the incision at the time of this operation having to be placed in the fundus because the patient was a kyphotic dwarf. Following the rupture, which was not immediately diagnosed, the woman remained at home for 24 hours and, by the time she reached hospital, was desperately ill. She recovered after hysterectomy. The baby, lying free in the abdominal cavity, was dead
Rupture of the uterus in labour is outside the scope of this work. Rupture of the pregnant or non-pregnant uterus causes severe lower abdominal pain which is usually followed by collapse due to intraperitoneal bleeding from the tear. If the rupture is incomplete a broad ligament haematoma results. Shock is not always present, or is slow to develop, if the rupture occurs through an avascular scar. The contents of the uterus - pus, blood or a conceptus - are extruded in part or whole, and produce peritonitis or peritonism. After resuscitation the patient is treated by immediate laparotomy. The uterus is then repaired or removed according to the circumstances. Perforation The uterus is easily perforated by a sound, a cervical dilator or a curette, or during the insertion of a contraceptive device, especially if there is difficulty in negotiating the cervical canal and if the uterus is retroflexed. The accident is more likely if the uterine wall is soft, friable or thin - as it is in pregnancy (Fig. 15.15) or immediately afterwards, in old age and when invaded by cancer.
Injuries form a large tumour which, if the bleeding is not arrested, spreads extraperitoneally into the space of Retzius and up the anterior or posterior abdominal wall. The haematoma is nearly always unilateral. If neglected, a broad ligament haematoma can become infected. Causes
Fig. 15.15: This drawing of a necropsy specimen dates back to the preantibiotic era. It shows a recently pregnant uterus with injuries to the cervix and a perforation into the left broad ligament which resulted from the criminal induction of abortion. The woman concerned died from puerperal sepsis
The dangers of perforation are haemorrhage and the dissemination of any infection or malignant disease which may be present. Moreover, if the accident is not recognized, the intestine may be injured. If the uterus is empty and the operation is a clean one, no harm results as a rule. If the perforation occurs during attempts at criminal abortion, or during the evacuation of a septic abortion, peritonitis or cellulitis is almost inevitable. Treatment varies with circumstances but is guided by the following rules. If the uterus is empty, laparotomy is usually unnecessary but if not, laparoscopy allows inspection of the uterus before and during removal of any remaining contents. Any spread of infection is counteracted by appropriate antibiotics. Laparotomy is indicated if abdominal contents prolapse through the hole or if there is any likelihood of their having been injured before the accident was discovered; if there is a lesion such as cancer or pyometra in the body of the uterus; if laparoscopy reveals the perforation to be getting larger during evacuation; or if laparoscopy is not possible or practical and the uterus still contains products of conception. The uterus is then repaired or removed according to the circumstances. BROAD LIGAMENT HAEMATOMA Pathology A collection of blood in the cellular tissues of the broad ligament is not common but is a serious condition. It can
• Haemorrhage from operation sites or from lacerations in the uterus, cervix and upper vagina. Incomplete haemostasis is a serious and not uncommon immediate complication of lower segment caesarean section; the resulting haematoma may be in the uterovesical space or in the broad ligament. • Incomplete rupture or perforation of the uterus. • Direct injury with a penetrating instrument. • Haemorrhage from tumours of the uterus, fallopian tube, ovary or pelvic ligaments. • Extraperitoneal tubal rupture of an ectopic pregnancy. • Spontaneous haemorrhage. This is most likely to be seen following labour and especially when blood coagulation failure complicates abortion or abruptio placentae. Clinical Features The general condition of the patient suggests the occurrence of internal haemorrhage. She complains of pain low down in one or other iliac fossa and shows varying degrees of shock. Mild pyrexia is the rule after the acute phase. Bladder irritability, retention of urine, diarrhoea and rectal tenesmus are common. The diagnosis is made by feeling a fixed tender swelling lying to one or other side of the uterus and apparently continuous with the uterus. It may be palpable abdominally as well as bimanually. Treatment A large haematoma is evacuated through the vagina or by an extraperitoneal abdominal approach. The bleeding point is secured if possible and the broad ligament drained. A small haematoma can be left to become absorbed. GENITAL TRACT FISTULAS Communications between the genital tract and the urinary or alimentary tracts may occur singly or in combination. Fistulas may be of various types.
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Vaginoperineal
Causes
A tract between the posterior vaginal wall and the perineum (Fig. 15.6) is usually the result of incomplete healing of an ordinary obstetrical perineal tear, but can be the sequel to the very rare condition of central tear of the perineum. It is usually symptomless and rarely requires treatment. If it causes symptoms it can be excised. Preoperatively a sinogram should be done. Intraoperatively injection of a dye, e.g. gentian violet into the sinus is useful; sometimes these fistulas can have wide ramifications in the perineum which are shown up by the dye and complete excision is then possible.
Congenital Malformation
Faecal Faecal fistulas can be classified according to the level at which they open in the genital tract. Tubointestinal This condition is mostly seen in association with a pyosalpinx, especially the tuberculous variety. The fistula may develop by spontaneous rupture of the pyosalpinx into the intestine, or it may arise as a result of attempts at surgical interference. A faeculent discharge through the uterus can ensue, but is unusual because the tube is likely to be closed.
Perineal or vaginal anus: incomplete partition of the cloaca (see page 216, Fig. 13.22).
Foreign Bodies (vagina, bowel or peritoneal cavity) These erode the mucosa and cause a perforation.
Obstetrical Injury The foetus itself, if its delivery is obstructed, can cause pressure necrosis of the rectum. Instruments used to assist its birth may perforate the vagina and rectum. The rectum may be included in a suture during repair of a perineal tear. The majority of obstetrical rectovaginal and perineoanal fistulas, however, represent the end results of incomplete healing of third-degree perineal tears (Fig. 15.7).
Operation Injury The rectum may be opened during total hysterectomy, or during any of the many operations which involve puncture, incision or dissection of the posterior vaginal wall and fornix. If the injury is not recognized and successfully repaired, a fistula results.
Uterointestinal
Extension of Disease
A communication of this kind usually involves the colon rather than the small intestine. The causes are malignant disease, diverticulitis, pelvic abscess and tuberculosis; the lesion is nearly always primary in the bowel rather than in the uterus. A discharge of flatus and faeces through the cervix and vagina is the patient’s complaint. The fistula can be demonstrated by hysterography or a barium enema X-ray but extensive investigation is necessary to elucidate the underlying lesion. Treatment may involve hysterectomy and resection of the bowel.
Any pelvic abscess can open into both rectum and posterior vaginal fornix; an abscess secondary to diverticulitis may discharge through the vagina; a perianal abscess may burst onto the perineum. Tuberculosis and lymphogranuloma inguinale are other causes of rectovaginal fistulas. Carcinoma of the cervix is not by itself a common cause of a faecal fistula because the pouch of Douglas intervenes between the cervix and rectum. Carcinoma of the vagina is more likely to be a cause but, unless the patient has had radiotherapy previously, a malignant rectovaginal fistula nearly always means a primary lesion in the bowel.
Vaginointestinal, Perineointestinal It is usually the pelvic colon or the rectum which communicates with the vagina. Rarely, the small intestine communicates, usually in the case of malignant disease. An opening on the perineum links with the anus or lower rectum.
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Radiotherapy Heavy irradiation of any type, and especially that delivered by megavoltage apparatus, may cause ischaemic necrosis of the bowel and lead to a fistula, usually with a stricture below it, 3 months to several
Injuries years after treatment. A combination of tumour and radiation reaction is one of the commonest causes of faecal fistulas.
Only in exceptional cases is colostomy necessary as a preliminary to closure of the fistula. Otherwise, the preoperative and postoperative management is the same as for complete perineal tear.
Clinical Features: Diagnosis The complaint is incontinence of faeces and flatus. A large fistula is readily identified. A small one can be difficult to find and to track; the elucidation of its anatomy may require proctoscopy, sigmoidoscopy and observations on the behaviour of introduced radioopaque and coloured fluids. Treatment Some form of surgery is nearly always indicated but its type depends on the position and cause of the fistula. For an anoperineal fistula the best procedure is to lay open the track and allow it to granulate. When diverticulitis is the underlying cause of a rectovaginal fistula, resection of the affected portion of the bowel may be necessary. If the basis is a malignant state the choice may lie between exenteration and colostomy. It should be recognized, however, that the patient may prefer to have faecal incontinence through the vagina than through the abdominal wall. When cancer has been eradicated by radiotherapy, removal of all the vaginal epithelium and obliteration of the cavity (colpodeisis) can give good results (see below). Some radiation fistulas, and nearly all traumatic ones, can be cured by careful dissection and suture of bowel and vagina, but success depends on delaying the operation for 3-6 months after the appearance of the fistula. All tissue reaction must be allowed to subside to offer easy dissection and good healing. A pinhole-sized traumatic fistula is readily closed but breaks down surprisingly often. Most faecal fistulas opening into the vagina are best tackled through the vagina but a very high one, communicating with the upper rectum or the colon, may require an abdominal approach. I have seen a case where the rectum was accidentally opened while opening the peritoneum of the pouch of Douglas at vaginal hysterectomy. Although the surgeons recom-mended a colostomy, a primary direct closure was done and the patient did well. A fistula which is the consequence of partial healing of a complete perineal tear, is best converted into a complete tear and then repaired as such.
Urinary
Types Urine may escape into the genital tract from the ureter, bladder or urethra (Fig. 15.16). In the case of the first two, the communication may be with the uterus, cervix or vagina. Urethral fistulas always enter the vagina. The urethra may be completely destroyed or severed (Fig. 15.18). The commonest fistula is the vesicovaginal, the opening in the bladder being in the trigone near the middle line. It varies from a pin-head in size to complete destruction of the bladder base and urethra. When the opening is sufficiently large the bladder wall prolapses through it (Fig. 15.17). Fistulas resulting from accidental, surgical and obstetrical trauma are produced in two ways. They can be caused by direct injury such as cuts and perforations and they then manifest themselves immediately by haematuria and incontinence. Alternatively, they are the outcome of pressure necrosis (including involvement of the tissues in a ligature), or of ischaemia; in such a case the hole does not develop and give rise to urinary incontinence until 7-14 days after the accident, operation or confinement.
Fig. 15.16: The commonest sites for fistulas: (1)vesicocolic; (2) uterocolic; (3) vesicouterine or vesicocervical; (4) vesicovaginal; (5) ureterovaginal; (6) rectovaginal; (7) urethrovaginal; (8) vaginoperineal
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Fig. 15.17: A vesicovaginal fistula occurring as a complication of total hysterectomy. B - the mucosa of the bladder ballooning into the vagina. (Photograph presented by Professor Chassar Moir)
Causes
Congenital Malformations Aberrant ureter and persisting urogenital sinus.
Accidents Crush injuries to the pelvis, becoming increasingly common as a feature of road accidents, can cause perforation of the bladder and urethra by bone fragments, or avulsion of the urethra.
Operative Injury This is the commonest cause of urinary fistulas in the West. One analysis from the USA put the causes as: pelvic surgery 45 per cent, cancer with or without radiotherapy 34 per cent, obstetrical trauma 15 per cent. Of fistulas coming to operation, 70 per cent are gynaecological and 30 per cent obstetrical. This is to be contrasted with the situation in tropical Africa and most developing countries where 85-95 per cent of the very numerous urinary fistulas are obstetrical. In nearly all gynaecological operations one or other part of the urinary tract is in danger.
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The ureter is at risk in total hysterectomy, especially radical hysterectomy, and during the removal of broad ligament tumours. It can be damaged at the pelvic brim during division and ligature of the infundibulopelvic ligament; it is sometimes lifted up and divided during the dissection of adnexal masses fixed in the floor of the pelvis or at the lateral pelvic wall. The lower ureter is at risk during vaginal hysterectomy and prolapse repair operations. The bladder is liable to injury during total hysterectomy and during all operations involving the anterior vaginal wall. I have seen a vesicovaginal fistula caused by placement of sutures through the bladder base when the vaginal cuff was sutured. The sutures could be seen at cystoscopy! The bladder dome can also be injured while opening the abdominal cavity, especially if there is a previous incision and scarring. With the use of laparoscopy in recent years for hysterectomy, colpourethropexy, etc. endoscopic bladder injury has also been reported, especially in patients with prior pelvic surgery and endometriosis. The urethra is threatened during anterior colporrhaphy and sling operations in particular.
Obstetrical Injury In developing countries, obstructed labour is a common problem for a variety of reasons. Women are economically underprivileged, illiterate, married early and have poor access to family planning and medical services. Teenage pregnancy is common and antenatal care unavailable to the vast majority of women in rural areas. Women with cephalopelvic disproportion or malpresentations may be in prolonged obstructed labour which leads to ischaemic vascular injury from compression of the soft tissues between the foetal head and maternal pelvis. Ischaemic tissue necrosis leads to the development of a genitourinary fistula in the puerperium, usually after 7-10 days. The fistula resulting from pressure during long and difficult labour always involves the trigone of the bladder which is nipped between the presenting part and the back of the symphysis pubis. This proves that the bladder is not lifted into the abdomen–an old belief which many are reluctant to discard. The lower end of the ureter, the bladder base and the urethra may be directly injured by instruments. Forceps rotation of the foetal head is a particular threat (Figs 15.18A and B).
Injuries
Figs 15.18A and B: Complete division of the urethra 1-2 cm above the external meatus, which was caused by a difficult forceps rotation and delivery of a woman’s first baby. She did not suffer incontinence of urine because the defect is well below the internal sphincter. On the contrary, her complaint was attacks of retention caused by contracture of the scar tissue at the lower end of the upper segment of urethra. She was successfully treated by periodic dilatation of the upper urethra without anaesthesia being necessary, (A) The lower end of the urethra leads into the vagina, (B) The fibrosed false meatus within the vagina
During lower segment caesarean section, the bladder base may be torn, rendered ischaemic or included in a suture to result in a fistula which usually communicates with the uterus or the cervix. When haemorrhage from tears at the angles of a transverse lower segment incision requires ligation of the main branches of the uterine vessels, the ureters are at risk. Rupture of the scar of a previous lower segment operation can implicate the adherent bladder base.
Extension of Disease Processes Carcinoma of the cervix and vagina, acting alone or in conjunction with radiotherapy, is one of the commonest causes of vesicovaginal fistula but the growth itself rarely invades the ureter. Genitourinary tuberculosis and schistosomiasis are rare causes of urinary fistulas.
Radiotherapy Excessive, misapplied and even well-applied irradiation for carcinoma of the cervix causes a vesicovaginal fistula
Fig. 15.19: A fistula between the vagina and the upper urethra resulting from an injury sustained during anterior colporrhaphy. This caused continual urinary incontinence because it involved the internal sphincter. The fistula was successfully closed and the internal sphincter tightened with restoration of continence
in the same way as it causes a rectovaginal fistula by ischaemic necrosis. It is therefore a late complication, sometimes taking several years to develop. Clinical Features and Diagnosis True incontinence caused by a fistula has to be distinguished from urethral incontinence. When there is a fistula the urine escapes continuously, day and night. If the patient never needs to void, it signifies that the fistula communicates with the bladder. If, however, the bladder fills and empties as well, it suggests a fistula into one ureter. Unless they involve the upper half including the internal sphincter, urethral fistulas give little trouble because the urethra is normally empty of urine (Fig. 15.19). However, during micturition urine passes through the fistula and may then fill the vagina to dribble away during body movement for a short time afterwards. Mid-vaginal fistulas may be located below the interureteric ridge. These are usually caused by a misplaced radium applicator or anterior colporrhaphy, but sometimes may also be the result of difficult forceps delivery.
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Jeffcoate’s Principles of Gynaecology High fistulas usually include the anterior cervical lip. They may be obstetrical or radiation-induced. Fistulas following hysterectomy are also high at the vault. These fistulas are supratrigonal and the margins may be very close to the ureteric origin. Large fistulas may be seen in which most of the anterior vaginal wall has been destroyed. The pubic bone may also be exposed. Conversely, sometimes the defect can be difficult to find if it is small. The complaint of true incontinence is so typical as to leave little doubt as to the existence of a fistula. In such cases examination in the knee-chest position can be helpful because air then enters the bladder and bubbles through the hole when the woman coughs. Another test is to place three large pledgets of cotton wool in the vagina, one above another, and to run methylene blue solution into the bladder (3swab test of Moir). If only the lowest swab stains, the fistula is urethral; if the middle or upper swabs stain, the fistula is vesical; if none of the swabs stains but the upper one is wet, the fistula is ureteric. Every case needs investigation to determine the exact position of the fistula, and the anatomy and function of the rest of the urinary tract, before treatment is planned. The minimum requirements are examination of the urine, pyelography, cystoscopy and renal function tests. Those women who have already had an unsuccessful operation for closure of a fistula involving the bladder may have intravesical stones and phosphate deposits with a nucleus of unabsorbed suture material. These should be removed at least 6 weeks prior to repair to allow inflammation to settle. A remarkable feature of vesicovaginal fistulas, even those with concomitant rectovaginal fistulas, is that they are almost never complicated by cystitis, and this despite the ready pathway which they provide for the entry of organisms. Although this might be explained by the continual ebb of urine to leave the bladder empty, it should shake the belief of those who think that all women are cystitis-prone because the shortness of their urethras allows easy ascent of bacteria. Most vesicovaginal fistulas are painless but radiation fistulas are associated with severe pain. A biopsy from the margin of the fistula is recommended to rule out persistent or recurrent disease.
Menouria A rare but interesting syndrome is one in which a uterovesical fistula causes haematuria at the times of
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menstruation, the patient remaining free from urinary incontinence. The whole of the menstrual discharge may occur via the urethra. The presence of the fistula can be demonstrated by hysterography but not by cystography. This syndrome is seen when the fistula (usually following caesarean section) opens into the uterus above the isthmus. The latter is assumed to prevent any cervical outflow of urine by its sphincteric action. Treatment The woman with a constant dribble of urine is in a miserable plight with contaminated and smelly clothing and vulva, the latter becoming excoriated. Protective pads and waterproof underclothing are of little avail. So the woman shuns all social contacts and, in turn, is shunned by friends and relations. She not uncommonly develops secondary amenorrhoea, this presumably reflecting a subconscious and strong desire to arrest any sort of outflow from the vagina. In these cases menstruation becomes reestablished as soon as the fistula is cured. All this emphasizes the need for efficient treatment, the principles of which are as follows.
Conservative Treatment This is worthwhile for recently formed fistulas. A ureteric leak may cease of its own accord. A vesico-vaginal fistula sometimes closes if the bladder is drained continuously for 3 weeks to 3 months, the patient meanwhile being kept in the prone or Sims’ position. This latter treatment has been tried even if a fistula has been present for several months and is recorded as being successful after years of incontinence. Such fistula repairs, however sometimes break down a few weeks later. If conservative treatment fails, surgery on the following lines is indicated. It has been the standard practice as in the case of faecal fistulas, to defer any reconstruction operation for 3-4 months after the initial injury, or after a previous attempt at repair, to allow all tissue reaction to subside. However, with small, non-complicated fistulas an earlier repair can be planned within 1-8 weeks and has been shown to be curative in 80 per cent of patients. Those who fail to heal can undergo a second, usually successful repair 6-8 weeks later. Although success rates with the standard delayed method are in the range of 95-98 per cent, this method of early repair allows for an overall decrease in the number of wet days and greater
Injuries patient comfort. Proper selection of cases is essential. Postirradiation fistulas may take 6 months to 2 years to be ready for repair. Very rarely, some small vesicovaginal fistulas less than 3 mm in diametre have been treated with superficial bladder fulguration using electrocautery or laser. However, there should be no history of previous attempts at repair and the vesicovaginal septum should not be too thin, otherwise the fistula size can increase with considerable scarring of the margins.
Surgery for Ureteric Fistulas Here the possibilities are repair of the ureter; transplantation of the upper cut end into the bladder or into a rolled flap of bladder (Boari operation); replacement of the defect by a loop of ileum; ureteric diversion into the colon or the formation of an ileal conduit; or sacrifice of the ureter and kidney. The last is to be avoided if at all possible.
Surgery for Uterovesical Fistulas This often requires an abdominal operation. The usual operation is to identify the fistulous tract, suture the uterine and bladder defects in layers and interpose the vesical peritoneum. A hysterectomy is required if the fistula is large. If the patient has some degree of cervical descent and the fistula is low, a vaginal repair may rarely be possible.
Surgery for Vesicovaginal Fistulas Preoperative cystoscopy helps to evaluate the size and location of the fistula and its distance from the ureteric orifices; accordingly the repair can be planned. Ureteric catheterisation before repair prevents their encirclement with a suture or obstruction by postoperative oedema if the ureters are close to the fistula margin. Unless the loss of tissue is very extensive nearly all these fistulas can be closed by dissection and suture from the vaginal aspect. The results are usually better than those obtained by a transvesical approach. The operation is one for an expert who is prepared to modify the technique to suit the individual case. Adequate dissection and mobilisation of tissues, excision of the fistula tract and all scar tissue, and good haemostasis are essential for a successful outcome. Synthetic, delayed absorbable polyglactin or polyglycolic acid sutures (3-0) are used nowadays. The first row of sutures in the bladder is the most important.
This is tested with methylene blue, reinforced if necessary and followed by a second covering layer in the muscularis, broad surface to broad surface without tension. The vagina should also be closed without tension, and not necessarily perpendicular to the bladder sutures. In fact, the least tension is usually in the transverse direction. Simple posthysterectomy vesicovaginal fistulas at the vaginal vault can be closed vaginally by Latzko’s partial colpocleisis after ureteral catheterisation. The transperitoneal transvesical approach is reserved for the following situations: the fistula margins are close to the ureteric orifices; an omental flap is to be used; ureteroneocystostomy is required; bladder patching or augmentation with sigmoid colon, ileum or caecum is to be done. Problems of fistula exposure can often be managed by a Schuchardt incision. It is important to avoid suturing tissues under tension. Wherever there is excessive loss of tissue with inadequate mobilization, a graft can be employed. The Martius graft using the bulbocavernosus pad of muscle and fat may be used in vaginal repairs. It is a simple procedure and I have always had gratifying results. It leaves an asymmetrical vulva with a scar, but I have never seen any patient complain, such is her relief after successful surgery! In abdominal repairs, the omentum can be interposed between the layers. Other autografts which have been used include peritoneal flaps, gracilis muscle and rectus abdominis flap. The ischaemia which prevents radiation fistulas from healing may be overcome by living muscle transplants. An important part of treatment is the aftercare; it is essential to keep the bladder empty by continuous suction drainage for 2 or 3 weeks. This is generally arranged by way of the urethra but, in the case of fistulas involving the urethrovesical junction, supra-pubic cystotomy is often preferable. Adequate fluid intake is essential to ensure a high output of dilute urine and prevent catheter blockage. The output should not be less than 50 ml/hour, and outputs of 100 ml/hour are not uncommon. Some patients may continue to have incontinence after adequate healing. This may be due to scarring at the bladder neck and anatomic alteration of the normal relationship of the bladder neck and upper urethra, or to a dyssynergic detrusor muscle with a small bladder capacity.
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Surgery for Urethrovaginal Fistulas When the urethra is destroyed a new one can be created by turning in a U-shaped vaginal flap to form a tube, or by other specialized technique. A Martius graft is used in cases with deficient tissues. The ordinary urethrovaginal fistula, however, can usually be closed by layer suturing after wide dissection. The easiest and most successful technique for this is first to divide the floor of the urethra from the external meatus up to the site of the fistula (Figs 15.20A to D). This permits good exposure. Again, after these operations the bladder needs to be drained continuously for at least 14 days.
Surgery for Complicated Fistulas The term ‘complicated fistulas’ includes those which are very extensive, those that have had unsuccessful attempts at repair, combined fistulas involving the urethra, vesical neck or ureters, postradiation or postmalignancy fistulas and those associated with intestinal fistulas. In these cases, additional special techniques may be necessary. The combined transvaginal-transvesicaltransperitoneal approach may be used. Grafts, as described above, are used more often to allow better support and neovascularisation. Fistulas characterized by gross loss of tissue are sometimes best circumvented by transplantation of both ureters into an isolated loop of ileum or into the colon. A colonic implant is now generally avoided unless the expectation of life is in any case short; the creation of a ureteroileocolostomy is preferable. Exenteration may be indicated occasionally, especially when active malignant disease is still present. When it is not, however, large radiation fistulas, including those in which both the bladder and the rectum communicate with the vagina, can be successfully managed by colpocleisis. In this operation, the defect is covered with a flap of vaginal skin and the remainder of the vaginal wall is completely removed; the resulting cavity is then obliterated and the introitus closed. In the case of combined fistulas this may still leave a communication between the bladder and the rectum but this is so planned that the flow of contents is from bladder to rectum and not vice versa. Sometimes, the operation may need to be done in stages when traumatic or postradiation vesico-vaginal and rectovaginal fistulas are present simultaneously, the rule is to do a preliminary colostomy. The fistulas are
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then closed, sometimes at the same sitting but sometimes the vesicovaginal fistula first and the rectovaginal fistula later. When the fistulas have healed, the colostomy is closed.
Prevention of Fistulas Improvement in obstetric care will reduce the incidence of fistulas in developing countries: prevention of teenage pregnancy, access to antenatal care, use of the partogram, timely referral and caesarean section where necessary. In gynaecological practice, dissection of the bladder is very important. Sharp dissection is preferable to blunt dissection, especially in cases with previous surgery like caesarean section or Fothergill’s operation. In cases of severe endometriosis or pelvic inflammatory disease, it may be necessary to visualize the ureter to ensure its safety. Sometimes it may be wiser to perform a subtotal hysterectomy when the danger of removing the cervix is greater than that of leaving it in. Early recognition and appropriate repair of injuries is an important feature of prevention. Ideally, the injury should be recognized intraoperatively by seeing urine spurt into the field or by instilling methylene blue diluted with sterile saline into the bladder in high-risk cases. In the postoperative period, abdominal pain, distention, paralytic ileus, haematuria or dysuria should point to the possibility of bladder injury. Patients with ureteric damage or ligature may have flank pain and an unusually hectic postoperative period. Pregnancy after Cure of Vaginal Fistulas If a woman conceives after cure of a urinary or faecal fistula communicating with the vagina, it is usually wise to deliver the baby by elective classical caesarean section. This does not always apply after the closure of a rectovaginal fistula which was part of a complete perineal tear. Episiotomy in labour protects this sort of operation scar. ACQUIRED ATRESIA AND STENOSIS OF THE GENITAL TRACT Pathology Trauma or disease can result in complete or partial obstruction, narrowing, adhesions and strictures in any part of the genital tract (gynatresia).
Injuries
Figs 15.20A to D: A technique for the repair of a urethrovaginal fistula which gives better results than mere local dissection and closure of the track. It ensures good exposure, easy dissection and accurate closure in layers, (A) Fistula defined with a sound, (B) The floor of the urethra is divided from the external meatus up to and including the fistula. The vaginal wall is then widely freed from the urethra, the dissection being carried higher than the opening to permit tightening of the internal sphincter above, (C) Closure of the urethra is from above downwards. Only one row of sutures is shown but two are desirable. During the closure the lumen can be protected by a polythene tube of small bore, (D) The vaginal wall is now closed and a catheter placed in the urethra to provide continuous drainage for at least 14 days. Alternatively, drainage for the same period of time can be provided
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Causes
Senility Contracture of the introitus and vagina is the inevitable accompaniment of senile atrophy, although it is controlled to some extent by regular coitus. If infection is superimposed, adhesion formation is likely and this is seen particularly around the clitoris (Fig. 15.21) and in
Fig. 15.21: Senile contracture of the introitus in a woman aged 72 years. It is unlikely to cause any symptoms other than dyspareunia
Fig. 15.22: Stenosis of the vulva following repeated partial vulvectomy for recurrent Paget’s disease. The opening to the vestibule appears only as a black spot (arrow). The skin around appears dark because in life it was red. The stenosis ultimately caused retention of urine and had to be dealt with by a plastic operation. The woman in this case ultimately died from previously unrecognized cancer of the cervix. She had been seen regularly for many years but the stenosis precluded vaginal examination and cervical cytology
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the upper vagina (adhesive vaginitis). Stenosis of the cervical canal is another possible manifestation of senility. Operative and Other Injuries
Vulva Stenosis is commonly caused by overenthusiastic perineorrhaphy. After both simple and radical vulvectomy, contracture can be several enough to obstruct the outflow of urine (Fig. 15.22). Burns, obstetrical and accidental injuries, ‘female circumcision and infibulation practised by certain African tribes can all lead to gross distortion and bizarre adhesions (Figs 15.23 and 15.24). These ritual procedures are carried out in infancy or childhood to reduce erotic sensation and protect virginity. In circumcision the clitoris and surrounding tissue is crudely excised. Infibulation involves the additional removal of the foreparts of the labia to leave raw areas which are then fastened together. The resulting obstruction to the introitus may later have to be divided to permit consummation of marriage.
Vagina The vagina can become stenosed, closed or the site of adhesions as a result of burns, lacerations and operations especially if infection is superimposed. In the treatment of prolapse in old women, the surgeon often deliberately narrows the vagina. In colpocleisis he obliterates it.
Fig. 15.23: Adhesions and distortion of the vulva of a Somalian woman, resulting from ritual circumcision in childhood
Injuries
Fig. 15.24: The result of ritual circumcision or infibulation in childhood, as seen in a woman from Southern Egypt. The clitoris and the labia minora, except for a remaining fragment on the left side, have been removed and there is considerable scarring over the pubes
Fig. 15.25: Haematometra associated with stenosis of the cervix which followed the introduction of radium to induce the menopause
Radiotherapy Unintentional obstruction of the vagina after colporrhaphy operations is sometimes due to the formation of adhesions between the incisions on the anterior and posterior walls. These are easily broken down 2 or 3 weeks after operation but, if overlooked at that time, become firm fibrous bands.
Cervix The commonest injuries causing stenosis of the cervix are amputation and excessive cauterisation. Cone biopsy does not usually result in stenosis. It is more likely to leave the cervix incompetent or so fibrotic that it fails to dilate in a subsequent labour. Patients who have undergone transcervical resection of the endometrium may develop stenosis which responds well to simple dilatation.
Corpus Uteri Partial or complete obliteration of the cavity of the uterus is a rare sequel to brutal curettage in the presence of infection, and to any form of cauterisation.
Fallopian Tube The tube may be divided or ligated during operation.
Radium and caesium are potent agents in causing cervical and vaginal stenosis and closure. A menopausal dose may be followed by haematometra and pyometra (Fig. 15.25). A cancericidal dose of radium or caesium and X-rays almost always results in closure, not only of the cervix but also of the upper vagina; unless the patient uses dilators regularly immediately post radiotherapy; this does not often cause trouble, however, because menstrual function is suppressed simultaneously. A collection of blood in the uterus often means a recurrence of active growth. Infections and Epithelial Disorders
Vulva Closure of the introitus can result from chronic infections such as tuberculosis, granuloma inguinale and lymphogranuloma. It is seen as a complication of chronic vulvar epithelial disorders. Non-specific vulvitis in old women can lead to adhesions between the labia minora but when adhesive vulvitis is found in the adult it can date back to infancy, having been overlooked during the years (Figs 15.26A and B). Adhesive vulvitis or agglutination of the labia minora (and the condition has several other names) is not uncommonly enountered in babies. The initial inflammation generally passes
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Figs 15.26A and B: Closure of the adult vulva by adhesion of the labia minora. The patient concerned was aged 47 years, married 11 years, nulliparous and unaware that the marriage had never been consummated. She complained of postmenopausal bleeding for one year and, despite her virginity, was found to be suffering from a Stage III squamous cell carcinoma of the cervix. It seems likely that the adhesions had been present throughout life, or at least since childhood when their cause could have been vulvitis. (A) Introitus closed except for the tiny opening anteriorly through which the woman urinated and menstruated; the occluding membrane is demonstrated by lifting it with a sound, (B) The membrane, consisting of no more than adherent labia minora divided to reveal a normal vulva and introitus. The line of adhesion is indicated by the fine dark line of blood
unnoticed, or is not regarded as significant, but it raws the edges of the labia minora which then stick together in the middle line, leaving only a small opening anteriorly or posteriorly for the escape of urine (Figs 15.27A and B). If this is hindered, dysuria or general soreness of the vulva can lead the child to attract the mother’s attention to the vulva. In at least one-third of the cases, however, the condition is symptomless and the mother discovers it incidentally. She usually concludes that the deformity is congenital and the medical attendant may also think likewise. One maternal diagnosis is absence of the vagina. By the time medical advice is sought the baby is likely to be 1-3 years old.
Vagina Vaginal adhesions and contracture occur as a result of granulomatous conditions, senile vaginitis and secondary infection of injuries.
Uterus Partial or total obliteration of the uterine cavity and intrauterine adhesions (synechiae) are complications of
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postabortal infections and tuberculous endo-metritis. Overzealous curettage can lead to this situation by removing even the basal endometrium. If the diagnosis is suspected, it can be confirmed by hysteroscopy. Adhesions may be thin, flimsy and easily broken by the hysteroscope itself; thick and fibrous, a fleshy and vascular. They can also be categorized according to the extent of cavity they occupy and whether the ostia are visible or not.
Fallopian Tube Infection of any type is the main cause of tubal obstruction but endosalpingiosis can also operate (see Chapter 22).
Tumours Benign tumours of the vulva, vagina and uterus distort the genital canal but they do not narrow it. Thus cysts, polyps and leiomyoma in the cervix never hold back the menses. Malignant growths, however, commonly obstruct; two of the commonest causes of pyometra and haematopyometra are carcinoma cervix and carcinoma corporis.
Injuries
Figs 15.27A and B: Adhesive vulvitis in infancy, (A) The vulva of a child aged 3 years with closure of the introitus except for a tiny opening through which the girl passed urine. This abnormality is commonly assumed by the mother to be congenital but it is usually if not always the result of previous and often unrecognised vulvovaginitis. (B) Separation of the labia minora along the line of adhesion reveals a normal vestibule, urethra and vagina within
Effects
Dystoda
These naturally vary with the site and extent of the obstruction, with the age of the patient and with other circumstances.
Stenosis of the cervix, vagina and vulva, or failure of these tissues to stretch and dilate, causes obstructed labour. If the obstruction is overcome by tearing, severe haemorrhage can occur.
Retention of Discharge The hold-up of menstrual blood causes haematocolpos, haematometra and haematosalpinx. Partial retention, as seen sometimes with stenosis of the cervix causes spasmodic dysmenorrhoea. Other possibilities are hydrocolpos, pyocolpos, hydrometra, pyometra, hydrosalpinx and pyosalpinx. When the uterine cavity is obliterated, or most of the endometrium destroyed (Asherman’s syndrome, see Chapter 37), the symptom is amenorrhoea and not cryptomenorrhoea.
Apareunia and Dyspareunia; Inferility Coital problems arise only when the lesion affects the vulva or vagina. Obstruction at any level interferes with conception.
Urinary Symptoms Bladder irritability and retention are caused by haematocolpos and pyocolpos. Closure of the vulva can be so extensive as to cause retention of urine, dysuria or dribbling (Fig. 15.22). Treatment Obstruction of the vulva, vagina and cervix can be treated by separation or incision of adhesions, excision of membranes, dilatation under anaesthesia or by plastic surgery according to circumstances. The subsequent local application of an acriflavine in liquid paraffin dressing, or of a corticosteroid preparation, daily for 14 days helps to prevent recurrence of the trouble. Agglutination of the labia in infancy may be treated by simple incision or
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Jeffcoate’s Principles of Gynaecology digital separation under general anaesthesia, keeping them apart with a lanoline dressing for 1-2 weeks afterwards. This gives excellent results but is said to be unnecessary in that the labia can, in 90 per cent of cases, be persuaded to fall apart spontaneously merely by the regular application of an oestrogen ointment for 2-4 months. Uterine adhesions can be broken down with cervical dilators and a curette if they are flimsy, or they can be divided under direct vision at hysteroscopy, using flexible or semi-rigid scissors, the monopolar needle electrode or the Nd:YAG laser. Postoperatively the uterine cavity may be held open with a small intrauterine
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contraceptive device (IUCD). The other alternatives are: the insertion of a Foley catheter into the uterine cavity and distension of the balloon with gradually increasing volumes of fluid (up to 20 ml) during the next 1-2 months; and the administration of oestrogen and progestogen, alone or in conjunction with insertion of an IUCD or the catheter treatment. Obstruction of the fallopian tube causing infertility. Sometimes the genital tract above the level of the obstruction is best removed; this applies particularly to haematometra and pyometra occurring in women past the years of childbearing.
16
Pelvic Organ Prolapse
CHAPTER
Uterine and Vaginal Prolapse Prolapse of the Ovaries
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Pelvic organ prolapse refers to protrusions of the pelvic organs into or out of the vaginal canal. UTERINE AND VAGINAL PROLAPSE Prolapse, procidentia (from the Latin procidere, to fall) or downward descent of the vagina and uterus is a common and disabling condition. Vaginal prolapse can occur without uterine prolapse but the uterus cannot descend without carrying the upper vagina with it.
Supports of Uterus (Figs 16.1A and B) Apart from the normal position- anteverted anteflexed there is a three tier system consisting of the following: – Upper – Middle (strongest and important) – Lower
Upper Tier • • • • •
Weak Mostly by maintaining the uterus in anteverted position Endopelvic fascia Round ligaments Broad ligaments with intervening pelvic cellular tissues
Middle Tier • Strongest support of uterus • Cervico vaginal junction • Pelvic cellular tissue
Inferior Tier • Indirect support to the uterus • Principally given by the musculofascial tone of the hollow vagina which is amply supported by the fascial condensation at the vault and by the pelvic floor at the lower end.
Jeffcoate’s Principles of Gynaecology
Types
Uterine (Uterovaginal) Prolapse The pelvis may be said to consist of 3 compartments: the anterior, middle and posterior. Descent of the anterior compartment results in cystocele and urethrocele, that of the middle compartment in descent of the uterine vault and enterocele, and that of the posterior compartment in rectocele. In order to descend, the uterus becomes slightly retroverted to lie in the axis of the vagina. When the prolapse is reduced, however, the uterus is often found to be anteverted. The imperfection of the grading systems are evident from the number of systems that have been developed over the years. Various classifications have been described. According to one scheme, three degrees of uterine descent are recognised (Fig. 16.2A). First degree: Descent of the uterus but the cervix remains within the introitus. Second degree: Descent to the extent that the cervix projects through the vulva when the woman is straining or standing.
Figs 16.1A and B: Different supports of uterus
A third degree, i.e. complete procidentia or general prolapse: The entire uterus prolapses outside the vulva. The whole vagina, or at least the whole of its anterior wall, is everted. In Shaw’s classification, descent is classified into four degrees - the first degree remains the same as above, but the second degree is one where the cervix descends to the level of the introitus; the third when it projects through the vulva; and the fourth degree is complete procidentia. Baden’s system of grading is similar to Shaw’s but uses the hymen as a reference point. Each component is graded from 0 to 4 with the patient straining. Urethrocele, cystocele, prolapse, rectocele 0 Normal 1 Descent to half way to hymen 2 Progression to hymen 3 Progression halfway through hymen 4 Maximal progression through hymen
Figs 16.2A and B: (A) Degrees of uterine prolapse, (B) The anatomy of second-degree uterine prolapse associated with cystocele and enterocele. A rectocele is not present. The supravaginal cervix is elongated
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Enterocele 0 Normal. Maximum of 2 cm of cul-de-sac between posterior cervix and rectum 1 Herniation of cul-de-sac to one-fourth of distance to hymen
Pelvic Organ Prolapse 2 3 4
Herniation to two-fourths of distance toward hymen Herniation to three-fourths of distance toward hymen Herniation to hymen
Chronic perineal laceration 0 Normal (no more than hymenal laceration) 1 Involvement of anterior half of perineal body 2 Involvement of perineal body but not anal sphincter 3 Involvement including anal sphincter 4 Involvement including anal mucosa However, these systems do not provide accurate quantification for scientific comparison, lack reproducibility and specificity and may not accurately describe the structures associated with the sites of prolapse. To address these problems, the International Continence Society has therefore approved a new system, the Pelvic Organ Prolapse Quantification (POPQ) staging system, which measures in centi-meters the positions of 9 sites on the vagina and perineal body in relation to the hymen (Figs 16.3A and B). These 9 sites are as follows: Aa - located 3 cm proximal to the urethral meatus on the anterior vaginal wall; Ba - the most distal position of the upper anterior wall; C - the most distal edge of the cervix or vaginal cuff; D - the location of the posterior vaginal fornix; Ap - located 3 cm proximal to the hymen on the posterior vaginal wall; Bp - the most distal position of the upper portion of the posterior vaginal wall. In addition, the diameter of the genital hiatus (gh), width of the perineal body (pb), and the total vaginal length (tvl) are measured and recorded on a grid form
(Fig. 16.3B). A final prolapse stage from 0 to 4 can be assigned according to the severity of the greatest degree of prolapse. It is important to recognise that these measurements can change according to the position of the patient, e.g. standing or lithotomy, and by insertion of a speculum. It is also important to mention whether the patient was straining or whether traction was applied. Measurements at points gh and pb are completed first. A speculum is then placed in the vagina to allow introduction of a spatula and measurement of tvl. Points C and D are next measured during maximal valsalva effort. Lastly, points Aa, Ba, Ap and Bp are measured. Complete procidentia is not common and many cases so diagnosed are really examples of severe second-degree prolapse. The mistake is made because elongation, hypertrophy, congestion and oedema of the cervix account for such a large protrusion of tissue as to make it appear that the whole uterus must be outside the vulva (Fig. 16.8). In fact, the uterus cannot escape from the introitus unless it remains small; when it does, a failure in all the genital supports is implied — a condition of total or general prolapse. Vaginal Prolapse
Anterior Compartment Defects The prolapse may involve mainly the upper or the lower anterior vaginal wall and, according to the structure underlying it, the condition is then termed cystocele or urethrocele (Fig. 16.4).
Figs 16.3A and B: (A) Graphic representation of points used to quantify prolapse (see text), (B) Line diagram showing contrasting measurements of normal supports (a) and post-hysterectomy vaginal eversion (b) International Continence Society Standardisation of Terminology of Female Pelvic Organ Prolapse and Pelvic Floor Dysfunction. (Reproduced with permission from Bump et al., Am J Obstet Gynecol, 1996,175:12-14)
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Fig. 16.4: Cystocele
In cystocele, the bladder base descends with the vaginal wall and ultimately forms a pouch which, when the patient strains, reaches a lower level than the internal urethral meatus (Fig. 16.10). The part distal to the interureteric ridge in the bladder is called an anterior cystocele and that proximal to it is called the posterior cystocele. Both types usually coexist. An anterior cystocele represents a weakness in the support of the bladder neck, urethrovesical junction and proximal urethra, caused by weakness of the pubocervical fascia and the pubourethral ligaments. This weakness may be paravaginal, i.e. at the lateral
attachments of the pubocervical fascia to the pelvic side walls; transverse, i.e. where the pubocervical fascia blends into the pericervical ring of fibromuscular tissue in front of the cervix; central, i.e. above the vaginal mucosa in the midline; distal, i.e. where the urethra passes through the urogenital diaphragm. Combinations of these defects may occur. An anterior cystocele is commonly associated with genuine stress urinary incontinence because of the loss of the normal urethrovesical angle. A posterior or true cystocele may be asymptomatic or may be noticed protruding through the vaginal introitus. If it is very large it leads to difficult or incomplete emptying of the bladder. It is not usually associated with genuine stress incontinence unless an anterior cystocele coexists. In urethrocele the urethra is dislocated from the subpubic angle and is displaced backwards and downwards on straining. This lesion means damage to the triangular ligament which ordinarily fixes the urethra forwards; the urethra itself is not dilated. Radiologically, there is a resultant loss of the urethrovesical angle.
Middle Compartment Defects This includes enterocele and massive eversion of the vagina. The enterocele (Figs 16.2 and 16.5) is a herniation of the pouch of Douglas which contains loops of small bowel, as the name suggests, or omentum. This is an important condition because if its correction is overlooked at the time of surgery, the patient may present with a recurrence of the prolapse.
Figs 16.5A and B: Uterine prolapse with an enterocele bulging behind a congested and oedematous cervix
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Pelvic Organ Prolapse Three types of enterocele are identified: • Pulsion enterocele: The vaginal vault is pushed outward by conditions which increase intraabdominal pressure, e.g. chronic respiratory problems, lifting of heavy weights, etc. • Traction enterocele: A pre-existing weakness in the anterior compartment and uterine descent pull down the vault. • Iatrogenic: This follows a vault suspension procedure or procedures such as Burch or Marshall-MarchettiKrantz which produce a change in the vaginal axis and subject the vault to abnormal pressures. Massive eversion of the vagina or vault prolapse may or may not exist with cystocele, rectocele and enterocele. Patients with enterocele and vault prolapse present with backache, pelvic heaviness and pressure or a ‘bearing down’ sensation.
rectovaginal examination and in the erect position, if necessary, the exact location and type of defect, i.e. upper, mid or lower third of the vagina; linear or transverse. Assessment of the levator plate by palpation between the two fingers inside the vagina and the thumb outside on the perineum is also an essential part of the assessment. Integrity of this plate is vital to maintaining the vagina in its correct position. Adequacy of vaginal length so that its apex is well above the levator plate is essential for preventing recurrence of the prolapse. The only exception to this rule is in the case of radical surgery where, despite a short vagina, prolapse is never seen. This is because of the extensive scarring which occurs around the vagina consequent to extensive tissue dissection.
Posterior Compartment Defects
The epithelium of the prolapsed vaginal walls and of the portio vaginalis, being constantly exposed to the air and possibly to trauma, becomes thickened, corrugated and white with keratin (Figs 16.8A and B).
Rectocele and perineal body descent are the main components of the posterior compartment defects. The importance of perineal body descent has been recognised as an additional component in the New York modification of the POPQ staging system. Rectocele (Figs 16.6 and 16.7A and B) is caused by the weakening of the fibres of the rectovaginal fascia (Denonvillier’s fascia). As with anterior compartment defects, it is important to assess the condition by
Fig. 16.6: A small rectocele
Complications
Keratinization of the Vagina
Decubital Ulceration Ulceration of the prolapsed tissue is often said to be caused by friction with the thighs and clothing. Although this may be partly true, it is notable that the ulcer is nearly
Figs 16.7A and B: (A) Gross prolapse of the vaginal wall and, without further investigation, it is impossible to say whether it is a cystocele or rectocele. (B) Insertion of a speculum to hold back the anterior vaginal wall shows that the lesion is a rectocele
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Jeffcoate’s Principles of Gynaecology always on the most dependent part of the cervix or vagina, and not at the sides where friction is greatest (Figs 16.8 and 16.9). It is to be regarded, therefore, more as the result of circulatory and nutritional changes than of trauma, and as being aetiologically similar to a varicose ulcer of the leg. Hypertrophy of the Cervix
Elongation of the Supravaginal Cervix (Fig. 16.2B) If the lower cervix and vaginal vault descend while the upper cervix remains well supported, the supravaginal cervix becomes elongated. In this way the total length of the uterus can become considerably increased and a cavity measurement of 12 or 15 cm is by no means uncommon. This change does not occur in total prolapse where all the supports of the uterus fail.
Congestion and Oedema (Fig. 16.5) The downward displacement of the uterus puts tension on the descending vascular connections of the cervix, interfering with the venous and lymphatic drainage.
Obstructive Lesions of the Urinary Tract A large cystocele, with angulation of the urethra during straining, causes difficulty in emptying the bladder; this results in hypertrophy of the bladder walls and trabeculation (Fig. 16.10). The downward movement also involves the lower ends of the ureters, so they become attenuated and constricted in the ureteric canals at the sides of the uterus. The drag is manifested by an exaggeration of the interureteric bar (Fig. 16.10). Back pressure from the bladder and obstruction of the lower ureter lead ultimately to hydroureter and hydronephrosis (Fig. 16.11). Infection of The Urinary Tract: Renal Failure If the pouch of a cystocele is low it may not be emptied during micturition. In such circumstances and if the cystocele is chronically unreduced, a calculus can form in the pouch. The residual urine favours the growth of organisms so cystitis complicates cystocele sooner or later. There may also be pyelitis and pyelonephritis, especially if the upper urinary tract is dilated. The final outcome may be renal failure.
Glandular Hypertrophy (‘adenomatous change’) The state of chronic congestion sometimes leads to actual hypertrophy or hyperplasia of the glandular and connective tissue elements in the cervix.
Incarceration of the Prolapse
Fig. 16.8: Uterovaginal prolapse with healing decubital ulcers. The vaginal epithelium is keratinized as a result of exposure. The cervix is hidden behind the prolapsed vaginal walls
Fig. 16.9: Uterovaginal prolapse with decubital ulceration of the cervix. Without further investigation it is impossible to say whether this represents prolapse or complete procidentia
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The extruded cervix and adjacent vaginal walls sometimes become so congested and oedematous that
Pelvic Organ Prolapse
Fig. 16.10: Lateral urethrocystography to show the effect of gross uterovaginal prolapse with cystocele on the urethra, bladder and ureters. The uterine cavity is marked by a metal stem. Inset: Explanatory tracing of the radiograph. The crenated outline of the bladder indicates hypertrophy of the detrusor muscle. The ridge, marked by an arrow on the inset, is the hypertrophied interureteric bar. The bladder hypertrophy is the result of efforts to empty the cystocele during voiding and because of difficulty caused by angulation of the urethra. The lower ends of the ureters are dragged down to the level of the ischial tuberosities. (By permission of Mr Henry Roberts and of the Editor, J Obstet Gynaecol Br Emp)
the patient finds the prolapse irreducible. For the medical attendant the problem is not difficult; all that is necessary is to grip the whole mass and squeeze it back in reverse order, that is, the lower vaginal wall first and the cervix last. Only once have I seen a prolapse which could not be reduced. If true incarceration does occur, it is first treated by keeping the patient lying flat with the foot of the bed raised for 1-3 days, and applying ice packs to the congested tissues. Carcinoma of the Cervix or Vagina It is a remarkable fact that, irrespective of chronic irritation and ulceration, cancer of the cervix or vagina is rarely seen in untreated cases of prolapse. When it is, the symptoms of prolapse often disappear as the tissues become fixed. Genital Prolapse and Pregnancy If the woman suffering from genital prolapse conceives, no special problems usually arise. In the first trimester, increased uterine weight associated with relaxation and congestion of pelvic tissues tends to accentuate the
Fig. 16.11: Dilated and displaced ureters associated with uterovaginal prolapse, demonstrated by intravenous pyelography
prolapse. Later, however, when the uterus and its contents rest on the pelvic brim, the prolapse is often less troublesome. Nevertheless the uterus sometimes remains low in late pregnancy and delivery at term through a cervix lying outside the vulva is described. Aetiology The occurrence of prolapse implies failure of one or more of the supports of the uterus and vagina which are described in Chapter 2. In 95 per cent of cases of prolapse, the patient is multiparous and the implication is that childbearing is an important causal factor. Nevertheless, it should be recognised that the majority (probably not less than 80%) of middle-aged women are parous, and that those who do develop prolapse might have done so even if they had remained childless. The part played by childbirth should not, therefore, be overestimated. Predisposing Factors
Congenital or Developmental Weakness of the Supports This is the most important of all factors and it operates in multiparous as well as nulliparous prolapse. It may explain why prolapse often follows easy rather than difficult
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Jeffcoate’s Principles of Gynaecology labour, the inherent weakness of the fibromuscular tissues allowing rapid dilatation of the birth canal as well as subsequent prolapse. Sometimes, during the examination of a young nulliparous woman, it will be noted that the vaginal wall is atonic and that the uterine supports are weak; it is then possible to foretell that, if she ever has a baby, she will inevitably develop prolapse. Syndromes such as the Ehlers-Danlos syndrome are characterized by fascial and connective tissue weaknesses. These women have a high incidence of urinary incontinence and most authors believe that the incidence of pelvic organ prolapse is also increased in this group. Congenital weakness of pelvic floor ligaments and fascia may also be found with spina bifida or bladder extrophy. Other developmental features which favour prolapse are: shortness of the vagina; deep uterovesical and uterorectal peritoneal pouches; and, possibly, uterine retroversion, but this is not as important as was formerly believed. The part played by an inherent defect in the supporting tissues is also evidenced by the fact that prolapse, both nulliparous and multiparous, has a strong familial incidence (Figs 16.12A and B). True congenital prolapse is rare but cases are described in which the uterus is displaced outside the vulva at birth. When the baby is otherwise normal, this happening may be related to prolonged pressure of the birth canal
on the foetal abdomen during breech delivery. In such a case, immediate replacement of the uterus is said to be followed by ‘permanent’ cure; it is difficult to believe that the prolapse does not recur in adult life.
Injury Sustained During Childbirth The delivery of a child inevitably disturbs, stretches and sometimes tears the supports of the pelvic viscera; if these are already weak, they subsequently fail. The exact injury and the mechanism whereby it is sustained is unknown. One possibility is premature bearing down or fundal pressure before full dilatation of the cervix. Traction on the presenting part before the cervix is fully dilated could damage the cardinal ligaments, so care is necessary in using the vacuum extractor during the first stage of labour. Denervation changes have been documented in the pelvic floor and anal sphincter following vaginal delivery. These are thought to lead to temporary, and sometimes permanent, urinary and faecal incontinence. Use of positions other than squatting for delivery may increase the incidence of prolapse. Perineal and vaginal tears, even if they become infected, do not cause prolapse although they are alleged to do so. Indeed, it will often be noted that a scarred area of the vagina is the only part which does not prolapse, and that the uterus sometimes depends for its support on a deep laceration in the cervix and vaginal vault. Moreover, it is a well-accepted clinical observation that it is very uncommon to see descent of either the uterus or the vaginal walls in cases of unhealed complete perineal tear. Good puerperal rehabilitation by proper exercises is important in preventing prolapse. To summarize, the evidence so far available suggests that overstretching or prolonged distension of the vagina with disruption of its fascial envelope is more conducive to vaginal prolapse than is obvious tearing, and that a perineal laceration or episiotomy which allows a quicker second stage may be protective although there are some who doubt this. As regards uterine prolapse, little can be said except that it is rarely seen in women who have only been delivered by caesarean section!
Surgical Injury Figs 16.12A and B: Nulliparous uterovaginal prolapse occurring in sisters, (A) Virgin aged 50 years, (B) Virgin aged 45 years. A third sister had had one child and was operated on for prolapse 5 years previously
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Contrary to what is often stated, hysterectomy is not a cause of subsequent vaginal or vault prolapse. This operation does, however, sometimes reveal a pre-existing weakness. Thus, a very large or well-supported uterus
Pelvic Organ Prolapse may hold up a vagina whose own supports are weak and this defect may become apparent when hysterectomy is carried out. Vault prolapse is as likely to occur after subtotal than after total hysterectomy, despite the fact that the latter involves division of more elements of the transverse cervical ligaments. But it does leave more fibrosis and the scar tissue might have a supporting role. If the cervix is not removed it may act like the apex of an intussusception and encourage the vault to evert. Vaginal hysterectomy is alleged to be more commonly followed by vault prolapse than is abdominal hysterectomy. But this is because many gynaecologists only adopt the vaginal approach when there is some degree of prolapse already present. If they fail to strengthen the vaginal supports and to excise any enterocele while removing the uterus, subsequent vault prolapse is almost inevitable. Other things being equal, vaginal hysterectomy is no more likely to be followed by vaginal prolapse than is abdominal hysterectomy; it should be less likely because it offers the surgeon an opportunity to correct any weakness already present. Vaginal or uterovaginal prolapse is sometimes seen following abdominoperineal excision of the rectum and is said to be a late complication of 4 per cent of such operations.
(for example, nursing a sick friend or relative) and straining at stool. • Increased weight of the uterus resulting from subinvolution, myohyperplasia or a small tumour. A uterine tumour which is so large that it rests on the pelvic brim prevents prolapse. • Traction on the uterus by vaginal prolapse or by a large cervical polyp. In other words, descent of the vagina can precede and possibly cause uterine prolapse. The rough surgeon can precipitate prolapse by pulling strongly on the cervix during an operation. Symptoms The amount of discomfort and inconvenience experienced by the patient is extremely variable. Some women suffer complete procidentia for many years without being seriously incapacitated, and without having to restrict their activities. On the other hand, other women complain bitterly when they suffer only a moderate degree of uterine or vaginal descent; the difference may in part be explained on the basis of resistance offered by the supporting ligaments. Little resistance, as in gross uterovaginal prolapse, means little discomfort. As a rule, only a few of the following possible symptoms are seen in any one case. The characteristic of nearly all symptoms is that they are immediately and completely relieved by lying down.
Atrophy of Supporting Tissues at the Climacteric Congenital or developmental weakness of the pelvic supports, and obstetrical injuries to them, often do not become manifest until after the menopause. Until that time, the supports remain adequate but the atrophy which follows cessation of ovarian function is the ‘final straw’ and is followed by prolapse within a few years. Prolapse sometimes suddenly appears 3 or 4 weeks after delivery, whereupon the woman rests for a few days and then often has no more trouble until the menopause. Nulliparous prolapse is mostly seen at or after the menopause but I have known it to occur in unmarried girls in their late teens.
A Sensation of Swelling or Fullness in the Vagina This, or a complaint of ‘something coming down outside’ is common. The swelling or ‘something’ may be the cervix, cystocele, rectocele or all three. A Dragging Discomfort in the Lower Abdomen and Pelvis This sort of symptom is also described as a ‘bearing down sensation’ because the swelling in the vagina gives the woman a desire to evacuate it. Urinary Symptoms
Activating Factors If a weakness is present, the circumstances likely to precipitate the onset of prolapse are as follows: • Increased intra-abdominal pressure caused by a chronic cough, chronic constipation, ascites, tumour formation, lifting heavy weights, doing extra work
These depend on descent of the anterior vaginal wall and on displacement of the bladder and urethra.
Frequency This at first is only diurnal and is due to mechanical irritation of the trigone on incomplete voiding. When
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Jeffcoate’s Principles of Gynaecology the frequency becomes nocturnal as well as diurnal and is accompanied by scalding, it means that the situation is complicated by cystitis. Urgency may also occur but it is important to exclude other causes such as detrusor instability.
for prolapse it is most often because the operation provides the patient with a period of enforced rest. Vaginal prolapse certainly does not cause backache; if uterine prolapse does, it is because of traction on the uterosacral and cardinal ligaments.
Difficulty in Emptying the Bladder
Discharge
The patient finds it difficult to empty the pool of urine in a large cystocele and the more she strains the greater the difficulty. Thus when she relaxes at what she believes is the completion of the act, she has a desire to pass urine again immediately. In severe uterovaginal prolapse the urethra may become so acutely angled that retention results (Fig. 16.10). The intelligent woman gets over these difficulties by digitally holding up the prolapse during micturition.
A purulent and sometimes bloodstained vaginal discharge is a manifestation of decubital ulceration. Leucorrhoea can be caused by increased activity of the cervical glands associated with congestion.
Stress Incontinence Although traditionally regarded as a symptom of prolapse, stress incontinence of urine occurs as frequently in women without, as in those with, genital prolapse. In both groups the incidence is 40 per cent. Urethral incompetence is not related to the type or severity of the displacement of the uterus and anterior vaginal wall, nor to the position of the bladder and urethra in the pelvis. The cure of stress incontinence is not dependent on the anatomical success of an operation for prolapse. For these and other reasons, urethral incompetence is best dissociated from prolapse. Difficulty in Emptying the Rectum This is a common symptom of rectocele, although many women are too embarrassed to mention it spontaneously. Faeces collect in the forward bulge of the bowel and cannot be evacuated unless the rectocele is held back digitally. Symptoms are sometimes disproportionate to the degree of defect. Backache This is in the midline at the lumbosacral or sacral level and is diffuse, deep seated and unaccompanied by local tenderness. It is completely and immediately relieved by rest and is never experienced in bed or on rising in the morning; it comes on gradually during the day. Contrary to what was formerly believed, prolapse is a rare cause of backache; when this symptom is cured by an operation
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Physical Signs The presence, type and extent of prolapse and presence of stress incontinence, if any, can usually be determined by asking the patient to bear down or to cough during examination. Minor degrees of uterine prolapse may only be recognized by feeling descent of the cervix while the patient is straining. Rectal examination is useful to demonstrate rectocele and to distinguish it from enterocele. Sometimes fairly severe degrees of prolapse are not evident at the time of examination because: the woman is not straining hard for fear of causing an escape of flatus or faeces; she may have been resting immediately prior to examination; if she has been wearing a pessary for a long time it may be several days or weeks before the prolapse becomes obvious again. If there is doubt the patient should be asked to stand or walk for some time before examination. Occasionally it is necessary to test for uterine descent by pulling on the cervix with a volsellum. Differential Diagnosis From the standpoint of symptoms and signs, prolapse has to be distinguished from the following. • A vulvar tumour or any polypoid tumour which projects through the vulva on straining. A cervical polyp (Fig. 16.13) and a urethral caruncle are the most frequent causes of confusion. Metastases from uterine tumours, e.g. adenocarcinoma or choriocarcinoma may be seen. • Hypertrophy and elongation of the cervix. • Vaginal or periurethral cysts. These may be congenital, e.g. Gärtner’s cyst or inclusion dermoid cysts following trauma or surgery. They simulate cystocele or rectocele but are different in that they
Pelvic Organ Prolapse
Figs 16.14A and B: A vaginal cyst simulating prolapse, (A) The tumour presenting at the vulva, (B) Lateral displacement shows that the tumour is a cyst arising from the side wall of the vagina and therefore probably wolffian duct in origin Fig. 16.13: A cervical polyp simulating prolapse. The woman in this case, aged 55 years, had had a repair operation for prolapse several years previously. Her complaint was a ‘recurrence of the prolapse’. The tumour, however, proved to be a cystic adenoma arising from the cervical stump (cervix previously amputated) of a well-supported uterus
cannot be reduced (Figs 16.14A and B). If there is doubt, a rectal examination or the passage of a sound into the bladder indicates the anatomy of the swelling. • A diverticulum or prolapse of the urethra. This can be mistaken for urethrocele or cystocele. • Inversion of the uterus • Inversion of the bladder • Varicose veins of the vulva or vagina, haemorrhoids and rectal prolapse • Congestion of the vagina associated with vaginitis which gives a sensation of fullness and is often mistaken by the patient for prolapse • All other causes of low backache • All other causes of bladder symptoms. Although prolapse can usually be recognised easily, it may be difficult to say whether it is responsible for the patient’s particular symptoms, especially if the prolapse is not severe and the complaint is an ache or a pain. If there is doubt a pessary test should be applied. Only if the discomfort is relieved by a ring, and if it returns when the ring is removed, can it be credited to the prolapse with reasonable certainty.
Prevention
During Labour and the Puerperium • Avoid attempts at delivery, by the patient as well as by the attendant, before the cervix is fully dilated. • Avoid an unnecessarily long second stage by episiotomy and, if need be, by low forceps or vacuum extraction. • Repair all tears and incisions accurately in layers. • If possible, use delayed absorbable sutures for the repair of the muscle layer. • Do not express the uterus when attempting to deliver the placenta. • Encourage pelvic floor and other postnatal exercises. These favour involution of all the pelvic tissues. Early ambulation is more likely to prevent than to cause prolapse. • Treat puerperal constipation in order to avoid strong bearing down efforts while supporting ligaments are slack. • The correction of puerperal retroversion, once advocated strongly, is of no value.
At Hysterectomy Many suggest that the chance of subsequent vaginal prolapse can be reduced if, during abdominal hysterectomy, the stumps of the uterosacral and cardinal
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Jeffcoate’s Principles of Gynaecology ligaments are stitched to the vaginal vault. A deep cul-desac should be obliterated by Moschowitz sutures. Sacropexy can be done in high-risk situations, e.g. collagen disorders. During vaginal hysterectomy, excision of redund-ant peritoneum, tightening of the cardinal and uterosacral ligaments and their inclusion in the vaginal vault are important prophylactic steps. The increasing acceptability of oestrogen replacement therapy in postmenopausal women may decrease the incidence and severity of prolapse. Treatment
Physiotherapy When there is only a minor degree of prolapse, and especially during the 6 months following delivery, Kegel’s pelvic floor exercises carried out regularly are of some value. Their effect is limited, however, because they only influence the voluntary muscles, i.e. the bulbocavernosus, superficial and deep transverse perineal and levator ani muscles and not the main fascial supporting tissues. Vaginal cones of increasing weight have been tried by some with limited success.
Pessary Treatment Palliative treatment consists of preventing the descent of the uterus and vaginal wall by means of a supporting pessary of which there are many types. Those most commonly employed are ‘rings’. The insertion of a pessary may be indicated in the following circumstances. • During pregnancy • Immediately after pregnancy and during lactation • When further childbearing is intended in the near future. This is a debatable indication. • Medical disorders which make operation unsafe • Refusal of operation on the part of the patient • As a therapeutic test to determine if symptoms are due to prolapse • To promote the healing of a decubital ulcer prior to operation. A pessary does not cure prolapse; it merely holds up the tissues. Sometimes, however, if a slight prolapse is controlled for some months the supports recover tone and the patient may then be able to manage without the pessary for some time. This is particularly true in the
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puerperium. However, without concomitant exercises the symptoms gradually worsen and the size of pessary required may increase with time. Operative Treatment
Indications Some sort of surgical procedure is nearly always the best treatment for established prolapse but is only necessary if the condition is causing symptoms or is interfering with the woman’s normal activities. If the prolapse is an incidental finding, and if it is not certain that a patient’s symptoms are attributable to it, operation is best deferred. Nothing is lost by waiting and, even if the condition becomes worse in the meantime, the subsequent operation is not technically more difficult; indeed it may be easier. Youth and the intention to have more children in the future are not contraindications to operation, although they may modify surgical technique (see below). Even if the prolapse recurs after further pregnancies, and this is not inevitable if the manage-ment is good, the original operation is not to be regarded as a waste of time. It is unreasonable to advise the young and potentially active mother and wife to persevere with makeshift measures until she is too old and inactive to enjoy the comfort which surgery can give. Equally, old age and ill health are not necessarily contraindications, for the operation involves little risk if care is taken over anaesthesia. It is easily performed under regional anaesthesia in old women.
Preoperative Management In assessing and correcting the general health of the patient before operation, particular attention should be paid to the urinary system. Urinalysis and blood urea estimations are essential in all cases, pyelography and renal function tests in some. Urinary tract infection should be eliminated lest it show an exacerbation postoperatively. If the vaginal walls are senile and atrophic, oestrogens may be administered in the form of conjugated equine oestrogens, 0.625 mg daily, 3-4 weeks before operation. Alternatively, daily application of oestrogen cream in the vagina may provide the same benefit. The object is to improve the healing power of the tissues. Although some say it is unnecessary, decubital ulceration should be treated before operation. The ulcer
Pelvic Organ Prolapse is always secondarily infected and its very presence means that the tissues have a low healing capacity. To cure it, admit the patient to hospital and keep her lying flat in bed as much as possible. The prolapsed organs are replaced and are packed in position by a tampon of gauze which is changed every day. Impregnation of the tampon with an antiseptic is unnecessary because its action is only to restore the circulation by keeping the organs in normal position. By this method fairly large ulcers heal in 7-14 days. The above treatment, while giving excellent results, means prolonged hospitalization and the physical immobility of the patient may encourage thromboembolism. To avoid these the prolapse can be temporarily controlled, in many cases, by means of a ring pessary. Provided this is made of non-irritant plastic material and does not press directly on the ulcer, it restores the circulation of the tissues so well that healing of a decubital ulcer can be expected in 2-3 weeks.
an intact triangular ligament and compressor urethrae. The bladder is well separated from the uterus and displaced upwards; the pubovesicocervical fascia and the pubo-urethral ligaments are then stitched together in the midline to support the bladder and the vaginal wall is closed. It is important to avoid over-correction of the posterior cystocele to prevent a run-off type of urinary incontinence. The surgical management of stress incontinence is often done at the same time. It is also important to use delayed-absorbable sutures in all cases. In fact, some go so far as to advise the use of a first layer
Types of Operation The aim of surgery is to restore the normal anatomy. A normal vaginal length should be maintained with its axis directed towards S3-S4. Hysterectomy is not essential but it facilitates the repair of an enterocele. In the postmenopausal woman it allows the removal of an organ which may harbour unsuspected disease or be a focus for such a problem in the future. Most importantly, the strength of various supporting structures should be assessed and surgery planned accordingly, supplementing ligamentous and fascial repair with synthetic materials attached to alternate supports, e.g. the sacrospinous ligament, sacrum, etc. if required. In the repair of vaginal prolapse, it is important to identify whether the deficiency is in the central or lateral compartments and whether the split of the fibres is transverse or longitudinal, so that accurate repair is done for optimal results.
Anterior Colporrhaphy This is designed to cure cystocele and urethrocele. The vaginal wall is dissected free from the fascia, bladder and urethra and its redundant part excised. The excised portion is usually elliptical or triangular with its base at the cervix and its apex near the urethral orifice (Fig. 16.15). If there is a transverse ridge about 1 cm above the urethral orifice it is best not disturbed because it marks
Fig. 16.15: The principles of the Manchester operation for uterovaginal prolapse, (A) Incisions for anterior colporrhaphy and for amputation of the cervix, (B) Incisions for posterior colporrhaphy, a procedure included in the classical operation but unnecessary unless a rectocele is present, (C) Suturing of the bases of the cardinal ligaments in front of the cervix before completing the covering of the cervical stump with vaginal epithelium. Suturing the pubocervical fascia before closing the vaginal wall from above downwards, (D) Sutures placed in the edges of the levatores ani before closure of the vaginal wall and perineum. Not shown here, but essential in every repair of this kind, is the opening of the pouch of Douglas behind the cervix immediately after the amputation. All redundant peritoneum is then excised and a culdoplasty done
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Jeffcoate’s Principles of Gynaecology of non-absorbable sutures for fascial support, covered over with a second row of delayed-absorbable sutures. Paravaginal defects can be repaired through an abdominal retropubic approach, through a vaginal retropubic incision or laparoscopically, all of which aim to reattach the pubocervical fascia to the arcus tendinus and to the fascia overlying the obturator internus muscle.
Steps of Anterior Colporrhaphy Principles • To excise a portion of the relaxed anterior vaginal wall • To mobilise the bladder and push it upwards after cutting the vesico cervical ligament • Bladder is permanently supported by tightening the pubocervical fascia
Operative steps (Figs 16.16A to H) • Traingular vaginal flaps including the fascia separated from endopelvic fascia • Line of cleavage vesico vaginal space • Vesico cervical ligament is divided • Bladder is pushed upwards • Pubo cervical fascia is plicated with interrupted O catgut sutures • Thus closing the hiatus through which bladder herniates • Redundant portion of the vaginal mucosa is cut on the either sides • Cut margins of the vagina apposed.
Enterocele Repair At vaginal hysterectomy, an enterocele sac should always be looked for and excised after dissection from
Figs 16.16A to H: Steps of anterior colporrhaphy
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Pelvic Organ Prolapse above downwards. A high ligature of the peritoneum can be done by a purse-string ligature which incorporates the round and the uterosacral ligaments as well. The third important step is colporrhaphy to shorten the cardinal-uterosacral complex support of the vaginal cuff. When the uterosacral ligaments are long and strong a McCall-type of culdoplasty is indicated. If, on the other hand, the strength of the cardinal-uterosacral ligaments is doubful, it is safer to anchor the vaginal vault to the sacrospinous ligament as a primary procedure. The enterocele can corrected abdominally by obliterating the pouch of Douglas by the Moschowitz or Halban technique.
Posterior Colpoperineorrhaphy This is a similar type of operation for rectocele and a defective perineum. Ordinarily, a roughly triangular portion of the posterior vaginal wall is excised, the base of the triangle being at the introitus and the apex just above the level of the rectocele. In case of a high rectocele, dissection right up to the cervix and excision of redundant peritoneum of the pouch of Douglas are necessary. The underlying rectovaginal fascia is sutured and the edges of the levatores ani are brought together in the midline. The vaginal wall is then sutured and finally the superficial perineal muscles and skin. The operation has the effect of lengthening the perineum and tightening the introitus. The goal is a normal vaginal axis and a depth of about 10 cm, which can take the vault above the levator plate and prevent later development of enterocele. Endorectal or transrectal repair and placement of a mesh between the vagina and rectum to support the rectovaginal fascia may be indicated in some cases. Postmenopausal women who have undergone repair operations should be advised to continue local oestrogen applications lifelong. If there are no contraindications, they can also be advised standard HRT regimens. The traditional routine performance of posterior colpoperineorrhaphy as a part of all operations for genital prolapse has a historical rather than a sound anatomical basis. Repair of the posterior vaginal wall and perineum is not necessary in at least 50 per cent of operations for prolapse, and then only for the cure of undoubted rectocele (which is the least common form of prolapse). The advantages of avoiding perineorrhaphy in association with other procedures for repair of cystocele
and uterine prolapse are that the patient hardly ever has postoperative retention and cystitis, is relatively free from postoperative local discomfort and is unlikely to suffer anatomical dyspareunia subsequently. Here it must be emphasized, however, that adequate preoperative examination is essential, otherwise a weakness in the posterior wall left uncorrected may set the stage for recurrence of prolapse. Fothergill or Manchester operation: This operation, variously credited to Donald and to Fothergill, both of Manchester, combines anterior colporrhaphy, amputation of the cervix and posterior colpoperineorrhaphy in one procedure. Fothergill did not always carry out a posterior repair, whereas Donald did. It is appropriate in young women with any degree of uterovaginal prolapse. It is avoided in women anxious for more children because amputa-tion of the cervix is associated with a high incidence of infertility, premature delivery and cervical dystocia. Dilatation and curettage is performed as the first step of the operation to facilitate creation of the vaginal flaps and to rule out malignancy. The most essential feature of the operation is the suturing of the cut cardinal ligaments and other paracervical tissues in front of the stump of the cervix. This has the effect of tightening the cardinal ligaments and of maintaining anteversion by pulling the cervix upwards and backwards; it also lengthens the anterior vaginal wall- an important technical point. If an enterocele is present, it is corrected. Extended Manchester operation: Improper attention to an enterocele or a deep cul-de-sac may lead to a recurrence of the problem. In the extended Manchester operation, the cul-de-sac is opened, the peritoneum excised and the uterosacral ligaments plicated together. Shirodkar dissected the uterosacral ligaments and sutured them in front of the cervix, as he believed that these ligaments were more important supports of the uterus than the cardinal ligaments. Further, in his operation, amputation of the cervix was avoided, thus offering a better alternative for women who desired further childbearing.
Vaginal Hysterectomy with Anterior Colporrhaphy and Posterior Colpoperineorrhaphy Vaginal hysterectomy with posterior culdoplasty and colporrhaphy is preferred in premenopausal patients when prolapse is complicated by uterine haemorrhage
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Jeffcoate’s Principles of Gynaecology or disease; or when some condition such as diabetes or obesity indicates a higher than average risk of the subsequent development of uterine cancer; or when the patient is over 70 years of age. In postmenopausal patients, removal of the uterus facilitates hormone replacement therapy in that there is no withdrawal bleeding and no need for progesterone or for monitoring of endometrial changes. In this latter group, both tubes and ovaries may be removed vaginally at the same time. Vaginal hysterectomy by itself does not cure prolapse. For this purpose it remains essential, after the uterus is removed, to excise any redundant peritoneum, to strengthen the vaginal vault by approximating the uterosacral and broad ligament pedicles and to tighten the pubocervical fascia. If proper attention is paid to these matters, it is not necessary to add posterior colpoperineorrhaphy unless a rectocele is present. Other Operations
Abdominal Sling Operations Abdominocervicopexy- (Purandare’s Cervicopexy) Designed for young women with II or III degree prolapse and who are desirous of retaining their child bearing and menstrual functions. Rectus sheath used as a sling and are anchored to isthmus of the uterus anteriorly with non absorbable sutures. Shirodkars abdominal sling Technically difficult. Merseiline tape is passed through the substance of isthmus posteriorly at the level of attachment of uterosacral ligament with nonabsorbable sutures other end is attached to the anterior sacral ligaments and periosteum in front of sacral promontory. Khanna’s sling Merselene tapes is fixed to the isthmus and the two free ends brought out retro-peritoneally to emerge out at the lateral margins of rectus abdominus and then anchored laterally to the anterior iliac spine on either side. Ventrofixation is of no value for uterine prolapse unless it is combined with some form of vaginal plastic procedure. A modified Gillianis operation is sometimes combined with a limited vaginal repair, or with tightening of the uterosacral ligaments, in the treatment of uterine prolapse in young women, especially when they wish to preserve uterine function, fertility and a functional vagina.
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Other sling operations have been described in young women with congenital prolapse which include abdominal operations a modified Gilliam’s operation using a strip of fascia from the anterior rectus sheath; fixation to the anterior superior iliac spine with mersilene tape; sacrospinous fixation. Transvaginal sacrospinous uterine fixation has also been described and this may carry the advantage of a decreased potential for adhesion formation. Abdominal hysterectomy is sometimes needed when prolapse surgery needs to be combined with the removal of pelvic tumours or when suprapubic colpourethropexy for severe genuine stress incontinence is planned. Redundant anterior and posterior vaginal walls can be excised and the deep cul-de-sac obliterated by the Moschowitz technique. Partial obliteration of the vaginal lumen by creating a septum between the anterior and posterior vaginal walls (Le Fort’s operation) is sometimes advocated for severe prolapse in old women, and for vaginal eversion after hysterectomy. The Manchester operation, however, is just as safe and the results are better, especially if the surgeon is prepared to sacrifice coital function by making a ‘pencil vagina’. Moreover, the drag of the septum, created in Le Fort’s operation is liable to open the internal urethral sphincter to cause stress incontinence. The Le Fort’s operation can be done under local anaesthesia and this may be of value in some old women with severe medical problems.
Operations for Vaginal Prolapse after Hysterectomy Eversion of the vagina following hysterectomy in an older and more sedentary patient is best treated by a transvaginal vault suspension with anterior colporrhaphy and posterior colpoperineorrhaphy. This method is also suitable for women with a previous abdominal hernia repair with a mesh in situ or with a history of intestinal obstruction or adhesive disease. Sacrospinous ligament fixation is a suitable method in these patients. Injury to the pudendal vessels and nerves can occur. It is important to identify and correct an enterocele and narrow the vagina, if necessary. Abdominal sacral colpopexy provides the surest and strongest correction for vaginal vault prolapse and is preferred in younger patients with more strenuous physical activity or those with associated diseases that increase intra-abdominal pressure chronically, e.g.
Pelvic Organ Prolapse asthma, chronic obstructive pulmonary disease, chronic constipation, etc. It is also the preferred operation in patients with previous failed repairs and a shortened, scarred vagina. Mersilene or teflon mesh is used to attach the vault to the anterior longitudinal ligament of the first sacral vertebra. The mesh is peritonealized to avoid bowel entrapment. The venous plexus in front of, and the pelvic nerves lateral to, this ligament can be injured. A culdoplasty by the Halban or Moschowitz technique is done as an essential part of the procedure. The vaginal vault can also be attached to the anterior abdominal wall by mersilene mesh. Strips of fascia from the anterior rectus sheath have been used but these have poorer longterm results and occasionally the patient develops a hernia. Stress incontinence may occur or be aggravated in 10-25 per cent of cases if there is excessive tension on the anterior vaginal vault, for which reason some would also recommend performing a Burch colpourethropexy routinely. Laparoscopic sacrocolpopexy has been undertaken but long-term results are awaited. Results of Operations The results of operations for prolapse depend very much on the skill of the surgeon, and on selection of operation according to the case and the surgeon’s own experience. In general, the anatomical results are good, being permanently satisfactory in at least 90 per cent of cases. Symptomatic results are also good except in respect of the following.
Stress Incontinence If the woman treated for prolapse happens also to suffer from urinary stress incontinence, this symptom is not always cured by anterior colporrhaphy alone even though the anatomical result of anterior colporrhaphy is satisfactory. Moreover, anterior colporrhaphy, by interfering with the internal urethral sphincter, causes stress incontinence in 2-3 per cent of women who do not have this complaint previously. It is essential to have adequate and appropriate preoperative assessment of all women with urinary symptoms and prolapse and perform additional procedures accordingly.
Dyspareunia It is not always realized how often women suffer dyspareunia and apareunia after surgical treatment for prolapse. Twenty-five per cent of women coming to
operation for prolapse have already discontinued coitus. This is usually because of waning libido in husband or wife. Another 25 per cent, however, find that the cure of prolapse brings an end to marital relations. The reasons for this are as follows. • Fear that coitus will impair the result of the operation. • An early attempt at coitus, before tenderness has subsided and without the realization that the introitus is narrower, causes pain. This, together with fear of injury, causes vaginismus. • Often the operation is done at an age when senile atrophy is to be expected. Coitus is discontinued for several months and, when it is attempted again, contracture has taken place. Resignation then takes the place of persistence, especially as the sex urge is weakening in both husband and wife. • Narrowing and shortening of the vagina and introitus is the most important cause. Errors in surgical judgement arise because no allowance is made for involution of overstretched tissues, for muscular relaxation induced by general anaesthesia (and particularly by relaxant drugs), and for senile atrophy. Much of the trouble arises over unnecessary perineorrhaphy. The introitus should be about two fingers loose at the end of surgery. Posterior colpoperineorraphy is to be avoided unless it is clearly indicated, the assessment being made before the woman is anaesthetized. It is also important preoperatively to ask every woman, no matter how old she may be, whether she still practises coitus. If she does, a careful operative technique should be followed by explanation and guidance about the subsequent resumption of the practice. Postoperative HRT is of benefit in improving the results of operation by improving the tone of the tissues and also reducing symptoms of atrophy such as dyspareunia. Failed Operations The following are the reasons for failure to cure prolapse. • An ill-chosen operation • Poor surgical technique, especially in the region around the cervix • Omission to recognize and treat an enterocele. • Shortening of the anterior vaginal wall • Developmental and inherent weakness of the supports. This explains why prolapse is more difficult to cure in nulliparae than in multiparae. • Another pregnancy after the operation.
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Pregnancy after Repair Operations The effects of operations for prolapse on subsequent pregnancies vary with the technique employed. Some are related to amputation of the cervix, some to colporrhaphy.
Amputation of the Cervix The higher the level of amputation, the more likely is childbearing to be affected. The possible effects are: • No effect • Infertility. Many women avoid conception after operation but 75-90 per cent of women with opportunity to conceive fail to do so after cervical amputation. This may be due to a loss of cervical mucus and distortion of the cervical canal. • Abortion and premature labour. The incidence of these complications is decidedly increased. They occur in 20-50 per cent of subsequent pregnancies and are due to cervical incompetence. • Precipitate labour. This occurs because of the absence of cervical resistance. • Cervical dystocia. Excessive fibrosis interferes with cervical dilatation and results in obstructed labour, or in delivery at the expense of a deep laceration in the cervix. The injury may extend to involve the lower segment. Cervical dystocia calls for caesarean section. • Traumatic intrapartum and postpartum haemorrhage. This occurs from tearing of rigid tissues in the cervical stump. Women in whom the cervix has been amputated should be delivered only in a fully equipped hospital because of the risks to both mother and baby.
Colporrhaphy The possible effects of this procedure on childbearing are as follows: • No effect • Dyspareunia, apareunia, and therefore infertility • Delay in the second stage of labour. This is due to failure of scar tissue in the vagina and perineum to stretch. The delivery may ultimately be achieved at the expense of extensive perineal tears.
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• Recurrent prolapse: The chance of prolapse recurring after a subsequent labour is difficult to compute; it varies with the type of operation. After a Manchester operation there is little risk of pregnancy and labour causing a return of prolapse. If, however, anterior colporrhaphy and posterior colpoperineorrhaphy are carried out without amputation of the cervix, as is often the case in young women, there is a high recurrence rate after labour. If the operation has consisted only of perineorrhaphy, vaginal delivery does not usually cause a return of trouble providing episiotomy is carried out. • Stress incontinence of urine cured by urethropexy and anterior colporrhaphy frequently relapses with a subsequent pregnancy or labour. Previous colporrhaphy always calls for delivery in a fully equipped hospital. Caesarean section is indicated not less than 20 per cent of all cases and should be made the rule for women cured of urinary stress incontinence. When the vaginal route is chosen for delivery, episiotomy should be carried out as a routine to shorten the second stage and to minimize stretching and tearing of the paravaginal supports. PROLAPSE OF THE OVARIES This is a relatively unimportant example of prolapse. The ovaries can be very mobile but they are not often significantly low in the pouch of Douglas unless they are the seat of a tumour, or unless there is an associated retrodisplacement of the uterus. The only symptom likely to be produced is occasional sharp deep-seated sickening pain when one or other ovary is touched during coitus. This sensation is reproduced by pressure on the ovary during bimanual examination. In fact, deep-seated dyspareunia attributed to prolapsed ovaries is mostly caused by pressure on the associated retroverted uterus. Symptomatic treatment is preferable; dyspareunia, for example, can nearly always be avoided by modifying coital posture. If an operation is carried out, usually for some other reason, the ovary is usually suspended from the cornu of the uterus by shortening the ovarian ligament, with or without an associated ventrosuspension of the uterus.
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Other Displacements of the Uterus
CHAPTER
Upward Displacement of the Uterus Lateral Displacement of the Uterus Forward Displacement of the Uterus Backward Displacement of the Uterus Retroverted Gravid Uterus Inversion of the Uterus
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The uterus normally has a limited range of movement, so its position in the pelvis is affected by filling of the bladder and rectum, by increasing the intra-abdominal pressure through coughing, laughing and bearing-down effort, and by alterations in posture. The uterus is lower when the woman is standing than when she is lying, and lowest when she is squatting. Nevertheless, the supravaginal cervix is relatively fixed and movement or displacement of the uterus often consists of rotation of the organ around this axis, or of bending of the corpus on the cervix. UPWARD DISPLACEMENT OF THE UTERUS The uterus can be lifted upwards to become an abdominal organ, and the external os may be above the level of the upper border of the symphysis pubis and out of reach of the vaginal examining fingers. Causes • • • • •
A vaginal or paravaginal tumour Haematocolpos A broad ligament tumour and especially a low cervical leiomyoma Any tumour impacted in the pouch of Douglas A collection of pus or blood in the pelvis.
Treatment Treatment is directed to the cause, the displacement itself being of no consequence. LATERAL DISPLACEMENT OF THE UTERUS There may be lateral deviation of the uterus as a whole, or lateral tilting with the corpus directed to one side and the cervix to the other. Except as a sign of the lesion causing it, a displacement of this type is of no significance.
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Causes • A unilateral tumour, inflammatory exudate or collection of fluid, especially if situated in the broad ligament, pushes the uterus to the opposite side. • Adhesions can pull the uterus to one side. Malkani described the deviation of the uterus and cervix to one side of the pelvis as a sign of genital tuberculosis, wherein post-infection scarring results in contractures and pulls the uterus to the affected side. • Operative removal of one adnexum often leaves the uterus leaning towards the side of the operation site. • Unicornuate or bicornuate deformity • Idiopathic. It is common for the uterus to lie or lean to one side without there being an abnormality (Fig. 17.1). In this case the uterus is mobile and can be manipulated temporarily to a normal position. Treatment No treatment other than that of the cause is necessary. FORWARD DISPLACEMENT OF THE UTERUS Forward displacement of the uterus as a whole is usually the result of a tumour or a collection of fluid in the pouch of Douglas, and is then associated with upward displacement. It can also be explained by a previous ventrofixation operation. Acute anteflexion of the uterus
(or forward displacement of the corpus) is not to be confused with acute anteflexion of the cervix (cochleate uterus). It is a normal finding in early pregnancy when the fundus is heavy and the supravaginal cervix is soft and atonic. A fundal leiomyoma or an ovarian tumour can push the corpus downwards. These displacements have no importance in themselves. This was not recognised in bygone centuries, and it is of interest to recall that one of the early uses of mechanical pessaries was to correct anteversion, even normal anteversion, rather than retroversion. BACKWARD DISPLACEMENT OF THE UTERUS Backward displacement of the uterus as a whole (retropronation or retroposition) is the normal reaction to a full bladder and can be caused by any tumour occupying the front compartment of the pelvis. It also occurs as a developmental peculiarity in certain women. In no circumstances is it of any significance. More important are the states of retroversion and retroflexion with which the remainder of this section is concerned. Definitions Retroversion: In this condition the axis of the cervix is directed upwards and backwards in relation to a line drawn through the long axis of the trunk (Figs 17.2C, D, E). Retroflexion: In this condition the long axis of the corpus is bent backwards on the axis of the cervix (Figs 17.2 C, E, F). According to these definitions it is theoretically possible to have retroflexion in an anteverted uterus and anteflexion in a retroverted uterus; such states are described although they are of academic interest only. In practice, retroversion and retroflexion usually occur together and they are often both loosely called retroversion or retrodisplacement. No attempt is made to separate them here, although it may be noted that, of the two, retroflexion is more likely than retroversion to cause symptoms. Degrees of retroversion and retroflexion are also described but are of no practical value. Frequency
Fig. 17.1: Lateral deviation of the uterus, which is common and not significantly abnormal
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Retrodisplacement of the uterus is found in approximately 15 per cent of women.
Other Displacements of the Uterus
Figs 17.2A to F: Uterine version and flexion. (A) Normal anteflexion and version. (B) Cochleate uterus or acute anteflexion of the cervix. The axis of the cervix indicates retroversion but the angle of anteflexion is increased so that the corpus is in normal position in the pelvis. (C) Retroversion and retroflexion. (D) Retroversion. (E) Extreme retroflexion and retroversion. (F) Cochleate type of uterus in reverse; an essentially anteverted uterus (from the direction of the cervix) is sharply retroflexed
Causes
Developmental (congenital) Retrodisplacement of the uterus is most often a developmental anomaly. It is not a congenital malformation because the uterus is without version and flexion at birth. Nearly all cases of retroversion and retroflexion in nulliparous women are of this type, and there is no reason to believe that the same is not true for multiparous women. One physical sign frequently noticeable in these cases is a shallow anterior vaginal fornix; the anterior vaginal wall and cervix appear to be almost continuous. The vagina, too, sometimes appears shorter than average.
Prolapse As the uterus descends it comes into line with the vagina, that is, it is slightly retroverted. Many declare that the retroversion precedes and favours prolapse but the evidence is flimsy; it can just as well be argued that the prolapse causes the retroversion (Fig. 17.3).
Tumours and Adhesions A tumour lying in front of the uterus pushes it backwards; adhesions behind may pull it backwards.
Fig. 17.3: Second degree prolapse
Endometriosis of the uterosacral ligaments and pouch of Douglas is very commonly found in association with retroversion and is a cause of displacement of a previously anteverted uterus.
Puerperal Retrodisplacement is often found to be present when the uterus involutes after pregnancy because, it was once said, it falls backwards while its controlling ligaments are slack and subinvoluted. The uterus is certainly unusually mobile and plastic during the weeks after delivery, and I have often noticed that a uterus which is retroverted 3-6 weeks after delivery becomes anteverted within the following months and vice versa. When the uterus remains permanently retroverted after pregnancy, it is generally safe to conclude that it was in a similar position before pregnancy and that it has merely returned to its normal state. This happening explains why puerperal retrodisplacement, even if treated, usually recurs after each pregnancy. It also accounts for the old observation that if retroversion does not occur after the first pregnancy it is unlikely to do so after subsequent ones. Pregnancy and faulty involution are therefore not very common causes of permanent retrodisplacement of the uterus.
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Symptoms
Rectal Symptoms
It cannot be emphasised too strongly or too often that a mobile retrodisplacement of the uterus is nearly always symptomless, and that it can be regarded as a normal physical trait of many women. Its only real disadvantage is that it favours perforation of the uterus when a sound or other instrument is inserted, in or out of pregnancy. If, however, the uterus is fixed backwards, symptoms are usually present, these being caused by the lesion fixing the uterus rather than by the retrodisplacement itself. These are considered elsewhere. The possible clinical manifestations of a mobile retrodisplacement and their mechanisms are as follows.
Uterine retrodisplacement alone never produces pressure on the rectum or symptoms referred to the lower bowel.
Spasmodic Dysmenorrhoea Developmental retrodisplacement does not affect menstruation but, if the uterus is cochleate in type, spasmodic dysmenorrhoea can be associated. The symptomatology and treatment are the same as for acute anteflexion of the cervix; the retroflexion is incidental and does not need correction.
Pelvic Congestion Syndrome When the uterus assumes or resumes a position of retroversion and retroflexion after pregnancy, involution may be slightly retarded, or so it is said. In explanation it is postulated that the torsion of the broad ligament interferes with the venous and lymphatic return, leaving the pelvic organs congested and oedematous. Persistence of such a circulatory error might later lead to congestive dysmenorrhoea, menorrhagia, polymenorrhagia, premenstrual low back pain, diffuse suprapubic pain, dyspareunia and leucorrhoea. This is an entirely theoretical concept and it is extremely doubtful whether such symptoms — which are features of the ‘pelvic congestion’ syndrome are ever attributable to uterine retrodisplacement. They certainly cannot be if the displacement is developmental in origin because the circulation will be adapted to this. Some of these patients have psychosomatic and psychiatric complaints as well.
Low Backache and Pelvic Pain Despite statements to the contrary, a mobile retroversion probably never causes these symptoms.
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Dyspareunia This is one of the few genuine symptoms of retrodisplacement but is present in only a minority of cases, depending possibly on the length of the vagina. The pain is deep seated and is caused by direct pressure on the uterus itself rather than on an associated prolapsed ovary. It is position-dependent and change of coital position may avoid or reduce discomfort. Some of these patients may have endometriosis.
Infertility Although women with retroversion ordinarily conceive readily, a few find it difficult and it is postulated that this is because the cervix is directed forwards away from the seminal pool, and the ejaculation of semen directly into the external os is less likely. Moreover, the external os tends to be closed by the anterior vaginal wall when coitus is complete (Fig. 17.2E). More importantly, however, some of these women may have associated pelvic pathology such as endometriosis or pelvic inflammatory disease which is the cause of both the retroversion and the infertility.
Abortion Contrary to former belief, retrodisplacement of the uterus is not an important cause of abortion, unless the uterus is impacted in the pouch of Douglas and there is a disturbance in the uterine vascularity. In such cases, it may be a factor in a few cases, operating between the tenth and fourteenth weeks. Physical Signs Inspection of the cervix through a vaginal speculum is often enough to make a provisional diagnosis of retroversion. It is characteristic that the cervix comes into view unusually easily and that the external os points forwards. On bimanual examination the position and direction of the cervix are again valuable signs, especially if it is difficult to define the corpus.
Other Displacements of the Uterus To be certain of the diagnosis, the body of the uterus should be felt in the pouch of Douglas and recognised by its size, shape and continuity with the cervix. Tenderness is a striking although unexplained feature of the retroflexed uterus, even when there is no associated disease (hence the dyspareunia). In the past, when more importance was attached to retroversion, uterine position was often confirmed by passing a sound. This is now rarely done except as a precaution preliminary to the insertion of an instrument or an intrauterine contraceptive device. Differential Diagnosis Uterine retroversion and retroflexion have to be distinguished from the following. • Acute anteflexion of the cervix, confusion arising because of the forward direction of the cervix • A tubal or ovarian swelling prolapsed in the pouch of Douglas or adherent to the back of the uterus • Faeces or other mass in the lower bowel • A tumour such as endometriosis in the pouch of Douglas or in the rectovaginal septum, pelvic haematocele and an abscess • A leiomyoma or other tumour in the posterior wall of the uterus.
Prevention Preventive measures used to be suggested during the weeks immediately after abortion or labour and they consisted of the following. • Regular emptying of the bladder to avoid overdistension • Pelvic floor exercises • Early ambulation • Posture. The puerperal woman used to be advised to lie face downwards for ½—1 hour once or twice daily with the idea of encouraging anteversion. If this treatment had any value the most important time for it was between the tenth and twenty-eighth days after labour; before then the uterus is so large that the sacral promontory prevents retroversion. • Pessary treatment. The above is in line with tradition and, since a puerperal retroversion usually represents merely a return to a prepregnancy state, it does not require treatment of any kind. So, as a rule, the finding should be made without comment, or at most the patient told to report within the first 3 months of her next pregnancy. Replacement of the Uterus and Insertion of A Pessary
Management and Treatment
Principles of Treatment
When retroversion or retroflexion of the uterus is diagnosed, it becomes necessary to determine whether the uterus is fixed or mobile. This is done by attempting to replace it by moving the cervix backwards and by pushing the fundus upwards. Only very rarely is examination under anaesthesia necessary to ascertain mobility. When the uterus is fixed, treatment should be directed primarily to the disease causing the fixation and the symptoms. If the patient has other symptoms and limited mobility of the uterus, a laparoscopy may help to establish the correct diagnosis. If the uterus is found to be mobile, the general conclusion should be that it is not causing symptoms and that no treatment is required. In most of these cases the patient should not even be informed of the presence of the retroversion or, if she is, she should be assured that it is a normal feature of her development. The possible lines of treatment for uterine retrodisplacement are discussed below.
A supporting pessary inserted into the upper vagina will hold the uterus in normal position temporarily, but it cannot cure a retrodisplacement except possibly in the puerperium. The most efficient instrument for this purpose is the Hodge type pessary. The pessary achieves its objective by putting tension on the posterior vaginal fornix and the overlying uterosacral ligaments, and this in turn holds the cervix backwards. The pessary does not press on the body of the uterus; this stays forward merely because its backward rotation is prevented by fixation of the cervix (Fig. 17.4). A pessary therefore only exerts its effect after the uterine position has been corrected.
Indications for Insertion of a Pessary A fixed retroversion cannot be replaced and a pessary is therefore of no value in its treatment. A mobile retroversion may be treated with a pessary under the following circumstances.
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Fig. 17.4: Correction of retroversion by means of a Hodge pessary
Pessary Test When there is reasonable doubt whether the symptoms are caused by the displacement, a therapeutic test can be applied. It has to be kept in mind that the insertion of a pessary can have a good effect psychologically in an over-anxious patient with vague complaints, and this possibility has to be excluded. The pessary is put in place and the woman asked to report the effect on her symptoms at the end of one month. No indication is given to her as to whether relief is expected or not. If the symptoms are not improved, the retroversion is blameless and requires no further consideration. If they are improved, the pessary treatment is continued for 2-3 months in all and the device is then removed. At that time the patient is assured that the malposition is corrected and that nothing more is required. In fact, the retroversion recurs immediately but the patient is unaware of this so, if she returns promptly with a recurrence of symptoms, it may be concluded that her observation is without prejudice and that treatment is indicated.
During Pregnancy Pessary treatment is rarely required but may be used if the uterus does not correct its own position by the tenth to twelfth week (see below).
Technique of Replacement of the Uterus • Bimanual manipulation of the uterus is one method, the secret of success being to move the cervix backwards. This automatically rotates the fundus forwards until
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it can be caught by the abdominal hand and manoeuvred into the final position. • The easiest and best method is to use the pessary as a lever for replacement of the uterus. This gives the patient very little discomfort, often she does not realise that the uterus is being repositioned. The pessary is inserted while the uterus is still retroverted; its upper rim then lies in front of the cervix. Finger pressure on the upper part of the pessary then forces the cervix backwards and the fundus begins to rotate forwards (Fig. 17.4). As the cervix moves backwards the rim of the pessary slips past and comes to lie in its proper place, the posterior fornix. If anteversion is not then complete, the pessary can be used to pull the cervix further backwards by ‘stroking’ the upper posterior vaginal wall. An advantage of this method is that there is no opportunity for the retroversion to recur between the replacement manoeuvre and the insertion of the pessary. • A finger inserted into the rectum may help to push the corpus forwards. In a difficult case the knee—chest position can be of help. Rarely, general anaesthesia is necessary to allow the manipulation. If the pessary itself is used to lever the uterus into position, anaesthesia is hardly ever required.
Size of Pessary, Management of Pessary Has been discussed elsewhere. Operative Treatment for Retrodisplacement
Indications Operative treatment is rarely necessary and is only indicated in the following circumstances. • When the displacement has been proved to be causing symptoms by an adequately controlled pessary test. • When a retroflexion is causing severe dyspareunia. This is a definite indication but, even so, an operation can often be avoided by instructing the couple to change coital posture so that the woman’s back is towards the man (coitus a tergo). • As part of an operation for an associated condition such as pelvic infection, endometriosis and leiomyoma. • In a few cases of infertility and habitual abortion when all other causes have been eliminated.
Other Displacements of the Uterus
Techniques More than 200 operations for retrodisplacement have been described and these include the following. • Various methods of intraperitoneal looping and shortening of the round ligaments and uterosacral ligaments. In the Baldy Webster operation, round ligament loops are passed through the anterior and posterior leaves of the broad ligament stitched together behind the uterus, creating a hammock-like effect. • Bringing a loop of each round ligament out through the internal abdominal ring and suturing it to the back of the rectus sheath (modified Gilliam’s operation) using a permanent suture. This again has the effect of shortening the round ligaments. Provided the loops are kept extraperitoneal, it is the method which I favour. It has no ill effect on subsequent pregnancy and childbirth. • Laparoscopic ventrosuspension is favoured by some operators. • Shortening of the uterosacral ligaments may be attempted at laparotomy and is useful when combined with a modified Gilliam suspension but care must be taken to avoid excessive tucking which can result in kinking or ligature of the ureter and also cause dyspareunia. RETROVERTED GRAVID UTERUS The uterus is retroverted during the early weeks in 15 per cent of all pregnancies. Outcome and Effects
Spontaneous Correction of the Position of the Uterus This occurs by the tenth week of pregnancy in nearly all cases. Since many women do not take medical advice before this time, the previous presence of the displacement is often not known. The capacity of the uterus to correct its own position is remarkable. It succeeds even in the presence of adhesions, presumably because they soften and stretch in pregnancy, as evidenced by the following. Two patients attended a clinic for infertility for years. Both had widespread endometriosis in the pelvis and ultimately laparotomy was carried out. Tarry cysts were dissected from the ovaries but the uterus was fixed
backwards by adhesions which were so dense that it was impossible to separate them without injury to the bowel. The uterorectal pouch was obliterated. Both women had ovulation suppressed for 9 months with a combined oestrogen and progestogen pill. In both cases, the uterus was retroverted and limited in mobility prior to conception. Subsequently both women became pregnant and the uterus in each patient was, of course, still retroverted when seen at the eighth and tenth weeks, respectively. By the twelfth and fourteenth weeks, respectively, each uterus was inclined forward and out of the pelvis. The pregnancy in each case progressed uneventfully. Impaction of the Uterus
Pathology Very, very occasionally the fundus of the uterus fails to clear the promontory of the sacrum, and becomes impacted in the pelvis at the twelfth to fourteenth week. The uterus then fills the pelvis and displaces the fundus of the bladder upwards and the base of the bladder forwards. The first symptom may therefore be bladder irritability but the one which usually brings the patient for advice is acute retention of urine. The latter is caused by the tumour interfering with the opening of the internal urethral sphincter posteriorly, not by lengthening and attenuation of the urethra as is so often stated. Acute retention of urine is often precipitated by an episode of excessive drinking, or by a circumstance interfering with the woman emptying her bladder when she first feels the urge. That is, it is brought on by over-distension of the bladder. Impaction of the pregnant uterus is most likely to occur when the pelvis is small and has an overhanging sacral promontory. The fact that pelvic contraction of severe degree is disappearing probably explains why this complication, once comparatively common is now comparatively rare. A leiomyoma in the posterior wall of a pregnant uterus sometimes determines impaction.
Diagnosis The diagnosis can be made with reasonable certainty whenever a woman of reproductive age complains of acute retention of urine associated with 3-4 months’ amenorrhoea. On examination, a soft tender tumour is found arising from the pelvis and may be mistaken for the uterus. It is in fact the distended bladder (Fig. 17.5).
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Jeffcoate’s Principles of Gynaecology if the catheterisation is properly managed, but this is an overstatement. If correction does not occur, the bladder is kept empty by continuous drainage and a large-sized pessary is inserted into the vagina. This exerts continuous slight pressure in the posterior fornix and backward traction on the cervix, and usually restores the position of the uterus to normal within a few days. Failing this, the uterus may be manipulated by one of the methods described previously, with or without general anaesthesia. It is said that, as a last resort, laparotomy may have to be carried out. I have never encountered a case in which this proved to be necessary, even when the uterus was known to be bound down by adhesions. Sacculation of the Uterus Fig. 17.5: Retention of urine associated with an impacted retroverted gravid uterus. A multiparous woman with 15 weeks’ amenorrhoea complained of inability to void. The uterus was entirely in the pelvis and the abdominal ‘tumour’which reached well above the umbilicus was the distended bladder
Vaginally, it is difficult to find the cervix, which is drawn high up in the anterior fornix; behind and filling the pelvis is the tense but soft uterus. The condition has to be distinguished from all others causing retention of urine, and from other tumours which may occupy the pouch of Douglas — particularly a large haematocele associated with ectopic pregnancy. Confusion with ectopic pregnancy is a very real possibility because the presence of some uterine bleeding may be wrongly attributed to threatened abortion associated with the retroversion.
Treatment The immediate treatment is to catheterise the patient and this can be done easily because the urethra itself is not compressed. Care is necessary since rapid release of the contents of an overdistended bladder can cause collapse of the patient. Sudden decompression is also said to precipitate rupture of the rapidly refilling blood vessels of the bladder wall but this theory is no longer acceptable. Haematuria, when it occurs, is evidence of severe cystitis which can even progress to gangrene. Slow emptying of the bladder, the patient meanwhile being kept prone or in an exaggerated Sims’ position, often results in correction of the retroversion. Some authorities say that spontaneous cure always occurs
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A very rare outcome is for the fundus to remain beneath the sacral promontory, the pregnancy continuing to grow by expanding the anterior wall of the uterus. This ultimately produces a saccule or diverticulum of the uterus. If this condition passes unrecognised, the main body of the uterus remains in the pelvis throughout pregnancy and acts as a tumour which obstructs the delivery of the foetus from the sacculation. The only safe treatment then for this exceptional state of affairs is by caesarean section. Management of the Uncomplicated Retroverted Gravid Uterus A practical problem is the management of symptom-less retroversion found during routine examination early in pregnancy. Bearing in mind that the uterus is almost certain to correct itself, many take the view that no treatment is necessary. The only advice necessary is to tell the patient to make sure that she does not allow her bladder to get too full. This is not usually a problem as frequency is often the case in early pregnancy. However if, for example in hot weather, the patient has a lot of fluid to drink, she should be advised to empty her bladder frequently. INVERSION OF THE UTERUS Inversion is a condition in which the uterus turns inside out, the fundus prolapsing through the cervix. It is rare, interesting but dangerous. Inversion varies in degree from a mere dimpling of the fundus to involvement of the whole uterus and cervix (Fig. 17.6). It is seen in acute and chronic forms.
Other Displacements of the Uterus
Fig. 17.6: Degrees of inversion
Acute Inversion This occurs during, or immediately after, the third stage of labour. The cervix is then open and atonic, and the fundus passes through it because of: mismanagement of the third stage of labour; pressure on the fundus by the attendant; traction on the umbilical cord of an unseparated placenta; or if insufficient time has been allowed for Syntometrine to work effectively in the active management of the third stage. If the degree of inversion is gross, the fundus (with or without the placenta attached) appears outside the vulva. Otherwise, it remains inside the vagina or the lower part of the uterus and the diagnosis may then only be made by exploring the vagina and uterine cavity with a hand. Even if it does not cause postpartum haemor-rhage, acute inversion nearly always produces a severe degree of shock which can be quickly fatal. It was said that shock is produced by pressure on the ovaries which, together with the fallopian tubes, are drawn inside the inverted fundus (Fig. 17.7). In fact, examination of specimens shows that the ovaries are usually clear of the ring. So the shock is due to cervical distension and traction on the peritoneum and on peritoneal ligaments. It may even come from stimuli arising in the uterine wall itself. It might be thought that alteration in the height and shape of the fundus would be obvious on abdominal examination immediately after delivery, and thus make the diagnosis easy. This, however, is not the case; the uterine mass generally feels reasonably normal. Acute inversion is an obstetrical problem and suffice it to say here that the most important part of treatment is to remove the cause of the shock, that is, to anaesthetise the patient and to replace the fundus. This is usually done manually or by hydrostatic pressure obtained by filling the vagina with fluid. Traction on the round ligaments
Fig. 17.7: Acute puerperal inversion of the uterus in a woman who died from the resulting shock during the third stage of labour. The autopsy specimen shows the fundus of the uterus completely inverted with the tubes and ovaries dipping into the ring at the top. The placenta is still attached to the inverted fundus.
at laparotomy is only occasionally necessary. The transfusion of blood and other fluids should be carried out simultaneously but by itself is not likely to cure the shock. If attempts to replace the uterus are deferred in the hope that the general condition will improve, they are likely to be forestalled by the patient’s death. Replacement of the uterine fundus under general anaesthesia takes precedence over resuscitation. CHRONIC INVERSION PUERPERAL
Pathology Occasionally the uterus undergoes incomplete inversion at the time of delivery without producing much shock; or perhaps shock is ascribed to postpartum haemorrhage or other cause, the partial inversion being overlooked. It is also possible that the process of inversion can occur gradually during the puerperium. At any rate, there are cases in which the inversion is ‘chronic’ in the sense that it is only discovered a few weeks or months after delivery. By that time the exposed endometrial surface is invariably infected and ulcerated (Fig. 17.8).
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Fig. 17.8: Chronic puerperal inversion with ulceration and infection of the inverted fundus of the uterus. The patient from whom the specimen was obtained was aged 44 years and was treated by hysterectomy when the condition was discovered 3 months after labour.
shoulders. Tight vaginal packing around the cup keeps it in place, and the woman’s discomfort is relieved by analgesics. This treatment is generally successful within a few days. One of the secrets of replacing either an acute or chronic inversion is to lift the uterus high in the pelvis. This puts traction on the round ligaments which in turn pull the fundus out of the inversion cup. This view, put to Professor Jeffcoate by Dr A.B. Johnson of New York, would explain why filling the vagina with saline solution (O’Sullivan’s method), and the repositor, achieve their effect; it would also account for spontaneous cures with posture and vaginal packing. More commonly however, the uterine fundus can often be lifted up into place by traction on the round ligaments at laparotomy. This procedure is also applicable to acute inversion. In longstanding and resistant cases, replacement may require incision of the constricting ring of the cervix. This can be done abdominally (Haultain’s operation) or vaginally (Spinelli’s operation). The former is more common. Hysterectomy, vaginal or abdominal, may be indicated, especially if further childbearing is not important to the patient.
Clinical Features The complaint is vaginal discharge and irregular bleeding dating from a confinement, and there may be a history of postpartum haemorrhage or obstetric shock. Other symptoms are low backache and chronic pelvic pain. On examination, an infected haemorrhagic mass is found in the vagina and is likely to be confused with a sloughing polyp, a retained portion of placenta, an ulcerated prolapsed cervix and even a malignant neoplasm. The diagnosis is made by recognising that the mass is coming through the cervix, and by demonstrating the shortness of the uterine cavity with a sound.
Senile Inversion Spontaneous inversion of the uterus is sometimes seen in old age, especially if the cervix has previously been amputated at a high level (Fig. 17.9). The inversion is
Treatment The first objective is to clear up the infection by keeping the patient lying flat in bed, by douching and by antiseptic packing of the vagina. Occasionally this treatment results in spontaneous cure of the inversion. When inversion persists, and when the prolapsed fundus is clean, a special repositor (Aveling’s repositor or its modification), consisting of a cup on a metal stem, can be placed over the inverted fundus. Continuous pressure is applied by bracing it to the patient’s waist and
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Fig. 17.9: Spontaneous inversion of the uterus associated with recurrent prolapse. The patient concerned was senile and had had a Manchester operation several years previously. The factors causing the inversion are probably high amputation of the cervix and senile change in the tissues
Other Displacements of the Uterus
Figs 17.10A and B: Inversion of the uterus caused by tumours, (A) A fundal leiomyoma is the cause in this case; the specimen is unusual because the tumour is not polypoidal. (B) Diagrammatic representation of the more common type of leiomyoma causing inversion
Fig. 17.11: Figure shows a polyp projecting from the os
probably due to cervical atony and incompetence. The symptoms and signs are the same as those of chronic inversion. The condition is usually mistaken for ulcerated prolapse. Hysterectomy is the best treatment. Inversion Due to Pedunculated Tumour When a tumour (usually a myoma) arises by a stalk attached to the interior of the uterus, it tends to be expelled into the vagina. If the pedicle is stout and reluctant to stretch, the traction produces a dimple in the uterine wall and ultimately quite a severe degree of inversion (Figs 17.10A and B). The patient’s symptoms are those of the polyp and the associated inversion may be missed unless the possibility is kept in mind. If it is overlooked, the result can be disastrous because, in dividing what is regarded as the pedicle of the polyp (Fig. 17.11), the surgeon cuts across the fundus of the uterus and opens into the peritoneal cavity. Before any such polyp is removed, the length of the uterine cavity
Fig. 17.12: Figure shows a prolapsed gravid uterus which is replaced and kept in place by a pessary
should always be tested by sound. Moreover, if there is any possibility of an inversion being present, the tumour should be removed by shelling it from its capsule rather than by dividing its pedicle. Rarely gravid uterus may prolapse completely and these have to be pushed back and treated conservatively till delivery, by the use of pessary (Fig. 17.12).
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Torsion of Pelvic Organs
Torsion of the Normal Organs Torsion of Abnormal Organs Aetiology Differential Diagnosis Treatment
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TORSION OF THE NORMAL ORGANS Uterus A minor degree of rotation of the uterus around its long axis is common and insignificant (Fig. 18.1). It is seen especially in pregnancy when the twist is nearly always to the right, that is, clockwise as seen from above. Torsion sufficient to obstruct the blood supply probably never occurs in the normal uterus. Tube and Ovary Torsion of the normal ovary alone is exceptional, but torsion of the normal fallopian tube with or without the ovary is not very rare. Sometimes only the free outer end of the tube is involved. The torsion may be partial and self-correcting but it then tends to recur. In the fully developed condition the tube can undergo several complete turns. The effect is first to obstruct the venous return, causing extreme congestion and extravasation of blood. Ultimately the arterial supply is affected and Fig. 18.1: Rotation of the normal uterus as revealed by the tissues distal to the hysterography. The degree of twist is not of significance but twist become gangre- radiographs showing this sort of picture are often misinterpreted as showing a uterine malformation nous.
Torsion of Pelvic Organs The patient is usually a child or an adolescent. She complains of a sudden onset of severe pain in the lower abdomen, to one or other side of the midline. This may be intermittent with a previous history of a similar pain. It can cause vomiting, and sometimes bladder and bowel irritability. Shock is rarely present, the temperature remains normal at first but the pulse rate may be raised. Slight uterine bleeding often occurs within a few hours. Muscle guarding or rigidity over the lower abdomen is usual. Since the patient is nearly always young and virginal, pelvic examination is difficult. Rectally there may be tenderness to one side of the uterus but the swelling of the adnexa is usually too small to feel. The clinical features are those of a twisted ovarian cyst without a tumour being found. When these occur in a young girl the diagnosis should always be entertained, although it cannot be made for certain without laparoscopy or laparotomy.
same as for torsion of the normal tube except that a tumour is more likely to be found on examination. At operation it is often difficult to say whether the tube was previously normal or the seat of a hydrosalpinx (Fig. 18.2). Torsion of the tube can occur with the rare carcinoma of the fallopian tube. Torsion of the tube also inevitably occurs when there is torsion of a paraovarian (fimbrial) cyst because the tube is tightly stretched over the wall of the cyst. Ovary Ovarian tumours are commonly complicated by torsion of their pedicle and part or all of the tube may be involved as well (Figs 18.3 and 18.4). Involvement of the ovary in torsion of a hydrosalpinx or fimbrial cyst depends on the exact site at which the twist occurs in relation to the mesovarium. AETIOLOGY
TORSION OF ABNORMAL ORGANS This is much more common than is torsion of normal organs.
The factors determining the axial rotation of organs and tumours are as follows. Unusual Mobility of Organs
Uterus Symptom-producing significant degrees of torsion of the uterus, either pregnant or non-pregnant, only occur when the uterus is asymmetrical because of a tumour or müllerian duct fusion deformity, or when it is twisted by an adjacent lesion. The torsion is usually at the level of the supravaginal cervix so the uterine vessels are obstructed; the uterus then becomes engorged, infiltrated with blood, and ultimately gangrenous. The condition is rare. The patient complains of severe abdominal pain of sudden onset, and this is followed by shock which may be fatal. Vomiting and slight uterine bleeding are usual. Muscle guarding and uterine tenderness are found on examination.
Physiological mobility of organs in childhood and adolescence explains why torsion of a normal tube and
Pedunculated Leiomyoma Torsion of the pedicle of a subserous leiomyoma is common. Tube The lesion of the tube preceding torsion is mostly a hydrosalpinx. The interference in blood supply converts this to a haematosalpinx. The clinical features are the
Fig. 18.2: Spontaneous torsion of the outer end of a fallopian tube, possibly the site of a hydrosalpinx. Below the tube is a normal and uninvolved ovary containing a recent corpus luteum
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Fig. 18.4: Torsion of the pedicle of a solid ovarian tumour (granulosa cell). The fallopian tube is involved in the torsion. Note the extravasation of blood throughout the tissues distal to the twist
Fig. 18.3: Torsion of solid ovarian tumour
ovary is mostly seen at these ages. Instability of the outer end of the tube, caused by resection of the middle portion for purposes of sterilisation, can also result in its torsion (Figs 18.5A and B). For similar mechanical reasons it is the small rather than the large tumour, with a long pedicle, which is most likely to be affected by this complication. Asymmetrical growth of a tumour may determine the initial twist. Pregnancy and the Puerperium Torsion of tumours is more often seen during pregnancy or in the puerperium when abdominal wall tension and intra-abdominal space are altering rapidly. Changes in the size of the uterus also act as rotating forces. Movement of the Trunk Torsion can be started by certain movements and often appears to follow turning over in bed. Defaecation and Micturition
Figs 18.5A and B: Acute torsion of the outer half of one fallopian tube following division of the tube as part of a Pomeroy sterilisation operation. The two segments of the tube are shown, the inner one being unaffected while the outer one has twisted on its broad ligament attachment and is distended with extravasated blood. Below is the outer part of the other unaffected tube for comparison
These can operate by altering intra-abdominal relations. Adhesions, Bands and Tumours in Adjacent Organs A normal fallopian tube can become twisted around a ventrofixation band. This sort of accident is described after various operations for uterine retroversion.
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Whatever be the force which commences the rotation of the pedicle or mesentery, it is widely believed that the further twisting is brought about by haemodynamicspossibly by pulsation in the vessels supplying the tumour or organ.
Torsion of Pelvic Organs
Idiopathic In many cases there is no obvious cause.
menstrual function of the patient, and by the position of a tumour. TREATMENT
DIFFERENTIAL DIAGNOSIS Torsion of a pelvic organ or tumour has to be distinguished from: acute salpingitis; ruptured cyst; ectopic pregnancy; all causes of intraperitoneal haemorrhage; acute appendicitis and diverticulitis; rupture of an endometriotic cyst; ovulation pain; degeneration in a leiomyoma; retroplacental haemorrhage during pregnancy; intestinal obstruction; and renal colic. Before operation it may be impossible to say which organ or tumour has undergone torsion, although guides are offered by the age, previous history and
If torsion is suspected or diagnosed, immediate laparotomy is required; the surgical procedure then depends on the exact nature of the findings. If the torsion is incomplete or recent, the tissues may still be viable; it is then possible to conserve them and to stabilise them by suture. Ovarian cystectomy, as distinct from removal of the whole ovary with its tumour, is sometimes a reasonable procedure. If the organ has undergone more than 3 twists, blood supply is occluded beyond correction. When the tissues are gangrenous or beyond recovery, they have to be removed.
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Infections Including STD
The Natural Defences of the Genital Tract 308 Sexually Transmitted Diseases 310 Other Sexually Transmitted Infections 316 Genital Tuberculosis 323
Sarcoidosis Actinomycosis Schistosomiasis (bilharzia) Amoebiasis
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THE NATURAL DEFENCES OF THE GENITALTRACT The genital tract forms a continuous open pathway from the exterior to the peritoneal cavity, and a natural defence system against ascending infection is therefore necessary. This is all the more important in view of the proximity of the urethra and anus to the vaginal orifice. Defence Mechanisms
Vulva The vulva and perineum of the mature woman have a remarkable inherent resistance to infection; so incisions and tears, even if contaminated, heal well if sutured with care over haemostasis. Additionally, the secretion of the apocrine glands is said to be rich in undecylenic acid which is fungicidal. These properties, as well as closure of the introitus by apposition of the labia, protect the genital tract above.
Vagina • Closure by apposition of its anterior and posterior walls. • A well-developed stratified squamous epithelium, unbroken by entrances to glands. • Vaginal acidity. • Vaginal flora: All manner of organisms ordinarily inhabit the vagina but the Gram-positive anaerobic lactobacillus is normally predominant and it is this which, by its production of lactic acid, keeps the others in check. The efficiency of the vaginal defence is directly proportional to the relative number of lactobacilli present. Organisms that do not attach to the underlying tissue are swept away by the mucus stream and do not produce tissue damage or local inflammatory response. Glycoprotein and carbohydrates seem to be the factors responsible for adherence.
Infections Including STD • The mucosal immune response - antibodies are present although titres are low. Phagocytic cells and cytokines have also been identified.
Cervix Functional closure of the cervix is effected by mucus which is also said to be bacteriolytic.
Uterus Periodic shedding of surface endometrium during menstruation tends to eliminate any infection which may try to gain a hold. The cavity of the uterus was formerly regarded as being sterile but it is now known that it often harbours non-pathogenic anaerobic streptococci, especially after abortion and labour. These may well play a beneficial scavenger role in clearing away debris after menstruation and pregnancy. Variations in the Efficiency of Defence Mechanisms
With Age The defences are imperfect during childhood and after the menopause when the vagina has thin and vulnerable epithelium, when its content of glycogen and lactobacilli is low, and when its pH approaches 7. The endometrium is also poorly developed or atrophied at these ages and does not undergo cyclical shedding and reformation.
clots and fragments of decidua offer a nidus for infection; and the patient’s general resistance is lowered by the strain of pregnancy and possibly by anaemia and malnutrition. These circumstances are the basis of what was, in the past, the scourge of midwifery - puerperal sepsis - and which, with the development of antibiotic resistance by organisms, is again becoming a threat (Figs 19.1 and 19.2). Types of Infecting Organisms The organisms commonly causing infection of the genital tract are Treponema pallidum, Neisseria gonorrhoeae, Gardnerella vaginalis, Haemophilus ducreyi, Prevotella spp., Bacteroides, Peptostreptococcus, Calymmatobacterium granulomatis, Chlamydia trachomatis, Mycobacterium tuberculosis, the parasite Trichomonas vaginalis, Candida albicans, the viruses herpes simplex virus (HSV) types 1 and 2, human papillomavirus (HPV) and the greatest scourge of recent times - the human immunodeficiency virus (HIV). Almost all the pathogenic organisms known, however, can be responsible at times and those worthy of mention are: Streptococcus (aerobic and anaerobic, haemolytic and non-haemolytic species), Staphylococcus, Pneumococcus, Escherichia coli, Clostridium tetani, Clostridium welchii, Salmonella typhi and S. paratyphi, the
With Menstruation During menstruation the cervical plug is absent and vaginal acidity is lowered by the alkaline menstrual discharge. Gonococcal infection is therefore more virulent if contracted during menstruation and is more likely to ascend to the uterus and tubes at that time. Similarly, Trichomonas vaginitis tends to occur or relapse during menstruation.
During the Puerperium In the adult woman the genital tract defences are weakest during and immediately after abortion or labour because: there is a raw placental site; there are often breaks in the epithelial linings of the cervix and vagina; the tissues are bruised and devitalised; the vulva, vagina and cervix are wide open; the discharge of liquor and lochia (both alkaline) reduces vaginal acidity; degenerating blood
Fig. 19.1: Diagrammatic representation of the mode of spread and lesions produced in puerperal (including postabortal) infection
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Fig. 19.2: Puerperal infection caused by Clostridium welchii. A primigravida aged 20 years was found to be suffering from hydatidiform mole and bougies were inserted into the uterus in an attempt to induce labour. The patient died 4 days later with signs of an overwhelming infection. This was in the days prior to the discovery of sulphonamides and antibiotics. The specimens obtained at autopsy are, from left to right, a portion of the spleen, the uterus with the products of conception still retained and a slice of liver. All the tissues are riddled with gas-containing spaces
actinomycetes and other Streptothrix organisms, the filarial worms, Schistosoma haematobium, and amoebae. Many of the above organisms, even Cl. welchii, are frequently found in the vagina without being pathogenic. Their presence may represent either a normal or a carrier state. SEXUALLY TRANSMITTED DISEASES Sexually transmitted diseases, also called venereal diseases, after Venus, the Greek goddess of love, are infections acquired during heterosexual or homosexual intercourse with an infected partner. Historically, they comprised only gonorrhoea, syphilis and chancroid. Several other diseases can, however, be sexually transmitted although other modes of origin are possible. The true incidence of sexually transmitted diseases (STDs) is difficult to determine and all figures are an underestimate, as 80-90 per cent of cases are treated privately and not reported. Throughout the world increasing numbers of cases of syphilis and gonorrhoea are being reported annually along with other STDs. One important factor is that worldwide there are more people at risk each year. The expectation of life has increased, especially for women, so that the lowering of the age of
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puberty combined with a longer span of healthy life provides a much greater period for acquiring STD. The incidence of STD is rising. The commonest condition is a non-specific genital infection (urethritis in the male), with Chlamydia trachomatis probably responsible for 40-50 per cent of these cases. Reports from major cities in Europe, the UK and the USA reveal that up to 70 per cent of all cases of primary and secondary syphilis are in homosexual males. The introduction of penicillin and other antibiotics has had a marked effect on some of the STDs. For instance, gummatous, cardiovascular and neurological syphilis, as well as congenital syphilis, are now rare. However, indiscriminate use and inadequate doses of these drugs have resulted in the development of resistant strains of the gonococcus so that control of the disease may prove to be difficult in the future. Improvement in diagnostic methods and increased interest in STD have revealed other sexually transmissable agents, several of which are viral. The manifestations of this group of diseases vary from local discomfort to chronic disability, infertility, ectopic gestation, stillbirth and neonatal death. Cases of urethritis and cervicitis due to Chlamydia, Gardnerella and other agents greatly outnumber new cases of gonorrhoea and are increasing rapidly. Many patients with STD are between 18 and 24 years and in recent years there has been a marked increase in the number of girls aged between 16 and 17 years. The radical changes in attitudes to sex and in sexual behaviour during the past 25 years has resulted in a marked increase in STD. This is the price which girls and women everywhere are paying for their sexual liberation. The reasons for the world crisis in STD are as follows: • Promiscuity: This, the weakening of family life and the fact that modern conditions of life provide more opportunity for promiscuous behaviour are the most important factors. With so many individuals in any community having asymptomatic infections, it requires relatively few partners before an infected one is encountered • Modern methods of contraception, such as the oral contraceptive pill and intrauterine contraceptive devices, do not offer protection as did the older barrier methods, and at the same time they may encourage casual intercourse • The development of antibiotic-resistant organisms
Infections Including STD • Shifts in the population and overseas travel • The increase in world population and in life expectancy • Ignorance of the risk of becoming infected. The youth of today, especially in urban areas, is generally better informed on all matters pertaining to sex. But many refuse to accept that STD is anything more serious than the common cold and believe that it is readily cured without leaving any permanent ill effect. They adopt towards it an attitude of indifference if not contempt. Syphilis
Aetiology Syphilis is caused by a spirochaete, Treponema pallidum, and this organism is to be found in all lesions — primary, secondary and tertiary. The disease is sometimes congenital but is usually acquired by direct contact with another person who has an open primary or secondary syphilitic lesion. The site of infection may be on the hands as a consequence of touching a syphilitic lesion, a risk to which doctors and nurses are especially exposed if there is a break in their skin or mucous membrane. Ordinarily, however, the entry of the spirochaete is determined by sexual contact with an infected partner. This is true even when the primary lesion is on the breast, in the mouth or on the lips, the last sites being determined by genitooral coitus rather than by kissing or by drinking from infected containers - as used to be suggested. Here we are mainly concerned with syphilitic lesions of the female genital tract acquired as a result of sexual intercourse. Clinical Features
slight that it passes unnoticed, and it rarely has the characters of the typical chancre with a hard base as seen in the male. Indeed, any sort of discrete relatively painless ulceration on the vulva may be a primary syphilitic lesion. An inflammatory reaction in the surrounding tissues is unusual but oedema can be present. On the cervix, a chancre commences as a grey or purple nodule but, when it ulcerates, can resemble an erosion and be mistaken for one. Sometimes it presents as a diffuse induration of the cervix. The inguinal glands enlarge when the primary is on the vulva or lower vagina. They are hard and shotty but painless, and do not suppurate.
Secondary Stage The primary chancre heals spontaneously in 1-8 weeks and soon afterwards the secondary stage of syphilis, which results from entry of the spirochaetes into the bloodstream, is manifested by: general systemic upset with lassitude, anorexia, headaches and pyrexia which is usually less severe than in the male; macular, papular or pustular skin rashes which are typically non-irritant, pleomorphic, bilaterally symmetrical in distribution and copper coloured; occasional loss of scalp hair; white mucous patches in, or ulceration of, the mouth and pharynx; generalised adenitis - symmetrical enlargement of the epitrochlear glands is said to be diagnostic; iritis; and condylomata lata on the vulva and around the anus— these differ from the common multiple warts (condylomata acuminata) in that they are coarse, flattopped, moist and necrotic (Fig. 19.3). Sometimes secondary manifestations occur before the primary heals, or they may not occur at all. The first and second stages can last up to 2 years, during which time the woman is a source of infection.
Primary Stage The primary lesion or chancre is found most commonly on the labium majus, labium minus, fourchette, clitoris, urethral orifice or cervix, but it may be anywhere on the lower genital tract, even the vaginal wall. In 10 per cent of cases, more than one primary lesion is present. The chancre usually appears 10-20 days after exposure but the incubation period may be as long as 90 days. The first manifestation is a small papule which quickly breaks down to form an ulcer, the classical features of which are a sharply defined serpiginous outline and a brownish red colour. In practice, however, the lesion is often so
Tertiary Stage In untreated syphilis this stage occupies many years during which the spirochaetes attack bones, joints, eyes, blood vessels, the heart and the central nervous system. Tertiary syphilis is also characterised by the formation of localised granulomas (gummas) in any part of the body. Gummas of critical organs like the heart, brain and liver can be fatal. Gummas of the genital tract are rare, but when they do occur, are most often found on the vulva where they break down to form ulcers with a serpiginous outline and surrounding oedema. They are
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Fig. 19.3: Secondary syphilitic lesions on the vulva. These consist of brownish, slightly raised plaques and a few flat-topped coarse condylomas
not painful unless secondarily infected. These late forms are rarely seen nowadays.
Latent Syphilis After infection with T. pallidum there are periods when the patient is seroreactive but shows no evidence of disease. They should all be evaluated for signs of tertiary disease. Diagnosis The diagnosis during the primary stage is made by examining serum from the base of the primary chancre for the presence of T. pallidum, using dark-ground illumination microscopy. Treponemes can also be seen in fluid from most lesions of secondary syphilis. Routine culture of the organism is not yet possible. Serological tests are positive in all but the earliest stage of primary syphilis (they are negative until about 2 weeks after the appearance of the chancre, i.e. about 3-5 weeks after infection) and sometimes in very late syphilis. In suspected congenital syphilis or when the infection has progressed beyond the second stage, the diagnosis can
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only be determined by serological tests. The serological tests for syphilis may be grouped into those which are non-specific or non-treponemal and those which are specific or treponemal. Most laboratories carry out a test of each type. The non-specific tests are complement fixation or flocculation tests. The Wasserman (WR) test was the prototype of complement fixation tests and in its various modified forms remains the mainstay of this type of test. A flocculation type of test for a non-specific antibody, reagin, namely the Venereal Disease Research Laboratory (VDRL) slide test, is the most commonly used non-specific test for screening purposes. The VDRL test may be positive in the absence of specific tests, i.e. a biological false-positive reaction. This can occur in pregnancy, during or shortly after any infective illness such as infectious mononucleosis, measles, chicken pox, mumps, herpes simplex, herpes zoster or viral pneumonia, or following recent immunisation. The false-positive reactions are of a temporary nature but may persist in certain chronic diseases such as leprosy, tuberculosis and autoimmune diseases (lupus erythematosus, haemolytic anaemia, thyroiditis and rheumatoid arthritis). Antibody to cardiolipin is also measured by the rapid plasma reagin (RPR) test. Although this is an autoantibody (hence the term ‘non-treponemal antibody’) it provides a useful marker of activity of disease and is helpful in follow-up, especially where only a few samples are being run at a time. The VDRL test is used in conjunction with specific tests for treponemal antibody, e.g. the Treponema pallidum haemagglutination (TPHA) test, to confirm or refute the findings of the non-specific test. Tests should be repeated after 2 or 3 weeks to ensure that no test has become positive during that time, as can occur in early syphilis. In high-risk situations, repeating the test in the third trimester of pregnancy is recommended. Once positive, the VDRL may remain positive for life. All serological tests may be negative despite the presence of a primary lesion. The TPHA test will be positive in the secondary stage but only in about 60 per cent of patients with primary syphilis. It is also the last test to become positive. The specific tests do not distinguish the different treponemal conditions; they only distinguish between treponemal and nontreponemal disease.
Infections Including STD Interpretation of the serological tests may be difficult if there is a past history of other treponemal infections, particularly the non-venereal tropical disease yaws which is endemic in the West Indies. The causative organism of yaws, Treponema pertenue, is morphologically identical to T. pallidum and gives indistinguishable serological results. As well as giving positive serological tests, this disease also has three stages — primary granulomas or papules, de-squamation, and ulceration - and can cause visceral and periostotic lesions. The skin lesions are commonly seen on the vulva, breasts and legs. In the absence of a satisfactory history of treatment for yaws the patient should be regarded as having a treponemal disease which might be syphilis and treated accordingly. Treatment The treatment of syphilis is a matter for the specialist venereologist. Local treatment is useless because the spirochaetes invade deeply and spread by vascular channels at an early stage. The best medication for early syphilis is penicillin to which the treponemes have not so far developed a resistance. A single dose of 2.4 million units of benzathine penicillin intramuscularly appears to cure primary or secondary syphilis. If there is any doubt about the duration of disease or where it is known to have been present for longer than a year, 3 weekly doses are recommended. Intramuscular injection of 600000 units of aqueous procaine penicillin daily for 8 days is equally efficient. The treponemes usually disappear from active lesions within 24 hours, and serological tests become negative in weeks or months. Observation for 2 years following treatment is desirable. For patients sensitive to penicillin, ceftriaxone (1 g i.v. on alternate days for 5 doses), oxytetracycline (500 mg 6-hourly for 30 days) or erythromycin (500 mg 6 hourly for 30 days) may be substituted. Late syphilis is also treated with penicillin, but the schemes of dosage and number of courses vary with its manifestations. Treatment should be preceded by radiological examination of the heart and aorta, and by tests on the cerebrospinal fluid. The rare Jarisch-Herxheimer reaction is a minor acute febrile reaction of this type accompanied by headache, myalgia and other symptoms which occurs in 50 per cent of patients after the first administration of any therapy
for syphilis and warning of this should be given. It is seen particularly when there are lesions in the larynx, meninges, heart and aorta, but can be seen in one-third of patients of primary syphilis and two-thirds of secondary syphilis. Therapy need not be discontinued. Most cases can be managed by reassurance of the patient and administration of ibuprofen or aspirin. Prednisolone is not usually necessary. In pregnancy, the treatment is the same as above. The woman who is allergic to penicillin should be treated with ceftriaxone. Erythromycin does not reliably cure the foetus. The baby should be assessed at birth, and at 6 weeks and 3 months after birth. Gonorrhoea
Pathology and Clinical Features Gonorrhoea is an infection caused by a Gram-negative diplococcus - Neisseria gonorrhoeae (the gonococcus)— and, in the adult woman, is contracted by sexual contact with an infected male. Transfer by other means is little more than a theoretical possibility except in babies, who can be infected during their passage through the birth canal, the most serious result being ophthalmia neonatorum. There is usually an interval of 2-5 days between exposure and the development of symptoms, but this interval varies from 1 to 10 days. However, an asymptomatic carrier state can persist for weeks or even months and throughout this time infection can be transmitted. The bacteria attack first those tissues of the lower genital tract which are not covered by stratified squamous epithelium - the endocervix, the urethra (including the paraurethral tubules) and the ducts and acini of Bartholin’s glands (Fig. 19.4). Gonococci also commonly spread to the anorectum; they may sometimes be implanted there during anal coitus. The initial complaints of the patient are a purulent vaginal discharge, dysuria and frequency. This discharge causes soreness but not pruritus unless there is an associated Trichomonas infection. In severe cases the whole vulva becomes reddened and swollen (Fig. 19.5). When the vulvar reaction is acute, inguinal adenitis is the rule and some constitutional upset is likely. Cystitis and proctitis can develop. In exceptional cases gonococcal septicaemia is described and may be manifested by pyrexia and even a vesicular or pustular dermatitis. Gonococcal tonsillitis or pharyngitis occurs as the result of genito-oral contact. Lesions involving
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Fig. 19.4: Diagrammatic representation of the mode of spread and the sites of infection in gonorrhoea
Fig. 19.5: Acute gonorrhoea with right-sided bartholinitis and associated oedema of the labia. The purulent discharge can be seen escaping from the vagina
joints, tendons and ligaments, once regarded as gonococcal, are usually explained by an associated nongonococcal infection (see Reiter’s disease) but gonococcal arthropathy does occur and the organisms can be cultured from the joint effusion. Generally the infection remains limited to the lower genital tract but, in 10 per cent of cases of proven gonorrhoea, it spreads upwards to cause salpingooophoritis of varying degree. The organisms ascend through the uterus to the tubes, producing a fleeting acute endometritis on the way. The last is not clinically evident, being overshadowed by the symptoms of salpingitis. Both tubes are always involved and the essential lesion is an endosalpingitis. The organisms pass through the abdominal ostia to produce pelvic peritonitis and oophoritis. Generalised peritonitis is rare. It has long been the belief of gynaecologists that gonococcal salpingitis is a self-limiting disease in that the bacteria in the tubes die within 3-4 weeks. Nevertheless, positive cultures are sometimes obtained as long as 6 months after the original infection. Moreover, even if the gonococci die out, a pyosalpinx is often secondarily infected. The pathology of gonococcal salpingo-oophoritis is described in Chapter 20. The above is the classical clinical picture of gonorrhoea with some of its rare and even bizarre
variations. It must be emphasised that it is not often encountered. Most women, even in the acute and subacute stages of the primary infection, notice nothing more than slight frequency, dysuria and discharge, so slight that they pay little attention. Indeed, 60-70 per cent of women from whom gonococci can be cultured from the lower genital tract are free from symptoms and obvious physical signs of the disease. It is these who are responsible for the spread of infection and they can only be found and treated by an efficient system of ‘contact tracing’. Routine mass screening using meticulous bacteriological techniques is, according to most reports, of little value. One study of 1000 pregnant women (selected as being at special risk because of symptoms or an irregular domestic background) revealed gonococci in only two; both of these had symptoms and signs which would have inevitably prompted investigation. Even salpingitis can develop without producing an acute picture and in a subclinical degree is probably quite common. No matter whether it has a dramatic or quiet onset, gonorrhoea persists as a chronic but contagious disease for many years. The organisms linger in the endocervix, Bartholin’s glands, periurethral tubules and rectum but give rise to no symptoms or, at most, to a slight chronic mucopurulent vaginal discharge.
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Infections Including STD The most important and tragic sequel to gonorrhoea is tubal damage and closure which threaten future reproduction. Unlike the situation in the male, urethral stricture following gonococcal urethritis is almost unknown in the female. Disseminated gonococcal infection is a rare complication in less than 3 per cent of cases. These patients may also present with endocarditis and meningitis. Diagnosis In the classical case, the diagnosis of gonorrhoea is usually suggested by the history of exposure, the acuteness of the onset of a purulent discharge, the associated urethritis, and the appearance of zones of congestion (maculae) around the orifices of Bartholin’s ducts. In practice, it is the occurrence of urethritis in the patient’s consort which often brings the woman to investigation, she herself having no symptoms. Sixty per cent of women with proven gonorrhoea also suffer from Trichomonas vaginalis and/or Chlamydia trachomatis. Candida albicans, herpes simplex virus, etc. are also associated. So the disease should be suspected whenever there is a complaint of vaginal discharge. The diagnosis can only be proved by the demonstration of gonococci in the genital tract secretions or in the lower rectum. In the female it is rare to find typical Gram-negative intracellular diplococci in direct smears of vaginal discharge, unless a very acute infection is present. The setting up of cultures is therefore mandatory and material for these is obtained from the endocervical canal. Cultures of the urethra, anal canal and pharynx are recommended (see below), but produce only a slight increase in the yield. When gonococcal septicaemia, pharyngitis or arthritis is suspected, it is necessary also to prepare cultures from the blood, throat swabs and synovial fluid. Gonococci will survive on ordinary swabs for approximately 2 hours. A longer interval than this between the collection of specimens and their arrival in the laboratory means the use of transport media such as Stuart’s agar and crystal violet, or one of the proprietary preparations on the market. Alternatively, plates of warmed chocolate agar or of Thayer—Martin medium can be inoculated directly by the patient’s bedside. The woman should not have passed urine or used a douche before examination. Having wiped its orifice clean, the urethra is milked to obtain discharge from the paraurethral glands. Further material is obtained by milking Bartholin’s glands and their ducts. Swabs are
next taken from the endocervix and finally from the anal canal and rectum. In proven cases of gonorrhoea, the organisms are found in Bartholin’s ducts in 30 per cent, in the endocervix in 90 per cent and in the rectum in 5060 per cent. The last two are therefore the most important sites to study and it is stated that a combination of their findings provides an almost 100 per cent accurate diagnostic test. Nevertheless, negative findings, even when repeated, are never conclusive and it is impossible to be certain that a woman does not have gonorrhoea. Similarly, tests of cure are unsatisfactory although negative bacteriological findings on three occasions are the accepted criteria. The best time to perform these is immediately after menstruation. Enzyme-linked immunosorbent assay (ELISA) tests have been developed which offer greater reliability. Whenever gonorrhoea is diagnosed or suspected, it is essential to entertain the possibility of the patient having contracted syphilis at the same time. The case must therefore also be investigated from this stand-point and, meanwhile, no treatment given which might mask, without curing, this disease. Antibiotic sensitivity of the organism is becoming important because of the resistant or less sensitive strains. The detection of penicillinase-producing strains of N. gonorrhoeae which are totally resistant to penicillin and relatively insensitive to several other antibiotics is important as these strains are spreading throughout the world. Treatment If there is a severe systemic reaction, or if acute salpingitis is present, the patient should be put completely at rest in hospital and given intensive antibiotic therapy in divided doses. Otherwise she can remain ambulant but should be warned against coitus until pronounced cured. Except for the drainage of an abscess, local treatment should be avoided lest it encourage the spread of infection. Penicillin used to be the remedy of choice in gonorrhoea. A single intramuscular injection of 4.8 mega units of procaine penicillin can be curative but the emergence of penicillinase-producing strains of N. gonorrhoeae led to the use of another agents. Further, some authorities felt that this dosage was inadequate in case of concomitant syphilis. Although, in general, this is very rare nowadays, there may be some settings where this is relevant.
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Jeffcoate’s Principles of Gynaecology Several of the newer quinolones, e.g. ciprofloxacin and ofloxacin have been used successfully as single-dose regimens, 500 mg and 400 mg, respectively. Quinoloneresistant strains have emerged in some Pacific and Asian countries, but CDC continues to recommend these in areas where there is no problem of resistance. However, quinolones should not be used in pregnant women. Ceftriaxone is recommended by CDC for the treatment of uncomplicated gonorrhoea in a single, intramuscular injection of 125 mg. It cures rectal and pharyngeal gonorrhoea as well. Some patients allergic to beta-lactam antibiotics may show reaction. Ceftixime is a useful oral alternative. Spectinomycin, 4 g in a single intramuscular injection, is useful in treating anogenital gonorrhoea but does not treat pharyngeal gonorrhoea. Because of the high incidence of associated chlamydial infections, therapy should be followed by azithromycin or doxycycline to treat this as well. Sex partners should be treated, especially those exposed within two weeks prior to onset of symptoms or four weeks prior to diagnosis in an asymptomatic patient. Each authority and clinic tends to have its own favourite drugs and combinations of these; their choice is largely determined by knowledge of the drug sensitivities of the gonococci prevalent in the area. Repeat cultures for test of cure are no longer recommended for all patients as cure rates of currently used regimes approach 90 per cent. They may be indicated if there is a doubt of patient compliance. The treatment of gonococcal Bartholin abscess, salpingitis and infantile vulvovaginitis is described elsewhere. Chancroid (Soft sore) Chancroid is becoming increasingly rare everywhere but is still an important STD in some areas in developing countries. It is much commoner in men than in women.
Each ulcer is ringed with a bright red zone of congestion and surrounded by oedema. The ulcers bleed easily on gentle cleaning. Oedema is a striking physical sign. The draining lymph nodes are usually unilateral and inguinal. They are painful and tender and become ‘matted’ together in a unilocular abscess — a distinguishing feature from syphilitic adenitis. Secondary infection is common and can produce much tissue destruction. Untreated, the inguinal abscess bursts onto the skin, forming a sinus. The infection does not spread and, although it can cause malaise and pyrexia, has no serious systemic effects.
Diagnosis The clinical features may be suggestive but the diagnosis can only be made by the demonstration of H. ducreyi in the discharge from the ulcers or in pus obtained by aspiration of an inguinal node or by polymerase chain reaction (PCR). Chancroid lesions can be confused with those of Behcet’s syndrome, the type and sites of the genital ulcers being identical. Treatment Experience is now so limited that it is difficult to judge the best antibacterial agent to use. H. ducreyi were initially susceptible to sulphonamides, trimethoprim, tetracycline, streptomycin and chloramphenicol. Presently, azithromycin (1 g orally single dose), erythromycin (500 mg 6-hourly for 7 days) or ceftriaxone (250 mg intramuscularly single dose) are the recommended drugs. Along with antibiotics the patient is advised to rest during the acute stage of ulceration and her pain can be relieved with analgesics. If the inguinal nodes suppurate, the abscesses are aspirated. Healing usually occurs within two weeks. OTHER SEXUALLY TRANSMITTED INFECTIONS
Pathology and Clinical Features The infection is caused by a Gram-negative streptobacillus — Haemophilus ducreyi. The disease appears 2-5 days after coitus and takes the form of multiple small papules or vesicles which quickly break down to leave acutely painful shallow ulcers which discharge offensive pus. These are usually multiple, but can be single, and are distributed on the labia majora and minora and sometimes within the introitus and around the anus.
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Many other infections of the female genital tract can be acquired by intercourse with an infected partner but can also arise in other ways; in some cases the latter are the more important. The following infections can, or possibly can, be transmitted during the close bodily contact involved in coitus. The first six are described in this section, the following four elsewhere; the last two are listed merely for completeness.
Infections Including STD • • • • • • • • • • • •
HIV infection and AIDS Genital Human Papillomavirus (HPV) Chlamydia trachomatis infections Lymphogranuloma venereum Genital mycoplasmas Granuloma inguinale Genital herpes Trichomoniasis Vulvovaginal candidiasis Pediculosis pubis Genital molluscum contagiosum Genital scabies Bearing in mind its relationship to the previous practice of coitus and infection with HPV, some would now include carcinoma of the cervix occurring in later life as a sexually transmitted disease. Hepatitis B virus is a major cause of acute and chronic liver disease including primary liver cancer. The detection of the virus in saliva suggests that sexual transmission may be involved and there is good evidence for infection resulting from both heterosexual and homosexual contact. Direct transmission from the mother to the foetus or neonate is also of importance in areas where the carrier rate is high. The development of an effective vaccine offers hope of controlling the spread of the virus. Human Immunodeficiency Virus (HIV) Infection and Acquired Immune Deficiency Syndrome (AIDS) AIDS is a disease of the immune system caused by a retrovirus, the Human Immunodeficiency Virus (HIV) that results in the development of either life-threatening opportunistic infections or the development of unusual malignant lesions or both. Although AIDS is classified as an infectious disease, its transmission requires sexual contact or direct entry of virus-infected blood or blood products into the circulation. There is little evidence that AIDS is transmitted by any non-sexual form of personto-person contact. The first recognised cases of AIDS occurred in male homosexuals and such individuals constitute the main risk group (about three-quarters of reported cases occur in homosexual or ‘bisexual’ males). Drug users who share infected needles constitute another high-risk group. AIDS has been diagnosed in female sexual partners of affected males and this is the predominant mode of transmission today, although this has always been the case in Africa. Vertical transmission occurs from mother
to foetus. In Asia, the infection is now moving into the low-risk general population and is likely to move from the urban to the rural areas. Occupational transmisson of HIV from patients to health care and laboratory workers is a small but definite risk. While the converse is theoretically possible, it is very rare. HIV has been isolated from the blood, semen and saliva of affected individuals. Some individuals who have been exposed to, or are infected by, the virus do not show any evidence of such disease. This suggests either a long incubation period or the operation of other factors during the incubation period which, together with the HIV, precipitate the loss of cell-mediated immunity. It is estimated that 36 million people are infected with HIV, with approximately two-thirds in Africa and one-fourth in Asia. Explosive patterns of the disease are being seen in India and Thailand. In the twenty-first century, it is expected that the magnitude of the epidemic in these regions will exceed that in subSaharan Africa. Pathology The human immunodeficiency viruses, HIV-1 and HIV2 belong to the family of human retroviruses and the subfamily of lentiviruses. HIV-1 is the commonest cause of HIV disease throughout the world but different subtypes are prevalent in different areas. HIV-2 was originally seen in West Africa but has now been identified in Europe and America as well. HIV infection results in a progressive decline in the number and function of helper T lymphocytes, e.g. the CD4 cells and monocytes. This results in the development of a profound immunodeficiency state with clinical manifestations in virtually all systems of the body. CD4 counts greater than 800 cells/mm 3 are considered normal. In the early stage of disease the count is >500 cells mm3, in the intermediate stage 200-500 cells mm3. HIV-positive patients in the advanced stage with CD4 counts less than 200 cells/mm3 are defined as having AIDS regardless of the presence of symptoms or opportunistic infection. The duration of time from initial infection to AIDS can vary from 3 years to several decades, the median time being 10 years. Clinical Features About 30-70 per cent of patients who contract HIV infection develop an acute illness after an incubation period of 7-10 days. The symptoms are non-specific, i.e.
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Jeffcoate’s Principles of Gynaecology fatigue, fever, sore throat, weight loss and myalgia. Some patients may develop cervical lymphadenopathy, a diffuse skin rash or ulcerations of the mouth or genitalia. The diagnosis is usually not made at this stage, but may be retrospectively diagnosed later in the course of the illness. In the stage of clinical latency, patients may remain entirely asymptomatic. As CD4 counts decline, the appearance of an opportunistic infection may be the first manifestation of HIV disease. Persistent generalised lymphadenopathy is also a feature of early symptomatic disease. Oral manifestations develop in almost all patients at some point in the course of their disease depending on the type, frequency and severity of disease. Various manifestations seen in the early stage include oral hairy leukoplakia, candidiasis, HSV infection, aphthous ulcers and gingivitis. Impaired skin immunity leads to cutaneous manifestations: molluscum contagiosum, herpes zoster, HSV infection, seborrhoeic dermatitis, scabies and folliculitis. Thrombocytopenia manifests as bleeding gums, pete-chiae and easy bruisability. Peripheral neuropathy can occur at all stages of the disease. Aseptic meningitis occurs in all but the very late stages. Later in the course of the disease, HIV-infected individuals present with oesophagitis, diarrhoea, malabsorbtion and weight loss. There is a ten-fold increase in the incidence of pneumonia. Pneumocystis carinii pneumonia (PCP) is pathognomonic of AIDS and is generally seen when CD4 counts are less than 200 cells/mm3. Similarly, tuberculosis is also generally seen with CD4 counts of less than 200 cells/mm3. While pulmonary tuberculosis in early stage HIV has a presentation similar to that in non-HIV patients, AIDS patients have an atypical presentation characterised by diffuse pulmonary infiltrates. Other secondary infections include infection with Toxoplasma gondii, Cryptosporidia, Cryptococcus, Cytomegalovirus, Treponema pallidum, Histoplasma and Bartonella. Kaposi’s sarcoma is another presentation virtually pathognomonic of AIDS. Ocular manifestations are seen, the most serious being cytomegalovirus retinitis. Endocrine disorders in these patients may be consequent to general debility. These include adrenal insufficiency and hypogonadism. HIV-associated nephropathy, myocarditis or dilated cardiomyopathy have also been described. Infection of the central nervous system results in an AIDS-dementia
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complex in the majority of patients late in the course of the illness. Seizures occur frequently and may be caused by neoplasms, opportunistic infections or HIV encephalopathy. Mother-to-infant transmission occurs in about 25 per cent of cases. The risk is increased in advanced stages of the disease and higher levels of viral replication, and can be reduced by zidovudine therapy (see below). The presence of vulvovaginal candidiasis which is persistent, recurrent or responding poorly to therapy; moderate or severe cervical dysplasia; carcinoma cervix in situ or pelvic inflammatory disease, especially if complicated by a tubo-ovarian abscess in an HIV-infected individual places the case in category B, i.e. these are attributed to HIV infection or it is considered that their clinical course or manage-ment are complicated thereby. The presence of invasive cervical cancer in an HIVinfected individual places the case in Category C, i.e. it is now listed in the AIDS surveillance case definition. The incidence of abnormal Papanicolaou smears of the cervix is about 60 per 1000 in women with HIV infection while it is approximately 5 per 1000 in otherwise healthy women. Diagnosis The diagnosis of HIV infection requires the demonstration of antibodies to HIV or its direct detection. ELISA is the standard screening test which detects antibodies against HIV-1 and HIV-2 with a sensitivity of over 99.5 per cent. Antibodies can be detected 4 to 12 weeks after infection. However, false-positive results may occur due to auto-antibodies, hepatic disease, recent influenza vaccination and have also been reported in women taking oral contraceptives. Therefore, if ELISA is positive or indeterminate, the Western blot test is done and is considered positive if it contains bands to at least two of the following gene products: p24 gp41 and gp 120/160. If the Western blot test is indeterminate it is repeated after one month. A PCR test can also be done and is the most specific. DNA and RNA PCR are both possible. The high cost of PCR and the problem of false-positive results due to contamination have resulted in its being used only when standard serologic tests fail to provide a definite answer. HIV-1 disease markers like CD4 cell count and plasma HIV-1 RNA levels are important indicators of disease stage and are used in laboratory monitoring of patients. β2-microglobulin and neopterin levels correlate
Infections Including STD with disease progression and are predictive of progression to AIDS independent of the CD4 count. Treatment Counselling of the patient regarding the natural history of the disease, transmission, nature and goals of therapy should be done in all cases. Support systems with qualified personnel are essential. Antiretroviral therapy is the cornerstone of treatment. Zidovudine (ZDV) was the first drug used. It is a nucleoside analogue which functions as a reverse transcriptase inhibitor. Its major side-effect is bone marrow suppression. Proximal myopathy is also commonly seen. Emergence of strains which are resistant to ZDV has limited its use as long-term monotherapy. Several other antiretroviral agents have now been identified. Combination therapy is generally preferred. The best regimen still has to be worked out. Zidovudine and didanosine have been the mainstay of therapy but other regimes with zalcitabine and lamivudine have been tried. Protease inhibitors in use include saquinavir, retonavir, indinavir and nelfinavir. Combinations of protease inhibitors with reverse transcriptase inhibitors, or of various protease inhibitors, or of nucleosides with non-nucleosides have all been tried. Prophylactic therapy is started in asymptomatic patients if the CD4 cell counts are less than 500 cells/ mm3; or even if CD4 counts are >500 cells/mm3, if HIV1 RNA titres are greater than 10000-20000 copies/ml or CD4 counts are decreasing at a rate greater than 10 cells per month. It helps to maintain the CD4 count, prolongs disease-free interval and inhibits viral antigen levels in the blood. It also decreases the severity of complications like the AIDS-dementia complex. Once started, it is continued for life. Prophylaxis for Pneumocystis carinii pneumonia is started if the CD4 count is less than 200 cells/mm3. If the patient develops fresh symptoms of AIDS, therapy must be started regardless of CD4 counts. In pregnancy, ZDV therapy is started in the second or third trimester. Intravenous ZDV administration during labour and therapy for the infant substantially decreases the risk of vertical transmission. The management of opportunistic infections is a very important aspect of care of the AIDS patient. Treatment regimes for all opportunistic infections have been clearly defined.
Prevention of HIV infection requires education of all adolescents and adults regarding the method of spread of disease, safe sexual practices, use of disposables and testing of blood products. Regular use of condoms can prevent HIV infection in a large number of cases. The addition of nonoxynol-9 improves the protection as it is toxic to HIV. It also improves the contraceptive efficacy. Partners of HIV-positive patients must be instructed in the use of condom protection even if they are using other contraceptive methods. Physicians and surgeons must observe universal precautions at all times as 90 per cent of HIV-infected individuals are asymptomatic. Postexposure prophylaxis with ZDV 200 mg thrice daily for 4 weeks has been recommended by CDC in the case of percutaneous exposure to blood infected with HIV. Lamivudine, indinavir and saquinavir are also used. Genital Human Papillomavirus (HPV) Papillomaviruses are a group of small DNA viruses that produce epithelial cell proliferation (papillomas). More than 30 HPV types infect the genital tract. These have been grouped into high- and low-risk types, based on the malignant potential.
Pathology and Clinical Features HPVs are epitheliotropic and their replication depends on the presence of differentiating squamous epithelium. HPV-infected epithelium characteristically has a hyperplastic prickle cell layer (acanthosis). The stratum corneum consists of 1-2 layers of parakeratosis. There are deep dermal papillae and a sharp border with the dermis. Koilocytes have been considered a marker for HPV infection. They are mature squamous cells with a large, clear perinuclear zone. The nuclei are enlarged and hyperchromatic; double nuclei may be present. Koilocytes may be scattered throughout the outer cell layers. Koilocytic changes may, however, be mimicked by other cellular changes or may be subtle. HPV infection is commonest in young, sexually active women, and is seen in 20-25 per cent of women in the third decade. Not all of these women will become symptomatic. Very often the infection disappears spontaneously after 1 to 2 years. Women over the age of
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Jeffcoate’s Principles of Gynaecology 30 years with persistent HPV infection are most likely to manifest disease. Two major manifestations of genital HPV are: genital warts which can be seen by the naked eye (usually caused by type 6 or 11) and squamous intraepithelial lesions (SILs) of the cervix that are detected by cytology and colposcopy (usually caused by type 16 or 18). Although SILs are seen in the vulva, vagina and penis also, the clinical significance of these is unclear. The clinical diagnosis and management of SIL and of cancer cervix is discussed elsewhere. The four morphological types of genital warts are condylomata acuminata, which have a cauliflower appearance; papular warts, which are flesh-coloured, dome-shaped, 1-4 mm in diameter; keratotic warts, which have a thick, crusty layer, resembling common skin warts; and flat-topped macular warts. Generally, condylomata occur on moist, partially keratinised epithelium, keratotic and papular warts on fully keratinised epithelium, and macular warts on either partially or fully keratinised epithelium. The diagnosis and management of warty lesions is discussed elsewhere.
Chlamydia Trachomatis Infections Chlamydia trachomatis is being increasingly recognised as the pathogen responsible for a variety of conditions, many of which resemble gonococcal infections. However, many chlamydial infections produce few or no symptoms in women and escape detection. Moreover, lack of adequate laboratory facilities for testing has led to the high prevalence of these infections in several parts of the world. Prevalence ranges from 3-5 per cent in asymptomatic women to over 20 per cent in those attending STD clinics. In industrialised countries this is now recognised as the commonest cause of pelvic inflammatory disease (PID). Pathology Chlamydia trachomatis is one of four species within the genus Chlamydia. The chlamydiae have a unique growth cycle. They are obligate intracellular parasites and cannot be cultivated on artificial media because they depend on their host for ATP and nutrient supplies. They survive by a replicative cycle that results in death of the infected host cells. Thus they can never be part of the normal flora of the genital tract and are always pathogenic when present.
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Virtually all chlamydial infections are sexually transmitted. Infants may acquire the infection by passage through an infected birth canal and develop ophthalmia neonatorum. Many serotypes have been identified based on an immunofluorescent antibody typing system of which L1, L2 and L3 are associated with lymphogranuloma venereum and D, E, F, G, H, I, J and K have been associated with non-gonococcal urethritis, cervicitis, salpingitis, proctitis, epididymitis, inclusion conjunctivitis and pneumonia of newborns. Extensive subepithelial inflammation, epithelial ulceration and scarring are the end result. Clinical Features Infections caused by C. trachomatis are very similar to those caused by N. gonorrhoeae in terms of the pattern of infection and sequelae (see above). However, chlamydial infections are more insidious in onset and generally produce very mild or no symptoms at all. Patients may present with mucopurulent discharge from the endocervical canal and hypertrophic ectopy of the cervix which bleeds on touch. On colposcopy they may be seen to have immature squamous metaplasia. Dysuria and frequency of micturition with bacteriuria < 10 5 organisms/ml of urine is pathognomonic of chlamydial infection in young, sexually active women. Clinical evidence of Bartholinitis may be due to chlamydial infection alone or in combination with gonococcal infection. Menorrhagia and metrorrhagia, often seen in association with salpingitis, may be the manifestations of concomitant endometritis. ‘Silent’ salpingitis is the hallmark of chlamydial infection which results in tubal scarring and infertility or ectopic pregnancies. The Fitz-Hugh-Curtis syndrome of perihepatitis with salpingitis, long considered a complication of gonococcal infection, has now been recognised as being commoner with chlamydial infection. Patients present with right upper quadrant abdominal pain, fever, nausea or vomiting. While salpingitis may not be diagnosed clinically, laparoscopy shows extensive tubal scarring, adhesions and inflammation. Periappendicitis may also occur. Among men, it is estimated that 35-50 per cent of cases of non-gonococcal urethritis are caused by C. trachomatis. Reiter’s syndrome has also been linked to C. trachomatis. This is a combination of non-specific
Infections Including STD urethritis, polyarthritis and conjunctivitis, sometimes with uveitis and skin lesions. The sexually transmitted variety is almost always confined to young adult men. Diagnosis The first cultures of C. trachomatis were done on hen’s egg yolk sacs. Cell culture plates are expensive, hence non-culture diagnostic tests which detect the antigen are used which are equally reliable e.g. direct fluorescent antibody (DFA) and ELISA. Samples are taken with cotton-tipped swabs which after mopping should pick up columnar epithelial cells from the exudate. DFA is the reference standard; ELISA can be done in larger numbers than DFA but is less reliable. PCR is used in developed countries even as a screening modality, but widespread use of these methods is still not available in developing countries. Treatment Tetracyclines administered in a dose of 500 mg 6-hourly for 7 days eradicates C. trachomatis. Erythro-mycin 500 mg 6-hourly for 7-14 days, ofloxacin 200 mg twice daily for 7-14 days, doxycycline 100 mg twice daily for 10 days or azithromycin 1 g as a single dose are all effective in uncomplicated chlamydial infection. In pregnancy, erythromycin or amoxycillin can be used but a test of cure is recommended two weeks after therapy because of the lower efficacy in pregnancy.
lymphatics, and spreads (mainly by lymphatics) to involve not only the tissues of the vulva but also those around and within the vagina and anus. Between 3 and 4 weeks the inguinal lymph nodes are involved. These painful swellings may be the first sign of the disease. The double genitocrural fold is a sign typical of LGV which is seen in approximately 20 per cent of cases, caused by the formation of a groove between groups of inflamed inguinal lymph nodes. The nodes tend to undergo necrosis and to form abscesses which release an offensive discharge, leaving chronic deep sinuses and much surrounding fibrosis. If the ulceration of the vulva and perianal region is extensive, it also heals with scarring and contracture. Fenestration of the nymphae is a characteristic end result. Chronic lymphatic obstruction and induration can result in vulvar elephantiasis and makes the vaginal walls feel rigid or rubbery in consistency (Fig. 19.6). Destruction or stricture of the urethra can occur. Rectal strictures and fistulas are not uncommon and can give rise to erroneous diagnoses of malignant disease. When the rectum is involved, there is diarrhoea and the passage of blood and pus per anum. Constitutional upset and pyrexia accompany the active stages of the disease.
Lymphogranuloma Venereum (LGV) This disease is mostly seen in tropical countries. Elsewhere it is rare but is sometimes found in immigrants and in prostitutes in sea ports where it is introduced by sailors. It occurs most commonly among the African races, notably those in the West Indies and in India, and parts of South-East Asia and South America. It more often affects men than women and personal uncleanliness appears to be a predisposing factor. It is usually, but not always, contracted by sexual intercourse. It is caused by Chlamydia trachomatis serotypes L1, L2 and L3. Clinical Features The incubation period is 7-14 days. The initial lesion is a painless papule, pustule or ulcer on the vulva and may quickly disappear. The infection persists in the
Fig. 19.6: False elephantiasis resulting from healed lymphogranuloma venereum. There are also residual scars on the perineum and around the anus. The patient concerned gave a history of ulceration which persisted for 2 years
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Diagnosis This is suggested by the clinical features and by laboratory findings. The Frei test is no longer used. The diagnosis can be made by isolating the organism if facilities for culturing Chlamydia are available. The organism may be obtained either from a smear of material from lesions or from a lymph node abscess. Antibody against lymphogranuloma venereum serotypes can be detected by a microimmuno-fluorescent technique. A test for anti-Chlamydia antibody is available: the LGV complement fixation test. If the antibody titre exceeds 1 in 32, it is most likely to be due to lymphogranuloma venereum rather than other chlamydial infections. PCR may be used to demonstrate Chlamydia in infected secretions or tissues. Treatment The treatment of choice is to give one of the tetracyclines in a dose of 500 mg 6-hourly or doxycyline 100 mg bd for 21 days, and to aspirate the inguinal abscess repeatedly. Incision and drainage is contraindicated. If the response is unsatisfactory the tetracyclines are repeated after an interval of several days. Alternatively, chloramphenicol, erythromycin, minocycline or rifampicin can be used. The end results of tissue destruction and fibrosis sometimes require reconstructive surgery on the vulva, urethra and vagina.
Genital Mycoplasmas Mycoplasma hominis and Ureaplasma urealyticum are the most common mycoplasmas to be isolated from the genital tract. They can be acquired during passage through the birth canal or later, after puberty, usually as a result of sexual contact. Pathology and Clinical Features Mycoplasma belong to the class ‘Mollicutes’ and have developed from anaerobic bacteria by the process of gene deletion. Of the 16 mycoplasmas detected in human beings, six are known to inhabit primarily the genitourinary tract. Some of these may be found in the oropharynx because of orogenital contact. Genital mycoplasmas have been implicated in a wide variety of clinical conditions. They were initially implicated in the aetiology of non-gonococcal urethritis
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but this has not been supported. Ureaplasma urealyticum appears to play an important role in the aetiology of Chlamydia-negative non-gonococcal urethritis, though the severity of inflammatory response diminishes with repeated inoculations. M. hominis may have a role in pelvic inflammatory diseases; here ureaplasmas do not seem to have any significance. M. genitalium has not been shown to be involved in bacterial vaginosis (BV) but the role of mycoplasmas in BV needs further understanding. M. hominis can produce postabortal and postpartum fever. Ureaplasmas may also be causative in post-partum pyrexia. The genital mycoplasmas have a more important impact on disorders of reproduction. Treatment of ureaplasma infection has been shown to improve sperm motility and quantity in patients with infertility although the conception rates have not been shown to increase. Most importantly, a significant association has been shown between mycoplasmal infection and recurrent spontaneous abortion, preterm delivery, preterm premature rupture of membranes and chorioamnionitis. Ureaplasma infection has been associated with low-birthweight infants. Diagnosis Specialised media have been used to culture M. hominis but several mycoplasmas are fastidious and difficult to culture. Non-culture procedures are important in this latter group. Serological tests have been popular in this regard. Treatment Tetracyclines are the drugs of first choice. With the emergence of resistant M. hominis strains, clindamycin has become the next alternative. Azithromycin is sometimes used to treat non-gonococcal urethritis but some ureaplasmas may be resistant to it. In these cases, erythromycin or sparfloxacin may be used. In persistent or recurrent urethritis, prolonged treatment for more than a month with a tetracycline or a macrolide may be required. Granuloma Inguinale (Donovanosis) Donovanosis was first described from India and is now mostly seen in some developing countries. Whilst there is much confusion between this disease and the rather
Infections Including STD more common lymphogranuloma venereum, the regional lymph nodes are not involved in the early stages of this disease.
The end results of the destructive process may ultimately require plastic surgery or excision of the vulva in whole or in part.
Pathology
GENITAL TUBERCULOSIS
The infecting organism is a Gram-negative bacillus, Calymmatobacterium granulomatis, with large capsules which can be seen within mononuclear cells when stained by the Giemsa method. The disease usually manifests itself 10-50 days after coitus with an infected partner. The initial lesion is nearly always on the vulva and presents as a papule which breaks down to form a chronic red ulcer with rolled edges, features which simulate those of cancer or a chancre. The ulcer spreads directly, rather than by lymphatics, to involve the whole vulva, and sometimes the vagina, cervix, anus and the skin of the groins (the esthiomene stage). The condition is not particularly painful and ultimately heals to leave fibrosis, distortion of the tissues, and false elephantiasis or hypertrophy of the vulva. Sections of affected tissues often disclose epithelial unrest. Indeed, cancer can supervene. In pregnancy, the disease has a more aggressive course. In the active stage of the disease the inguinal nodes are enlarged but do not suppurate; this is a distinguishing feature from lymphogranuloma venereum.
Aetiology
Diagnosis The diagnosis of granuloma inguinale is proved by finding Donovan bodies within mononuclear cells in material obtained from the ulcer. These are encapsulated diplobacilli which show up with Giemsa and Leishman stains. It is common not to find these bodies and this leaves the diagnosis in doubt. No serologic tests are currently in use. However, the clinical picture is characteristic. Treatment This infection does not respond well to any treatment. Streptomycin and co-trimoxazole have been used in India and found to be effective for large lesions. The quinolones and high-dose ceftriaxone are also effective. Resistance is reported with tetracyclines. Azithromycin 500 mg daily for one week may emerge as the most costeffective therapy. In pregnancy, erythromycin is the drug of choice.
Tuberculosis of the female genital tract is common amongst all communities where pulmonary or other forms of extragenital tuberculosis are prevalent, and this despite early recognition and effective treatment of such lesions. Those who take a contrary view do not conduct a proper search for it sufficiently often. It follows that genital tuberculosis is nearly always secondary to a focus elsewhere in the body but the spread takes place at a very early stage of the disease - usually in adolescence or early maturity. Thus, by the time the genital lesion is found, which can be at any age, the primary has often healed and is inconspicuous. Nevertheless, 50 per cent of affected women give a past history of an extragenital infection, and a further number can recall, if questioned closely, contact with the disease in childhood or adolescence. The tubercle bacilli reach the genital tract by one of the following mechanisms.
Bloodstream This mechanism accounts for at least 90 per cent of cases, the primary focus being most often situated in the lungs, lymph nodes, urinary tract, bones and joints - in that order.
Descending In this type the infection reaches the pelvic organs by direct or lymphatic spread from infected adjacent organs such as the peritoneum, bowel and mesenteries nodes.
Ascending There is a theoretical possibility that a few cases of tuberculosis of the vulva and vagina, and of primary tuberculosis of the cervix, are explained by children sitting unclothed where others have spat or coughed, and in adults having coitus with a male suffering from urogenital tuberculosis. Pathology and Bacteriology When the pelvic disease is secondary to tuberculous peritonitis, or when the primary focus is in the lymph
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Jeffcoate’s Principles of Gynaecology nodes or bowel, the bovine bacillus (Mycobacterium tuberculosis bovis) is likely to be involved. In all other cases it is generally the human bacillus (M. tuberculosis) which is found. So, in those countries where cattle or their milk are relatively free from the tubercle bacilli, the human bacillus is found in 95 per cent of cases of genital tract infection. Any part of the genital tract can be affected but the common sites are the fallopian tubes and the endometrium. The tubes are involved in at least 90 per cent of cases and, following bloodstream spread, the genital disease probably starts there. It begins in the submucosa at their outer ends and gradually progresses inwards, bombarding the endometrium with bacilli. The finding of endometrial tuberculosis almost always means that the tubes are infected, but tuberculous salpingitis can exist without associated endometritis. The genital infection can be an acute and rapidly extending disease but is mostly indolent. There are several cases reported in which the disease appeared to commence, or to become violently active, immediately after pregnancy. In such circumstances fatal miliary spread is not uncommon.
Vulva and Vagina Tuberculosis of the vulva and vagina usually takes the form of shallow, superficial, indolent ulcers with undermined edges. The ulceration tends to spread slowly, healing in some areas with the formation of scar tissue. A vulvar hypertrophic lesion is less common and mostly represents inflammatory induration and oedema resulting from fibrosis and lymphatic obstruction.
19.7). Adhesions and partial obliteration of the cavity are also described. Ordinarily, however, tuberculous endometritis is only recognised by histological and bacteriological examination of the tissues (see below).
Fallopian Tubes The appearance of tuberculous tubes varies widely and depends to some extent on whether the infection is bloodborne or spreads directly from the peritoneum or bowel. In the one case the disease is primarily an endosalpingitis, in the other an exosalpingitis with the possibilities of tubercles on the surface and of dense surrounding adhesions. Sometimes the tubes look completely normal; more often they appear red, oedematous and swollen when the infection is active, and fibrosed when it is chronic. They do not always have tubercles on their surface. ‘Tubercles’ when seen on tubes and the peritoneum at laparoscopy or laparotomy are not always caused by tuberculosis. They may be an end-result of any chronic inflammation, whether infectious or non-infectious, e.g. talc or starch granulomas, or peritoneal deciduosis. The tubal lumina are closed in only 50 per cent of cases in which there is bacteriological and histological evidence of endometrial disease. In this respect, however, it seems likely that many examples of tubal obstruction of
Cervix Clinically recognisable tuberculosis of the cervix can be ulcerative but more often appears as a bright red papillary erosion which bleeds easily. It can be confused with carcinoma. As a histological finding, cervical tuberculosis is not uncommon in cases of endometrial tuberculosis.
Uterus The uterus usually looks normal to the naked eye although a typical tuberculous ulcer may rarely be seen in the endometrium. Extensive involvement can result in collections of caseous material to form a type of pyometra, or to cause abscesses in the myometrium (Fig.
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Fig. 19.7: Multiple tuberculous abscesses in a chronically thickened myometrium. This is a rare manifestation of tuberculosis and the appearance of the lesion might be mistaken for that of adenomyosis
Infections Including STD uncertain aetiology represent completely inactivated, and unprovable, old tuberculous lesions. In tuberculosis the obstructions are typically multiple and the tube wall is thickened and shotty. Sometimes a localised closure at the outer end results in the formation of a hydrosalpinx or a pyosalpinx with thick fibrous walls which can become calcified or even ossified (Figs 19.8 and 19.9). A tuberculous pyosalpinx is often remarkably free from adhesions and may be so large that the patient’s
complaint is the presence of an abdominal tumour (Figs 19.8 and 19.10). A hypertrophic form of endosalpingitis has the macroscopic and sometimes microscopic appearances of adenocarcinoma and can be mistaken for such. Secondary infection is often present and may itself account for symptoms or for exacerbations of the disease.
Ovaries The ovaries are infected in at least 30 per cent of cases of tuberculous salpingitis but ovarian tuberculosis without tubal involvement is rare. The disease can manifest by way of surface tubercles, adhesions and thickening of the capsule, retention cysts, and sometimes by caseating abscess cavities in the substance of the ovary (Fig. 19.11). Often, however, the ovaries have a normal macroscopic appearance and the diagnosis is only revealed by laboratory studies of excised tissue.
Fig. 19.8: Tuberculous pyosalpinges relatively free from adhesions, as they commonly are. There is also a small cyst in the right ovary. This specimen was removed from a nulliparous woman aged 40 years whose only complaint was the presence of a lower abdominal tumour
Fig. 19.10: Tuberculous pyosalpinges causing an abdominal tumour arising from the pelvis and extending to the umbilicus. (By courtesy of the Editor of J Obstet Gynaecol Br Commonw)
Fig. 19.9: Direct radiograph of the lower abdomen and pelvis before operation in the case illustrated in Fig. 19.8. The pyosalpinges are visible because of slight calcification in their walls. This appearance permitted a preoperative diagnosis of tuberculosis
Fig. 19.11: Tuberculosis of the ovaries.There are typical multiple caseating abscesses in one, and diffuse fibrosis and enlargement of the other
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Fistulas and Sinuses Tuberculous fistulas and sinuses involving the abdominal wall, tubes, uterus, vagina, bladder and bowel can arise spontaneously (Figs 19.12A and B), but are mostly the result of inadequate or injudicious surgery. Clinical Features
Tuberculosis of the Vulva and Vagina Vulvar lesions are usually painful and tender; vaginal ulcers, unless sited at the introitus, are painless. Both often cause a bloodstained purulent discharge.
Overt tuberculosis of the Cervix This is painless but causes the same type of discharge and also postcoital bleeding. A cauliflower growth which closely mimics malignancy is often seen.
Tuberculosis of the Uterus and Adnexa This is often a silent disease. It may be present for 20 or more years without producing any symptoms, the woman remaining in apparently excellent health. The
pelvic organs also feel normal on bimanual examination in 50 per cent of proven cases. The presence of pelvic tuberculosis is most often revealed by the investigation of childlessness and therefore is usually discovered in women aged 20-40 years. In developed countries, tuberculous infection of the uterus and tubes is now demonstrable in less than one per cent of all cases of infertility studied, varying with the prevalence of pulmonary tuber-culosis in any community 15-20 years previously. The frequency with which it is found in both symptomless and complaining women, however, depends on the care taken to look for it. Moreover, the symptoms credited to it, and their statistical importance, depend on the types of cases in which tests for tuberculosis are made. Thus, if the search is limited to all women complaining of infertility, one picture of associated symptomatology appears; if it is extended to all women complaining of amenorrhoea or to women with menorrhagia or postmenopausal bleeding, different pictures emerge. It should be routine practice to look for bacteriological and histological evidence of endometrial tuberculosis in
Figs 19.12A and B: A tuboretroperitoneal fistula resulting from tuberculous salpingitis. A woman aged 27 years complained of infertility and was first subjected to tubal insufflation and curettage. The insufflation was positive (misleadingly so as was subsequently shown) and the endometrium was histologically and bacteriologically negative for tuberculosis, (A) A salpingogram showing the right tube closed at its outer end. From the distal end of the left tube, which is dilated, there is a small track through which the medium passed, (B) A straight radiograph taken 24 hours later shows that the medium escaped not into the peritoneal cavity but extraperitoneally. Laparotomy confirmed that the outer end of the left tube communicated by way of a caseating abscess with the extraperitoneal tissues on the side wall of the pelvis
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Infections Including STD all cases of infertility and of amenorrhoea, and otherwise only when there are grounds for clinical suspicion. The special symptoms are as follows.
Unusual activity of the infection occasionally causes symptoms and signs of acute or subacute peritonitis. Exacerbations of this kind are sometimes precipitated by tubal patency tests.
Infertility Although 10 per cent of women with proven endometrial infection have had babies or abortions, the commonest symptom of pelvic tuberculosis is primary infertility. This is a feature of 70 per cent of cases and occurs even though the fallopian tubes are open. It then reflects abnormal tubal and endometrial function.
Ectopic Pregnancy Every woman who has, or has had, a tubal pregnancy should also be suspected of having tubal tuberculosis, active or healed, apart from the more obvious causes nowadays, including chlamydial infection. Indeed, tubes removed for this condition should still be examined bacteriologically from this standpoint.
Menstrual Disturbance In approximately 50 per cent of cases the menstrual function is normal. In the others it is generally held that the change is mostly in the direction of menorrhagia and polymenorrhoea. In my experience, however, and unlike other infections, tuberculosis more often causes amenorrhoea or oligomenorrhoea. This is sometimes explained by suppression of ovarian function; in such cases, compensatory overactivity of the anterior pituitary can result in a raised excretion of gonadotrophins. In other cases, however, there is evidence that ovulation continues; the amenorrhoea is then attributable to the endometrial damage. Menopausal and postmenopausal bleeding can have endometrial tuberculosis as a basis. Dysmenorrhoea rarely, if ever, occurs.
Intermenstrual Discharge This can be bloodstained if there is ulceration of either the cervix or endometrium.
Pain An intermittent chronic ache in the lower abdomen, often of long standing, is noted in 20-30 per cent of cases. Indeed, 20 per cent of sufferers from pelvic tuberculosis have previously had a normal appendix removed.
General Disturbances Conditions such as malaise, loss of weight, night sweats and pyrexia are only seen during an unusually active phase of the disease. Diagnosis The clue to the diagnosis of pelvic tuberculosis is to have the condition in mind; although the incidence of tuberculosis is falling in many countries, immigration may bring problems. The only difficulty arises over those cases, and there must be many, where infection in adolescence has become quiescent leaving no active organisms, merely residual damage and clinical suspicion. Some of the guidelines are as follows. Tuberculosis should be suspected and excluded in every woman whose infertility or amenorrhoea is not explained by other causes. Any virgin having symptoms and signs of chronic pelvic infection should be assumed to have tuberculosis until it is proved to the contrary. Any pelvic infection which is slow to respond to the ordinary methods of treatment is suspect, and so is one which shows an exacerbation after curettage or tubal patency tests, or one which is not accompanied by polymorphonuclear leucocytosis. Sometimes a previous history of peritonitis, appendicectomy with slow healing, pleurisy, and a prolonged illness in childhood, or a history of tuberculosis affecting other members of the family and childhood contacts, provides the lead. The finding of an active or healed extragenital lesion should always raise suspicions, as should the radiological demonstration of calcification in the tube or ovary or the classical appearance of isthmica nodosa on a hysterosalpingogram performed before the diagnosis is suspected or made. If tuberculosis is suspected and the lesion is accessible (as in the case of the cervix and vulva, or of the tube at laparotomy), the diagnosis is made by examining biopsy material both bacteriologically and histologically (see below). Otherwise, advantage is taken of the fact that the endometrium is nearly always involved and can be obtained for examination by endometrial biopsy or aspiration. Specimens should preferably be taken from
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Jeffcoate’s Principles of Gynaecology the cornual regions. The most likely time in the cycle to find evidence of endometrial tuberculosis is during the week preceding menstruation. This is because the tubercles and bacteria are mostly found in the surface layers which are shed during menstruation, and which have to be reformed and reinfected from the tubes downwards. The curettings or tissue fragments are divided into two portions and handled as follows. The specimen is fixed and sections made for microscopic study. The finding of epithelioid clusters with giant cells is highly suggestive but not conclusive evidence unless tubercle bacilli can also be demonstrated in specially stained preparations (Figs 19.13 and 19.14). Traditional Ziehl-Neelsen staining with basic fuchshin dyes is satisfactory. Modern laboratories processing large numbers of specimens use auraminerhodamine staining and fluorescence microscopy. This also applies to the histological examination of any tissue removed at operation. Lesions which simulate tuberculosis are foreign body giant cell reactions (such as talc granulomas) and sarcoidosis. • At the time of operation, some endometrium or tissue is kept aside for culture. If this test is omitted, and reliance is placed on histological examination alone, endometrial tuberculosis can be missed in up to 5075 per cent of cases. A positive culture is diagnostic. Specimens are inoculated onto egg-or agar-based medium, e.g. Löwenstein-Jensen or Middlebrook 7H10 and incubated at 37°C under 5 per cent CO2. Growth is detected after 4 to 8 weeks. Species identification is done on the basis of growth time, colony pigmentation and morphology and biochemical tests.
Fig. 19.13: Tuberculous salpingitis microscopic picture
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In many laboratories, liquid media with radiometric growth detection, e.g. BACTEC-460, and the identification of isolates by nucleic acid probes are used instead and these permit diagnosis in 2 to 3 weeks. The bacteriologist should also be able to report on drug sensitivity. • PCR can be done on endometrial tissue. However, PCR may be positive even with dead bacilli and need not reflect the activity of the disease. It may also be positive with other mycobacterial infections. If for any reasons endometrial sampling cannot be arranged, the first-day menstrual discharge is collected by pipette and this will sometimes give a positive culture. A negative finding, however, is not conclusive. A real problem is to diagnose tubal tuberculosis in the absence of endometrial involvement. Here, laparoscopy has a place providing tuberculous peritonitis and adhesion formation can be excluded with reasonable certainty. Biopsies and washings from the cul-de-sac can be subjected to the same tests described above. Salpingography sometimes reveals characteristic tubal patterns but is unreliable, and is so dangerous from the standpoint of causing an exacerbation that it should never be carried out if there is a real possibility of the disease being present. Despite meticulous investigation it is sometimes difficult to clinch the diagnosis and repeated tests may be necessary. I know of several patients with normal pelvic organs who had to have
Fig. 19.14: A high-power view of the giant cells system seen in Fig. 19.13
Infections Including STD endometrial sampling carried out three or four times over a few years before tubercle bacilli were found. It is also my practice, when carrying out tubal surgery for infertility, to send material for bacteriological culture for tuberculosis as well as for routine histological analysis. Treatment The choice of treatment depends to some extent on whether genital tuberculosis is found in association with an active lesion elsewhere, and must therefore be preceded by a full investigation from this stand-point. Radiological examination of the chest and an examination of the urine for tubercle bacilli are especially important.
General It is important to improve the patient’s natural resistance to the disease by attention to diet and general well-being. Women frequently ask whether there is any chance of their husbands contracting urogenital tuberculosis during coitus. This risk cannot be denied, although it is small and can be obviated by the use of a condom until the infection is under control.
Antibiotics The treatment of pelvic tuberculosis is similar to that of pulmonary tuberculosis. Initially therapy used to be given for 12 to 24 months. The introduction of rifampicin decreased the duration to less than 12 months. The realisation that pyrazinamide augments the potency of the isoniazid—rifampicin regimens led to the development of the 6-month regimen. Five drugs are considered first-line agents for treatment of tuberculosis: streptomycin, isoniazid, rifampicin, pyrazinamide and ethambutol. The last four can be given orally and are generally preferred. The principle of treatment is to give four drugs initially for 2 months, and preferably until the drug sensitivity is known, followed by two drugs for the remaining 4 months. Patients are usually commenced on isoniazid (INH) 5 mg/kg (maximum 300 mg daily); rifampicin 10 mg/kg (maximum 600 mg daily); pyrazinamide 15-30 mg/kg (maximum 2 g daily); and ethambutol 15-25 mg/ kg. Maintenance therapy is usually with INH and rifampicin in a combined tablet for 4 months. Pyridoxine 10-25 mg daily should be added to the regimen in patients at high risk of vitamin deficiency, e.g.
malnourished women, pregnant and lactating women; medical problems associated with neuropathy, e.g. diabetes mellitus, chronic renal failure, HIV infection or AIDS; and alcoholics. Patients with tuberculosis resistant to first-line drugs are treated with second-line drugs. These have a lower degree of efficacy and a higher degree of toxicity so these patients should ideally be referred to a specialised unit. Second-line drugs include kanamycin, amikacin and capreomycin which are injectable preparations and ethionamide, cycloserine, para-aminosalicyclic acid (PAS), ofloxacin, spar-floxacin, clofazimine, thiacetazone and amoxycillin/clavulanic acid which can be administered orally. Rifabutin is a long-acting rifamycin derivative under evaluation for cases resistant to rifampicin which may be effective in a once-weekly dose. During treatment, patients should be monitored for drug toxicity. The most important and commonest of these is hepatitis. Patients on rifampicin should be warned that their urine, saliva and other body secretions will be coloured orange-red but this should not be confused with the dark urine of hepatitis which is accompanied by loss of appetite. If there is marked derangement of hepatic function, drugs should be stopped and re-introduced one at a time after recovery. Other complications include optic neuritis with ethambutol, eighth nerve damage with streptomycin, autoimmune thrombocytopenia with rifampicin; the development of these warrants discontinuation of these drugs. Hyperuricaemia and arthralgia may develop with pyrazinamide but the drug is discontinued only if the patient develops gouty arthritis. Minor problems like gastrointestinal symptoms and pruritus are treated symptomatically without alteration of therapy. In the case of endometrial tuberculosis, the patient is subjected to endometrial aspiration after 6 months for a test of cure. Tuberculosis of the vulva, vagina and cervix is often cured quite dramatically by antibiotics. The results in the case of endometrial and tubal disease are more difficult to evaluate but experience suggests the following. • By itself, antibiotic therapy is usually inadequate when chronic caseating abscesses are present. • In the more favourable cases, with only microscopic foci, the infection is eradicated in the majority of cases. Sometimes, after an initial apparent cure, positive
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Jeffcoate’s Principles of Gynaecology endometrial cultures are obtained again 12 or more months later. This may happen in 5-10 per cent of cases. • Cure to the extent of restoring the patient’s fertility is not common, the total salvage being no more than two live babies for every 100 women treated. If the tubes are closed at the outset, permanent sterility is likely and attempts at salpingostomy following suppression of the active infection may be followed by reclosure. If the tubes are open, pregnancy is possible but, because of residual infection or of scarring and distortion of the endosalpinx, tubal implantation is likely. Indeed, ectopic pregnancy following antibiotic therapy for pelvic tuberculosis is now a recognised clinical syndrome. Abortion of intrauterine pregnancies is also common. Reported experience and our own indicates that of all women treated, only 8 per cent conceive, producing on an average 1.5 pregnancies each. Of the pregnancies, 50 per cent are tubal and 20-30 per cent end in abortion, leaving only 20-30 per cent resulting in live births. The subsequent obstetrical history of one patient was abortion, live baby, ectopic pregnancy. It is not always possible to relate subsequent fertility to treatment because spontaneous cure of the disease can happen, and because conception occasionally occurs despite the presence of active tuberculosis. In vitro fertilisation (IVF) is now one possible alternative.
Surgery When tuberculosis is localised to any site in the body, there is usually a place for excision of the affected area; this is true for genital tuberculosis where the disease can be remarkably localised and accessible. A hypertrophic lesion of the vulva which fails to respond to antibiotics may require excision. Removal of the uterus and adnexa for tuberculous salpingitis and endometritis is often decried on the grounds that it is a dangerous operation and likely to result in a fistula or chronic sinus. If, however, the cases are well chosen, this risk is small even without antibiotic cover. Now that surgery is covered by antibiotics it is even less dangerous.
Indications for Surgery • Progression or persistence of active disease despite adequate medical treatment
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• The presence of large inflammatory masses pyosalpinx, ovarian abscess and pyometra. Small symptomless adnexal swellings remaining after antibiotic therapy are best not disturbed. • The persistence of symptoms such as menorrhagia and pelvic pain after medical treatment • Each case has to be considered on its merits but one factor which has sometimes to be considered is proved closure of the tubes. In such a case, restoration of fertility is a forlorn hope, but conservative measures may still be justified because of the development of IVF.
Contraindications to Surgery • Active tuberculosis elsewhere in the body • The presence of plastic peritonitis and dense adhesions around the pelvic organs. It is in such cases that there is danger of injury to bowel, ureter and bladder. A history of tuberculous peritonitis in youth and the demonstration of bovine rather than human bacilli in the endometrium should warn off the surgeon.
Technique Any sort of surgery should be preceded by 3-6 weeks’ treatment with antituberculous drugs, in full dosage, and followed by the full course of treatment. When tuberculosis affects the upper genital tract the appropriate surgical procedure is usually total hysterectomy and bilateral salpingectomy. If the ovaries are obviously involved, and even if they look normal in a woman over the age of 45 years, they are usually removed as well. In a younger woman, howeyer, I always conserve at least one ovary if it looks reasonably healthy, trusting antibiotics to eliminate any microscopic foci in it. I have never seen harm come from this practice. SARCOIDOSIS Although not an infection, sarcoidosis is included here for comparison with genital tuberculosis. Sarcoidosis is mainly seen in peoples living in temperate climates - in Europe and North America. It is a granulomatous disease of the reticuloendothelial system with a wide distribution throughout the body. It occurs as a rarity in the uterus, tubes and ovaries, often symptomless but sometimes giving rise to a complaint of infertility. The diagnosis is
Infections Including STD a histological one, the lesions having microscopical appearances similar to those of tuberculosis with follicles consisting of an aggregation of epithelioid cells and a variable number of giant cells surrounded by a narrow zone of lymphocytes. Complete absence of caseation and a relative scarcity of lymphocytes distinguish it from the tuberculosis follicle (Fig. 19.15). Active sarcoidosis appears to be the result of an exaggerated cellular immune response to antigens, self or non-self, which stimulate predominantly or helperinduced T cell response. Sarcoidosis is self-curative in 50 per cent of cases but resolution can leave permanent tissue damage—in the fallopian tubes, for example. Nevertheless, it is best left untreated or attention paid only to relief of symptoms. The lesions disappear when corticosteroids are administered but return as soon as treatment is suspended. ACTINOMYCOSIS Actinomycetes, most often Actinomyces israelii, are occasionally found to be the cause of pelvic infection. Since the majority of infections reported in the past involved the right adnexum it was considered that the source of infection originated in the caecum or appendix or occurred as a result of bloodstream spread. Presently, an association between the use of an intrauterine contraceptive device (IUCD) and this infection is recognised and it is postulated that the vagina
is the portal of entry. Actinomycetes have been noted in cervical smears taken from asymptomatic IUCD wearers. The disease usually develops after at least 2 years of IUCD use. The organisms may persist in the genital tract for some time after the removal of the IUCD. Other possible routes of entry may be by orogenital sex, ascent from the rectum or spread from the appendix. The clinical manifestations of pelvic inflammatory disease caused by actinomycetes in association with an IUCD are more likely to be chronic rather than acute: fever, weight loss, abdominal pain, abnormal vaginal bleeding, discharge. Endometritis may progress to the formation of an adnexal mass or a tubo-ovarian abscess. A delay in diagnosis can lead to a ‘frozen pelvis’ which has to be differentiated from endometriosis or disseminated malignancy. Pseudomycelial-like clumps of organisms are seen in the Pap smear along with positive staining for fluorescein isothiocyanate-labelled antisera against A. israelii. For women who are symptomatic but do not have an adnexal swelling, the IUCD should be removed and sent for culture. Prolonged courses of penicillin for 6-12 months are recommended. Tetracycline is recommended for patients allergic to penicillin. Erythromycin, minocycline, clindamycin and cephalosporins can also be used but metronidazole and aminoglycosides are unreliable. If patients with pelvic masses do not respond to antibiotics, surgical excision of the masses may be required in addition. Asymptomatic patients are not treated. SCHISTOSOMIASIS (BILHARZIA)
Fig. 19.15: Sarcoidosis of the tube
Genital schistosomiasis is seen in all tropical and subtropical countries, notably Egypt, other countries such as Africa, India, Malaysia, Indo-China, and Central and Southern America, where the causal worm and its immediate host — a water snail — are prevalent. The worm, Schistosoma haematobium having entered the skin from infested water, spreads by the blood-stream to invade the tissues where it deposits ova which cause local inflammatory reactions. Adult S. haematobium worms live in the genitourinary veins. The lesions are predominantly in hollow viscera, especially the bladder and rectum, but any part of the genital tract from the vulva to the ovaries can be involved. The commonest genital site is the cervix; vulvar lesions are mostly seen in children. The infestation is chronic and can persist for a lifetime, the carrier
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Jeffcoate’s Principles of Gynaecology continually excreting ova which contaminate the environment. The inflammatory reaction is a severe one with each ovum being surrounded by a giant cell, epithelial cells, lymphocytes and eosinophils. In some respects the microscopic appearances resemble those of tuberculosis. Bladder and bowel symptoms predominate and the discomfort referred to the reproductive organs varies with the site infected. Schistosomiasis of the vagina and cervix can cause discharge, bleeding and dyspareunia; it also favours infertility in that antibodies to the disease are spermatotoxic. To the naked eye the disease appears in the form of nodules, plaques, ulcers or papillomas with surrounding induration. On the cervix the disease can simulate erosion and leucoplakia. In any site it can be mistaken for cancer. It is suggested that schistosomiasis occasionally favours the development of cancer. Praziquantel is effective against all human schistosomes and the dose is 40 mg/kg as a single oral dose. The organophosporus compound metrifonate is only effective against S. haematobium infections and is given orally. The prognosis is good for treatment in the early stage but poor in the late stages of the disease.
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AMOEBIASIS Amoebiasis of the genital tract occurs at any age wherever intestinal infection is common, that is amongst the less-privileged communities living in warm climates. The parasite (Entamoeba histolytica) spreads from the lower bowel when standards of hygiene are poor. It causes ulcerative lesions in the vagina, cervix and endometrium and these can be mistaken for cancer on naked-eye examination. Apart from any bowel symptoms, the patient complains of a blood-stained purulent vaginal discharge. The diagnosis is made by the microscopic demonstration of the parasites in stools, vaginal discharge and tissue sections; the finding of the organism incidentally during cervical cytology is also described. A negative gel diffusion precipitation test, or amoebic latex agglutination test, carried out on serum, excludes active disease but a positive finding may only mean a previous infection. The treatment of choice is metronidazole in large doses, 400-750 mg three times daily for 5-10 days. Metronidazole is relatively ineffective in chronic asymptomatic intestinal amoebiasis in which only cysts are present in the stool. In these cases diloxanide furoate is the drug of choice.
20
CHAPTER
Infections as They Affect Individual Organs
Vulvitis Bartholinitis Vaginitis Cervicitis Endometritis Metritis Salpingo-oophoritis
333 338 339 347 349 350 350
Oophoritis Pelvic Peritonitis Pelvic Cellulitis Pelvic Inflammatory Disease Suppurative Thrombophlebitis of the Pelvic Veins
356 356 357 359 360
VULVITIS Pyogenic Infections
Infection of Abrasions and Wounds Local injuries or abrasions resulting from sanitary towels and tight underclothing — often impregnated with irritant detergents left from washing — are common sources of vulvar dermatitis. Excoriation of the skin can also be caused by vaginal discharge, and by ammonia liberated by urea-splitting organisms when the vulva is exposed to constant leakage of urine. All these lesions can become secondarily infected to cause local pain and tenderness. Treatment consists of rest, warm baths and removal of the cause.
Intertrigo: Smegma Concretions Lack of cleanliness leads to a collection of irritating sebum and other secretions in the skin folds, and secondary infection follows. The only treatment required is care over hygiene. Inattention to the skin in the area of the clitoris can result in the collection of a concretion of smegma resembling a small stone under the prepuce. This may have to be removed (Figs 20.1A and B).
Furunculosis Infection of vulvar hair follicles leads to boils and carbuncles which are sometimes recurrent. Glycosuria must be excluded in such cases. Otherwise, recurrent boils mean that pathogenic staphylococci are being harboured in a carrier site (for example, the nose or axilla) of the patient or of a close associate. These have to be found and eliminated. For the vulvar skin the remedies are scrupulous attention to cleanliness, swabbing with an antiseptic solution and regular applications of topical
Jeffcoate’s Principles of Gynaecology
Infantile and Senile Vulvitis When the vulvar epithelium is thin and inactive, as in childhood and old age, any of the organisms to which it is normally resistant can set up a simple vulvitis. This sometimes leads to labial adhesions. This type of vulvitis is often associated with vaginitis. Its clinical features and management are described elsewhere. Acute Simple Ulcers (Figs 20.2A to C)
Herpes Genitalis
Figs 20.1A and B: A smegma concretion beneath the prepuce of the clitoris. Patient aged 70 years with a carcinoma of the fourchette extending onto the perineum, (A) The hidden concretion gives the appearance of a tumour or of hypertrophy of the clitoris, (B) The concretion being expressed; in this case a small incision was necessary to provide an exit
antibiotics. During a phase of active furunculosis, a full course of treatment with penicillin, or of other antibiotic appropriate to the infecting organism, should be given systemically, not locally.
Infection of Sebaceous and Apocrine Glands Single abscesses, often representing secondary infection of a retention cyst of an apocrine or sebaceous gland, have the clinical characteristics of a boil and are treated in the same way. If they recur in the same site the underlying cyst has to be excised when free from inflammatory reaction. Hidradenitis suppurativa, which is rare and more likely to be seen in hot climates, is a condition of chronic bacterial infection of many apocrine glands which shows periodic exacerbations. It occurs in the axilla and the vulva but only after puberty when the glands become active. On the vulva the disease presents as a series of tender nodules which suppurate and coalesce to form abscesses. Sinuses develop and these extend deeply and widely. Radical and repeated incisions to lay open all abscesses and tracts, combined with antibiotics, is the treatment. Diffuse hidradenitis, however, is very refractory and in healing leaves extensive scarring and distortion.
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Changing sexual habits in the last few decades have been associated with an increased incidence of genital herpes. Indeed, genital herpes simplex infections now have a higher incidence than syphilis and are the most common cause of genital ulceration in industrialized nations. Genital herpes is important not only because of its increasing incidence but also because of the physical and psychological trauma it can induce, the risk of serious complications including a link with cervical cancer and the risk of transfer of maternal infection to neonates. Disseminated herpes in the newborn is certainly one of the most severe manifestations of herpes infection. Prematurity and spontaneous abortion have also been associated with active maternal genital herpes. Herpes simplex genitalis is most often caused by infection with herpes simplex virus (HSV) type 2 (85%), which has usually been sexually transmitted by an infected partner, but may possibly be transmitted by orogenital contact. HSV type 1 infection accounts for about 15 per cent of cases. Infection is transmitted by secretions containing the virus and not by fomites or aerosolization, as the virus is readily inactivated at room temperature or by drying. Genital diseases caused by either of these viral types are clinically indistinguishable. As with other herpes infections, the virus replicates in the epithelium giving rise to painful symptoms and signs. These typically, but not invariably, follow a course which commences with redness and inflammation, leading to the formation of vesicles which progress to pustules. These pustules then erode to form multiple, small and shallow ulcers found on the labia and around the introitus. Lesions may also be found in the urethra and vagina, on the cervix and, occasionally, on the thighs and buttocks. These coalesce to form larger ulcers and resolve with crusting and healing. This cycle may take up to 3 weeks in a primary
Infections as They Affect Individual Organs
Figs 20.2A to C: Showing the appearance of the ulcers of chancroid (A), herpes (B), and syphilis (C). The ulcer of chancroid has irregular margins and is deep with undermined edges. The syphilis ulcer has a smooth, indurated border and a smooth base. The genital herpes ulcer is superficial and inflamed. (Modified from Schmid GP, Shcalla WO, DeWitt WE. Chancroid. In: Morse SA, Moreland AA, Thompson SE, eds. Atlas of sexually transmitted diseases. Philadelphia, PA: JB Lippincott, 1990)
infection. After a primary infection, the virus remains quiescent in the sacral ganglia and can reemerge to cause recurrences at a later time. The symptoms of recurrent genital herpes tend to be milder and of shorter duration, and are often preceded by a prodromal phase consisting of cutaneous itching or burning, and redness in the affected region. The frequency of recurrence can vary from days to years. Rarely, herpes genitalis can also cause meningitis, encephalitis and hepatitis.
Diagnosis and Management The presence of multiple painful ulcers is suggestive of the diagnosis but other causes of multiple painful ulcers like Behçet’s disease, chancroid, Stevens-Johnson syndrome and vulvitis should be excluded. In all instances a search should be made for extragenital lesions. When genital herpes is suspected it is important to confirm the diagnosis with laboratory culture, if possible, which also permits subtyping of the virus and can be
done within 1-4 days of the infection. HSV antigen detection by enzyme immunoassay (EIA) or fluorescent antibody (FA) and HSV DNA detection by polymerase chain reaction (PCR) are also possible. Serodiagnosis is useful in documenting first episode infection but in recurrent infection there may be no rise. Once the diagnosis is made a sympathetic explanation should be given to the patient, who may be very upset. The natural history of the disease should be explained and advice given on genital hygiene. It is obviously important to trace sexual partners, and it would be wise to inform the obstetrician if the patient is pregnant. In view of the possible link with cervical cancer, a cervical smear once a year would be a sensible precaution. Acyclovir (ACV) is the therapy of choice in primary herpes simplex genitalis and in severe recurrent attacks. It is an acyclic nucleoside analogue that is a substrate for HSV-specific thymidine kinase. In primary genital HSV infection, oral ACV (200 mg 5 times daily for 10-14 days), topical ACV (5% in polyethylene glycol in aqueous
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Jeffcoate’s Principles of Gynaecology ointment) or intravenous ACV (5 mg/kg 8-hourly for 5 days) can decrease the severity and duration of symptoms and reduce viral shedding, while preventing the development of new lesions. Concomitant urethral, cervical and oral infections are common in first episode infection so oral therapy is preferable to topical. Symptoms are reduced within 48 hours. The duration of viral shedding is also decreased with antiviral therapy. Doses of 400 mg thrice daily have also been used but there does not appear to be any benefit in prescribing higher doses of 800 mg 5 times daily, nor is there any benefit in combining topical with oral medication. ACV has a very low toxicity to cells which are not infected with herpes simplex. In very severe attacks, for patients in hospital or patients with serious complications, intravenous acyclovir may be appropriate. In recurrent disease, oral acyclovir, famciclovir and valcyclovir have all been shown to help in reducing the duration of the episode. Treatment should be initiated by the patient herself as soon as she notices the first sign or symptom of recurrence. If the patient is immunocompetent, therapy may not always be required as the episodes are self-limiting. Measures like local application of calamine lotion may provide relief. The topical preparation in aqueous base may provide better relief than the polyethylene glycol base. Suppressive therapy with long-term ACV therapy (200 mg thrice daily or 400 mg bd) has been used in some women having 4 to 12 episodes per year and who are emotionally disturbed or in severe physical discomfort. No serious side-effects have been reported. Treatment should be interrupted every 12 months to reassess the need for continued therapy. Acyclovir has been used in pregnancy, even in the first trimester, and no significant anomalies or sideeffects have been noted. However, the numbers are yet not many and it should be used with caution. If secondary infection is present it should be treated. Patients should be advised to have regular cervical smears, to avoid intercourse when lesions are present and to inform their medical attendants of a past history of herpes when pregnant. Syphilis (chancroid) is the next common cause of sexually transmitted genital ulcers (Fig. 20.2A to C). Diagnosis is made, based on history, clinically and serological test for syphilis. A painless, minimally tender
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ulcer without lymphadenopathy is likely to be syphilitic ulcer. May also present as vesicles mixed with small ulcers. Chancroid is usually one or two extremely painful ulcer with tender lymphadenopathy. Also inguinal bubo with ulcer is likely to be chancroid and without ulcer it is likely to be LGV. Recurrent Genital (and Buccal) Ulceration This is a not uncommon condition and the ulcers, identical in appearance with those described above, may be on the vulva alone, in the mouth alone, or simultaneously in both sites. When it is associated with conjunctivitis it becomes part of Behçet’s syndrome. It is not sexually transmitted. The clinical features, aetiology and treatment are described elsewhere. LGV and granuloma inguinale (Figs 20.3 and 20.4): Lymphogranuloma inguinale and granuloma inguinale (donovanosis) are rare sexually genital diseases. These are associated with an increased risk for HIV infections. Tuberculosis of the Vulva Abrasions: Due to injury see elsewhere. Fixed drug eruptions: rare. Schistosomiasis Carcinomas: see elsewhere.
Fig. 20.3: Granuloma inguinale
Infections as They Affect Individual Organs sodium bicarbonate solution gives temporary relief from pruritus but the specific remedies for the infection are local applications of ointments or powders containing one of the fungicides described elsewhere. An ointment combining a fungicide with hydrocortisone is especially helpful. Candidiasis
Fig. 20.4: Condyloma acuminata of the vulva
Noma Vulvae; Tropical Ulcer; Phagedaena This is a condition of acute necrosis or gangrene of the tissues of the vulva often associated with a fusospirochaetal infection. This is a term covering two microorganisms living in symbiosis — Fuso-bacterium and Spirochaeta. Both live anaerobically and can exist in a nonpathogenic form in the mouth and on the vulva. When found on ulcers they are considered by some to be secondary invaders rather than causal agents. It can arise as a complication of acute infectious fevers in debilitated children but is now rare in outside tropical countries. In these it is still seen in destitute malnourished children and adults. Because of the underlying debilitation of the patient, the condition can be fatal. Diabetic Vulvitis Glycosuria, whether it be due to diabetes mellitus or not, causes a diffuse inflammation which gives the vulvar skin a typical purplish red appearance. The symptom is intense pruritus. Although chemical changes in the epithelial cells may play a part, the vulvitis is mainly the result of infection with Candida albicans, this organism thriving in the presence of carbohydrates with which the vulva is contaminated. Treatment consists of controlling the glycosuria, and in instructing the patient to wash the vulva free from all urine (and sugar) immediately after micturition. Sponging with 1 per cent
Candida infection of the vulva also occurs without glycosuria and may or may not be associated with a similar infection of the vagina, perianal skin, hands and feet. It not infrequently follows the use of antibiotics which interfere with the normal flora of the vagina and bowel. The appearance of the vulva varies from a diffuse erythema to pallor and oedema, and is sometimes similar to that seen in diabetic vulvitis. Candidiasis typically causes pruritus vulvae. Its diagnosis and treatment are described on page 343. Tinea Cruris (Ringworm) Fungal infection of the vulva is rare in women, or at least is difficult to prove. Nevertheless, irritating vulvar skin changes are not uncommon in women suffering from some sort of fungus infection of the feet and hands. Pediculosis Pubis This affects the pubis rather than the vulva. The ‘crab louse’, Phthirus pubis, infects the hair-bearing area of the mons, and the parasites or their eggs can be seen clinging to the hairs. The infection is transferred from one individual to another by contaminated clothing or by close bodily contact including intercourse. The underlying cause is uncleanliness, the symptom pruritus. Treatment consists of shaving the vulva, frequent washing, and applications of malathion lotion or shampoo, or other pediculocides. Clothing has to be decontaminated. Elephantiasis This is a condition of chronic lymphatic oedema with associated thickening and hypertrophy of the epithelial tissues of the vulva. The skin is rough, warty and weeping. True elephantiasis is caused by infestation with the filarial worm Wuchereria bancrofti, but this is rare in temperate zones where the more common cause of lymphatic obstruction is any chronic infection which
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Jeffcoate’s Principles of Gynaecology heals by fibrosis. So it is seen as an end result of healed tuberculosis, lymphogranuloma venereum, granuloma inguinale and possibly syphilis, and is then called false elephantiasis (Fig. 19.6). Occasionally the cause is obscure. If the condition is severe enough to cause discomfort or dyspareunia, the affected tissue has to be excised. Even then it may recur despite the discovery and treatment of the underlying infection. Other Infections All types of infection can involve the vulva on occasion. Those worthy of mention are diphtheria, actinomycosis and tetanus; also any form of skin disease with an infective basis. BARTHOLINITIS Aetiology The occurrence of bartholinitis always raises the suspicion of a gonococcal infection but the disease can be caused by Escherichia coli, Staphylococcus, Streptococcus faecalis, Streptococcus pneumoniae, Haemophilus spp., Trichomonas vaginalis and, indeed, by any pyogenic organisms. Chlamydial infection may be present alone or in combination with the gonococcus. The role of bacterial vaginosis is unclear. Pathology Both duct and gland are involved and show the usual inflammatory reactions. The lining of the duct becomes swollen and its orifice can be seen as a small red macula of congestion. Acute bartholinitis may resolve completely but frequently an abscess forms and ultimately discharges through the lower vaginal wall. The infection sometimes persists in the chronic form with periodic exacerbations and abscess formation. The gland then becomes permanently enlarged and fibrotic so that it can be felt between the fingers like a small hard pea. The duct often heals by fibrosis with closure of the orifice; this leads to cyst formation. Many Bartholin ‘abscesses’ are secondarily infected cysts. Clinical Features The complaint is one of local discomfort which becomes very severe when an abscess forms. An acutely tender swelling appears beneath the posterior part of the labium
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Fig. 20.5: Psoriasis of the vulva. Note the extent of the lesion extending laterally to the inner thighs, and posteriorly to involve the perianal skin and cleft
majus extending inwards to the base of the labium minus. The overlying skin is reddened and the surrounding tissues indurated and oedematous. The position of the swelling at the junction of the anterior 2/3 and posterior 1/3 of the labium majorum is diagnostic (Fig. 20.6). The differential diagnosis is from adenoma and hamartomas, and in older women, from carcinoma. Treatment This consists primarily of rest in bed, the administration of antibiotics to cover gonococcal and chlamydial infection, as well as anaerobic bacteria and the relief of pain with analgesics and warm baths. When it is certain that an abscess has formed, free drainage is established by an incision placed outside the introitus; this is better than allowing the abscess to burst spontaneously. The operation of choice, however, is to marsupialize the edges of the abscess cavity to the skin of the introitus. By providing permanent drainage this reduces the chance of subsequent cyst or abscess formation. The operator should wear protective goggles. Excision of the gland and duct cannot be carried out while active infection is present but is indicated in the intervals between recurrent abscess formation when the gland remains palpable. This operation is more difficult than it sounds.
Infections as They Affect Individual Organs young child often the parent notices her crying during urination or scratching herself. The vulva is reddened, sometimes oedematous or excoriated, and bathed in discharge. If the discharge is bloodstained, the presence of a foreign body, or some other condition such as a cervical polyp (even the rare sarcoma botryoides), should be suspected and excluded.
Diagnosis
Fig. 20.6: A small left-sided Bartholin abscess which is distorting the vulva and pointing just within the introitus
VAGINITIS Vaginitis (Vulvovaginitis) in Infancy
Aetiology and Pathology Although local infection in infancy is essentially one of vaginitis, the urethra and vulva are usually involved as well. The common age is 1-5 years. The infection arises because vaginal resistance has not developed and the organisms are transmitted from adults or from another child by hands, clothing or utensils. The most serious form of infection is gonococcal, but this is now rare and other organisms such as Candida albicans, Streptococcus, Staphylococcus, Escherichia coli, the Pneumococcus and even Trichomonas vaginalis are more likely to be found. Threadworms (Enterobius vermicularis) can infest the infantile vagina as well as the lower bowel. Occasionally the basis of the infection is a foreign body inserted into the vagina by the child. The accidental entry of sand or shreds of clothing, especially from woollen pants, is another possibility.
Clinical Features The main symptom is a purulent discharge but the child may also complain of pain and soreness of the vulva. These interfere with walking and cause dysuria. In a
The diagnosis of infantile vulvovaginitis is usually obvious but the causal organism can only be determined by examining (including culturing) the discharge obtained by a swab or fine pipette inserted through the hymeneal opening. This also excludes the possibility of leucorrhoea of infancy exaggerated by a fussy mother. Digital vaginal examination is not possible, but if a small girl is laid on her side it is surprising how much of the vagina can be visualized. Rectal examination may enable a foreign body to be felt by counter-pressure against the symphysis pubis or against a hand placed on the abdomen. Ordinarily, however, the presence of a foreign body is excluded by sonography, examination under anaesthesia, and inspection of the upper vagina through an aural or nasal speculum, a baby’s laryngoscope, or a hysteroscope (vaginoscopy), or by radiography.
Treatment Any foreign body must be removed; for this purpose, aural forceps can be useful. Otherwise, treatment consists of administering antibiotics or fungicides, modifying the dose to suit the age of the patient. Treatment for pinworms is instituted where required. If the vulva is sore and excoriated the child should be kept at rest and the vulva sponged regularly. Adhesions of the labia can be prevented by applications of oestrogen cream locally. It is necessary to take steps to prevent the spread of infection to the conjunctiva and to other children. It is also important to avoid the young child becoming morbidly interested in her genital organs, which she quickly does – especially if the mother is overanxious. Senile Vaginitis (Atrophic Vaginitis)
Aetiology and Pathology This is caused by any of the common pyogenic organisms invading tissues which have lost their resistance. Senile
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Jeffcoate’s Principles of Gynaecology endometritis or vulvitis is sometimes present as well. The vaginitis is often granular, that is, it appears as small multiple reddened areas which are mostly seen in the vault and around the urethral orifice. Patchy ulceration can result in adhesions forming between the anterior and posterior walls to produce partial closure of the vagina — adhesive vaginitis.
Clinical Features and Diagnosis The main complaint is postmenopausal yellowish discharge, sometimes bloodstained, which causes excoriation and soreness of the vulva. Dysuria (from urethral involvement) and a sensation of fullness in the vagina are also common. The diagnosis can only be made by excluding other possible causes of postmenopausal discharge—senile endometritis or cancer of some part of the genital tract. Examination under anaesthesia, diagnostic curettage and cervical cytology or biopsy are therefore essential in all cases before vaginitis is assumed to be the cause of symptoms. Even if vaginitis is present, the patient may still have carcinoma of the uterus as well. Senile vaginitis should not be diagnosed merely on the finding of a speckled red vagina for this can be a normal climacteric change. A discharge must also be present.
Trichomonas Vaginitis and Urethritis (Trichomoniasis)
Aetiology This is the most common form of vaginitis and is found in approximately 50 per cent of women complaining of vaginal discharge and in 60 per cent of those with proven gonorrhoea. It occurs at any age from birth onwards but most often in the young adult. The Trichomonas group of organisms is a large one and certain members are commonly, if not normally, found in the mouth, bladder and large bowel. Trichomonas vaginalis, which is responsible for vaginitis, has morphological characteristics slightly different from the others. It is an ovoid motile flagellated parasite 1520 μm in length and 8-10 μm in width, although smaller forms are described. It has four anterior flagella and an axostyle which traverses its body to end in a spike (Fig. 20.7). In the vagina the parasite is invariably accompanied by staphylococci, streptococci, enterococci or coliform organisms but it is the trichomonads and not these which cause the vaginitis. The infection is often contracted during intercourse with a male harbouring the organisms in the prepuce,
Treatment The vaginal resistance is quickly restored by giving any of the oestrogen preparations in full dosage for 3 weeks, followed by an interval of 1 week and then repeated if necessary. Oestrogens can also be given locally, in the form of a cream to be inserted into the vagina each night. By any route they may induce uterine bleeding and the patient should be warned of this. Any uterine bleeding must be reported, however, as further investigation is then justified to exclude any more serious cause of postmenopausal bleeding. Local treatment with antiseptics or antibiotics is usually unnecessary. When hormone therapy is suspended the vagina atrophies again but, if the infection has been eradicated, the disease should not relapse.
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Fig. 20.7: Trichomonas vaginalis organisms, as seen in a preparation made from cultures of vaginal discharge
Infections as They Affect Individual Organs urethra or prostate, the incubation period being 3-28 days. The partner of a man with proved Trichomonas infection can nearly always be shown to carry the organisms. Some say that trichomonads can be found in the urethra of 2 per cent of all men and in 10 per cent after prostatic massage. Estimates of their frequency in cases of male nonspecific urethritis vary from 5 to 70 per cent, depending possibly on the efficiency of the tests. Nevertheless, the male carrier is generally symptom-free and it has clearly been shown that a man can transfer the organisms from one woman to another without himself developing any signs of the disease. This does not mean that Trichomonas vaginitis is always venereal in origin. It is not uncommon in virgins, children and old women. Transfer of the organism from one individual to another by indirect contact certainly happens. Contaminated domestic towels, bed linen and personal clothing, improperly sterilized surgical instruments such as specula, bath tubs and possibly swimming pools are likely media for transfer. Patients sometimes date the onset of symptoms to a stay in hospital where they may be exposed not only to infection by certain of the above means, but to diseases and treatments which convert a carrier to an infected state. Twenty per cent of asymptomatic pregnant and nonpregnant women harbour the parasites in the vagina so, if debilitating illness lowers their resistance, or if they are given antibiotics which alter the vaginal flora, the disease can become manifest. The effect of lowered local resistance is well illustrated by the fact that Trichomonas vaginitis often first manifests itself immediately after a menstrual period — during which the vaginal pH is raised. The optimum pH for the trichomonads is 5.5-6.5 and this or a slightly higher level is usually found in the vagina when the disease is present.
Pathology The infection is essentially of the vaginal epithelium and the parasites shelter between the rugae. It is possible that they may penetrate between the surface cells but no deeper, and they induce the usual tissue inflammatory reaction. In 70 to 80 per cent of cases the trichomonads can also be cultured from the urethra, where they cause acute or chronic urethritis. Bartholin’s glands and Skene’s tubules are sometimes infected. Trichomonas endocervicitis is also postulated but it is doubtful whether it exists as a clinical entity. There are
reliable reports of the organisms having been found in the cervix, the body of the uterus, the fallopian tubes and even in the bloodstream, but their significance in these sites is questionable.
Clinical Features The first symptom is usually a sudden onset of purulent vaginal discharge, often dating from menstruation. It is said to be cream-coloured and frothy but its physical characteristics vary widely. It may be profuse or scanty and the most constant feature is that it causes pruritus, the itching being felt around and within the introitus. At the outset, dysuria and frequency of urine are also common complaints. Vaginal tenderness and congestion result in dyspareunia. In the acute stage the labia minora and introitus are sometimes oedematous. The vagina may be diffusely fiery red in colour but often presents a strawberry appearance which, on the cervix, can be confused with erosion. The external urethral meatus is congested and pouting. Later, or when the reactions are less severe, the disease is manifested by a ‘granular’ vaginitis which is most obvious in the fornices, on the portio vaginalis and around the urethral orifice. The infection can become very chronic with pruritus more prominent than discharge, and is subject to periodic exacerbations over the course of many years. The same is true of the urethritis; so ‘recurrent cystitis’ in women is very often explained by flare-ups of a persistent Trichomonas urethritis. This sort of chronic infection is also the main if not only cause of the pseudocaruncle or granulomatous caruncle of the urethra which is so often mistaken for a true caruncle.
Diagnosis The diagnosis should be suspected in all cases where discharge causes pruritus but is made certain by demonstrating the presence of T. vaginalis organisms. Not infrequently they are discovered incidentally during routine cervical cytology. Ordinarily, however, they are looked for in the vaginal discharge or, in cases of suspected urethritis, in swabs taken from within the urethra. A single negative test is never conclusive and several studies may have to be made before the parasites are found. In the office, a wet smear preparation can be made. Specimens, uncontaminated by lubricant, are taken from the vagina or urethra by a swab or pipette and can be
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Jeffcoate’s Principles of Gynaecology examined immediately microscopically. For this purpose the material is mixed with saline solution on a warm slide, covered with a glass slip, and left unstained. The trichomonads are recognized by their shape, size (larger than a pus cell but less than half the size of a vaginal squame) and by their motile flagella and rotatory movements. However, this ‘bedside’ examination is very unreliable. Culture methods are more accurate. The specimen of discharge, or preferably the whole cotton tip of the swab, is added immediately to a small tube of Kupferberg’s or Feinberg-Whittington medium. The latter is a proteolysed liver and inactivated horse serum preparation with streptomycin and penicillin added. It eliminates all organisms except Trichomonas and Candida albicans; these thrive. Incubation preferably at 34°C rather than at 37°C, is followed by examination of drops of the fluid for organisms at 24 and 48 hours and, if need be, later. Providing care is taken to make sure the culture medium is satisfactory, this method reveals T. vaginalis in twice as many female patients as does direct microscopic examination of discharge. It is the only means of reliably testing the male. The finding of Trichomonas vaginitis indicates a need to exclude gonorrhoea as well. Candida and Trichomonas infestations also commonly coexist but the dual nature of infection is not always evident until the dominant organism (Trichomonas) has been eliminated. The persistence of symptoms after treatment with trichomonacides therefore calls for repeated cultures for both Candida and gonococci.
Treatment Systemic therapy is superior to topical therapy because T. vaginalis often infects the urethra and periurethral glands. These organisms can result in subsequent reinfection. The recommended regime is metronidazole, 2 g in a single oral dose, for both partners. An alternative regime in case of single-dose failure is one tablet of 400 mg given twice daily by mouth for 1 week or 2 g once daily for 3-5 days. For children less than 12 years of age the corresponding dose is 200 mg (half a tablet) and for infants, 50 mg administered with the same timing as for the adult. Whilst under treatment the patient should be told of the need for care in the disposal of her underclothing and to keep her own bath towel, in order to minimize
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the chance of her infecting other female members of the family. She should also be warned against coitus. The physical effect is irritant to inflamed tissue and the male partner may become infected. As many as 60 per cent of the husbands of women suffering from Trichomonas vaginitis can be shown to harbour the parasite in the urethra and its associated glands, or beneath the prepuce. Unless, during the period of abstinence, the organisms disappear spontaneously from the male urogenital tract, resumption of coitus when the wife’s treatment is complete results in her being reinfected. Because of this it is important to treat the consort of every woman suffering from Trichomonas vaginitis. He is given metronidazole simultaneously and in the same dosage. Even in standard dosage metronidazole sometimes causes slight nausea, metallic taste, dizziness, headaches and minor skin eruptions but these rarely necessitate interruption of the treatment. Transient neutropenia with WBC counts of 1000-1400/mm3 have been reported in 7.5 per cent of patients treated with multiple doses of metronidazole. Metronidazole has also been reported to prolong the prothrombin time in patients on warfarin. It has never been shown to be teratogenic in animals but, lest it have a mutagenic effect on the fetus, should not be given systemically during the first 12 weeks of pregnancy. Thereafter, it can be given with impunity despite the fact that it is known to cross the placenta. The drug is also excreted in the milk so it may be unwise to administer it to lactating women, unless absolutely necessary. It is generally stated that metronidazole administered orally is excreted in only small amounts through the vaginal wall; so its efficacy is difficult to understand. The fact that the treatment is generally efficient after total hysterectomy rather rules out the possibility of a significant secretion by the endometrial and cervical glands. It has been suggested that the real nidus of infection is in the bladder and urethra and it is this which is eradicated by a renal excretion of the drug. Oral medication with metronidazole is curative in 85-90 per cent of cases and the figure rises to 95 per cent if the patient’s consort is treated simultaneously. Tinidazole and secnidazole 2 g as a single oral dose are also effective and have lesser side-effects. Chronic trichomoniasis in old women sometimes proves resistant and, in such cases, treatment with the oral trichomonacide can with advantage be preceded by
Infections as They Affect Individual Organs or combined with oestrogen therapy as for senile vaginitis. According to laboratory studies, Trichomonas vaginalis is never resistant to metronidazole but clinically, resistance is occasionally encountered. This is possibly because other bacteria in the vagina break down the drug and make it ineffective but, more often, it is due to faulty absorption from the alimentary tract. The last can be overcome by doubling the dose. Otherwise, another trichomonacidal drug, such as tinidazole or secnidazole, 2 g initially and 1 g daily for 6 days, can be substituted and again given to both sexual partners. Patients taking metronidazole or any of these drugs should be warned of the possible disulfiram (Antabuse)-like effect of these drugs in association with alcohol. Unless patients are warned, they quite logically give up the tablets rather than the alcohol. There is rarely any need for local treatment of Trichomonas vaginitis but this does arise during the first trimester of pregnancy, when oral medication has to be discontinued because of the possibilities of teratogenicity and vomiting or other side effects; and possibly in the handling of resistant cases. In such circumstances intravaginal medication with metronidazole or clotrimazole, 100 mg pessaries, one per night for 7 nights, has been found effective. Nonoxynol9 and povidone-iodine are also trichomonacidal but these are not recommended for use in pregnancy.
Fig. 20.8: Candida albicans, showing hyphae and spores. This preparation was made from cultures of vaginal discharge
Candida Vaginitis
Aetiology This condition, also called vaginal thrush, is caused by the yeast-like organism Candida albicans, a small Grampositive fungus which develops pseudomycelial threads with septate divisions and clusters of blastospores (Fig. 20.8). It thrives on carbohydrate and likes an acid medium (pH 4.0-5.5). This explains why the patient’s symptoms are temporarily relieved by bathing or douching with 1 per cent sodium bicarbonate solution and during menstruation when the vagina is more alkaline. C. albicans has a wide distribution in the body but is ordinarily nonpathogenic, being kept in check by bacteria. It can be demonstrated in the mouths of 25 per cent of all women, on the perianal skins of 8 per cent, and in the vaginas of 20-25 per cent. Most vaginal (as well as alimentary and systemic) infections probably represent a change from the carrier state determined by circumstances which favour the growth of the fungus at the expense of other organisms. Candida vaginitis is often determined by glycosuria because of the availability of carbohydrate. It occurs frequently during pregnancy because the vagina then contains much glycogen, glycosuria is common, and the high vaginal acidity tends to destroy other bacteria. The taking of oral
Fig. 20.9: Trichomonas vaginalis. The protozoa are seen only in a wet film and are of varying shapes. They may be adherent to a squamous cell or they may be attached to pus cells
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Jeffcoate’s Principles of Gynaecology contraceptives favours the disease but, in nonpregnant women, the commonest cause is the taking of antibiotics, especially those covering a broad spectrum of bacteria. These, administered for incidental illnesses, alter the vaginal flora in favour of Candida. Indeed, the irresponsible use of these is mainly responsible for the present widespread manifestations of candidiasis in both sexes throughout all communities. Vaginal infection can be associated with lesions elsewhere in the body—the alimentary tract, hands, feet and perianal skin—of the patient or of her consort. It can also be contracted during coitus with a man suffering from urethritis and balanitis, or so it is said. In fact, these conditions are so uncomfortable as to prohibit intercourse; it is the asymptomatic male carrier who is more likely to be responsible. A combination of Candida and Trichomonas vaginitis is quite common, the dual infection again being possibly sexually transmitted.
appear diffusely reddened, oedematous or reasonably normal. A very rare complication of Candida vaginitis is wide dissemination of the parasites to produce a dangerous systemic infection.
Pathology and Clinical Features
The diagnosis of pruritus with discharge nearly always means either Candida or Trichomonas infection. A wet mount or saline preparation of the vaginal discharge should routinely be done which can identify the presence of mycelia and yeast cells, and also exclude clue cells and trichomonads. A 10 per cent potassium hydroxide preparation is even more sensitive as it dissolves the red and white blood cells and improves visualization. If on direct microscopy large numbers of white cells are seen and the pH is greater than 4.5, mixed infection should be suspected. If WBC are absent and the pH is 4.5; clue cells representing at least 20 per cent of the vaginal epithelial cells. The presence of clue cells is the most important criterion for diagnosis: A wet mount examination shows squamous epithelial cells covered with multiple bacteria, which gives the cells a stippled look with obscured borders (Figs 20.12A and B). Vaginal cultures are not as useful as G. vaginalis may be isolated even in the absence of BV. For the same reason, vaginal cultures cannot be used as a test of cure.
Oral Probiotic Therapy with Lactobacillus It has been seen that lactobacilli taken orally will pass through the G.I. tract and are seen to colonise the vagina via migration over the perineum. Other Vaginal Infections Some rare causes of vaginitis are the gonococcus and pneumococcus which are seen mainly in children. Infections due to diphtheria, Salmonella typhi and paratyphi are also very rarely seen. The term puerperal vaginitis is sometimes used to cover infection of vaginal lacerations sustained during childbirth.
Figs 20.12A and B: (A) Normal mature vaginal cells. The bacterial flora is dominated by lactobacteria (rod-shaped), and (B) the field dominated by “Clue cells”. Few lactobacilli are also seen
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Infections as They Affect Individual Organs
Vaginitis Emphysematosa (Colpitis Cystica) This is an uncommon but extraordinary condition, most of the recorded cases having been in pregnant women. It is characterised by numerous small bullae in the vaginal epithelium which are filled with a gas (Fig. 20.10B). The surrounding tissues are hard and indurated and give the impression of advanced malignant disease. The symptom is a profuse purulent discharge. The nature of the gas in the tissue spaces is almost certainly carbon dioxide. The cause of vaginitis emphysematosa is disputed but, in the great majority of cases, trichomonads can be found in the vagina. These parasites, possibly by unusually deep penetration of the vaginal wall, are the most likely agents. Gardnerella vaginalis is also blamed. The disease can cure itself spontaneously within a few weeks or months, often before the pregnancy is over. On the evidence, it should respond to treatment with metronidazole, although prior to the introduction of the drug the cysts often regressed spontaneously. Non-infective Vaginitis
Traumatic Infection and ulceration can be the result of foreign bodies placed in the vagina (see Chapter 15), and can complicate the anatomical and vascular changes which accompany uterovaginal prolapse. Occasionally, severe and recurrent vaginitis with ulceration is caused by self-inflicted trauma, prompted possibly by sexual perversion or other psychological upsets. This cause can be difficult to prove.
Burns Discussed elsewhere.
Allergy; Drug Sensitivity A local reaction to chemicals is not uncommon and the patient presents with discharge, pruritus and a fiery red vagina. Antiseptics such as arsenic, mercury, iodine, picric acid, phenol preparations and gentian violet used to be common causes. Presently, toilet preparations such as soaps, deodorants and bath salts; contraceptives such as rubber or materials used in the preparation of synthetic devices, the powder in which they are packed and chemical spermicides; and nylon underwear are the common causes.
The diagnosis is made by careful enquiry about the onset of symptoms, bearing in mind the possibility of skin sensitivity. The treatment consists of removing the cause and arranging for saline douches and warm baths. Antihistamines by mouth and local applications of hydrocortisone may also relieve symptoms. The reaction not uncommonly includes cystitis and urethritis.
Idiopathic There are some isolated cases of troublesome, chronic and resistant vaginal ulceration, sometimes multifocal, the causes of which are never discovered. These have been treated empirically by vitamins, antihistamines, antiseptics, various fungicides and trichomonacides and, in the case of postmenopausal women, with oestrogens. CERVICITIS Infection of the stratified squamous covering of the vaginal cervix as part of vaginitis is not usually regarded as cervicitis; this is a term reserved for inflammatory lesions in the endocervix including the glands and deeper tissues. Acute Cervicitis This is mainly gonococcal, chlamydial or puerperal in origin and the lesion is relatively unimportant in itself, the symptoms and physical signs being overshadowed by those caused by simultaneous infection of other tissues. Organisms gain entry through the gland openings in the endocervix, and through obstetrical and surgical injuries. The cervix is congested and enlarged with a swollen mucous membrane pouting at the external os. It is tender when touched or moved, and a profuse purulent discharge exudes from the cervical canal. Acute cervicitis may resolve completely or progress to a state of chronic cervicitis. Its treatment is that of the more widespread infection of which it is merely a part. Chronic Cervicitis
Aetiology Chronic cervicitis is variously estimated to be present in some degree in 35-85 per cent of women. It can probably arise as a result of vaginal organisms becoming
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Jeffcoate’s Principles of Gynaecology pathogenic; it occasionally follows chronic and repeated injury from pessaries, tampons and unsatisfactory contraceptive devices; it may be gonococcal but is usually the end result of puerperal cervicitis. The puerperal type is often associated with laceration of the cervix and with chronic cellulitis.
Although organisms can linger in the glands of the endocervix for many years, the condition of chronic cervicitis does not usually represent an active inflammatory state. It is the end result of injury and inflammation. The mucosa and deeper tissues are fibrosed, congested, and infiltrated with leucocytes and plasma cells. There may also be hypertrophy of glandular tissue to produce what was previously described as an adenomatous cervix. The ducts of certain glands become obstructed by plugs of epithelial cells and inspissated mucus, or by fibrosis, to cause retention cysts — Nabothian follicles. These are often visible to the naked eye and can become quite large (Fig. 20.13). A relationship between chronic cervicitis and the development of cervical cancer, once postulated, is no longer acceptable; and chronic cervicitis is not a cause of erosion as was once believed, and still is in some quarters.
injury and reaction are very severe do they cause symptoms, and all these, with the exception of discharge, mostly derive from an associated cellulitis. They tend to be worse premenstrually and include: mucopurulent discharge — the mucus is due to overactivity of the glands themselves; low backache which is only partly relieved by rest; aching in the lower abdomen and pelvis; deep-seated dyspareunia; contact bleeding; menorrhagia and congestive dysmenorrhoea possibly from associated endometritis; and infertility, alleged to result from changes in the physical characters of the cervical plug, from a decreased pH of the cervical canal and from an increased pH of the vagina — a profuse discharge can raise the vaginal pH to 5–7.5. The last symptom is questionable and certainly many women with gross chronic cervicitis conceive without difficulty. All manner of other conditions and symptoms have been ascribed to chronic cervicitis — arthritis, dyspepsia, pain on defecation and bladder irritability. Indeed, cauterization or other treatment of an allegedly infected cervix has been claimed to cure nearly all the ills to which the woman is subject. It should therefore be emphasized that the only symptom clearly attributable to cervicitis per se is discharge and this usually dates from an attack of infection, from abortion or from labour.
Clinical Features
Diagnosis
Chronic cervicitis is usually a histological diagnosis without clinical significance. Some evidence of it is found in nearly all multiparous, and many nulliparous, cervices submitted to histological examination. Only when the
The physical signs in the cervix which may lead to the diagnosis are: enlargement and congestion; ectropion; cystic glands; pouting and florid endocervix; fixation; tenderness to the touch; and pain when the cervix is moved or pierced with a volsellum. It can be difficult to distinguish chronic cervicitis from carcinoma and this may be impossible sometimes without biopsy. Vaginal cytology and colposcopy aid the diagnosis of malignancy (see Chapter 25). The exclusion of malignancy is especially important before using ablative methods of therapy.
Pathology
Treatment
Antiseptics
Fig. 20.13: Retention cysts (Nabothian follicles) in the cervix
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Since any infection is always deep seated, the superficial application of antiseptics by means of pessaries or paints is useless. Douching has only the merit of removing discharge and odour temporarily, but it may introduce
Infections as They Affect Individual Organs the discharge into the upper genital tract and is no longer recommended.
cone excision, and future fertility is not desired, hysterectomy is sometimes indicated.
Antibiotics
Special Forms of Cervicitis
Antibiotics are useful only in case of active infection, e.g. gonorrhoea or chlamydia.
Tuberculosis, syphilis, schistosomiasis, amoebiasis and other special infections and ulcers of the cervix have already been described along with vaginitis and in Chapter 19.
Cauterization, Cryotherapy or Laser Ablation Chemical caustics employed in the past are of little value and have been replaced by electric or diathermy cauterization, or cryotherapy, to destroy diseased areas. By cautery, cystic glands are punctured, ectropion corrected by deep linear burns, and any coincidental erosion coagulated. The cervical canal is treated only with caution or left alone. Cryotherapy is preferable to cautery. It is done using the probe which best fits the lesion and the entire lesion is frozen (see page 420). Laser ablation, e.g. with the CO 2 laser, has the advantage of cure rates similar to cryotherapy but with the transformation zone maintained in its normal position. Following cryotherapy it usually recedes into the endocervical canal and is not visible for further evaluation if required. These forms of treatment are office or outpatient procedures; general or even local anaesthesia is seldom required. Following treatment, a slough separates in approximately 10 days. This is attended by an increase in discharge and often by frank bleeding. Following cryotherapy and laser the discharge is extremely profuse and the patient should be advised replacement of electrolytes to avoid feeling very weak. Thereafter, the discharge slowly subsides in 4-6 weeks, which is the time taken for squamous epithelium to grow over the raw area. The late sequelae of overenthusiastic cauterization are: obstruction of the ducts to cause more cystic glands and cervical stenosis.
ENDOMETRITIS Acute Endometritis Apart from infections introduced at operations and by instrumentation, acute endometritis is either gonococcal or puerperal in type. Chronic Endometritis
Aetiology
The edges of lacerations can be excised and the cervix reconstituted by a plastic operation.
In theory, every case of acute endometritis might go on to chronic endometritis. In fact, the regrowth of new surface endometrium during each menstrual cycle prevents the persistence of any infection which is not deep seated. Chronic endometritis is therefore a rare disease between the menarche and the menopause, and only occurs when the uterus is permanently injured, or when there is opportunity for it to be continually reinfected. Its causes are: foreign bodies within the uterus; malignant disease of the uterus; infected polyps; retained products of conception; with inflammatory cells, including altered macrophages known as ‘foam cells’. Its lining epithelium becomes destroyed and converted into granulation tissue. This exudes pus, which tends to collect in the uterus to form a pyometra because the cervix is narrowed by senile change and because the atrophied myometrium is unable to expel it. The uterus enlarges by thinning its walls and spontaneous rupture followed by peritonitis is described as a rare complication. Sometimes, in response to pyometra, the endometrial epithelium undergoes metaplasia into a stratified squamous type. Senile endometritis is a condition associated with cancer. The ultimate growth is usually an adenocarcinoma but can contain squamous cell elements.
Hysterectomy
Clinical Features
If the condition of cervicitis is so severe that it cannot be treated satisfactorily with diathermy, cryotherapy or
A purulent and very offensive postmenopausal discharge, sometimes bloodstained, is the main
Trachelorrhaphy
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Jeffcoate’s Principles of Gynaecology complaint. When a pyometra forms, the discharge occurs intermittently, ceasing for a few days or weeks and then returning immediately after colicky lower abdominal pain. The uterus generally feels small and atrophic but, in the case of pyometra, may be enlarged, soft and cystic.
Diagnosis The clinical features are identical with those of carcinoma of the body of the uterus so the diagnosis of senile endometritis can only be made by curettage. If a pyometra is present, pus escapes as the cervix is dilated and conventional curettage then involves the risk of spreading the infection to cause cellulitis and peritonitis. To avoid this, curettage may have to be deferred for 1 or 2 weeks but must be carried out sooner or later if carcinoma is to be excluded. When it is done, a cover of antibiotics is desirable. Some form of suction curettage or endometrial lavage is less hazardous.
Treatment The drainage of the uterus afforded by dilatation of the cervix is enough to cure some cases. There is, however, much to be said for hysterectomy in all cases of senile endometritis if the patient is reasonably fit. This not only makes for certain cure; it circumvents the difficulty of excluding the presence of an underlying carcinoma and removes a potentially malignant organ.
entity in itself. Some degree of acute metritis is present in all cases of spreading puerperal endometritis. In prolonged labour with devitalization of the lower segment, and in certain cases of abortion complicated by Clostridium welchii infection or induced by the injection of chemical irritants, the uterine wall becomes gangrenous (Fig. 20.14). Curettage in the presence of endometrial infection can also cause metritis.
Pathology The myometrium shows the usual reaction to infection — congestion and inflammatory cell infiltration in its early stages, and possibly fibrosis ultimately. There may even be abscess formation (Fig. 25.8).
Clinical Features These are obscured by those of other inflammatory lesions which are always present. An abscess causes intermittent pyrexia and possibly pyaemia. SALPINGO-OOPHORITIS When the fallopian tubes are infected the ovaries are usually affected as well, although often to a minor extent. The term salpingitis should therefore generally be taken as meaning salpingo-oophoritis. Salpingo-oophoritis is nearly always bilateral (unless one adnexum has been removed) and is essentially a disease of the young adult.
Pyometra (Pyohaematometra) The collection of pus, or of a mixture of pus and blood, within the uterus is described in this and other chapters. It is convenient here to summarize the possible causes which are: congenital atresia of the vagina or cervix; stenosis of the cervix or vagina following operations, burns and radiotherapy; puerperal endometritis with retention of the lochia; tuberculous endometritis; senile endometritis; carcinoma cervix; and carcinoma corporis. The commonest of these are malignant states of the uterus, acting alone or in association with radiotherapy; after these, senile endometritis. Benign tumours of the uterus, even infected polyps, rarely if ever cause pyometra because they do not obstruct the cervix. METRITIS Aetiology The myometrium may be involved as part of a widespread pelvic infection but metritis is rarely an
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Aetiology
Ascending Infection Acute salpingitis is a polymicrobial infection. In gonorrhoea and chlamydial infection, the organisms ascend through the uterus and along the tube to produce an endosalpingitis. Other organisms like Gardnerella vaginalis, Bacteroides spp. especially B. fragilis, Peptostreptococci, Proteus and Klebsiella spp. may also originate from the vagina.
Puerperal and Postabortal The organisms concerned in puerperal infections are usually streptococci, staphylococci, Escherichia coli, the genital mycoplasmas and C. trachomatis. They spread from the uterus by lymphatics and veins to the peritoneum to cause pelvic peritonitis. The adnexa are only involved as part of the pelvic peritonitis and this explains why the old term for this condition was
Infections as They Affect Individual Organs
Fig. 20.14: Chronic abscesses in the uterine wall associated with chronic salpingo-oophoritis and pelvic cellulitis. This condition arose as a result of puerperal infection and caused death of the patient from pyaemia several weeks after delivery
perimetritis. Although intraluminal spread of infection occurs to a limited extent, the tube is attacked mainly from the outside (Fig. 19.1).
Tuberculous Elsewhere discussed.
Other Infections Rarely, the tubes are involved in actinomycosis, schistosomiasis and other special infections described elsewhere.
Pyogenic Infection of Pelvic Peritoneum The tubes and ovaries become involved in any state of pelvic peritonitis. Often the primary cause is in the alimentary tract (appendicitis and diverticulitis, for example) and the infection is a mixed one with the coliform organisms and Gram-negative Enterobacteriaceae being predominant. Whatever the nature of the original infection, secondary invaders from the bowel are common. These or the primary organisms show periodic phases of activity, so salpingo-oophoritis tends to be a recurrent disease. In the case of gonorrhoea, however, repeated attacks probably always represent reinfection. Pathology Ordinarily the endosalpinx is affected along its whole length but the gonococcus shows a predilection for the
Fig. 20.15: Bilateral tubo-ovarian abscesses, probably gonococcal in origin
outer part to leave permanent damage of a characteristic type. In the acute phase of any infection the tissues become reddened and oedematous showing, on microscopic examination, the usual inflammatory responses. Thereafter the following developments are possible.
Resolution The tubes and ovaries can return to normal structure and function if the infection does not cause appreciable tissue destruction.
Abscess Formation If the endosalpinx is destroyed in part or whole and converted into granulation tissue, pus is formed. This can escape into the peritoneal cavity or be retained within the tube depending on whether and when the abdominal ostium becomes closed. So it may collect in the tube to result in a pyosalpinx, in the ovary to form an ovarian abscess, in both to produce a tubo-ovarian abscess (Fig. 20.15), or in the pouch of Douglas to cause a pelvic abscess. The walls of a chronic pyosalpinx (Fig. 20.16) can ultimately become calcified, although such a happening generally betokens a tuberculous basis.
Healing by Fibrosis When this happens, the tube wall thickens in part or whole; the plicae adhere together to obstruct or distort the lumen; and the tube and ovary become adherent to adjacent organs, to the broad ligament and to the uterorectal pouch. The parts of the tube most likely to be obstructed are the abdominal ostium and the narrow
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Fig. 20.16: Pyosalpinx 3D ultrasound
isthmus. In the latter site, chronic infection causes beading and thickening which give rise to the name salpingitis isthmica nodosa. This old term describes nodular lesions felt in the tube and of uncertain cause. Some use the term for tuberculous infection although the nodules may be caused by either an endosalpingitis or a perisalpingitis.
Hydrosalpinx When the inflammation subsides to leave the fimbrial end sealed, but the tubal epithelium elsewhere intact, the natural secretions cannot escape and the tube gradually distends with watery fluid to become a hydrosalpinx. This is a retort-shaped swelling which only
Fig. 20.17: Hydrosalpinx. The retort-shaped enlargement of tube with closure of the outer end. Disappearance of the fimbria and absence of adhesions is typical and suggests a previous gonococcal infection. The ovary (indicated by an arrow) is separate from the tumour
exceeds the size of an orange in exceptional cases (Fig. 20.17). An extraordinary feature of a hydro-salpinx is that the inner end of the tube is nearly always open and yet the fluid does not drain into the uterus. Perhaps the tubal muscle is so damaged or stretched that it cannot expel the fluid; perhaps the tube normally drains into the peritoneal cavity rather than into the uterus. Examination of specimens suggests that the phenomenon is not explained by a valve mechanism at the uterine end. This feature is fortunate in that it enables the diagnosis to be made by hysterosalpingography (Figs 20.18A and B). An uncomplicated hydrosalpinx is
Figs 20.18A and B: Bilateral hydrosalpinges, revealed by salpingography, in a woman aged 24 years who complained of infertility. She gave a history of gonorrhoea and of one abortion prior to marriage but this condition is much more likely to be the result of gonococcal salpingitis than of postabortal infection, (A) Radiograph taken immediately after the injection of an oily radio-opaque material. The appearance of the globules in the dilated outer end of the left tube represents a failure of the oil to mix with the watery contents of the tube, (B) Twenty-four hours later the medium remains loculated in the hydrosalpinges
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Infections as They Affect Individual Organs usually too soft and flaccid to be palpable on bimanual examination. With high resolution transvaginal ultrasound and 3D, the diagnosis of hydrosalpinx can also be made. Classical ultrasound findings are elongated cystic mass with incomplete septations (Fig. 20.19). The pathogenesis of hydrosalpinx is not agreed. It has been suggested that it represents the end result of pyosalpinx — the pus having liquefied. Bearing in mind the comparatively thick walls of a pyosalpinx and the destruction of the endosalpinx which goes with it, it is difficult to believe that the thin-walled hydrosalpinx lined by normal although compressed endosalpinx can ever be its offspring. The outlook as far as fertility is concerned is unfavourable, for although the endothelium is able to secrete it is functionally impaired. Moreover, when a hydrosalpinx is found, there is usually no history of a severe previous infection; often there is no history of salpingitis sufficient to cause symptoms. Nevertheless, the most likely cause of this condition is a gonococcal infection whose aftereffects are limited to the ampullary area of the tube, one which produced few or no clinical manifestations when it happened. The apparent absence of fimbriae strongly supports this concept. Other possible backgrounds when there is no history of previous disease, are previously unrecognised subclinical infections related to Chlamydia and other
organisms, perhaps even including gonococcal or tubercular infections. In tuberculosis, however, the appearances are very variable depending on the site and mechanism of infection.
Tubo-ovarian Mass When a hydrosalpinx is adherent to an ovary containing one or more follicular cysts, the two conditions give the appearance of a single multilocular structure. Sometimes the dividing wall breaks down but, even if it does not, the lesion is called a tubo-ovarian mass. In Western countries, tubo-ovarian masses rarely exceed the size of a fetal head. In the Far East, however, they commonly develop to the size of a pregnancy at term and are difficult to distinguish from large ovarian neoplasms.
Peritoneal Cysts and Pseudocysts These not uncommonly result from adhesions following perimetritis. When such a cyst lies outside the ovary and has a wall formed by intestines and omentum, it is sometimes called a pseudocyst.
Puerperal and Postabortal Infection This, being essentially an exosalpingitis, results in peritubal and periovarian adhesions with thickening of the tube wall and ovarian capsule. Pyosalpinx and hydrosalpinx are not common and, when the adhesions are separated, the fimbriae are found in a reasonably healthy state; even the tube lumen may be patent and lined by normal epithelium. Infections arising from the alimentary tract also have a similar effect. Clinical Features
Acute salpingo-oophoritis
Fig. 20.19: Hydrosalpinx and pyosalpinx
This is a disease seen mainly in sexually active women of the reproductive age group. The clinical features mainly reflect pelvic peritonitis. The illness begins with acute lower abdominal pain, pyrexia, tachycardia, malaise and sometimes vomiting. The pain is situated diffusely across the lower abdomen or in both iliac fossae. A menstrual period may be delayed in onset by a few days or be precipitated early and it is often heavy and prolonged. There may be symptoms of urethritis as well. There is often a history of recent confinement or abortion, of a discharge suggesting gonorrhoea, of exposure to risk of infection, or of previous attacks of salpingitis.
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Jeffcoate’s Principles of Gynaecology Symptom-producing salpingitis hardly ever occurs during pregnancy. After the first 12 weeks, the decidua vera and decidua capsularis fuse and a new infection cannot ascend through the uterus, while a preexisting chronic infection may have caused tubal damage. Cases of acute salpingo-oophoritis in pregnancy are rare, except when secondary to acute appendicitis. Similarly it is rarely seen in premenarchal girls or post-menopausal women. Women on oral contraceptive pills are also at a lesser risk, possibly because of the thickening of the cervical mucus plug. The patient looks flushed and toxic and has a dirty mouth. The lower abdomen is tender with some muscle guarding. There may be obvious signs of lower genital tract infection but, on bimanual examination, it is often impossible to define either the uterus or the adnexa because of generalised tenderness. In any case the adnexa are not usually enlarged at this stage. A valuable test is to rock the cervix gently from side to side. This puts tension on the broad ligaments and adnexa and produces pain if salpingitis is present. There is a brisk polymorphonuclear leucocytosis and a raised erythrocyte sedimentation rate. With spreading peritonitis, intestinal distension and constipation are likely; a pelvic abscess causes a swinging temperature, diarrhoea, pain on defaecation and sometimes retention of urine. A very serious complication is rupture of a pyosalpinx which causes an ‘acute abdomen’ and sometimes extreme shock. Bacteraemic shock in its severest form may complicate gonococcal salpingitis. Acute salpingo-oophoritis has to be distinguished from the following: • Acute appendicitis: In this, the pain commences higher in the abdomen and becomes unilateral; anorexia and vomiting are more likely; muscle rigidity is localised and more obvious; menstrual disturbance and discharge are absent. • Ectopic pregnancy: Here the pain is mainly unilateral and causes collapse or fainting. There is little, if any, pyrexia and the leucocyte count is only slightly increased. • Torsion of the pedicle of a leiomyoma or ovarian cyst • Rupture of an ovarian cyst • Rupture of an endometriotic cyst • Ovulation pain and corpus luteum haematoma • Diverticulitis • Intestinal obstruction
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• Pyelitis and cystitis • Other causes of an ‘acute abdomen’.
Subacute Salpingo-oophoritis The onset of salpingo-oophoritis does not always produce the dramatic picture painted above. More often the disease is subacute from the beginning and can persist in this form for several weeks. The symptoms and signs are then less striking and the patient may be only moderately incapacitated, with less discomfort, less pyrexia and less pelvic tenderness. The clinical features in general are intermediate between those described above and those below.
Chronic Salpingo-oophoritis Chronic salpingo-oophoritis may follow an acute or subacute stage but, in the case of certain causal organisms, the disease is chronic from the outset. Also, a previous acute infection may have been subclinical and have passed unnoticed. Chronic salpingo-oophoritis is mostly asymptomatic and often is only discovered by the finding of obstructed tubes during the investigation of infertility or during surgery for ectopic pregnancy. Otherwise, the symptoms are chronic aching in the lower abdomen or in both iliac fossae, and sometimes in the lumbosacral region. The pain tends to be worse during the week preceding menstruation, and to ease gradually as congestion subsides during menstruation. Ovarian involvement results in more frequent periods, and uterine congestion to increased loss; so the complaint is of heavy and frequent periods. Except when the infection is tuberculous in type, amenorrhoea never occurs, even when there are bilateral ovarian abscesses. There is often a mucoid or mucopurulent vaginal discharge intermenstrually. Deep-seated dyspareunia and involuntary infertility are other common complaints; rectal discomfort and bladder irritability are seen occasionally. General health is affected by way of malaise, anorexia, lethargy, increased irritability and sometimes loss of weight. Examination may disclose no abnormality. On the other hand, bimanual palpation may reveal generalised tenderness and fixation of the pelvic organs. According to their pathology the adnexa may be palpably enlarged. Often they feel nodular and hard. A fixed retroversion of the uterus and some degree of cellulitis in the uterosacral or broad ligaments are common findings.
Infections as They Affect Individual Organs Chronic salpingo-oophoritis has to be distinguished from the following: • Ectopic pregnancy • Appendicitis, diverticulitis and other diseases of the bowel, especially if adhesions have occurred • Ovarian tumours, especially bilateral ones • Pelvic endometriosis • Congestive dysmenorrhoea and premenstrual syndrome • Colonic and rectal spasm — irritable bowel and distended caecum syndromes. Treatment of Acute Salpingo-oophoritis The treatment of acute salpingo-oophoritis is always conservative in the first place, hence the importance of distinguishing this disease from abdominal conditions requiring emergency surgery. Treatment should be preceded by taking cervical, rectal and urethral swabs to determine the nature of the infection.
General Admission to hospital maybe required. It ensures adequate rest, constant observation and efficient treatment. Once the diagnosis is made, all local interference such as pelvic examination should be avoided. Even if she is not kept in bed continually the patient’s physical activity should be severely restricted until her temperature and pulse rate have been normal for at least 5 days.
Relief of Pain Warmth to the lower abdomen is soothing and, once the diagnosis is reasonably sure, pain should be relieved by analgesics, anti-inflammatory agents or even opiates.
Antibiotics These are given in full dosage as for gonorrhoea, Chlarnydia or postabortal infection.
Surgical Treatment This is only indicated in the following circumstances: when there is evidence of spreading peritonitis despite adequate medical treatment; rupture of a pyosalpinx or ovarian abscess; intestinal obstruction resulting from adhesions; pelvic abscess formation; if the diagnosis is in reasonable doubt; if it is difficult to be sure that the condition is not one of acute appendicitis or other lesion
requiring urgent surgery. Laparoscopy is sometimes suggested in the acute phase if the diagnosis is uncertain but if there is any real possibility of peritonitis and adhesion formation, laparotomy may be safer. In cases of salpingitis, laparoscopy will reveal tubal hyperaemia and oedema, sticky exudates on the tubal surface and/ or pus pouring out of the tubal ostia. It is generally wise to leave the pelvic organs untouched, except for taking a swab from any pus for bacteriological analysis, and, even if laparotomy has been performed, to close the abdomen without drainage. It is amazing how apparently hopeless tubes can recover to the extent of being functional. When there are large pyosalpinges, they are sometimes best removed - even in the acute phase. Treatment of Subacute and Chronic Salpingo-oophoritis Before initiating treatment it is again important to investigate bacteriologically for the source of infection. When the disease is chronic, however, and excepting tuberculosis or other rare special infection, it is unlikely that a significant organism will be found. Tests may need to be repeated several times before the organism is isolated.
Conservative Treatment An important part of treatment is a period of physical rest. Appropriate antibiotic therapy is indicated for the subacute disease but rarely helps if the salpingitis is truly chronic and consisting of little more than residual damage resulting from previous infection. Pelvic heat applied by means of hot water bottles 4 hourly, or by shortwave therapy, is comforting and sometimes appears to assist resolution of a subacute inflammatory reaction. As swelling and fixation of the adnexa subside, as the uterus becomes more mobile, and when the temperature and pulse rate have remained normal for several days, the patient is allowed to resume activity gradually. Coitus should be forbidden until it is reasonably certain that the inflammatory process is completely inactive.
Surgical Treatment Indications • For persistence of symptoms despite trial of conservative measures
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Jeffcoate’s Principles of Gynaecology • • • • •
For recurrent attacks or exacerbations of the disease For fixed retroversion For persistence of gross enlargement of the adnexa Sometimes for infertility Surgery is only really safe and likely to give the best results if it is carried out during a quiet phase, that is when: the temperature has been normal for at least 2 weeks; there is no rise in pulse rate or temperature after a test vaginal examination; the white cell count is normal; and the erythrocyte sedimentation rate is normal.
Nature of Operation This necessarily depends on the findings at laparoscopy or laparotomy. For infertility the object is to try to restore tubal function by salpingolysis, salpingostomy or reimplantation of the tube into the uterus. Even if reproductive function has to be sacrificed, menstrual function should be preserved, if possible, in young women; ovarian function, in particular, should be preserved, because of the possibility of in vitro fertilisation at a later date. The disadvantages are that sometimes the ovaries later become cystic, and the patient may be left with menorrhagia for which hysterectomy ultimately becomes necessary. In the case of salpingectomy with conservation of the uterus, it is important to excise the cornu of the uterus which contains the intramural portion of the tube. This maybe infected and, if it is not removed, it can be the source of further symptoms. For widespread chronic pelvic infection with disorganisation of both adnexa, total hysterectomy with removal of both tubes (and sometimes both ovaries) is often the best treatment. Indeed, this is often the eventual outcome after previous conservative surgery. OOPHORITIS Oophoritis without salpingitis is rare and only occurs as a result of blood- or lymph-borne infection from elsewhere. Aetiology Oophoritis occurs as a complication of septicaemia, typhoid and paratyphoid fevers, pneumonia and viral diseases such as mumps and influenza. Of these the commonest is mumps, the oophoritis being the equivalent of the orchitis complicating parotitis in the male.
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Tuberculosis, sarcoidosis, syphilis and actinomycosis are very occasional causes. Pathology The acute inflammatory reaction nearly always subsides completely without permanent ill effect. However, abscess formation or healing with fibrosis and fibrocystic change are recorded. Mumps rarely has a sterilising or other ill-effect in the female because the capsule of the ovary is more elastic than that of the testis; so ischaemic injury to the graafian follicles is not likely. Even if some follicles are destroyed, enough remain for full reproductive function. Clinical Features The only evidence of oophoritis as a rule is the occurrence of lower abdominal pain for a few days during an acute infective illness. A single menstrual period may be disturbed in its onset, but it is difficult to know whether this is the effect of the oophoritis or of the general systemic upset. If an abscess forms, or if the condition does become chronic, the clinical features are those described under salpingo-oophoritis. Treatment In the acute phase no treatment other than that of the causal illness is required. If an abscess forms, the treatment is as described for salpingo-oophoritis. PELVIC PERITONITIS Aetiology • Any infection of the genital tract • Infection from the alimentary tract: appendicitis, diverticulitis • As part of general peritonitis: pneumococcal and tuberculous infections • Foreign bodies: These reach the peritoneum via the bowel, uterus or the posterior vaginal fornix, or are left at operations. • Rupture or perforation of an infected uterus • Following pelvic haematocele: Infection of blood clot is seen in ectopic pregnancy and also following pelvic operations. Postoperative pelvic peritonitis • Nearly always means inadequate haemostasis. • Chemical: This includes a variety of possible irritantsurine, bile, vernix caseosa, meconium (spilled at the
Infections as They Affect Individual Organs time of caesarean section), radio-opaque media used in salpingography, talc from gloves or drapes used at operations, and the contents of ruptured cysts. The fluid from endometriotic cysts is irritant but the worst in this respect is the sebaceous fluid from dermoid cysts. This, like vernix caseosa, can produce the most violent reaction which ultimately leads to very dense adhesions. Irritant fluids used for the purpose of douching, and especially those used by women themselves with the idea of inducing abortion, may pass through the uterus and tubes to produce pelvic or general peritonitis. A favourite in the past was a solution of soap and large quantities of this fluid had to be removed from the abdominal cavity. The risk of this accident taking place is minimal after the uterine cavity is filled with a pregnancy. Abortifacient pastes are another cause.
ani. It occurs most obviously in the bases of the broad ligaments (parametritis) and the uterosacral ligaments (posterior parametritis). Acute and Subacute Cellulitis
Aetiology Organisms travel to the cellular tissue from infected adjacent pelvic organs by way of lymphatic channels but they can also gain direct access through perforations and tears, surgical or obstetrical, in the vaginal fornix, cervix, uterus, rectum and bladder.
Adjacent Infections
The initial acute inflammatory reaction may subside or be followed by exudation and pus formation. Although complete resolution is possible, pelvic adhesions are left in most cases. Pus can collect to form a pelvic abscess and the causes of this condition are all those stated above. If neglected, the abscess ultimately bursts into the rectum or bladder but very rarely into the vagina whose investing fascia is strong.
• Cervicitis and endometritis, including secondary infection complicating neoplasms and foreign bodies. Cellulitis associated with cancer of the cervix makes it difficult to define the extent of the growth. • Salpingo-oophoritis: Some degree of parametritis invariably accompanies severe salpingo-oophoritis. It accounts in large measure for the fixation of the pelvic organs in this disease. • Diverticulitis, carcinoma of the rectum and other conditions of the large bowel can lead to cellulitis of the uterosacral ligaments. • Carcinoma of the bladder and cystitis, if extensive, can cause cellulitis in the uterovesical space.
Clinical Features
Pelvic Operations
These are the same as for acute salpingo-oophoritis and, in the case of residual pelvic adhesions, as for chronic salpingo-oophoritis. The leading symptoms of acute pelvic peritonitis, with or without abscess formation, is often diarrhoea.
• Dilatation and curettage, especially if carried out in the presence of endometritis • Ablative procedures on an infected cervix • Hysterectomy: Some degree of cellulitis of the tissues at the vaginal vault is common after total abdominal or vaginal hysterectomy, but is usually preceded by haematoma formation. • Lower segment caesarean section: In this case the cellulitis is anterior rather than lateral, and often represents secondary infection of a haematoma. • Other obstetrical operations • The insertion of intrauterine contraceptive devices or of instruments to terminate pregnancy.
Pathology
Treatment In the acute stage the treatment is the same as for salpingo-oophoritis, except that any cause such as a foreign body or ruptured cyst must be removed. A pelvic abscess or a collection of infected blood requires drainage; this is usually best established through the posterior vaginal fornix, not the rectum. Sometimes abdominal drainage is more efficient. Residual pelvic adhesions only require surgery if they cause symptoms. PELVIC CELLULITIS Pelvic cellulitis is a condition of inflammation affecting any of the loose cellular tissue lying above the levatores
Radiotherapy Radiotherapy in the presence of infection can cause cellulitis. This risk is mostly seen in the case of malignant disease, but cellulitis following the insertion of radioisotopes does occur.
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Jeffcoate’s Principles of Gynaecology A special form of non-infective ischaemic ‘cellulitis’ is seen as a late complication of radiotherapy. Pathology Anaerobic streptococci, staphylococci and Escherichia coli are the most likely pathogens. The loose connective tissue reacts by inflammatory infiltration and oedema; an indurated mass results. The possible further developments are: complete resolution; abscess formation, the pus tracking according to the distribution of the cellular tissue and its connections; and healing by fibrosis and scar formation. One complication is suppurative thrombophlebitis of the veins of the broad ligament and the clinical features of this can obscure those of cellulitis. Cellulitis of the broad ligament and paracolpos is nearly always unilateral and, in puerperal infection, is most often left-sided, as are cervical lacerations. Puerperal cellulitis is also more extensive and obvious because the amount of cellular tissue is increased and the vascular channels are dilated by pregnancy. Cellulitis of the uterosacral ligaments is usually bilateral and appears as a horseshoe-shaped swelling with the two arms passing back beside the rectum. Clinical Features Symptoms and signs do not usually make their appearance until 7-14 days after the original infection. The typical picture is presented by puerperal cellulitis. This ordinarily becomes manifest about the tenth day when the patient experiences a rise in temperature and pulse rate accompanied by malaise. On reviewing the case it may be noted that slight evening pyrexia has been present for some days previously for no apparent cause. The patient does not appear to be seriously ill, but may complain of discomfort in the lower abdomen or pelvis on the affected side. The pain is not severe and muscular rigidity is absent because the lesion is extraperitoneal. Other possible complaints are frequency of micturition, dysuria, diarrhoea and painful defaecation. The formation of an abscess brings further general sytemic disturbance with a high swinging temperature and rigors. The physical signs are very striking. The cellulitis gives the impression of a hard mass, continuous with the uterus and extending towards the wall of the pelvis. It may be so large as to be palpable abdominally, otherwise it is detected on pelvic examination. Induration of the
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uterosacral ligaments is often felt more easily per rectum. If the broad ligament is involved, the swelling is unilateral and pushes the uterus to the opposite side. The mass is tender, woody in consistency and fixes all organs in its vicinity, especially the uterus. An abscess may point: into the rectum; into the bladder; into the vagina; on the lower anterior abdominal wall, especially above the inguinal ligaments; over the femoral canal; in the thigh via the obturator foramen; or in the buttock via the sacrosciatic notch. Diagnosis The diagnosis is usually easy but confusion may arise over the following. • Acute salpingo-oophoritis and pelvic peritonitis: In this condition the pain is bilateral and more intense, abdominal rigidity is present and the temperature is usually higher. Diarrhoea is more likely. Any swelling is separate from the uterus. • Malignant disease: Extension of growth from the cervix, corpus or ovary into the broad or uterosacral ligaments • Diverticulitis and carcinoma of the lower bowel • Ectopic pregnancy, especially if it is intraligamentary • Broad ligament haematoma. Treatment
Medical and General As for acute salpingo-oophoritis.
Surgical An abscess which is pointing and easily accessible should be drained; otherwise, surgery is to be avoided. The ideal drainage route is through the posterior vaginal fornix but the site of incision is determined to a large extent by where the abscess points. An extraperitoneal inguinal approach is best in certain cases.
Prognosis Except in old and debilitated women the prognosis is good and the cellulitis usually resolves completely. It sometimes heals by fibrosis (see below). Unlike salpingooophoritis, and because the endosalpinx is not affected, cellulitis does not lower fertility. Moreover, future pregnancies do not involve any special risk of reawakening the infection.
Infections as They Affect Individual Organs
CHRONIC CELLULITIS
PELVIC INFLAMMATORY DISEASE (PID)
Aetiology and Pathology Chronic cellulitis is a condition of fibrosis, or of long persisting inflammatory exudation, in the broad and uterosacral ligaments. It usually represents the quiescent end result of acute cellulitis, but can be a response to a chronic low-grade infection in an adjacent organ such as the cervix and rectum, an infected cancer for example.
Pelvic inflammatory disease (PID) is a clinical syndrome associated with ascending spread of microorganisms from the vagina or cervix to the endometrium, fallopian tubes and/or contiguous structures, not associated with pregnancy or surgery. In the foregoing sections, you have read about infections as they affect individual organs. What follows here is a summary to present the condition as usually encountered in clinical practice.
Clinical Features
Aetiology
The symptoms are chronic aching pain in the pelvis, often one-sided; deep-seated dyspareunia; sacral backache, especially if the uterosacral ligaments are involved; and menorrhagia and discharge if there is an associated congestion of the uterus and cervix. On vaginal examination a scar in the cervix and vaginal vault, with underlying induration in the broad ligament, is easily detected. When the uterosacral ligaments are implicated they feel prominent, hard and tender. The uterus is fixed on the affected aspect; attempts to move it reproduce the patient’s pain.
While most cases of PID are caused by Neisserria gonorrhoeae and Chlamydia trachomatis, other organisms can be encountered less frequently: Gardnerella vaginalis, Prevotella, Peptostreptococcus, streptococci, Haemophilus influenzae and pneumococci.
Diagnosis The diagnosis of chronic cellulitis should not be made a cover for all one-sided pelvic pains for which another cause cannot be found. Clear evidence of previous infection or of associated disease should be present. Posterior parametritis has to be distinguished from endometriosis of the uterosacral ligaments and rectovaginal septum. Treatment
Clinical Features and Diagnosis Some patients may be asymptomatic. The classic triad, however, is pelvic pain, cervical excitation pain and adnexal tenderness, often in the presence of fever. In severe cases, abdominal rebound tenderness may be present; vaginal discharge may be seen. Some women may have associated menorrhagia, metrorrhagia and urinary symptoms. The erythrocyte sedimentation rate, total leucocyte count and C-reactive protein may be elevated; tests for gonorrhoea, Chlamydia or other organisms may be positive and an endometrial biopsy, if performed, may show endometritis. Tubo-ovarian masses can be demonstrated by ultrasound. Laparoscopy will confirm the presence of salpingitis.
Medical and General
Sequelae
This is the same as for chronic salpingo-oophoritis.
The most important long-term sequelae of PID are chronic pelvic pain, ectopic pregnancy and infertility, the management of which is discussed elsewhere.
Nerve Block Injection in the ilioinguinal region with long-lasting anaesthetic solutions may relieve pain and tenderness, and can usefully be combined with treatment of associated cervical lesions.
Surgery Trachelorrhaphy, freeing of cervical and vaginal scars, and treatment of associated chronic cervicitis may give relief, especially if the complaint is dyspareunia.
Treatment The CDC guidelines for outpatient treatment of PID are as follows: cefoxitin (2 g i.m. single dose plus 1 g probenecid orally) or ceftriaxone (250 mg i.m.) or equivalent third-generation cephalosporin (e.g. ceftizoxime or cefotaxime) along with doxycycline (100 mg orally twice daily for 14 days). An alternative regimen consists of ofloxacin (400 mg orally twice daily for 14
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Jeffcoate’s Principles of Gynaecology days) along with either clindamycin (450 mg orally qid for 14 days) or metrogyl (500 mg orally bd for 14 days). Hospitalisation is recommended in cases of severe disease, suspected pelvic abscess, cases where the diagnosis is uncertain, adolescent patients and where there is failure of or noncompliance with outpatient therapy. In-patient regimens are as follows: Cefoxitin (2 g i.v. 6-hourly) or cefotetan (2 g i.v. 12-hourly) along with doxycycline (100 mg orally or i.v. 12-hourly). An alternative regimen consists of clindamycin (900 mg i.v. 8-hourly) along with gentamicin (loading dose 2 mg/kg body weight i.m. or i.v., followed by 1.5 mg/kg 8-hourly). This regimen is continued for at least 48 hours after the patient demonstrates significant clinical improvement, following which she is administered doxycycline (100 mg orally bd) or clindamycin (450 mg orally qid) for a total of 14 days of therapy. Patients are discharged when the temperature is normal for 24 hours and other signs decrease or disappear. Treatment of sexual partners is important. Indications for surgery are discussed on page 355.
Clinical Features
SUPPURATIVE THROMBOPHLEBITIS OF THE PELVIC VEINS
Since the original uterine infection is generally low grade and gives little evidence of its presence, the disease usually only becomes clinically manifest approximately 10 days (with a range of 2-30 days) after abortion or labour. The onset can then be dramatic with a sudden rise of temperature (to 39-40.5°C) accompanied by a rigor. This denotes a breaking off of infected clot into the bloodstream. There may be typical symptoms and signs of pulmonary embolism (or a ‘fainting attack’). The pulse rate rises, the patient feels ill, leucocytosis is present but localising symptoms, such as lower abdominal pain, are exceptional. Thereafter the temperature fluctuates and there may be recurrent pulmonary infarction. The fully established picture is one of pyaemia with the formation of embolic abscesses. The physical signs in the pelvis are not remarkable unless there is associated cellulitis. The most that is found is a suggestion of thickening and tenderness in one broad ligament; the veins themselves may be palpable but it requires an expert observer to detect this. Swelling of one or both legs gives evidence that the thrombosis has spread to the common iliac vein or to the inferior vena cava.
Definition
Treatment
Suppurative thrombophlebitis is a condition in which the veins of the broad ligament become thrombosed as a result of infection within their lumen. It is to be distinguished from phlebothrombosis in which the vessel wall and the clot are not infected.
General and Medical
Aetiology and Pathology
These combined with antibiotics are lifesaving and should always be given at the first sign of thrombosis or embolism.
Suppurative pelvic thrombophlebitis is nearly always the result of puerperal or postabortal infection with anaerobic streptococci or staphylococci. The thrombi in the uterine sinuses become infected, and the processes of thrombosis and infection spread to the venous plexuses in the broad ligament and ultimately to the ovarian and uterine veins. The ovarian veins are more often affected. Portions of the infected clot break away to cause pyaemia with repeated embolism. Some degree of parametritis is nearly always present but is not usually obvious. Neither is the primary uterine infection, although gangrene and abscesses of the uterus are rare concomitants (Fig. 20.14).
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This is the same as for postabortal infection, although massive doses of antibiotics may be required.
Anticoagulants
Surgery Ligature of the main vein proximal to the thrombosis is indicated only when recurrent embolism threatens life and cannot be controlled by other means. The ovarian and common iliac veins, and even the inferior vena cava, have been ligated with success in these circumstances. The need for such desperate measures is exceptional. It arises mainly only among poorly nourished women living in squalor, and in whom septic abortion (probably criminal) has been neglected.
21
CHAPTER
Genital Tuberculosis
Introduction Clinical Profile
361 361
INTRODUCTION Genital tuberculosis (TB) in females is found in 0.75 to 1 per cent of gynaecological admissions in India with considerable variation from place to place. The disease is responsible for 5 per cent of all female pelvic infections and occurs in 10 per cent cases of pulmonary tuberculosis. Although most of the affected belong to reproductive age-group, the disease has been reported in postmenopausal females as well. Lately, an increase in the trend of the disease has been reported which may be partly due to increase in the population with overall rise in tuberculosis cases. The other contributory factor may be HIV infection with increased incidence-of pulmonary and extra-pulmonary forms of tuberculosis including the drug resistant forms. A rare case of vaginal tuberculosis in an HIV seropositive female had been earlier reported by the author. The immunocompromised state due to HIV infection causes reactivation of endogenous tuberculosis infection to development of tuberculosis disease. Genital TB occurs mostly secondary to pulmonary tuberculosis, commonly by the haematogenous route in a manner similar to spread to other extra-pulmonary sites like urinary tract, bones and joints etc. The fallopian tubes are affected in almost 100 per cent of the cases followed by the endometrium in 50 per cent, ovaries in 20 per cent, cervix in 5 per cent and vagina and vulva in 40 Prognosis
R L
ENDOMETRIOSIS Superficial Deep Superficial Deep Superficial Deep
2/3 enclosure 4 16 4 16 4 16 4
If the fimbriated end of the fallopian tube is completely enclosed, change the point assignment to 16. Reprinted by permission from the American Society for Reproductive Medicine (Fertility and Sterility 1997; Vol. 67, No. 5: page 819)
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Jeffcoate’s Principles of Gynaecology
Figs 22.15A and B: (A) Ultrasound pictures of endometriotic cyst which shows fine stippling inside ovary (ground glass appearance) (B) Laparoscopy findings of endometrioma
• Carcinoma of rectum and colon, and diverticulitis • All causes of an acute abdomen, in the case of rupture of a tarry cyst • All causes of intestinal obstruction • All tumours of the umbilicus • Hernia and other swellings in the inguinal canal • All causes of haematuria. In endometriosis, haematuria is limited to the time of menstruation. Classification: Various classification systems have been proposed and these help to compare trials of therapeutic methods but they correlate poorly with the degree of symptoms experienced by the patient (Table 22.1). Treatment
Expectant The treatment of endometriosis varies with its extent, site and symptoms, and also with the age of the patient. If the lesions are small and multiple and are producing few symptoms, it may be best to leave them alone; they sometimes become inactive after a period of time. It is especially important to defer active measures in a young married woman because if she becomes pregnant, and she should be advised to try to do so, a spontaneous cure is likely. By the same token, if the complaint is infertility other appropriate procedures should be undertaken in the hope of facilitating conception. If a woman known to have endometriosis becomes pregnant there need be little fear about the outcome.
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Rupture of chocolate cysts during pregnancy does occur but is rare; a fixed retroversion corrects itself; even large masses in the pelvis rarely obstruct labour, they disappear as pregnancy advances. The following explanations are put forward to account for the disappearance or inactivation of endometriosis during pregnancy: the absence of follicular activity and ovulation; the suppression of menstruation and therefore of recurrent retrograde spill of endometrium; the conversion of ectopic endometrium to decidua, a change which favours its necrosis and absorption of the glands. This in fact is what happens when a state of pseudopregnancy is induced with progestogens (Fig. 22.16).
Surgery In most women with endometriosis, preservation of reproductive function is desirable. Therefore, the least invasive and least expensive approach that is effective should be used. The goal of surgery is to excise or coagulate all visible endometriotic lesions and associated adhesions—peritoneal lesions, ovarian cysts, deep rectovaginal endometriosis—and to restore normal anatomy. Surgical management of minimal endometiosis: The association between infertility and minimal to mild endometriosis is controversial and poorly understood. The clinical pregnancy rate (PR) per cycle after controlled ovarian hyperstimulation (COH) with or without
Endometriosis and Allied States
Fig. 22.16: The effect of oestrogen-progestogen antiovulatory preparations on endometriosis. Continuous administration in large doses causes proliferation and decidual reaction of the stroma -a progestogen effect. The glandular elements undergo ‘exhaustion’ atrophy and appear small and inactive
intrauterine insemination (IUI) is reportedly lower in women with surgically untreated minimal to mild endometriosis than in women with unexplained infertility. It is possible that prior laparoscopic removal of endometriosis has a positive effect on the clinical PR after COH and IUI. However many studies have not proved this on a large study. Tumours on the body surface are best excised. Deepseated lesions call for surgery when symptoms are acute, when the diagnosis is in doubt, when tumour masses are large and when hormone therapy fails or is ruled out. In general it can be said that laparoscopic surgery is now the method of choice in most women who require conservative surgery. It is less invasive, less expensive, has less morbidity and better postoperative results than laparotomy. Endometriotic lesions and adhesions are excised or coagulated using bipolar coagulation or CO2 laser. The cyst wall of an endo-metrioma is removed and the remnants, if any, are fulgurated by bipolar electrocoagulation or laser. If the cyst is very small, it should be vaporised. It is important to remove the cyst wall if recurrence is to be prevented. At the same time,
adhesiolysis and preservation of normal ovarian tissue is essential in the woman who desires fertility. In general, bipolar electrocoagulation results in lass adhesion formation than the laser, but recurrence rates are the same with both precedures. Where laparoscopic facilities are not available, the same conservative surgery can be performed at laparotomy too. Limited and incomplete excision of endometriosis is followed by surprisingly good results, even when ovarian function is not sacrificed. In young women the subsequent pregnancy rate is at least 30 per cent, even when hormones are not administered postoperatively. Ovarian Endometriosis Superficial ovarian lesions can be vaporised. Small ovarian endometrioma (3 cm in diameter) ovarian endometrioma should be aspirated, followed by incision and removal of the cyst wall from the ovarian cortex. To prevent recurrence, the cyst wall of the endometrioma must be removed, and normal ovarian tissue must be preserved. There is increasing concern that ovarian cystectomy with concomitant removal or destruction of primordial follicles may reduce ovarian volume and reserve and diminish fertility. However it was found that a higher incidence of recurrences of cyst when the cyst was not excied. Therefore, based on the current evidence, ovarian cystectomy appears to be the method of choice. Laparotomy is usually considered for patients with advanced stage disease, over the age of 40, where fertility is no longer required. In such cases it is often best to remove the uterus and both ovaries. While it is important to remove as much endometriotic tissue as possible, small fragments can be left behind if there is a risk of injury to the bowel because of dense adhesions, and will usually retrogress of their own accord. If there are dense adhesions with the bowel and bladder, a subtotal hysterectomy may be a safer option. Deep Rectovaginal and Rectosigmoidal Endometriosis: The surgical excision of deep rectovaginal and rectosigmoidal endometriosis is difficult and can be associated with major complications. Postoperative bowel perforations with peritonitis have been reported in 2 to 3 per cent of cases.
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Jeffcoate’s Principles of Gynaecology Oophorectomy and Hysterectomy: Radical procedures such as oophorectomy or total hysterectomy are indicated only in severe situations and can be performed either laparoscopically or, by laparotomy The exact procedure must vary from case to case. Rarely, in the case of obstruction, it is necessary to even resect the intestine.
Medical Treatment There is not much of role in starting medical line of management and making the woman have amenorrhoea for six to nine months as it is not effective and more over the woman becomes older and has fecundity lowered. In order to get amenorrhoea, medications are given to manipulate the endogenous hormonal milieu and this is the basis for the medical management of endometriosis. Progestins may exert an antiendometriotic effect by causing initial decidualisation of endometrial tissue followed by atrophy. They can be considered as the first choice for the treatment of endometriosis because they are as effective as danazol or GnRH analogues and have a lower cost and a lower incidence of side effects than these agents. In most studies, the effect of treatment has been evaluated after 3 to 6 months of therapy. MPA has been the most studied agent. It is effective in relieving pain starting at a dose of 30 mg/day and increasing the dose based on the clinical response and bleeding patterns. However, a recent randomised placebo controlled study reported a significant reduction in stages and scores of endometriosis in both the placebo group and the group treated with MPA, 50 mg/day, and placebo at laparoscopy within 3 months after cessation of therapy . These findings raise questions about the need for medical therapy. Hormone Therapy
Oestrogens and Progestogens Treatment with a combination of these hormones was introduced to mimic the conditions occurring during pregnancy which has long been known to have a beneficial effect. Large doses given continuously suppress ovulation and menstruation and often quickly bring about clinical improvement in the condition with relief of the patient’s symptoms. In the endometriotic lesions, they produce a widespread decidual change in the stroma and this in turn brings about glandular
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atrophy and quiet (Fig. 22.16). If this effect is maintained for a sufficiently long time, the glands may be destroyed and the endometriosis permanently cured. Generally, however, the result is only temporary and reawakening of the endometriosis can occur as long as 2 years after apparent cure. Oestrogen—progestogen therapy is less effective for adenomyosis than for extrauterine endometriosis because the endometrium in the former is relatively insensitive to hormones. Hormone therapy also generally gives unsatisfactory results when extrauterine endometriosis takes the form of large tumour masses and chocolate cysts. Its place is in the treatment of widespread multiple small lesions and as an adjunct to conservative surgery. In these circumstances a good or satisfactory response is seen in 80 per cent of cases, and 50 per cent of patients with opportunity subsequently conceive. Any of the low-dose oestrogen-progestogen oral contraceptive preparations can be used. It is usual to administer it continuously, and increase it if required, to suppress menstruation. Once the adequate level of dosage is reached it is continued daily for 6-9 months. The advantage of this regime is the low cost. The difficulties and disadvantages of this treatment are as follows. • Nausea, vomiting and malaise at the outset • Slight breakthrough bleeding often occurs but this is of little consequence and can be controlled by stepping up the dose. • It can cause gross hypertrophy of the uterus and enlargement of any leiomyomas which may be present. With this treatment, uterine leiomyomas may increase considerably in size. The explanation is probably oedema and degeneration, rather than hyperplasia and hypertrophy of the tumours. • During the treatment phase the patient is inevitably infertile. If pregnancy occurs, there may be risk to the foetus. • Long-term benefits are questionable. Progestogens Mainly because of the last disadvantage listed above, treatment with progestogens alone, continuously or intermittently, is now advocated. Again, any of several agents can be used but popular ones are medroxyprogesterone acetate (MPA), dydrogesterone and megestrol acetate. Injections of depot medroxyprogesterone acetate (DMPA) can also be effective.
Endometriosis and Allied States By any technique, treatment for 6-9 months is necessary. During this time ovulation may or may not be suppressed, even if menstruation is, so conception is possible. Progestogens are often used as a first line of medical management because they produce sympto-matic relief and their side-effects and cost are less. MPA is started at a dose of 30 mg/day, megestrol acetate at 40 mg/day and dydrogesterone at 20-30 mg/day. The dose is increased as required. DMPA is administered in a dose of 150 mg at intervals of 6-12 weeks. The disadvantages of this regimen are: • Nausea, weight gain, fluid retention • Breakthrough bleeding: This may require short-term oestrogen administration for about a week. • Mood changes, depression • DMPA should be avoided if fertility is desired as return of ovulation as well as menstruation is variable.
Danazol Androgens have a direct depressant action on the endometriosis and to achieve this the dose need not be so high as to suppress menstruation. Methyl testosterone was used till the introduction of danazol. Danazol is a synthetic 2, 3-isoxazol derivative of 17 α-ethinyl testosterone, an orally active 19-norsteroid with minimal androgenic activity. It appears to have multiple actions at various levels of the reproductive system, including direct inhibition of GnRH and/or gonadotrophin secretion, interaction with intracellular androgen and progesterone receptors, direct inhibition of multiple enzymes of steroidogenesis and alteration of endogenous steroid metabolism. It also reverses some of the immunelogical changes known to occur in endometriosis (see above). The net result of danazol administration is a pseudomenopause state. There is no stimulant phase comparable to that seen in the pseudopregnancy state with oestrogen and progestogen preparations but primary atrophy of the ectopic endometrium occurs. This leads to more rapid symptomatic relief, usually in 2-4 weeks with danazol, compared with 12-16 weeks for pseudopregnancy regimens. The complex pharmacological actions of danazol make it an effective agent for the medical treatment of endometriosis but it is expensive and therefore will not always be the first-choice therapeutic agent. The dosage regimens vary from 400
to 800 mg but the lowest dose to produce relief of symptoms is the most appropriate. The drawbacks of this treatment are: • Nausea, weight gain, fluid retention • Androgenic side-effects: acne, oily skin, hirsutism, reduced breast size • Hot flushes, atrophic vaginitis, emotional instability, reduced libido • Fatigue, muscle cramps • Liver dysfunction • Androgenic effects on the foetus if conception occurs.
Gestrinone Gestrinone is a synthetic trienic 19-norsteroid which has mild androgenic and antigonadotrophic effect. It binds to the progesterone and androgen receptors, but not to oestrogen receptors thus resulting in progressive endometrial atrophy. The basal gonadotrophin levels are maintained but the mid-cycle surge is inhibited, ovarian steroidogenesis is diminished and the sex hormonebinding globulin (SHBG) levels are reduced. Symptomatic relief is seen in 80-90 per cent of patients within two months. The dosage is 2.5-5.0 mg orally twice weekly for 6-9 months. Side-effects include weight gain, reduced breast size, muscle cramps and breakthrough bleeding but frank androgenic effects such as hirsutism and voice change are less common. Although it is not yet widely available, it is poised to replace danazol in the treatment of endometriosis.
Gonadotrophin Releasing Hormone Agonists GnRH agonists stimulate the synthesis and release of follicle stimulating hormone (FSH) and leutinising hormone (LH) by binding to pituitary GnRH receptors, eventually leading to a loss of pituitary receptors and downregulation of GnRH activity. FSH and LH levels decline leading to an inhibition of production of ovarian steriods. Thus this is another method of inducing a pseudomenopause. Presently, several GnRH agonists are available: buserelin, nafarelin, goserelin, leuprorelin and triptorelin. The earliest ones were administered by intranasal spray up to five times daily. Depot formulations are now available for intramuscular and for subcutaneous use. The intramuscular preparation can
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Jeffcoate’s Principles of Gynaecology be administered once every 4 weeks and has greater patient acceptability. Doses vary with the agent used, e.g. buserelin 300-400 μg intranasally tds; nafarelin 200 μg intranasally bd; goserelin 3.6 mg subcutaneously monthly; leuprorelin 3.75 mg intramuscularly monthly (see Chapter 41). Results with GnRH agonists are similar to those with danazol or progestogens. Side-effects are related to oestrogen deprivation. Hot flushes occur but these disappear rapidly after cessation of treatment, as do other atrophic symptoms. Significant bone loss occurs: 3-5 per cent in vertebral bone. Reversibility of bone loss is equivocal, especially if serum oestradiol levels are lower than 30-45 pg/ml. Add-back regimens have been proposed to compensate for this and to treat vasomotor symptoms while maintaining the efficacy of treatment: conjugated equine oestrogens along with medroxyprogesterone acetate; norethisterone alone; or tibolone. Medroxyprogesterone acetate (150 mg) given intramuscularly every 3 months is also effective for the treatment of pain associated with endometriosis, but it is not indicated in infertile women because it induces profound amenorrhoea and anovulation, and a varying length of time is required for ovulation to resume after discontinuation of therapy. Megestrol acetate has been administered in a dose of 40 mg/day with good results . Other treatment strategies have included dydrogesterone (20 to 30 mg/day, either continuously or on days 5 to 25) and lynestrenol (10 mg/day). The effectiveness of natural progesterone has not been evaluated. Side effects of progestins include nausea, weight gain, fluid retention, and breakthrough bleeding due to hypoestrogenaemia. Breakthrough bleeding, although common, is usually corrected by short-term (7-day) administration of oestrogen. Depression and other mood disorders are a significant problem in about 1 per cent of women taking these medications. Local progesterone treatment of endometriosisassociated dysmenorrhoea with a levonorgestrelreleasing intrauterine system for 12 months has resulted in a significant reduction in dysmenorrhoea, pelvic pain, and dyspareunia; a high degree of patient satisfaction; and a significant reduction in the volume of rectovaginal endometriotic nodules. Although the results are promising, none of these pilot studies included a control group. Further randomised evidence is needed to determine whether intrauterine progesterone treatment is effective in the suppression of endometriosis.
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Progesterone Antagonists Progesterone antagonists and progesterone receptor modulators may suppress endometriosis based on their antiproliferative effects on the endometrium, without the risk for hypo-oestrogenism or bone loss that occurs with GnRH treatment. Mifepristone (RU-486) is a potent antiprogestagen with a direct inhibitory effect on human endometrial cells and, in high doses, an antiglucocorticoid action. The recommended dose for endometriosis is 25 to 100 g/day. In uncontrolled studies, mifepristone, 50 to 100 mg/day, reduced pelvic pain and induced 55 per cent regression of the lesions without significant side effects. In an uncontrolled pilot study, mifepristone, 5 mg/day, resulted in pain improvement, but there was no change in endometriosis lesions, suggesting that this dosage is probably too low . Combined Medical and Surgical Therapy Medical treatment has not much of place preoperatively but more postoperatively to deal with residual macroor microscopic disease. In women who desire fertility, it is a matter of speculation whether patients should be subjected to further suppression or induction of ovulation. In general, it is agreed that if adequate surgery has been possible, the sooner the patient is allowed to conceive the better, as the best outcome for fertility is immediately after surgery. Compared with surgery alone or surgery plus placebo, postoperative hormonal treatment has no effect on pregnancy rates. Postoperative medical therapy may be required in patients with incomplete surgical resection and persistent pain. Based on several retrospective studies, several investigators have suggested that the pregnancy rate after IVF may be lower in women with endometriosis than in women without the disease.
Treatment of Recurrent Endometriosis Therapeutic options and decisions remain the same in recurrent endometriosis, but before planning repeated conservative surgery in a patient with severe symptoms it may be in her best interests to discuss the benefits of a radical surgical approach.
Aromatase Inhibitors Treatment of rats with induced endometriosis using the nonsteroidal aromatase inhibitor fadrozole
Endometriosis and Allied States hydrochloride resulted in a dose-dependent volume reduction of endometriosis transplants, but these products have so far not been used in published human studies. Treatment of severe postmenopausal endometriosis with an aromatase inhibitor, anastrozole, 1 mg/ day, and elemental calcium, 1.5 g/day for 9 months, resulted in hypoestrogenism, pain relief after 2 months, and after 9 months a 10-fold reduction in the 30-mm diameter size of red, polypoid vaginal lesions, along with remodelling to gray tissue. No other data are available, except this case report .
Selective Estrogen Receptor Modulators Raloxifen: In animal models, raloxifene therapy resulted in regression of endometriosis. The effect was seen in both a surgically prepared, rat uterine explant model and in Rhesus macaques diagnosed with spontaneous endometriosis before exposure.
to ovarian hormones is limited; often it does not menstruate at all, and tarry cysts when present are small and few (Figs 22.2 and 22.3). Secretory activity in the glands during the luteal phase of the cycle is found in only 10-30 per cent of specimens and is then limited. This is because the adenomyoma is composed of basal type endometrium which is normally insensitive to an endocrine stimulus. On the other hand, the fibromyomatous tissue reaction is well developed and, to the naked eye, the resulting tumour looks like a myoma, its cut surface having a similar striated and whorled appearance. The distinguishing features are that adenomyosis has no capsule, and it usually produces a diffuse enlargement of the uterus in contrast to the well circum-scribed nodules characteristic of leiomyomas. When adenomyosis is localised it is most likely to be situated in the posterior wall of the uterus.
Assisted Reproduction and Endometriosis
Mechanism of Origin
The treatment of endometriosis-related infertility is dependent on the age of the woman, the duration of infertility, the stage of endometriosis, the involvement of ovaries, tubes, or both in the endometriosis process, previous therapy, associated pain symptoms, and the priorities of the patient, taking into account her attitude toward the disease, the cost of treatment, her financial means, and the expected results. Assisted reproduction, including controlled ovarian hyperstimulation with intrauterine insemination, IVF, and gamete intrafallopian transfer, may be options for infertility treatment in addition to surgical reconstruction and expectant management. IVF is the method of choice when distortion of the tuboovarian anatomy contraindicates the use of superovulation with intrauterine insemination or gamete intrafallopian transfer.
The established view is that adenomyosis always represents a downgrowth from the basal layer of the endometrium. No matter how deeply it may be situated, a gland, it is said, can always be shown by serial sections to communicate with the uterine cavity. It is sometimes suggested, however, that adenomyosis arises de novo in the myometrium and that the change may commence in
ADENOMYOSIS Pathology Adenomyosis usually involves the corpus, sometimes only one of its walls or a part of it. Rarely, it is found in the cervix (Fig. 22.17). Cervical endometriosis has special facets. What follows is concerned with corporeal adenomyosis. The myometrial lesion has the general characteristics of endometriosis. Its special feature is that its response
Fig. 22.17: Endometriosis of the cervix with multiple small tarry cysts
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Jeffcoate’s Principles of Gynaecology multiple sites. This is not unreasonable, bearing in mind that all uterine tissues have a common origin. The finding of adenomyosis unconnected with the endometrium might also be explained on the basis of venous or lymphatic embolism of endometrial elements.
Clinical Features and Diagnosis The most common symptom is menorrhagia which is found in approximately 75 per cent of cases. It is gradually progressive over several years and is caused by enlargement of the uterine cavity (bleeding area) and by an increased blood supply. Other theoretical causes for the menorrhagia are impaired contractility of the myometrium and associated endometrial hyperplasia. Dysmenorrhoea is noted by only 30 per cent of patients and, when it occurs, is mainly intramenstrual. It is more likely when the myomet-rium is deeply penetrated and is probably caused by disturbed uterine contractions rather than by tarry cyst formation. The increased size of the uterus can cause diurnal frequency, a sensation of weight in the pelvis, and a noticeable abdominal tumour. The patient may also complain of infertility. The enlargement of the uterus is detected on bimanual examination. The organ is mobile and there is usually no evidence of extrauterine endometriosis. The symptoms and signs are so similar that it may be impossible to distinguish clinically between adenomyosis and leiomyoma. Pointers in favour of adenomyosis are: it tends to occur at a younger age; it rarely enlarges the uterus to more than the size of a 1214 weeks’ pregnancy; it causes a regular rather than a nodular uterine enlargement. A clinical suspicion of adenomyosis can be suggested by imaging studies, including transvaginal ultrasonography (TVUS) and magnetic resonance imaging (MRI). ‘Blurring’ of endomyometrial interface, subendometrial linear striations, echogenic nodules, asymmetric myometrial thickness and myometrial cyst are indicative for the diagnosis of adenomyosis by TVUS. The deep penetration of the glands is said to give rise to a characteristic hysterographic appearance but this finding more often means endometrial hyperplasia. Gland openings may be visible on hysteroscopy. The junctional zone thickness value specific for the diagnosis of adenomyosis has been debated and evaluated by various studies. TVS has several advantages over MRI. It is widely available, relatively inexpensive compared to MRI. It is
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well tolerated by most patients and generates high quality images not limited by patient size or uterine position. However, it has its limitations. It is operatordependent and may not be reproducible in patients on follow-up. The presence of intramural fibroids can hinder assessment of the adjacent myometrium. MRI, on the other hand, is less operator-dependent. Treatment
Surgical If symptoms are present the primary line of treatment is by operation. This is the only means of making the diagnosis certain. Unfortunately the tumour cannot be removed easily because it has no capsule. Hysterectomy is therefore usually necessary although, in young women desirous of having children, resection of the main portion of the diseased uterine wall has rarely been carried out. In such cases some of the adenomyosis was often left behind but this was not necessarily incompatible with a good result. Indeed, pregnancy has been reported subsequently and this without any special postoperative therapy. Palliative and Medical
Medical Treatments With the establishment of diagnostic criteria for imaging studies, it is now possible to offer women the options of non-surgical treatments. These range from local treatments such as intrauterine devices (IUDs) to systemic preparations of gonadotrophin releasing hormone (GnRH) analogues.
The Levonorgestrel Intrauterine System (LNG-IUS) Although the intrauterine device was originally designed as a method of contraception, the addition of progesterone to the device means that it can now be used for managing menstrual disorders. Although the majority of the studies have been in women with heavy menstrual bleeding, LNG-IUS also has the potential to be used in women with endometriosis and adenomyosis. The LNG-IUS releases 20 mg levonorgestrel per day and has been shown to result in a profound reduction in menstrual blood loss in women with heavy menstrual bleeding; 20 per cent of the women using the LNG-IUS are amenorrhoeic after 1 year’s of treatment. The LNGIUS, which has contraceptive efficacy for 5 years, has
Endometriosis and Allied States also been reported to improve dysmenorrhoea. It is likely that some of the women with dysmenorrhoea may also have undiagnosed adenomyosis. A major disadvantage of the device is frequent and variable intermenstrual bleeding and spotting during the first few months of use. There are several mechanisms that could explain the role of the LNG-IUS in adenomyosis. Use of the LNG-IUS is associated with decidualisation of the endometrium followed by atrophic changes. As a result there is a marked reduction in menstrual blood loss. Levonorgestrel also acts directly on the adenomyotic deposits. Downregulation of oestrogen receptors, which are present in both glandular and stromal endometrial tissues, occurs shortly after placement of the device and persists for at least the first year of use. Local LNG levels following uterine placement of the LNG-IUS result in very high endometrial levels of LNG compared to those in serum. ENDOSALPINGIOSIS Tubal epithelium has the same origin as endometrium and has similar potentialities. Certain cases of ovarian endometriosis are thought by some authorities to be endosalpingiosis. This is because the lesions do not menstruate and because, on section, they show a tubal type of epithelium without typical endometrial stroma. Endosalpingiosis of the tube causes no symptoms other than infertility and, as a rule, is only diagnosed by microscopic examination of the excised tissue. In the ovary, too, it is only a histological diagnosis. CERVICAL ENDOMETRIOSIS In cervical endometriosis, the ectopic glands are truly endometrial and menstruate to some extent (Fig. 22.17). Their presence is explained by direct implantation, by embolism, or by metaplasia of the müllerian duct tissue. The condition is not uncommonly seen after operations which involve simultaneous injury to the cervix and spill of endometrium, for example, curettage with amputation of the cervix. Endo-metriosis of the posterior cervix may represent a spread from a lesion in the rectovaginal septum. Sometimes, however, the disease begins spontaneously in the substance of the cervix, and then extends in the same manner as cervical cancer - to the endocervix to produce polypoid masses, to the posterior fornix to produce cysts and sinuses, to the bases of the broad ligaments to surround and obstruct the ureters (Figs 22.18A and B).
Figs 22.18A and B: Endometriosis of the cervix in a woman aged 30 years and complaining of a bloodstained vaginal discharge for 18 months in addition to infertility, (A) A polypoid mass of endometriotic tissue protruding through the external os.The lesion was primarily in the posterior wall of the cervix but fungated into the cervical canal and also caused an opening into the posterior fornix. Extension into the right broad ligament produced physical signs similar to those of a Stage II or Stage III cancer of the cervix, (B) Pyelography reveals obstruction of the lower end of the right ureter by the extension of the endometriosis into the broad ligament on that side. The patient was ultimately treated by total hysterectomy and bilateral salpingo-oophorectomy because of the threat to renal function
The lesions vary. They may be merely superficial tiny blood cysts on the portio; they may be deep seated to cause distortion and fibrosis of the cervix with adhesions to the bladder base. Sometimes the cervix is grossly enlarged, completely fixed and ulcerated, the physical signs being similar to those of cancer except for the absence of friability. Cervical endometriosis may cause no symptoms. Otherwise the complaints are irregular bleeding and discharge, contact bleeding, dyspareunia and bladder irritability. If surgical treatment becomes necessary because of failure to respond to drug therapy, extracervical adhesions and spread can create great technical difficulties. It is usually impossible to dissect broad ligament endometriosis from around the ureters, and renal function is sometimes only saved by resecting the ureter or by sacrificing both ovaries. In one case it proved necessary to form an ileal conduit because of ureteric obstruction.
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23
CHAPTER
Polycystic Ovary Syndrome
Pathophysiology Puberty and PCOS Menstrual Irregularities Hirsutism Metformin Long Term Monitoring
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By far the most common, although the least understood, cause of androgen excess is polycystic ovary syndrome (PCOS), accounting for a vast majority of patients seen. PCOS affects 4 to 6 per cent of women, the full blown syndrome of hyperandrogenism, chronic anovulation and polycystic ovaries. Approximately 75 per cent of anovulatory women of any cause have polycystic ovaries and 20 to 25 per cent of women with normal ovulation demonstrate ultrasound findings typical of polycystic ovaries (Fig. 23.1). Since there are so many clinical and biochemical features in PCOS, the exact definition of PCOS can be confusing. At a recent joint European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM) consenses meeting (Rotterdam criteria), a refined definition of PCOS was agreed : namely the presence of two out of the following three criteria : 1. Oligomenorrhoea and/or anovulation 2. Hyperandrogenism (clinical and/or biochemical) 3. Polycystic ovaries, with the exclusion of other aetiologies PATHOPHYSIOLOGY (FIG. 23.2) The hyperandrogenism and anovulation that accompany PCOS may be caused by abnormalities in four endocrinologically active compartments, (a) the ovaries, (b) the adrenal glands, (c) the periphery (fat), and (d) the hypothalamus-pituitary compartment. In patients with PCOS, the ovarian compartment is the most consistent
Fig. 23.1: Normal and polycystic ovary
Polycystic Ovary Syndrome
Fig. 23.2: Pathophysiology
contributor of androgens. Dysregulation of CYP17, the androgen-forming enzyme in both the adrenals and the ovaries, may be one of the central pathogenetic mechanisms underlying hyperandrogenism in PCOS. The ovarian stroma, theca, and granulosa contribute to ovarian hyperandrogenism and are stimulated by LH. This hormone relates to ovarian androgenic activity in PCOS in a number of ways and they are : • Total and free testosterone levels correlate directly with LH levels • The ovaries are more sensitive to gonadotropic stimulation, possibly as a result of CYP17 dysregulation • Treatment with a gonadotropin-releasing hormone (GnRH) agonist effectively suppresses serum testosterone and androstenedione levels • Larger doses of a GnRH agonist are required for androgen suppression than for oestrogen suppression. The increased testosterone levels in patients with PCOS are considered ovarian in origin. The serum total testosterone levels are usually no more than twice the upper normal range (20 to 80 ng/dl). However, in ovarian hyperthecosis, values may reach 200 ng/dl or more. High intraovarian androgen concentrations inhibit follicular maturation. Although ovarian theca cells are hyperactive, the retarded follicular maturation results in inactive granulosa cells with minimal aromatase activity for conversion to oestrogens.
The adrenal compartment also plays a role in the development of PCOS. Although the hyper functioning CYP17 androgen-forming enzyme coexists in both the ovaries and the adrenal glands (30), DHEAS is increased in only about 50 per cent of patients with PCOS. The hyper responsiveness of DHEAS to stimulation with ACTH, the onset of symptoms around puberty, and the observation that 17, 20-lyase activation (one of the two CYP17 enzymes) is a key event in adrenarche have led to the concept of PCOS as an exaggerated adrenarche. The peripheral compartment, defined as the skin and the adipose tissue, manifests its contribution to the development of PCOS in several ways. • The presence and activity of 5α-reductase in the skin largely determines the presence or absence of hirsutism • Aromatase and 17β-hydroxysteroid dehydrogenase activities are increased in fat cells, and peripheral aromatisation is increased with body weight • The metabolism of oestrogens, by way of reduced 2-hydroxylation and 17α-oxidation, is decreased. The hypothalamic-pituitary compartment also participates in aspects critical to the development of PCOS. • An increase in LH pulse frequency is the result of increased GnRH pulse frequency. • This increase in LH pulse frequency typically results in elevated LH and LH-to-FSH ratio. • FSH is not increased with LH, probably because of the synergistic negative feedback of chronically elevated oestrogen levels and normal follicular inhibin. About 25 per cent of patients with PCOS exhibit elevated prolactin levels. The hyperprolactinaemia may result from abnormal oestrogen feedback to the pituitary gland. In some patients with PCOS, bromocriptine has reduced LH levels and restored ovulatory function. Genetic association and linkage analysis studies presently under way suggest an oligogenic origin for PCOS. Pathology Macroscopically, ovaries in women with PCOS are 2 to 5 times the normal size. A cross-section of the surface of the ovary discloses a white, thickened cortex with multiple cysts that are typically less than a centimeter in diameter. Microscopically, the superficial cortex is
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Jeffcoate’s Principles of Gynaecology
Fig. 23.3: Pathology
fibrotic and hypocellular and may contain prominent blood vessels. In addition to smaller atretic follicles, there is an increase in the number of follicles with luteinised theca interna. The stroma may contain luteinised stromal cells (Fig. 23.3). Clinical Features Biochemical, and Metabolic Features of PCOS Menstrual dysfunction typically occurs in PCOS, ranging from oligomenorrhoea to amenorrhoea. As a rule, patients with PCOS exhibit anovulation. Even in hyperandrogenic women with regular menstrual cycles, the rate of anovulation is about 20 per cent. Severe acne in the teenage years appears to be a common findings of PCOS. Obesity is found in over 50 per cent of patients with PCOS. The body fat is usually deposited centrally (android obesity), and a higher waist-to-hip ratio indicates an increased risk of diabetes mellitus and cardiovascular disease in later life. Insulin resistance and hyperinsulinaemia are commonly exhibited in PCOS. Insulin resistance is now recognised as a major risk factor for the development of type 2 diabetes mellitus. About one-third of obese PCOS patients have impaired glucose tolerance (IGT), and 7.5 to 10 per cent have type 2 diabetes mellitus. Abnormal lipoproteins are common in PCOS and include elevated total cholesterol, triglycerides, and low-density lipoproteins (LDL), and low levels of high-density lipoproteins (HDL) and apoprotein A-I. Other observations in women with PCOS include an increased incidence of hypertension over the years that reaches a 40 per cent incidence by perimenopause, a greater prevalence of atherosclerosis and cardiovascular disease, and an estimated sevenfold increased risk for myocardial infarction.
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Approximately 70 to 80 per cent of women with PCOS demonstrate frank elevations in circulating androgens, particularly free testosterone, and 25 to 50 per cent will have elevated levels of the adrenal androgen metabolite, DHEA-S. Prolactin levels are usually normal, although they may be slightly elevated (generally 88 cm or 35 inches) 2. Triglycerides >150 mg/dL 3. HDL-C 130/85 5. Fasting blood sugar of 110-126 mg/dL and 2-h glucose from oral glucose tolerance test of 140-199 mg/dL.
Many women with PCOS will give a history of infrequent cycles and may be about three to six menstrual periods per year. As long as these are not unduly heavy or painful no particular medical therapy may be needed. In obese women, weight loss should be the first line of treatment. In patients who succeed to lose > 5 per cent of their body weight, this alone may restore normal menstrual regularity. A reduction in body weight of 5-10 per cent will cause a 30 per cent reduction in visceral fat, which is often sufficient to restore ovulation and reduce markers of metabolic disease. Weight loss is associated with a reduction of circulating insulin and androgen levels, which can also be achieved by using insulin-sensitising drugs. Often an oral contraceptive can be a useful treatment for women with PCOS. Oral contraceptives can have the benefit of contraception, protection against endometrial cancer and improve skin manifestations of PCO such as hirsuitism and acne. Oral pills which contains 35 microgram of ethinyl oestradiol and 2 mg of cyproterone acetate may be a good option in patients who also have hyperandrogenism (hirsuitism and acne) associated with menstrual irregularity. Skin Manifestations Skin manifestations of polycystic ovarian syndrome include acne, hirsutism, alopecia and acanthosis nigricans. • Acne: Acne is seen in approximately one-third of PCOS patients. Mild acne can be treated topically with keratolytics such as azaleic acid, retinoids, or with antibacterials such as benzoyl peroxide, clindamycin 1 per cent lotion and erythromycin 2 per
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Jeffcoate’s Principles of Gynaecology cent gel. More severe forms generally require oral antibiotics such as the tetracyclines, erythromycin and trimethoprim. For severe case, isotretinoin is prescribed and produces long term remission in more than 70 per cent of patients. In PCOS anti-androgens are most effective because acne occurs as a result of overstimulation of the pilosebaceous unit by androgens. Antiandrogens that can be used are cyroterone acetate, spironolactone, flutamide and finasteride. Cyphroterone acetate can be given as a combine oral contraceptive pill (as mentioned above). This minimal dose has proven effective in almost 100 per cent of cases. In more severe cases, cyproterone acetate in dose of 10-100 mg/day can be given on the first 10 days of the combine oral contraceptive pill. It will take 3-5 months before any improvement can be seen. Acne will be cleared in 60 per cent of patients in 6 months and after 12 months, 95 per cent should be free of acne. Spironolactone an aldosterone antagonist has antiandrogen action. Flutamide a non-steroidal antiandrogen can be used for the treatment of hirsutism and acne. However because of rare reports of hepatotoxicity it is not commonly used. Finasteride acts by inhibiting 5 α reductase can be taken orally in dose of 1-5 mg/day. It does not have much side effects. When spironolactone, finasteride and flutamide is taken, contraception is advised to avoid the potential risk of feminisation of a male foetus. It is important to inform patients that clinical response takes time and patients have to be on long term maintenance treatment to avoid relapse. The longer the duration of treatment (at least in the ethinyl oestradiol/ cyproternone acetate oral contraceptive pills), the less the chance of relapse within a given periods of time. HIRSUTISM Patient may present with excess hair as their main problem (see Fig. 24.1). Hirsuitism can be treated with physical therapy such as bleaching, shaving, plucking, depilatory creams, electrolysis and laser. Bleaching of the hair with hydrogen peroxide is used to disguise pigmented facial hairs. Repeated plucking of hair is another method but may lead to permanent hair follicle matrix damage, resulting in finer, thinner hairs. Side effects include postinflammatory hyperpigmentation, folliculitis, pseudofolliculitis and, rarely scarring. Chemical depilators are usually thioglycates that disrupt the disulphide bonds of hair shaft. Electrolysis is a proven
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method of hair removal. Three forms exist, galvanic (direct current electrolysis), thermolysis (alternate current electrolysis) and the blend (galvanic electrolysis and thermolysis). Side effects include erythema, hyperpigmentation and hypopigmentation, blistering and pain. Usually several treatments are required to improve efficacy. A combined oral contraceptive pill will usually prevent new areas of excess hair from occurring but rarely are sufficient alone to cause regression of excess hair. This usually necessitates the addition of an antiandrogen therapy such as cyproterone acetate (CPA). Most women notice a regression of excess hair within four to six months but typically treatment needs to be continued for at least 1-2 years to substantially reduce hair growth and then maintenance therapy is required to keep the problem under control. Typically this is a low dose combined oral contraceptive pill. Another useful antiandrogenic treatment is spironolactone. This may be used alone or in combination with a contraceptive pill. Flutamide and Finasteride are also drugs that help reduce hirsuitism. Alopecia Some patients may present with alopecia. Treatment includes psychological support and hairstyling. Drugs such as minoxidil, cyproterone acetate, spironolactone and finasteride can be used but have limited role. Infertility Infertility is a common presenting problem in patients with polycystic ovarian syndrome. PCOS is associated with approximately 80-90 per cent of women who suffer from infertility due to anovulation. There are several methods in inducing ovulation and basically they are reduction of insulin concentrations, follicular stimulating hormone (FSH) stimulation or a reduction of luteinising hormone (LH) concentration – or a combination of these. Weight Loss The first step in ovulation induction is weight loss. Obese women (BMI>30 kg/m2) should be encouraged to lose weight. Even patients who are overweight (BMI>27 kg/ m2) are associated with a reduced chance of ovulation. Weight loss improves the endocrine profile, and the likelihood of ovulation and a healthy pregnancy. Achieving weight reduction is, however, extremely
Polycystic Ovary Syndrome difficult, particularly as the metabolic status of the patient with PCOS conspires against weight loss. Different strategies can be used to affect weight loss. Dieting and exercise should be encouraged. Clomiphene Citrate The simplest mode of ovulation induction is the use of clomiphene citrate. Patients can be started with 50 mg a day orally, for 5 days starting from day 2 to day 5 of a spontaneous or progesterone induced bleed. Serial transvaginal ultrasound is a good method of looking at the follicles. This can be done on the day 10 or 11 of her cycle and depending on the presence and size of follicle, serial scans can be done to assist patients to determine her fertile period. Another method is the use of urinary LH test. There is controversy as to, for how long can one be on clomiphene citrate and what is the maximum dose of clomiphene citrate that can be taken. If the patient did not ovulate with 50 mg of clomiphene citrate, then the dose can be increased to 100 mg. However, if the patient is ovulating with a low dose, there is no benefit in increasing the dose because high dose has other side effects, which include thickening of the cervical mucus and antioestrogenic effect on the endometrium and larger the dose more than 150 mg per day may lead to ovarian hyperstimulation and its effects like hyperstimulation syndrome and multiple pregnancy. Addition of dexamethasone at the follicular phase of the cycle has given better results. Besides clomiphene citrate the other antioestrogen that can be used is tamoxifen. Letrozole an oral aromatase inhibitor is another drug that may have potential in ovulation induction. METFORMIN Metformin improves insulin sensitivity. Metformin treatment (500 mg 8 hourly) reduces hyperinsulinaemia, basal and stimulated LH levels and free testosterone concentrations in overweight women with polycystic ovaries.
Mechanism of Action of Metformin Metformin therapy improves insulin sensitivity shown by a reduction in fasting plasma glucose and insulin concentrations. It is not effective in the absence of insulin.
a. Metformin decreases basal hepatic glucose output in patients, producing an important mechanism through which the drug lowers fasting plasma glucose concentration. b. Metformin has increased glucose disposal in most studies using hyperinsulinaemic -euglycaemic and hyperglycaemic - clamp procedures, with muscle implicated as its main site of action. c. Metformin also increases the uptake and oxidation of glucose by adipose tissue as well as lipogenesis. However the actions of metformin on peripheral tissues in vitro require high concentrations and are slow in onset. d. Metformin increases the binding of insulin to its receptors, phosphorylation and tyrosine kinase activity of insulin receptors in vivo, but these action may be due to reduced plasma glucose concentrations, since they cannot be reproduced in vitro. e. Metformin also increases translocation of the GLUT1 and GLUT-4 isoforms of glucose transporters in different types of cells, and it prevents the development of insulin resistance in cultured hepatocytes and adipocytes for long periods to high insulin concentrations. Firstly there should not be any contraindications of metformin use. The contraindications include diminished renal function, cardiac diseases, severe pulmonary diseases, liver dysfunction, pancreatitis, concomitant use of diuretics and hypersensitivity to metformin. Patients must be informed about the adverse effects, which include gastrointestinal symptoms such as diarrhoea, nausea, vomiting especially during the initial treatment periods. These symptoms are usually transient and resolve spontaneously. Gastrointestinal symptoms can be avoided if metformin is taken with meals and if the dose is increased slowly like one per day for the first week and two per day the next week and making into three per week through out the treatment period will reduce the GI problems. Probably because of the gastrointestinal side effects, some patient may have weight loss. Patients may return to ovulatory cycles. Insulin sensitising agent troglitazone appears to be of benefit to PCOS patient but it has been withdrawn from the market because of reports of death from hepatotoxicity. The other thiazolidinedione that is being investigated is rosiglitazone.
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Jeffcoate’s Principles of Gynaecology In addition to difficulty conceiving, women with PCOS are at increased risk of miscarriage following either spontaneous or assisted conception. The intriguing question is, will insulin sensitising drug prevent early pregnancy loss in PCOS? Some reports say that metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with PCOS. In patients who do not ovulate while on metformin, clomiphene citrate can be added to induce ovulation. If the above attempt fails, then there are several strategies. The first is laparoscopic ovarian drilling. The other is ovulation induction with parenteral gonadotrophic therapy. There is still debate as to which one should be done first. Laparoscopic Ovarian Drilling Laparoscopic ovarian drilling is a simple procedure whereby several punctures are made in one or both the polycystic ovaries. This technique has superseded ovarian wedge resection. The controversy is how many diathermy points and at what wattage is to be used during ovarian cautery. It is now recommended that each ovary only about five to eight points are done with 300400. The risk of ovarian diathermy is periovarian adhesions and the possibility of ovarian failure. Abdominal lavage has helped reduce these periovarian adhesions. Besides diathermy, laser can be used to perform ovarian drilling (Fig. 23.8). Gonadotrophin Therapy Gonadotrophin therapy is indicated for women with anovulatory PCOS who have been treated with
Fig. 23.8: Laparoscopic ovarian drilling (LEOs)
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antioestrogens, either if they have failed to ovulate or if they have a response to clomiphene that is likely to reduce their chance of conception (e.g. persistent hypersecretion of LH, or negative post coital tests due to the antioestrogenic effect on cervical mucus). The aim is for unifollicular development and this can be challenging. There are many protocols available but the more recent and probably the best protocol is the sequential step up, step down protocol. Patients are started with very low dose gonadotrophin (FSH) and the dose is gradually increased. When the leading follicle reaches 14 mm, the FSH threshold dose is reduced by half. This protocol appears to reduce the number of lead follicles when compared with a classic step up protocol. The aim of this low dose step up protocol is to reduce the risk of both multiple pregnancies and ovarian hyperstimulation syndrome, both of which are increased in women with PCO compared with normal ovaries. Treatment cycles can be very long, up to 28-35 days. When the leading follicle reaches 17 mm in its largest diameter, human chorionic gonadotrophin (hCG) 10,000 units is given to trigger ovulation. Some believe that there may be benefit in waiting until the follicle reaches 20 mm. Sometimes there may be sudden increase in the number of follicles. When this happen the cycle can be cancelled or converted to invitrofertilisation. In some patients, invitrofertilisation (IVF) or even intracytoplasmic sperm injection (ICSI) may be the only option for pregnancy. Patient with PCOS with tubal blockage or with husband/male partners with low sperm counts may have to undergo IVF or IVF-ICSI. Many protocols are available when performing IVF. The most commonly performed protocol for IVF is the long protocol using gonadotrophin agonist to downregulate and followed by gonadotrophin stimulation of the ovary. This protocol is ideal for patients with PCO. The reason is that PCO patients have high LH levels. This is detrimental to pregnancy rates and also causes high miscarriage rate . As such, by pituitary downregulation, serum LH is reduced. It is also important to start these patients with low dose FSH. These patients must also be monitored closely with daily ultrasound from day eight of stimulation. Collection of immature oocytes from PCOS patient is being researched. The immature oocytes can be matured in vitro and inseminated or intracytoplasmic sperm injection (ICSI) could be performed.
Polycystic Ovary Syndrome
LONG TERM MONITORING There have been suggestions in the literature that women with PCOS are at increased risk of developing a number of chronic conditions and that, consequently, their health should be monitored. Insulin resistance and resulting hyperinsulinaemia have been recognised features of PCOS for many years. It is now believed that insulin resistance is the underlying disorder of PCOS. Women with PCOS may be at increased risk of developing non-insulin dependent diabetes mellitus (NIDDM). Clinicians have been concerned for sometime about the possibility of an increase in cardiovascular disease in women with PCOS, due to the disturbance in insulin resistance and lipid profiles that often accompany this diagnosis. Lipid studies showed that there are poorer
lipid profiles among women with PCOS compared with control women. The association between exposure to unopposed oestrogens and an increased risk of endometrial cancer has been well established. Obesity has been shown consistently to be an important risk factor for endometrial cancer and is therefore likely to contribute to cancer risk in overweight women with PCOS. Diabetes and hypertension have been associated with an increased risk of endometrial cancer in some studies but, overall, the findings have been inconsistent and the relationship is not well defined. So whether PCO per se increases the risk of endometrial cancer is inconclusive but with added obesity and diabetes the risk is increased. There is also probably no association between PCOS and breast cancer. The risk of ovarian cancer in women with PCOS is not well studied.
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Hirsutism
Virilisation amd Masculinisation Diagnosis of Hyperandrogenism Late-onset Adrenal Hyperplasia
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Hirsutism is the presence of terminal (coarse) hairs in females in a male-like pattern. Excessive growth of coarse hairs of the lower forearms and lower legs alone does not constitute hirsutism, although women suffering from hirsutism may note an increase in the pigmentation and growth rate of hairs on these body areas. Hirsutism should be viewed much as polycystic ovaries, as a sign rather than a diagnosis. Most commonly hirsutism is associated with androgen excess. Although the term “idiopathic hirsutism” was coined to identify the presence of hirsutism without other identifiable cause or abnormality, this may actually reflect our limited ability to assess androgen action in the peripheral compartment or even in the circulation (Fig. 24.1). VIRILISATION AND MASCULINISATION Virilisation includes the appearance of sagittal and frontal balding, clitoromegaly, and severe hirsutism. Furthermore, if androgen levels are extremely elevated for a substantial period of time the features of virilisation may be accompanied by masculinisation of the body habitus, with atrophy of the breasts, an increase in muscle mass, a redistribution of body fat, and a deepening of the voice. Premenopausal patients with virilisation or masculinisation are almost always amenorrhoeic. In general, virilisation or masculinisation should raise the suspicion of an androgen-secreting neoplasm or classic adrenal hyperplasia. Occasionally girls suffering from severe insulin-resistance syndrome may exhibit a moderate degree of virilisation. Fig. 24.1: Hirsute women
Hirsutism Hirsutism: This is most often manifested as increased “midline hair” on the upper lip, chin, ears, cheeks, lower abdomen, back, chest, and proximal limbs. The interpretation of what constitutes excessive growth is subjective and may range from an occasional hair on the upper lip to a full male-pattern beard. The psychological implications of hirsutism must not be underestimated. Aetiology Excessive growth of sexual hair may be due to excessive production of androgens, increased sensitivity of the hair follicle to androgens, or increased conversion of weak androgens to potent androgens. Potential sources of increased androgens include the ovaries, the adrenal glands, exogenous hormones and other medications.
Physiology of Hair Growth The hair follicle and its sebaceous gland together make up the pilosebaceous unit. The hair follicle begins to develop within the first 2 months of gestation, and by birth, a child possesses all of the hair follicles he or she will ever have. Hair first appears as vellus hair, which is fine, short, and lightly pigmented. During puberty, adrenal and ovarian androgen levels rise, converting vellus hair to terminal hair, which is coarse, long, and more heavily pigmented. Hair growth is cyclic. The three phases of the cycle are (1) anagen (growth), (2) catagen (rapid involution), and (3) telogen (inactivity). The length of each hair is determined by the relative duration of anagen and telogen and varies with different locations on the body, although each hair follicle has its own growth cycle independent of adjacent hair follicles. Scalp hair has a long anagen, from 2 to 6 years, with a short telogen. The growth and development of the hair follicle may be influenced by several factors. First, the pilosebaceous unit is sensitive to the effects of sex hormones, especially androgens. During puberty, adrenal and ovarian androgen levels rise, converting testosterone to dihydrotestosterone, which can initiate growth and increase both the diameter and pigmentation of hair. Although conversion of vellus hair to terminal hair is essentially irreversible, removal of the androgenic stimulus will slow hair growth and stop the conversion of vellus to terminal hair. Conversely, oestrogens can retard the growth rate and result in finer hair with less pigmentation (Figs 24.2 and 24.3).
Genetic factors may also influence the pilosebaceous unit. Although males and females are born with equal numbers of hair follicles, racial and ethnic differences are noted in the concentration of hair follicles; Caucasians have a greater number of hair follicles than AfricanAmericans, who in turn have a greater number than Asians. Different ethnic groups within each race may also exhibit differences in hair follicle concentrations. Understanding the role of exogenous factors on the pilosebaceous unit allows one to better understand how pathologic hirsutism develops, and what factors may affect the severity of the disease process.
Androgens Androgenic hormones include those that stimulate terminal hair growth and cause voice and muscle changes, hair loss, clitoral enlargement, and reduction in breast size. The most common androgens are testosterone and androstenedione. Dehydroepiandrosterone sulfate (DHEAS) is an androgen precursor.
Fig. 24.2: Hair growth
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Jeffcoate’s Principles of Gynaecology
Fig. 24.3: Excessive hair growth
Testosterone is the most potent androgenic hormone. In women, testosterone is secreted in equal amounts from the adrenal glands and from ovaries, and these sources account for 50 per cent of the total testosterone found in the circulation. The remaining 50 per cent is produced by peripheral conversion of androstenedione, which is also secreted by the adrenal glands and ovaries. Normal circulating concentrations of testosterone in women range from 20 to 80 ng/dL. This range is far lower than the concentrations found in men, which range from 300 to 800 ng/dL. Approximately 80 per cent of testosterone is bound to sex hormone–binding globulin (SHBG). In women, approximately 19 per cent of the remaining testosterone is loosely bound to albumin, which leaves approximately 1 per cent in the free and active form. Androstenedione is produced in equal amounts by the adrenal glands and the ovaries, and most of the androstenedione secreted is converted to testosterone. Androstenedione is a less potent androgen than
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testosterone but can produce significant androgenic biological effects when present in excess amounts. Normal serum concentration of androstenedione in women ranges from 60 to 300 ng/dL. Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are androgen precursors produced almost exclusively by the adrenal glands. DHEA is metabolised quickly. As a consequence, measurement of its serum concentration does not reflect adrenal gland activity. DHEAS has a much longer half-life than DHEA, and measurement of its serum level is used to assess adrenal function. Levels of DHEAS in women vary widely, with a normal range of 38 to 338 μg/dL. Dihydrotestosterone (DHT): Testosterone is converted to DHT by 5α-reductase, an enzyme found in many androgen-sensitive tissues such as skin. DHT is a very potent androgen and is primarily responsible for androgenic effects on hair follicles. Hirsutism in women with normal androgen levels may indicate increased activity of 5α-reductase. Sex hormone–binding globulins (SHBGs). Because androgenicity is determined mainly by unbound testosterone, the circulating concentration of SHBG influences the hormonal state. Testosterone and insulin both decrease SHBG levels, whereas oestrogen and thyroid hormone increase its levels. Symptoms of hyperandrogenism may be seen in a patient with a normal total testosterone level if the level of SHBGs is decreased enough to significantly increase the free testosterone concentration.
Causes of Hyperandrogenism Five major causes of hyperandrogenism have been identified: hyperandrogenemic chronic anovulation syndrome, late-onset adrenal hyperplasia, tumors of the ovary or adrenal glands, Cushing syndrome, and idiopathic or drug-induced processes. A. Hyperandrogenemic chronic anovulation syndrome: In 1935 Stein and Leventhal described seven women who were amenorrhoeic, obese, and hirsute and who had cystic ovaries. From this initial description, the term Stein-Leventhal syndrome was used to identify other similarly affected women. Because of the cystic changes found within the ovaries of affected patients, the terms polycystic ovary syndrome (PCOS), and polycystic ovary disease (PCOD) were also used to describe these patients. However the new term is PCOS (details are in the chapter on PCOS).
Hirsutism B. Late-onset adrenal hyperplasia: The most common adrenal enzyme defect is 21-hydroxylase (21-OH) deficiency. Deficiencies of 11β-hydroxylase and 3βhydroxysteroid dehydrogenase are rarely seen. The 21-OH converts progesterone to deoxycorticosterone, or 17-OHP to deoxycortisol. A deficiency in the activity of this enzyme causes a decrease in cortisol production, which results in increased pituitary secretion of adrenocorticotropic hormone (ACTH). Increased stimulation of the adrenal gland by ACTH may result in the production of increased amounts of the deoxycortisol precursor 17-OHP. Androstenedione is produced from 17-OHP by the enzyme 17α-hydroxylase-17,20-desmolase. Androstenedione is in turn converted to testosterone by 17-ketosteroid reductase. Increased levels of 17-OHP result in increased secretion of androstenediol and testosterone from the adrenal gland. Elevated basal levels of 17-OHP and increased release of 17-OHP by the adrenal gland in response to ACTH stimulation are seen in patients with late-onset adrenal hyperplasia. In an anovulatory woman, basal levels of 17-OHP should be measured in the morning and should be less than 200 ng/dL. Levels exceeding 200 ng/dL require ACTH-stimulation testing. Patients with late-onset hyperplasia have 17-OHP levels higher than 1200 ng/dL in response to a 250 mg dose of ACTH after 1 hour. Only 3–5 per cent of hyperandrogenemic patients can be shown to have a partial deficiency in 21-OH. This percentage is approximately the same as the expected prevalence of partial 21-OH deficiency in the general population. C. Androgen-producing ovarian or adrenal tumours: Tumours of the ovary or adrenal gland that secrete androgens are quite rare. The presence of an androgen-producing tumour is suspected on the basis of clinical findings. Palpation of an adnexal mass in a patient with symptoms of hyperandrogenism or rapid onset of virilisation even in the presence of normal testosterone levels should prompt a workup for a pelvic tumour. Testosterone levels exceeding 200 ng/dL warrant concern about the presence of an ovarian or adrenal androgen-producing tumour. A concentration of DHEAS exceeding 1000 μg/dL suggests the possibility of an adrenal androgenproducing tumour. D. Cushing syndrome: Patients with Cushing syndrome usually are identified easily by specific physical findings such as moon facies, increased nuchal fat (buffalo hump), abdominal striae, facial erythema,
and truncal obesity. This syndrome may result from excess levels of ACTH from a pituitary adenoma (Cushing disease), ectopic ACTH production, adrenal overproduction of cortisol, an ovarian tumour, or, rarely, ectopic production of corticotropin-releasing hormone. Increased 24-hour urinary excretion of free cortisol and inability to suppress fasting serum or plasma cortisol levels to less than 5 μg/dL 12 hours after oral administration of 1 mg of dexamethasone are laboratory tests used to confirm the diagnosis of Cushing syndrome. Further studies including a highdose dexamethasone suppression test and radiographic imaging are required to determine the cause of the disorder. E. Idiopathic and drug-induced hirsutism: Idiopathic hirsutism is diagnosed in individuals who are hirsute but who do not demonstrate abnormal findings on the standard laboratory tests ordered to identify known causes of hirsutism. Although estimates vary depending on the study cited, it is calculated that perhaps 5–15 per cent of all hirsute patients may have idiopathic hirsutism. Because the presence of hirsutism is a biological manifestation of hyperandrogenism, the inability to identify a specific androgen that is elevated in patients with idiopathic hirsutism may simply reflect a lack of knowledge about the androgen responsible for the condition.An alternative explanation is based on the hypothesis that patients with idiopathic hirsutism demonstrate increased skin sensitivity to androgens. It has been suggested that patients with idiopathic hirsutism convert testosterone to DHT in greater quantities than normal due to increased activity of 5αreductase. Occasionally drug ingestion may be responsible for hirsutism. Danazol, a 17 α-ethinyl derivative of testosterone used for treatment of endometriosis, and methyltestosterone, used in hormone replacement therapy, are two examples of drugs that may cause iatrogenic hirsutism. DIAGNOSIS OF HYPERANDROGENISM History and Physical Examination Hyperandrogenism may be diagnosed if biological signs of androgen excess are present. These signs include excessive sexual hair growth, male pattern baldness, deepening of the voice, enlargement of the clitoris, reduction in breast size, and male muscular development. A careful breast examination should be performed to look for galactorrhoea. Symptoms of a
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Jeffcoate’s Principles of Gynaecology thyroid disorder should be investigated. Signs of hyperinsulinaemia such as presence of acanthosis nigricans, should be sought. Laboratory Evaluation Measurements of serum or plasma androgen levels may be obtained to diagnose hyperandrogenism. Testosterone and androstenedione levels are commonly measured. DHEAS levels should be determined to assess adrenal gland androgen production. Levels higher than 700 ng/ dL are considered markers for abnormal adrenal function. Levels of 17α-hydroxyprogesterone (17-OHP) should be determined. Levels of prolactin should be checked and thyroid function tests performed as well. The role of 17-OHP in the development of hyperandrogenism is described later in this chapter in the section on adrenal hyperplasia. Hyperprolactinaemia and thyroid disorders may produce hyperandrogenism directly by affecting androgen production and indirectly by creating an anovulatory state. Because hyperandrogenism and hyperinsulinaemia are often associated, a comprehensive workup includes assessment of insulin function. Diabetes mellitus may be excluded by determining that the fasting glucose level is lower than 116 mg/dL. Impaired glucose tolerance is indicated by a fasting glucose level of between 116 and 126 mg/dL. Diabetes is diagnosed by a fasting glucose level exceeding 126 mg/dL. A fasting glucose to insulin ratio of less than 4.5 is consistent with insulin resistance. Treatment Treatment of the patient with hirsutism or hyperandrogenism depends on what the cause is and whether or not pregnancy is desired. Treatment of patients with hyperandrogenemic chronic anovulation syndrome depends on their desire to conceive. If pregnancy is not desired, therapy is directed toward stopping the development of new hair growth, removing existing excessive hair growth, and regulating the menstrual cycle. Hirsutism is slow to respond to hormone suppression, and results may not be seen for up to 6 months. In addition, previously established hair patterns do not change with androgen suppression. Mechanical methods of hair removal such as shaving, waxing, depilatories, and electrolysis should also be considered. a. Oral contraceptive preparations (OCPs) diminish circulating gonadotropin levels and increase SHBG levels. Lowering of gonadotropin levels results in
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decreased ovarian androgen secretion, which produces lower circulating levels of androgens. Increasing SHBG levels result in less free testosterone available for conversion to DHT in the hair follicle. Progestins also decrease activity of 5α-reductase. Lowered total and free androgen levels in women treated with OCPs cause a reduction in the formation of new androgen-dependent hair growth and androgen-stimulated acne. All low-dose OCP preparations are believed to have similar results. However, one particular combination OCP (ethinyl oestradiol and norgestimate) has received Food and Drug Administration approval to be prescribed specifically for the treatment of acne. If therapy with OCPs is disappointing, addition of an antiandrogen such as spironolactone or finasteride is recommended. Newer OCP’s with cyperoteroneacetate and drosperinone have a good antiandrogenic effect and are helpful in managing hirsutism. Cyperoterone acetate pills are better as they have more antianderogenic activity than drosperinone (30%). b. Medroxyprogesterone acetate: If combination OCPs are contraindicated or not desired, medroxyprogesterone acetate given as 10 mg for 10–12 days every month or every other month may be used to produce regular withdrawal bleeding to reduce the risk of menorrhagia or endometrial hyperplasia or both. Patients should be cautioned that, unless contraception is used, pregnancy is possible with cyclical progestin therapy. c. Spironolactone therapy is often initiated if OCP use is not an option for treatment of hirsutism or if results from OCP therapy are not optimal. An aldosterone antagonist, spironolactone is a steroid compound originally dispensed as an antihypertensive agent. Its activity as an antiandrogen was detected after men receiving the compound developed gynaecomastia. It is now known that spironolactone inhibits the binding of DHT to its receptor and directly inhibits 5α-reductase. Spironolactone also decreases androgen synthesis by inhibiting 17α-hydroxylase and 17, 20-lyase. After 6 months of therapy at 100– 200 mg/day, reduction in the diameter of terminal hair and cessation of new terminal hair growth are observed. Doses may be tapered down to a maintenance dose of 25–50 mg/day. Because of potential adverse effects on the development of the external genitalia of male foetuses, spironolactone should be used together with contraception in sexually active women. Side effects include diuresis,
Hirsutism fatigue, dysfunctional uterine bleeding, hyperkalemia, and breast enlargement. d. Flutamide is a nonsteroidal antiandrogen that blocks the binding of androgen to its receptor. It was developed initially for the treatment of prostate disease. When administered in a dosage of 250 mg/ day, decreased terminal hair diameter and cessation of new hair growth are observed. Side effects include dry skin and a rare but severe hepatotoxicity. Liver function should be monitored. During pregnancy, flutamide may have a detrimental effect on male foetal development. Therefore, concurrent therapy with OCPs or other contraception is encouraged. e. Finasteride: An inhibitor of type II 5α-reductase, finasteride was developed initially as a treatment for prostate hypertrophy and cancer. By inhibiting 5αreductase, the drug decreases DHT activity at the hair follicle. Two types of 5α-reductase enzyme activity exist, type I and type II. Although finasteride treatment prevents new hair growth and decreases the terminal hair shaft diameter, it does not appear to completely inhibit type I 5α-reductase, which is present in skin. Finasteride is orally dosed at 5 mg daily. As of yet, no major side effects have been associated with this drug. There is potential risk during pregnancy as DHT participates in the development of male external genitalia. Adequate contraception should be used. Finasteride is also available in a lower-dose preparation, 1 mg (Propecia), and has been approved for the treatment of hair loss in men. If pregnancy is desired by individuals with hyperandrogenemic chronic anovulation syndrome, assistance with ovulation induction frequently is required. f. Cosmetic treatment of hirsutism is useful when permanant hairs have grown (Fig. 23.4).
Fig. 24.4: Cosmetic treatment of hirsutism
genemic chronic anovulation may be used in individuals with late-onset adrenal hyperplasia. OCPs or antiandrogens may be used successfully to treat hirsutism, alone or in combination with dexamethasone. Ovulationinducing drugs may also be used to treat infertility.
Androgen-producing Ovarian or Adrenal Tumours Androgen-producing ovarian or adrenal tumours usually are treated surgically. Depending on the type of tumour, additional treatment with chemotherapy or radiation therapy may be required.
Cushing Syndrome Surgery of the pituitary or adrenal gland may be required to treat Cushing’s disease or adrenal hyperplasia causing Cushing’s syndrome.
Idiopathic Hirsutism LATE-ONSET ADRENAL HYPERPLASIA Individuals diagnosed with late-onset adrenal hyperplasia may be treated by administration of glucocorticoid agents to restore ovulation. This treatment also reduces circulating androgen levels. Glucocorticoid administration is therefore appropriate therapy for infertility or hirsutism in individuals with late-onset adrenal hyperplasia. In patients with 21-OH deficiency, prednisone, 5 mg before bedtime, is used to suppress endogenous ACTH.Alternatively, the same hormone therapy indicated for individuals with hyperandro-
The same medications used to treat hirsute patients with hyperandrogenemic chronic anovulation may be used to treat patients with idiopathic hirsutism. Hyperinsulinaemia. Hyperandrogenism has been associated with hyperinsulinaemia and insulin resistance. Insulin resistance is defined as a reduced glucose response to a given amount of insulin. Acanthosis nigricans is a graybrown velvety discolouration of the skin and is a reliable indicator of insulin resistance and hyperinsulinaemia. It is often seen in obese patients with hirsutism and is usually found in the groin, neck, axilla and vulva.
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25
CHAPTER
Epithelial Abnormalities of the Genital Tract
Vulva Vagina Cervix Uterine Corpus Fallopian Tube
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The clinical and histological appearances of the various parts of the genital tract can vary considerably, although in many instances, the pathological changes are part of a continuing process. In some cases this process may be reversible, in others it may be static, while in some it may be irreversible and the possibility of malignant change increased (Figs 25.1 and 25.2A to D). VULVA The skin of the vulva is commonly the site of chronic and resistant changes, the pathogenesis of which is obscure. Comparable changes are seen in the male and affect the scrotum and phallus. They have been the source of confused literature, views and nomenclature. Pathology Epithelial abnormalities of the vulva may appear clinically as white patches or plaques (so-called leukoplakia from the Greek leuco = white and plax = a flat plate), as reddened areas, or as a combination of both. The naked eye appearances give little clue (Fig. 25.3) to the underlying histological features and yet it is these which will determine the outcome. The term leucoplakia, which is commonly used to describe the clinical appearance of the vulva should not be used as a definitive diagnosis. It is imprecise and as such may be easily misinterpreted. To avoid this ambiguous term, Professor Jeffcoate in 1966 introduced the term dystrophy into the nomenclature of benign vulvar epithelial
Fig. 25.1: A hyperkeratotic form of chronic vulvar epithelial disorder, the classical appearance of what in the past was called clinical leukoplakia. This vulva on section showed in different areas histological appearances varying from atrophic epithelium to invasive cancer (see Fig. 25.2)
Epithelial Abnormalities of the Genital Tract
Figs 25.2A to D: Varying histological appearances in different parts of the vulva shown in Fig. 25.1. (A) An atrophic but hypertrophic epithelium with subepithelial degenerative changes and hyalinisation. The picture is typical of lichen sclerosus. (B) This area shows hyperkeratosis and a thicker acanthotic epithelium, (C) A higher-power view showing epithelial cells exhibiting pleomorphism, lack of orientation and atypia; a picture of vulvar intraepithelial neoplasia (VIN). (D) This field shows changes indicative of invasive squamous carcinoma
Senile Atrophy Atrophy and shrinkage of the labia in old age, with some contracture of the introitus, is a normal physiological change attributable to withdrawal of the hormone influences of the ovary and adrenal. The histological features are those indicative of atrophy of the epidermis and dermis. Except that it causes dyspareunia, senile atrophy of the vulva, usually associated with a similar change in the vagina, is symptomless.
Lichen Sclerosus Lichen sclerosus is the commonest white lesion of the vulva. It is most often seen in postmenopausal women. It appears as white, glistening sheets with clearly defined Table 25.1: Classification of Epithelial Vulvar Diseases (ISSVD 1989) Fig. 25.3: A chronic vulvar epithelial disorder showing hyperkeratosis and contracture around the clitoris and the foreparts of the vulva. Elsewhere the skin is atrophic. Patchy ulceration from scratching is shown. This appearance might, in the past, have been described as atrophic leucoplakia, kraurosis or primary atrophy
lesions. The term dystrophy is no longer used either. The epithelial abnormalities which are characterised by epithelial growth and maturation are now grouped together under the general term ‘non-neoplastic epithelial disorders of skin and mucosa’ at the recommendation of the International Society for the Study of Vulvar Disease (ISSVD) (Table 25.1).
•
Non-neoplastic epithelial disorders of the skin and mucosa – Lichen sclerosus (formerly hypoplastic dystrophy) – Squamous cell hyperplasia (formerly hyperplastic dystrophy) – Other dermatoses • Mixed non-neoplastic and neoplastic epithelial disorders • Intraepithelial Neoplasia Squamous intraepithelial neoplasia – VIN I – VIN II – VIN III Non-squamous intraepithelial neoplasia – Paget’s disease – Tumours of melanocytes, non-invasive • Invasive tumours
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Jeffcoate’s Principles of Gynaecology margins and involves the labia, the perineum and the perianal region. The labia minora are adherent to the labia majora, the clitoris is buried and the introitus shrinks. Although the epithelium is not thickened, the naked-eye picture clearly resembles that of what is often called leukoplakia; an alleged difference is that leukoplakia does not extend around the anus. Histologically, lichen sclerosus shows not only a thin and inactive epithelium, but also hyperkeratosis, loss of elastic tissue, hyalinisation of the collagen layer and subepithelial infiltration with leucocytes. Extravasated red cells are commonly seen. Some say that lichen sclerosus can transform to intraepithelial neoplasia and this in turn to cancer; the majority, however, take the view that lichen sclerosus is never a forerunner of malignant change. Skin which shows gross injury — with excessive keratinisation and destruction of the dermis — may have reached a stage from which recovery is impossible. This change may represent a permanent degree of damage from ischaemia. Indeed, the development of male and female genital ‘leucoplakia’ to a stage of irreversibility has been studied in cases of aribo-flavinosis occurring in the tropics.
therapeutic trials indicate the following possibilities. Some of these are discussed elsewhere which should be read in conjunction with this.
Aetiology
Autoimmunisation
Familial incidence is well recognised and may involve both sexes, e.g. a father and a daughter. It has also been seen in identical and non-identical twins. The unusual character of the skin changes in nonneoplastic epithelial disorders is probably explained by environmental factors. The skin in other sites exposed to warmth and moisture tends to react in a similar way. The lesions produced by fungus and other infections between the toes and around the arms closely resemble those of clinical leucoplakia. The mouth and tongue have a similar environment and suffer similar diseases variously described as leucoplakia and lichen. Skin anywhere can be made ‘leucoplakic’ by exposure to warm wet poulticing. Finally, it has been shown that grafts of skin from an extragenital site, when used to cover the raw area after vulvectomy for epithelial disorders, often develop the disease. Even more important, abnormal skin transplanted from the vulva to an extragenital site can spontaneously return to normal. The factors that initiate changes in the vulvar skin are not known for certain, but investigations and
A weak link with autoimmunisation is established. Twenty-one per cent of patients have an autoimmune disease, 22 per cent a family history and 44 per cent have one or more antibodies in significant concentration.
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Chronic Mechanical Irritation Constant scratching and rubbing produce lichenification of the skin, the appearances of which are quite different from those of any of the epithelial abnormalities. Although a scratch habit can produce local injury and even neurodermatitis, it is not the cause of an epithelial abnormality. It is the epithelial abnormalities which makes a woman scratch, not the reverse, and the resulting lesions are easily distinguished.
Deficiency States Various external genital epithelial disorders (in males and females) can accompany states of deficiency in iron, folic acid, vitamin B12, riboflavin, and possibly other essential factors. Thus they are seen in cases of anaemia and pellagra. The deficiency can arise from errors in diet, as in the case of the elderly living alone. They can also result from malabsorption syndromes, achlorhydria and chronic diarrhoea.
Metabolic Upsets Diabetes mellitus, in addition to causing diabetic vulvitis, is sometimes associated with leucoplakic changes in the vulva.
Infection Many women with epithelial abnormalities have evidence of fungus infection elsewhere, on the hands and feet particularly (Fig. 25.4). Digital lesions are rarely caused by Tinea, more often by Candida or Corynebacterium minutissimum. Vulvar and vaginal candidiasis is often demonstrable by culture. Whenever the perianal skin is involved, an alimentary or local fungus infection should be presumed. Sometimes it is the patient’s husband who has ‘athlete’s foot’ or some other fungal lesion.
Epithelial Abnormalities of the Genital Tract described in childhood when they may or may not cause itching. These usually undergo spontaneous cure at puberty. Diagnosis
Fig. 25.4: A chronic interdigital infection (? fungus) associated with a chronic vulvar epithelial disorder. The photograph shows the space between two toes, these being held apart by the examining fingers. The skin is hyperkeratotic, sodden, cracked and peeling, producing a lesion very similar in appearance to the one on the vulva. This sort of condition is commonly found in women suffering from vulvar and perianal epithelial changes and pruritus
That candidiasis can cause hyperkeratotic skin abnormalities is well shown by the fact that Candida balanitis in the male can result in leucoplakic or lichenlike lesions on the glans penis which persist for weeks despite applications of fungicides. In the case of Tinea pedis infections, the associated vulvar epithelial disorder is more likely to represent an epidermo-phytide reaction than a spread of the fungus to the vulva. The spirochaete Borrelia burgdorferi was implicated in the causation of lichen sclerosus but this has not been fully substantiated. Symptoms Some epithelial abnormalities are symptomless and progress insidiously for many years without the patient’s knowledge. Usually they cause pruritus which is intense and persistent. When the skin cracks, or is broken by scratching, it becomes secondarily infected and painful. Dyspareunia can result from this or from contracture of the introitus. The average age at which the patient presents for treatment is 45 years. Nevertheless, vulvar epithelial disorders, and especially lichen sclerosus, are
Non-neoplastic epithelial disorders have to be distinguished from leucoderma, a condition of patchy depigmentation of otherwise normal skin. More clearly defined skin diseases such as psoriasis have also to be excluded. The first step in the investigation of a non-neoplastic epithelial disorder is to take portions of affected skin from several sites for histological examination. This is primarily to exclude vulvar intraepithelial neoplasia (VIN), invasive cancer and epithelial activity which carry a threat of cancer in the future. It may also sometimes distinguish the vulvar lesion from a recognised skin disease such as psoriasis. Biopsy is essential in all longstanding lesions, irrespective of their appearance. It is best taken with the 4 or 6 mm Keyes punch under local anaesthesia. Knife biopsies tend to be tangential and often do not reach the deeper layers. The second step is to attempt to determine a possible underlying cause of the abnormality; the more carefully this is done the more likely it is to be successful. Attention should be paid to the points already mentioned under aetiology while taking the history. Full physical examination should include a search for extragenital lesions, especially in the mouth and ears, and on the hands and feet. The appearance of the vulva itself is not particularly diagnostic. The skin may be white or red or both in patches; it may be thin or thick. Special investigations to be performed in all cases are: repeated examination of vaginal and vulvar swabs for Trichomonas vaginalis and Candida albicans; examination of the blood; tests for achlorhydria; glucose tolerance test; tests for folate and vitamin B12 deficiencies; and skin sensitivity tests. Treatment Treatment depends on the cause and on whether biopsy reveals VIN or epithelial atypia which carries a threat of cancer.
General Treatment It is important to prevent the patient scratching and to ensure sleep by giving sedatives, if necessary. During
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Jeffcoate’s Principles of Gynaecology the day, cold cream applications or washing with 1 per cent sodium bicarbonate can provide temporary comfort. The vulva should be kept cool and free from sweat by the wearing of loose and light cotton underclothing. Nylon and similar materials should be banned. At night, a free circulation of air to the vulva should be ensured by supporting the bed clothes with a cradle.
Local Analgesia
Medical Treatment of the Cause
Division of Cutaneous Nerves; Nerve Block
Treatment is directed primarily to eliminating any aetiological factor discovered. Anaemia is corrected, folic acid or vitamin B12 administered if a deficiency is present, glycosuria controlled, candidiasis eradicated and proven antigens avoided. Fungus infections of the feet of either the patient or her husband are treated with fungicides. When a possible cause is not found, as happens in at least 50 per cent of cases, empirical treatment becomes necessary.
Division of all the cutaneous nerves by a circular incision around the vulva gives relief; the effect usually only lasts for 3-6 months but occasionally, and perhaps because it breaks a scratch habit, it is permanent. Multiple injections of absolute alcohol, presumably to block or damage cutaneous nerves, have been advocated but are rarely effective in the long term.
Empirical Measures
Corticosteroids Clobetasol propionate 0.05 per cent ointment is the definitive treatment of lichen sclerosus. Its safety and efficacy have been documented in a dose not exceeding 30 g over a period of 3 months. The skin immune response and reversal of squamous hyperplasia has been demonstrated in biopsies of treated patients. Monitoring is important. Response is usually sustained. A combination of steroid with antibacterial agents may be required in cases with secondary infection. Treatment may need to be continued for 6-12 months in some patients. After completion of therapy, an emollient cream may be applied regularly.
Oestrogens and Testosterone Oestrogen therapy only helps to clear up secondary infection of the vulva in postmenopausal women. Testosterone propionate 2 per cent in petrolatum was considered standard treatment for lichen sclerosus, applied twice daily for 3-6 weeks and then once or twice a week. However, nearly 70 per cent of patients have been found to discontinue therapy because of lack of response as compared to only 10 per cent with clobetasol propionate. Even when a response does occur, it is not sustained if therapy is discontinued. Overdosage can result in virilisation.
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Anaesthetic ointments containing procaine or similar agents should never be used; they give little symptomatic relief and very often produce severe local reactions. The local injection of anaesthetic solutions is also best avoided; it involves a high risk of abscess formation and does not usually improve symptoms.
Vitamins Large doses of vitamin A or riboflavin can be given orally or by injection. The results are unsatisfactory except when a deficiency state is proven. Atretin and etretinate have been effective orally. However, they have significant side-effects.
Fungicides Whenever a lesion is associated with evidence of an extragenital fungus infection, applications of fungicidal ointments to the vulva are worth trying and can have good results.
Other Local Applications When the skin is hard and tends to crack, emollient applications to the vulva help. Examples are crude cod liver oil, an emulsion of equal parts of lanoline and arachis oil and a cream made up of zinc oxide (40 parts) and olive oil (60 parts). Whatever treatment is applied, every patient suffering from an epithelial disorder requires continuous supervision for an indefinite period. If the lesion persists or recurs, further biopsies at intervals are required to exclude the possibility of changes in epithelial activity, if not cancer (Figs 25.5A and B). One of the remarkable things revealed by late followup is that sometimes when a patient, after years of misery, abandons all hope of cure and all treatment, a longstanding epithelial disorder disappears spontaneously.
Epithelial Abnormalities of the Genital Tract
Figs 25.5A and B: Moderate vulvar intraepithelial neoplasia (VIN II). (A) There is a layer of keratin on the surface and the underlying epithelium shows a disturbance of normal stratification, which is most severe in the basal two-thirds of the epithelium, (B) A high-power photomicrograph shows mitotic figures as well as hyperchromatic nuclei and pleomorphism. Hence the necessity for mandatory multiple biopsies when a vulvar epithelial disorder is present
Vulvectomy When a non-neoplastic epithelial disorder is localised, local excision or partial vulvectomy may be the best method of biopsy. Otherwise vulvectomy should be reserved mainly for those cases in which atypical epithelial activity is found histologically (Fig. 25.5). In these cases it is clearly indicated and need not be accompanied by lymphadenectomy. Whenever vulvectomy is performed, it should be followed by treatment of any aetiological factors revealed by investigation, and by regular supervision of the patient for an indefinite period. Invasive carcinoma can supervene despite vulvectomy. If there is no threat of cancer, empirical vulvectomy should be avoided. It is mutilating and gives poor results. The disorder recurs sooner or later in 50 per cent of cases treated by vulvectomy, and in skin which, had it been left in its normal site (well outside the labia), would not have become affected (Fig. 43.4). There is no role of vulvectomy in children with lichen sclerosus. Vulvar and Oral Epithelial Abnormalities Traditional leucoplakia of the vulva is often regarded as being a disease different from leucoplakia of the buccal
cavity and tongue. Clinical leucoplakia of the external genitalia is rarely seen in conjunction with oral leucoplakia in the same individual, male or female. Nevertheless, there are some extraordinary bonds between these two areas of the body. Both are erogenous zones; both are common sites for fungal infection; both are subject to recurrent (cyclical) ulceration; and both show epithelial changes in deficiency states such as anaemia and ariboflavinosis. Vulvar Intraepithelial Neoplasia
Incidence and Aetiology Vulvar intraepithelial neoplasia (VIN) is now being discovered with increasing frequency and this may be the result of the modern practice of submitting nonneoplastic epithelial disorders to biopsy, which is the means of bringing most cases to light. The increase appears to be among young, rather than old, women. In 40 per cent of reported cases the patients were less than 40 years of age. It is suggested that the modern involvement of the young is related to their acquiring sexually transmitted virus and other infections. In particular, the human papillomavirus is postulated as a causal agent. It is also seen more commonly in smokers.
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Pathology The diagnosis is essentially a histological one and the microscopic patterns fall into two main groups, these in the past having been regarded as separate diseases (Table 25.1).
Squamous Intraepithelial Neoplasia The pattern here is similar to that of dysplasia or in situ squamous cell cancer in any site. Depending on whether the lesion is VIN I (mild dysplasia), VIN II (moderate dysplasia) or VIN III (severe dysplasia or carcinoma in situ), changes are seen predominantly in the lower onethird, two-third or the whole thickness of the epidermis, respectively. The cells have malignant characteristics, showing pleomorphism, large irregular and hyperchromatic nuclei and mitotic activity. There is a disorderly arrangement of the cells with loss of stratification.
Hyperkeratosis and parakeratosis are variable findings (Figs 25.6A to C and 25.7A and B). An essential feature is failure of the cancer cells to penetrate the basement membrane. As in the case of the same condition in the cervix, a stage of microinvasion is described but is more closely related in behaviour to an invasive carcinoma. The term ‘Bowen’s disease’ has often been applied to some cases of intraepithelial neoplasia when large bloated ‘Bowen’s cells’ and sometimes ‘corps ronds’appear amongst the ordinary cancer cells. The former are large cells showing perinuclear vacuolation and nuclear fragmentation; the latter have small hyperchromatic nuclei and a cytoplasm which stains deeply with eosin. These features, also sometimes found in skin cancers in other sites, were once thought to denote a specific disease. It is now recognised that the large cells represent nothing more than malignant epithelial cells which have undergone degenerative change and nuclear
Figs 25.6A to C: Vulvar intraepithelial neoplasia (VIN III) of the vulva in a woman aged 35 years who had had pruritus for 5 years. Originally she was treated for proven Trichomonas and Candida infection with improvement in symptoms; 3½ years later she returned and the vulva was then rather pale and thickened with one hyperkeratotic plaque which lies medial to the examiner’s thumb and condylomatous areas in (A), (B) Photomicrograph of a biopsy specimen showing the junction of hyperkeratotic epithelium and a focus of Bowenoid VIN III. The epithelium shows loss of stratification, and pleomorphic cells with hyperchromatic nuclei, mitotic figures and koilocytes. (C) A higher-power view to emphasize these features. Subsequent simple vulvectomy revealed multiple abnormal foci scattered throughout the vulva on both sides, even in completely normal-looking skin
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Epithelial Abnormalities of the Genital Tract
Figs 25.7A and B: Vulvar and cervical intraepithelial neoplasia in the same woman who was aged 47 years. She had no complaints but had a routine cervical smear when she attended a special clinic and was also noted to have one small pale area on one labium. When the diagnosis was established she was treated by cone excision of the cervix and simple vulvectomy. (A) VIN III: One of the many separate foci found throughout the vulva, (B) CIN III: The entire thickness of the epithelium is occupied by darkly staining, hyperchromatic cells with high nucleocytoplasmic ratios and there is no normal stratification. These are separate lesions but they commonly coexist. Intraepithelial or invasive carcinoma of the cervix or vagina or both is found in 20-25 per cent of cases of VIN, reflecting a field change
clumping, and there is therefore no need to continue using the term ‘Bowen’s disease’ of the vulva. It is a pattern of VIN found in association with human papillomavirus infection, usually type 16. VIN occurs by itself but is sometimes a histological finding alongside invasive carcinoma in about 20-30 per cent of cases. VIN III can progress to invasive cancer in less than eight years, the incidence being significantly higher in untreated than in treated cases (87.5% versus 3.8%).
Fig. 25.8: Paget’s disease of the vulva. The section is from an extensive red lesion affecting the introitus of a multiparous woman. The lesion, which is an epithelial adenocarcinoma, recurred after repeated excision during 10 years without ever becoming invasive. In contrast to Paget’ s disease of the breast, where an underlying carcinoma is the rule, in only about 30 per cent of cases of vulvar Paget’s disease is an underlying invasive neoplasm identified. Large Paget’s cells with clear cytoplasm which were positive for mucin can be seen within the epidermis
secreted by apocrine glands (Fig. 25.8). This shows up with special stains such as PAS. It was once believed that Paget’s disease of the vulva was similar to Paget’s disease of the nipple in that the special cells are migrants to the epidermis from an underlying or neighbouring adenocarcinoma. Only 30-40 per cent of cases of Paget’s disease of the vulva are associated with an adnexal carcinoma. The remainder are intraepithelial neoplasms and the behaviour and treatment of the two groups are therefore different. Paget’s disease tends to recur, not necessarily because it is multifocal but because it is an in situ change and because excision is difficult as the edges are ill-defined and the cells extend beyond the apparent clinical limits. So Paget’s disease of the vulva is nothing more than a variant of vulvar intraepithelial neoplasia.
Paget’s Disease Paget’s disease of the vulva is a non-squamous intraepithelial neoplasia associated with proliferation of atypical glandular cells of the apocrine type. In this condition the epidermis contains large secretory cells arranged singly or in groups, often called ‘Paget’s cells’. Their nuclei are polymorphic and hyper-chromatic; their cytoplasm is pale and vacuolated and contains a mucopolysaccharide (mucin) similar to that normally
Clinical Features VIN occurs at any age. It is not infrequently associated with a past or present history of intraepithelial neoplasia or invasive cancer, of the vagina or cervix or both. This must reflect widespread epithelial unrest affecting the whole lower genital tract (‘field change’). In keeping with this idea is the fact that the lesions on the vulva are often multifocal.
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Jeffcoate’s Principles of Gynaecology The patient may complain of pruritus vulvae or slight soreness; she is sometimes aware of a change in colour or consistency of the skin. VIN I is never visible macroscopically while higher grades are nearly always visible. Characteristically, the lesion appears as a bright scarlet, slightly raised, velvety plaque with clearly defined serpiginous edges. This can be a feature of any of the histological types of the disease but is especially likely with Paget’s disease. It explains why carcinoma in situ was sometimes called erythroplasia of the vulva and in practice, care is necessary to distinguish the disease from psoriasis. Although this is the classical picture, the affected skin can look completely normal, brownish, thickened or white and hyperkeratotic (Fig. 25.6). VIN can arise in any part of the vulva but is mostly found around the introitus. From there it may spread internally to involve the urethral meatus and laterally to the skin of the groins. It is also not uncommon to find the perineal and perianal areas implicated, without much in the way of macroscopic skin change. Diagnosis The diagnosis can only be made by histological examination of excised tissue. Cytology for diagnostic or follow-up purposes is generally useless; the cancer cells are not desquamated and are rarely picked up in scrapings of the skin. Areas likely to be affected may be identified by their staining reaction to nuclear stains, specifically 1 per cent toluidine blue and tetracycline fluorescence, which make areas of increased metabolic activity show up. However, the test is of limited value, being non-specific and unreliable. Colposcopic assessment is of limited value as a screening procedure in demarcating areas before conservative surgery. If there are multicentric lesions, a skinning vulvectomy with or without skin grafting can be done. In this procedure, the involved skin is excised leaving the subcutaneous tissue intact. A split-thickness skin graft taken from the buttocks or from the inner aspect of the thigh may be substituted in its place. This procedure gives excellent cosmetic and functional results. Recurrences of VIN usually occur in the remaining areas of original vulvar skin and are seldom seen in the grafted area. Results are satisfactory in most patients, even without grafting. The skinning vulvectomy and skin graft procedure requires bed rest for a week, with its consequent potential
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for morbidity. In the elderly patient, therefore, a simple vulvectomy may be preferred. This also takes into account the likelihood of multiple microscopic foci, but does not guarantee against future recurrence. Destructive therapy using electrocautery, cryotherapy and laser ablation has been tried. This treatment leaves behind a painful ulcer which may take up to three months to heal. The best results are with the CO2 laser but great expertise is required to control the depth of destruction. This depth should be 2 cm, or there is evidence of extrauterine disease, pelvic lymph node sampling of even clinically negative lymph nodes is mandatory. Suspicious pelvic and para-aortic lymph nodes should be removed in all cases and sent for histopathological evaluation. The specimen is sent for histopathological examination and, if possible, for measurement of steroid hormone receptors and flow cytometry. Laparoscopically assisted vaginal hysterectomy (LAVH) with bilateral salpingo-oophorectomy and laparoscopic retroperitoneal lymph node sampling is being done at certain centres, which reduces the hospital stay and the overall complication rate, although the possibility of serious complications, e.g. ureteral injury, small bowel herniation through 12 mm ports, etc. may be increased. Radical hysterectomy has no place in the management of early endometrial cancer. For Stage II tumours, radical hysterectomy with bilateral salpingooophorectomy and pelvic lymphadenectomy has long been the standard practice but it now appears that the standard surgical approach as described for Stage I disease, followed by appropriate pelvic or extended field external and intravaginal irradiation can give equally good results. Similarly, for Stage III growths, the goal of surgery is total abdominal hysterectomy and bilateral salpingooophorectomy with selective lymphadenectomy, biopsies of suspicious areas, omental biopsy and debulking of tumour, followed by radiotherapy. Treatment has to be individualised in those with Stage IV tumours. Usually a combination of surgery, radiotherapy, hormonal therapy or chemotherapy is required. The objective is usually to control pelvic disease and offer palliation, but selected cases with central disease limited to the bladder or rectum may be suitable for pelvic exenteration.
Surgery alone will suffice for patients with Stage IA Gl or G2 tumours in whom there is no invasion of the lymph-vascular space, cervix or isthmus, peritoneal cytology is negative and there is no evidence of metastasis. The 5-year survival rate in these patients is 100 per cent. All other patients require some form of adjuvant radiotherapy. Surgery and Radiotherapy Postoperative vaginal vault irradiation is recom-mended in the following cases: Stage IA G3 tumours; Stage IB Gl and G2 tumours. By this method the incidence of vaginal vault recurrence can be reduced significantly from 15 per cent to less than 2 per cent, and the 5-year survival rate can be correspondingly increased from 75 per cent to 90 per cent. Patients with Stage IB G3, and Stage IIA Gl and G2 tumours are given either pelvic irradiation or vaginal cuff irradiation. For those with tumours in Stage 1C (all grades), Stage IIA G3, Stage IIB (all grades), Stage IIIA (all grades) or with lymph-vascular space invasion, external pelvic irradiation of 50 Gy is recommended in addition to vaginal irradiation. This may also be suitable for selected Stage IVA patients. All patients with positive pelvic lymph nodes receive external pelvic irradiation. The significance of positive peritoneal cytology is unclear. Although this places the tumour in Stage IIIA, the management of this group of patients is not clearly defined. Progestins and P32 therapy have both been tried but the benefits have not yet been clearly demonstrable. Patients with documented para-aortic and common iliac node involvement are additionally given extended field irradiation of 45 Gy. Patients with Stage IV disease with intraperitoneal spread may require whole abdomen irradiation along with systemic chemotherapy (see below). Whole abdomen irradiation (30 Gy) is also sometimes given in cases of papillary serous tumours which are likely to have upper abdominal spread. Radiotherapy Alone This is used in 5-15 per cent of patients who are unfit for operative treatment or when the growth is too advanced for surgery. Various techniques are employed but the main principle is to give a larger dose to the uterine cavity than in cervical cancer. Vaginal vault applications are sometimes used as well and the outer areas of the pelvis
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Jeffcoate’s Principles of Gynaecology can be covered by conventional external beam therapy. The total dose is similar to that used for carcinoma of the cervix. The results of radiotherapy alone are generally inferior to those obtained with other methods and most centres can obtain no more than 45-60 per cent (65% for Stage I) apparent 5-year cure rates. It has to be accepted that the patients are preselected as being advanced cases or poor surgical risks. Chemotherapy and Hormone Therapy Disseminated metastatic disease found either at the initial operation or as a recurrence requires systemic therapy. The efficiency of progestogen therapy in producing objective responses has been reported in approximately 30 per cent of patients with metastatic endometrial carcinoma. The ideal patient for hormone therapy is one whose metastatic disease recurs a few years after the original treatment, particularly when the lesion is well-differentiated. If facilities are available for assessing progesterone and oestrogen receptors, such an assessment will provide a guide as to the most appropriate cytotoxic therapy. We now use progestins in all patients with recurrent endometrial cancer. No difference has been observed with the type, dose or route of administration. Medroxy-progesterone acetate 50-100 mg orally three times daily or megestrol acetate 80 mg twice daily are administered for two to three months. The anti-oestrogen tamoxifen, 20 mg twice daily, may be of benefit when the tumour is oestrogen receptorpositive, even if progestogen therapy has failed. Tamoxifen increases the progestogen receptors in the uterus. The combined use of tamoxifen and progestins does not have any greater benefit than progestins alone. There is considerable debate as to whether progestogen therapy should be given to all cases. If peritoneal washings are positive and there is no other evidence of spread, it may be used but there is no obvious benefit when progestins are used as primary therapy. Chemotherapy in the form of cyclophosphamide, actinomycin D and cisplatin has not been as effective as anticipated. Partial response rates of 38 to 76 per cent are reported, with a median survival of less than 12 months. Treatment of Vaginal Metastases If nodules of growth arise in the vagina after operation, they are treated by irradiation (if this has not been used
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previously) or by local excision, and the results can be surprisingly good; some women live several years in comfort thereafter. A few patients may have exenterations performed if the recurrence is localised.
Results and Follow-up Overall 5-year survival rates for those with growths in Stages I and IIA vary from 83 to 96 per cent, depending on the grade of the tumour. Those with Grade 3 tumours in Stages 1C and IIA have a survival rate of about 73 and 60 per cent, respectively. For those in Stages IIB and IIIA, survival rates vary between 55 and 77 per cent, depending on the grade. It decreases to 42 to 59 per cent in Stage IIIC and 18 to 35 per cent in Stage IV. Follow-up is best done by history and examina-tion – 3-monthly for the first 2 years and 6-monthly thereafter. Nearly 80 per cent of recurrences can be detected by clinical methods. Chest X-ray done every 6-12 months can detect asymptomatic recurrences. CA-125 is useful as a marker but less so in the case of very early disease. Intravenous pyelography and CT scans are not indicated for routine follow-up. Choriocarcinoma Discussed elsewhere. Sarcoma of the Uterus Sarcomatous growths occur in the body of the uterus and in the cervix; both sites can be considered together. Uterine sarcomas are rare and represent not more than 1 per cent of malignant growths of the female genitalia, constituting about 2 to 6 per cent of uterine malignancies.
Pathology Sarcoma can arise from the stroma of the endo-metrium or from the connective tissue and muscle elements of the myometrium and cervix. They may be homologous or heterologous. Among the homologous are pure forms like the leiomyosarcoma and stromal sarcoma, or the mixed, i.e. carcinosarcoma. Among the heterologous are the pure forms like rhabdomyosarcoma, chondrosarcoma, osteosarcoma and liposarcoma, or the mixed, i.e. mixed mesodermal sarcoma or mixed müllerian tumour. Mixed müllerian tumours make up about 40 to 45 per cent, leiomyosarcomas about 40 per cent, endometrial
Tumours of the Corpus Uteri stromal sarcomas 15 per cent and other sarcomas about 5 per cent of uterine sarcomas. Endometrial stromal tumours include the benign endometrial stromal nodule and the endometrial stromal sarcoma. Two forms of endometrial stromal sarcoma are now recognised, low-grade and high-grade. Low-grade Stromal Sarcoma (Endolymphatic Stromal Myosis) This interesting but rare myometrial tumour is composed of endometrial stroma. There is some dispute as to whether it is an invasion from the endometrium or whether it arises due to metaplasia of the myometrial cells. It is undoubtedly a stromal cell tumour showing a mass of round and oval cells with 10 mitotic figures per 10 hpf. The 5year survival rate is approximately 25 per cent. Leiomyosarcoma These occur at a younger age than other uterine sarcomas, usually between 43 and 53 years. Sarco-matous change is reported to occur in 0.13-0.8 per cent of benign uterine leiomyomas. Up to 4 per cent of patients may have received pelvic radiotherapy previously. Twothirds of leiomyosarcomas are intramural, poorly circumscribed and cannot be shelled from the surrounding myometrium. The cut surface is bulging,
soft, fleshy, focally necrotic and haemorrhagic. The tumour loses its whorled appearance. Histologically, interlacing bundles of spindle cells with fibrillar cytoplasm, irregular and hyperchromatic nuclei and multiple mitotic figures are seen. The presence of coagulative tumour necrosis and pleomorphism are the most important diagnostic features specially when the diameter of the tumour is more than 5 cms. Previously it was considered that tumours with >10 mitotic figures per 10 hpf are associated with a frankly malignant behaviour and survival rate of about 15 per cent versus 98 per cent if there are