Dewhurst’s Practical Paediatric and Adolescent Gynaecology. [2nd ed.] 9781483162911, 1483162915

Table of contents :
Front Cover
Dewhurst's Practical Paediatric and Adolescent Gynaecology
Copyright Page
Table of Contents
Foreword
Preface
Chapter 1. Patterns of childhood and adolescent gynaecology
Health problems of adolescence
References
Chapter 2. Intersexuality
Sexual differentiation
Clinical features
Management of the parents
Presentation in the older child
The XY female
Androgen insensitivity
Surgical considerations
Transvestism and trans-sexualism
References
Surgical considerations
Chapter 3. Malformations of the genital tract
Abnormalities presenting in the newborn period. Abnormalities presenting in the pubertai patientReferences
Chapter 4. Vulvovaginitis and other vulval lesions
Vulvovaginitis
Vulvitis
Other vulval disorders
References
Chapter 5. Normal puberty
Physical changes of puberty
Characteristics of early menstrual cycles
Endocrine changes at puberty
References
Chapter 6. Precocious puberty
Aetiology
Clinical features
Investigation
Management
Isolated manifestations of precocious sexual development
References
Chapter 7. Delayed puberty
Clinical investigation
Secondary sexual development otherwise good. Secondary sexual development poor or absent Hypothalamic/pituitary lesion
Heterosexual puberty changes
References
Chapter 8. Menstrual disorders in the adolescent
Excessive menstrual bleeding
Clinical approach
Dysmenorrhoea
Secondary amenorrhoea
References
Chapter 9. Breast lesions and abnormalities of stature
Breast lesions
Stature and the gynaecologist
References
Chapter 10. Hirsutism and virilism
Hirsutism
Virilism
References
Chapter 11. Tumours of the genital tract
Vulval tumours
Tumours of the vagina and cervix
Ovarian tumours
References. Chapter 12. Sexual activity in the adolescent Sexual activity
Contraception for adolescents
Abortion in the adolescent
Pregnancy in the adolescent
Care of the babies of teenage mothers
Longer term effects of pregnancy in the teenager
The fathers of adolescent pregnancies
The parents of girls who have teenage pregnancies
Sexually transmitted diseases in adolescents
Sexual offences and the adolescent
Conclusions
References
Index.

Citation preview

Dewhurst's Practical Paediatric and Adolescent Gynaecology Second edition

Dewhurst's Practical Paediatric and Adolescent Gynaecology Second edition D. Keith Edmonds MB ChB, MRCOG, FRACOG Consultant Obstetrician and Gynaecologist, Queen Charlotte's and Chelsea Hospital, London

Butterworths London

Boston

Singapore

Sydney

Toronto

Wellington

All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, including photocopying and recording, without the written permission of the copyright holder, application for which should be addressed to the Publishers, or in accordance with the provisions of the Copyright Act 1956 (as amended), or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 7 Ridgemount Street, London WC1E 7AE, England. Such written permission must also be obtained before any part of this publication is stored in a retrieval system of any nature. Any person who does any unauthorized act in relation to this publication may be liable to criminal prosecution and civil claims for damages. This book is sold subject to the Standard Conditions of Sale of Net Books and may not be re-sold in the UK below the net price given by the Publishers in their current price list. First published by Marcel Dekker Inc., 1980 Second edition, 1989 © Butterworth & Co (Publishers) Ltd, 1989 British Library Cataloguing in Publication Data Edmonds, D. Keith (Douglas Keith) Dewhurst's practical paediatric and adolescent gynaecology — 2nd ed. 1. Young persons. Reproductive system. Disorders I. Title II. Dewhurst, Sir, C. John (Christopher John), 1920- Practical pediatric and adolescent gynaecology 618.1 ISBN 0-407-01520-5 Library of Congress Cataloging in Publication Data Dewhurst, John, Sir, 1920[Practical pediatric and adolescent gynecology] Dewhurst's practical paediatric and adolescent gynaecology. — 2nd ed./Keith Edmonds p. cm. Rev. ed. of: Practical pediatric and adolescent gynecology/John Dewhurst. cl980. Includes bibliographies and index. ISBN 0-407-01520-5 : 1. Pediatric gynecology. I. Edmonds, Keith. II. Title. III. Title: Practical paediatric and adolescent gynaecology. [DNLM: 1. Genital Diseases, Female - in adolescence. 2. Genital Diseases, Female - in infancy & childhood. WS 360 D519p] RJ478.D48 1988 618.92'098^dcl9

Typeset by TecSet Ltd, Wallington, Surrey Printed in Great Britain at the University Press, Cambridge

Foreword

The subject of paediatric and adolescent gynaecology is not new, children and adolescents having suffered from disorders of the genital tract since the human race began. But awareness of the importance of this subject is new. Twenty-five years ago, when I published my first book on the subject, only one other had ever been produced. Now with interest in these matters widespread there are several of which - in the words of the great C. Northcote Parkinson - 'this is the latest and best'! Every book should reflect its author and his experience, and in this respect it gives me the greatest possible pleasure to hand on the rewriting and updating of Practical Pediatric and Adolescent Gynecology, which I first published in 1981, to my

friend, colleague and - I am proud to say - pupil, Keith Edmonds. He has taken the subject from the point at which I left it on my retirement in 1985 and has further developed and refined it by the application of his admirable surgical skills and intuitive understanding of his young patients. If, as I believe, the reward of a teacher is the success of his pupil I have been amply rewarded. The author of this book is an accomplished paediatric and adolescent gynaecologist whose text reveals so well his knowledge and understanding of his subject, and his ability to pass on these things to his readers. His book merits the greatest success. I welcome it wholeheartedly. SIR JOHN DEWHURST

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Preface

The evolution of a special interest subject in paediatric and adolescent gynaecology has taken nearly 50 years. The first gynaecology ward for children and teenagers was set up in Prague in 1940 by Professor Peter, and for 20 years very little progress was made. It was not until professor Sir John Dewhurst published his first book in 1963, Gynaecological Disorders of Infants and Children, that the specialty was really established. The interest then spread to the USA, where Professor John Huffman in Chicago and Professor Vincent Capraro in New York followed the lead of Dewhurst, culminating in the publishing of The Gynecology of Childhood and Adolescence by all three in 1968, and a second edition in 1981. Thus, Jack Dewhurst may be looked upon as the doyen of this subject, and is internationally renowned for his contributions. But beyond all this is the overriding ability Jack Dewhurst possessed as a teacher. In 1980 Practical Pediatric and Adolescent Gynecology was published, which rapidly became

the standard reference textbook for management of these problems throughout the world. It is fitting, therefore, that this new edition of a practical guide to management should bear his name. The rapid changes and advances in this subject have led to the updating of this book and the considerable expansion of the reference section at the end of each chapter. The book remains, however, one which is aimed at offering real practical help for the clinician in the management of these disorders of childhood and adolescence. I must thank Jack Dewhurst for his encouragement and help which have led to this publication; to Lesley Brooke Barnett who typed the manuscript, and to Rosalind Brodie for preparing the illustrations. I hope this book is of value to others and reflects the teaching I have received from Jack Dewhurst in such a way that they and their patients can equally feel the benefit his contributions have made to medicine. D. KEITH EDMONDS

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Contents

1 2 3 4 5 6 7 8 9 10 11 12

Foreword Preface Patterns of childhood and adolescent gynaecology Intersexuality Malformations of the genital tract Vulvovaginitis and other vulval lesions Normal puberty Precocious puberty Delayed puberty Menstrual disorders in the adolescent Breast lesions and abnormalities of stature Hirsutism and virilism Tumours of the genital tract Sexual activity in the adolescent Index

V

vii 1 6 27 46 56 63 71 86 95 102 112 130 144

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1 Patterns of childhood and adolescent gynaecology

Gynaecological disorders during childhood and adolescence tend to occur in groups and at times which reflect the changing endocrine background of this period in life. During the first few weeks of life the newborn female enjoys a degree of passive oestrogen stimulation from her mother across the placenta. The effects of this may be seen for perhaps a month, rarely longer, and they are not abnormalities but physiological manifestations of hormone activity. The most obvious is breast growth which occurs to a small extent in nearly all children, male and female, born at term (Figure 1.1); sometimes the breast enlargement is more marked and there may be a small amount of fluid discharge - witch's milk from the nipple. Such breast enlargement requires no treatment. Indeed, it should be left strictly alone or else bruising of the breast tissue and infection may occur making the situation worse. During the newborn period most females also display some vaginal discharge (Figure 1.2). At this time the vagina is under the influence of maternal oestrogen and is lined by squamous epithelium many layers thick, the cells being rich in glycogen (see Figure 4.1); the discharge which occurs is acidic in reaction and is the same as that which characterizes the reproductive period of life. Sometimes the discharge may be streaked with blood as the infant's endometrium, which has also responded somewhat to the passive hormone stimulation, breaks down in the same manner as it does during the menstrual period. Perhaps 10% or more of infant females will lose some blood in this way. At this time the vulva shows a variety of appearances, some of which are illustrated in Figures 1.2-1.4. Some oedema, congestion, and discharge can generally be noticed while the hymen is evident

Figure 1.1 Breast enlargement in a six-day-old child. (From Dewhurst, 1963) as a prominent annular swollen structure. Remarkable changes occur quickly, however, as the effects of this passive hormone stimulation wear off (Figure 1.2). Premature babies do not show such pronounced features as mature ones; breast enlargement, for example, is less marked, probably reflecting the poor response from the imperfectly developed breast tissue. A feature of prematurity in the vulva

2

Patterns of childhood and adolescent gynaecology

(b) Figure 1.2 Alterations in the external genital appearances of two female infants. In each case the upper photograph is taken on the second day of life, and the lower at age 3 months. Note the amount of vaginal discharge at the vulva in (a) and the pronounced vulval congestion of oedema in (b) which has completely disappeared 3 months later

Figure 1.3 External genital appearances of two newborn females. Note the general swollen appearance of the tissues and the annular pouting hymens

Health problems of adolescence 3

Figure 1.4 A pronounced hymenal tag in a newborn which needs to be emphasized is the relative prominence of the clitoris which, if not recognized for what it is, may cause concern (Figure 1.5). These changes are all part of the physiology of the newborn period. They should be understood but not treated, and parents require a simple reassuring explanation. Another type of disorder - the malformations - also characterizes the newborn period. These are discussed in Chapters 2 and 3. The newborn period with its short-lived passive hormone stimulation is then replaced by 10 years or so during which the pelvic organs receive very little hormone stimulation. This oestrogen deprivation is reflected in vaginal discharge, vulval soreness, and labial adhesions (see Chapter 4). When the patient begins to produce her own oestrogens at puberty, a different group of conditions appears in which variations of growth and

secondary sexual development and menstrual disorders play a prominent part. These problems overlap into early adolescence when the physical and emotional associations of sexual activity must be considered; these and other disorders are discussed below and in Chapters 8, 9 and 12. All these various conditions, although tending to be grouped in the way described from the neonatal period onwards, are not rigidly confined to these limits. Genital tract malformations and intersex problems, for example, may present clinically for the first time around puberty, while the puberty changes themselves may be markedly precocious and occur at a very early age. Tumours (discussed in Chapter 11) may be seen at any time.

Health problems of adolescence Adolescence is the period when the individual matures from childhood to adulthood. It is probably described best by developmental changes, not by age limits or physical milestones. There is a dramatic acceleration of physical and emotional development to which the adolescent must adjust, starting at puberty and ending at adult maturity with selfdependence and self-determination. The range of ages at onset depends on hormonally directed alterations, and there is no statutory determined legal lower age to consider; at the other end of adolescence, however, there are a series of ages laid down for different occasions, none of which may really define the beginning of adulthood. In the UK the legal age of independence used to be 21 and is now 18, but the law recommends a series of ages for other actions considered by some to be adult. A person can consent to sexual intercourse at 16 years but cannot drive a car until 17 or buy alcohol until 18. In examining large groups of people, however, individual characteristics and developments are poor discriminants, and arbitrarily set age limits have to be used. People between 13 and 18 years will cover much of the adolescent population, although there will be extensions beyond this range, particularly in those countries where maturity starts earlier. Based on this age grouping, Table 1.1 shows Table 1.1 Total adolescent population of England and Wales by age and sex (1985). From OPCS (1988a)

Figure 1.5 Relative prominence of the clitoris in a premature female child

Age

Female

Male

Total

13 14 15 16 17 18

348 500 372 500 366 800 380 700 383 500 393 900

368 392 387 401 403 417

111 000 765 300 754 500 782 300 787 100 813 200

500 800 700 600 600 300

4

Patterns of childhood and adolescent gynaecology

the estimated total population of adolescents for England and Wales in 1985. Excess of males at birth is still reflected in these ages, and it is possible that the change in birth rate in the late 1950s and 1960s has led to an increase in the adolescent population in the late 1970s, but this has now reached a plateau and the estimated population by 1991 shows a decline (Table 1.2). Adolescents comprise just under 10% of the population, but since they are usually healthy they do not use the medical services to a proportional extent. Some young people may avoid formal medical care because to them the doctor represents the same age group or sector of society as their parents; they occasionally resent what they think to be an authoritarian approach. To a very small number the school medical officer may appear as an impersonal, but more easily approached, medical advisor. For some with special needs, clinics for young people have been arranged, e.g. the contraceptive clinics for young girls. In a study of 1315 Canadian adolescents, Sternlieb and Munan (1972) reported that 18% sought folk medicine and 10% chiropractors. In this study 39% gave specific reasons for limiting their visits to doctors: 27% quoted cost, 5.2% fear, and 2.9% lack of confidence in the doctor. The monetary factor has been removed from the UK but the other reasons may remain. This indicates, however, less resentment with organized medicine than many suspect. When considering the health problems of any group of the population, mortality information is essential background data. Obviously in this healthy age group such statistics represent only small figures. England and Wales have a very low death rate of adolescents (45 per 100 000). Most deaths were due to accidents (largely from motor cycles) or to self-poisoning. Adolescents from social classes IV and V had a much higher rate than did social class I. Mortality data, therefore, do not fully reflect the problems of adolescent gynaecology, and yet precise statistics about morbidity are harder to collect; hospital admission rates in England and Wales are derived from the Hospital Inpatient Inquiry which gives information about a 10% sample of hospital Table 1.2 Projected population aged 13-18 years. From OPCS (1988b) Age

1975

1978

1981

1984

1991

13 14 15 16 17 18

789 769 740 732 723 703

834 823 806 775 777 749

767 800 305 828 831 814

761 742 775 773 807 813

552 554 571 603 632 684

Total

000 000 000 000 000 000

000 000 000 000 000 000

000 000 000 000 000 000

000 000 000 000 000 000

000 000 000 000 000 000

4 456 000 4 754 000 4 845 000 4 671 000 3 596 000

discharges. This indicates that 5% of 15-19-year-old males are admitted to hospitals every year, compared with 12% of females in the same age group. The major diagnosis for males is injuries, and for females is childbirth with its allied disorders (see Chapter 12). The next most frequent diagnosis in both sexes is digestive disorders, including appendicitis and abdominal pain of unknown aetiology, a frequent and well-known symptom of emotional upset; this may include many patients seen by a gynaecologist. The data shown above do not include mental illness, since in the UK this is based on separate information from the Mental Health Enquiry taken from mental hospital admission figures. They only reflect the extremes of mental health; hospital admission commonly depends on the facilities available rather than the severity of the condition. Further, there is a reluctance to admit young people to mental hospitals where the bias of age groups may lead to a more geriatric atmosphere. With these criticisms in mind, data about admission for mental illness in the 15-19-year-old age groups were only a fifth of that of all ages. Another measure of mental health is the incidence rate of suicide, which among adolescents has been reduced in the last decade; but it has been estimated that for every suicide that occurs there may be 30-40 attempts which fail or are prevented. In this context Alderson (1974) has shown that the rates of emergency admissions for self-poisoning in young girls are higher than any other age group. The real incidence of psychiatric disorders in adolescents is difficult to obtain. Graham and Rutter (1973) quoted a problem rate in 21% of adolescents examined by self-assessment. They considered they had an illness, but many were not confirmed by parallel questioning of parents and teachers. The US National Center for Health Statistics (1974) showed that 3% of adolescents aged 12-17 had been in a mental hospital and 6% had been seen by a psychiatrist. The Child Developmental Study (Fogelman, 1976) indicated that 3% of the 16-year-olds in the UK had been at a child guidance clinic for emotional or psychological problems and 0.4% had been admitted to a hospital. The exact toll levied by psychological illness in adolescents is difficult to measure. Much more valid information on morbidity is likely to come from total population studies. Two such surveys in the UK and the USA have recently given some measure of the use that adolescents make of medical services. The National Child Development Study Group was the third follow-up of the babies born in the National Birthday Trust Survey in 1958. In the previous year 65% of the 16-year-olds had consulted a general practitioner, 13% attended a hospital outpatient's clinic, and 19% a casualty department; a further 9% had been

Health problems of adolescence 5 admitted to a hospital in that year. Of the adole­ scents interviewed, 45% had been absent from school with an illness for more than a week in the year, including 13% of the girls with dysmenorrhoea (Fogelman, 1976). The National Health Examina­ tion Study (1974) indicated that in the USA 44% of a similar group of adolescents would have contacted a doctor (compared with 65% in the UK). The difference of usage may reflect altered health or different consultation patterns related to income, parental level of education and race. In the Canadian study quoted earlier (Sternlieb and Munan, 1972) the adolescents were asked with whom they would have preferred to discuss their health problems. Their answers are summarized in Table 1.3 but the general practitioner is still in the

majority. The same respondents expected of their doctors understanding (in 93% of answers), friendli­ ness (84%), and personality (81%). Lesser degrees of ill-health, however, may not drive the adolescent for formal medical help and it is here that a sym­ pathetic parent or friend may be of more good than any number of doctors.

References ALDERSON, M. R. (1974) Self poisoning - what is the future? Lancet, i, 1040 DEWHURST, c. J. (1963) Gynaecological Disorders of Infants and Children, Bailliere Tindall, London FOGELMAN, κ. (1976) Britain's sixteen year olds. National Children's Bureau GRAHAM, p. and RUTTER, M (1973) Psychiatric disorder in the

Table 1.3 Preferred people with whom adolescents discuss their health problems in Quebec, Canada (n = 1315). Adapted from Sternlieb and Munan (1972) People

Number

General practitioner Psychologist/psychiatrist Friends Parents Clergyman Social worker Gynaecologist Teacher

629 548 516 464 195 169 112 109

Percentage

young adolescent: a follow-up study. Proceedings of the Royal Society of Medicine, 66, 1226 NATIONAL CENTER FOR HEALTH STATISTICS (1974). Report from

Cycle III of the National Health Examination Survey, Series II OFFICE OF POPULATION AND CENSUS STUDIES (1988a) Series

47.9 41.7 39.2 35.3 14.8 12.9 8.5 8.3

PP1, No. 13 OFFICE OF POPULATION AND CENSUS STUDIES (1988b) Popu­

lation Projection, Series PP2, No. 20 STERNLIEB, J. J. and MUNAN, L. (1972) A survey of health

problems, practices, and needs of youth. Pediatrics, 49, 177

2

Intersexuality

Our consideration of the gynaecological problems of the child and adolescent must begin with the most disturbing of all conditions - doubt about the patient's sex. If such a patient is managed correctly, he or she may live a happy, well-adjusted life and may even be fertile. If the patient is managed incorrectly, he or she may be doomed to live as a sexual freak in loneliness and frustration. The chances of a happy outcome are far better if full investigations followed by a careful choice on the sex of rearing is undertaken as soon after birth as possible.

Sexual differentiation To understand the problem of intersexuality, it is necessary to understand how normal sexual development occurs and how this process may be disturbed. A number of texts deal with this fully (Dewhurst, 1975; Josse, 1981; Liu, Kreiner and Rosenwaks, 1987). Here it will be considered only in sufficient detail to make clear the clinical account which follows. During the first 10-12 weeks of intrauterine life, important changes are taking place in those structures destined to be the genital organs of the more mature fetus. Until 9 weeks, the gonads remain indistinguishable and the external genitalia are undetermined. In both the male and female fetus, the Müllerian (paramesonephric) ducts and Wolffian (mesonephric) ducts are present during the early indifferent stage of development. Sex differentiation at this time requires genetic direction and it is the presence or absence of the Y chromosome which determines the gonadal differentiation. The Y chromosome produces a testicular determinant factor which changes the undifferentiated 6

gonad to a testis (see Figure 2.1). The testis contains two types of cell which produce two factors; the Leydig cells produce androgen (probably testosterone) which stimulates Wolffian duct development and the formation of the vas deferens, epididymis and seminal vesicles. Some of this testosterone is converted by 5a-reductase to dihydrotestosterone which induces external genitalia development of the scrotum and penis. The urogenital sinus undergoes typical masculinization, the penis forming from the greatly enlarged Müllerian tubercle, the urethra being prolonged downwards to its tip by fusion in the midline of the genital folds; the scrotum forms from the fused genital swellings. The Sertoli cells produce Müllerian Inhibitor Factor (MIF) which causes inhibition of the Müllerian duct and, thus, no male can have a uterus. The absence of the Y Undifferentiated gonad -H-Y antigen Testis^

Sertoli cells Müllerian inhibitor

Regression of Müllerian system (no male has uterus)

Leydig cells Androgen (Prob, testosterone)

/

Wolffian duct 5a-reductase development | Dihydrotestosterone

1

Vas deferens Epididymis Seminal vesicles

Figure 2.1 Male differentiation

I

f Penis Scrotum

Sexual differentiation 7 chromosome leads to the formation of the ovary, and as there is no androgen or MIF, the Wolffian system regresses and the Müllerian system undergoes further growth (Figure 2.2). The Müllerian ducts in the female grow towards the caudal end of the embryo, swing medially to meet in the midline and as fused structures reach the dorsal wall of the urogenital sinus. The separate cephalic ends of these ducts form the fallopian tubes, and the fused portion the uterus, which the vagina forms from that part which reaches the urogenital sinus; it seems probable that both ducts and sinus contribute to vaginal formation. The external genitalia form from further development of the primitive structures in the urogenital sinus region; the phallic and pelvic portions of the sinus are flattened to form the vestibule, and the bladder and urethra form from the vesicourethral portion of the sinus which lies above the Müllerian tubercle. The genital tubercle, which enlarges so significantly to form the penis in the male, remains small as the clitoris in the female. On each side of the Müllerian tubercle, two paired folds - the genital folds and the genital swellings develop into labia minora and majora, respectively. Thus the development of the male genital organs is due to the presence of the testes, and the development of female genital organs is due to the absence of testes. Whether ovaries are present or not, is immaterial. The stimulus for testicular formation is the presence of a Y chromosome with one or more X chromosomes (XY, XXY, etc.), and the testicular determinant is on the short arm of the Y chromosome. Ovaries form if there are two or more Xs without a Y (XX, XXX, etc.). The male-determining function of the Y chromosome may be due to the presence of the so-called H-Y antigen. H-Y antigen is present in individuals with testes and not in those with ovaries. However, H-Y antigen can be found in individuals with 45 X and thus H-Y antigen is probably a regulator of testicular development rather than being solely responsible for male differentiation. For further reading see Wachtel et al. (1975, 1976), Wachtel (1983) and Wolf (1981).

Putting these events in the order in which they appear, therefore: (1) If there are XY chromosomes, testes form. (2) If testes form normally and function normally, the genitalia become male. (3) If there is no Y chromosome, testes do not form. (4) If testes do not form, the genitalia become female. From this background we can outline the circumstances in which the genitalia are ambiguous. In the fetus with a Y chromosome If testes do not form or function normally, they produce insufficient androgens and Müllerian inhibitor leading to testicular failure. This failure may be anatomical where there is rudimentary development only of testes, or enzymatic if there is imperfect biosynthesis of androgens (5a-reductase deficiency). If the tissues are not completely sensitive to androgens (androgen insensitivity), ambiguity may result. In the fetus without a Y chromosome If androgens are produced from some other source during early embryonic development, they then masculinize the external genitalia of the fetus. The commonest condition responsible for this is congenital adrenal hyperplasia, or androgen may inadvertently be given exogenously to the pregnant mother. In fetuses which may be XY, XX or with an abnormal karyotype Rarely testicular and ovarian tissues form in the same fetus. Such an individual is a true hermaphrodite. The explanation of true hermaphroditism is unknown, but the demonstration that 46 XX hermaphrodites are H-Y antigen-positive (Wachtel et

Undifferentiated gonad ■ NO Y CHROMOSOME OVARY • NO MÜLLERIAN INHIBITOR MÜLLERIAN DEVELOPMENT (Uterus, tubes, upper vagina, ext. genitalia female)

Figure 2.2 Female differentiation

^

WOLFFIAN REGRESSION

8 Intersexuality al., 1976) suggests a possible mechanism. Affected children always have some degree of ambiguous sexual development. The testis and the ovary may be entirely separate structures, associated with an ovotestis or bilateral ovotestes may be present. A detailed account of true hermaphroditism has been undertaken by van Niekerk (1974). Finally, it may be pointed out that complete insensitivity to androgens or complete testicular failure do not present as doubtful sex but as failure to menstruate at puberty; it is at that point that the intersexual aspects of the case are discovered. These conditions are discussed later.

Clinical features Clinical examination of an intersex child seldom, if ever, determines the precise diagnosis. The genital appearances of an undermasculinized male, a masculinized female and a hermaphrodite are similar (Figures 2.3-2.5). There will usually be a phallus enlarged to a varying degree, with a small opening at some point along its ventral surface, at its base, or on the perineum. Through this opening urine is passed. Rarely a second opening - a probable vagina - may be identified as well. Tissues on either

Figure 2.3 External genitalia of an undermasculinized male child due to partial anatomical testicular failure. (From Dewhurst and Gordon, 1969, by permission)

Figure 2.4 External genitalia of a female child with congenital adrenal hyperplasia. (From Dewhurst and Gordon, 1969, by permission)

Figure 2.5 External genitalia of a true hermaphrodite

Clinical features

9

side of the midline usually show a degree of masculinization varying from rugose labia majora-like structures to a kind of scrotal sac. All these appearances may be present whatever the diagnosis. The palpation of a testis, if one can be certain of it, will eliminate a masculinized female, for although the commonest cause of this - congenital adrenal hyperplasia - also occurs in males, doubtful sex is not then a feature. A pelvic ultrasound to determine the presence of a uterus is valuable, and its presence makes the diagnosis of female pseudohermaphroditism most likely. The similarity of external genitalia appearances in all three conditions means that external examination alone is never sufficient to determine the precise diagnosis; the importance of careful examination of the external genitalia lies in the assessment of their capacity to function in the male role which, as we will see, is an important factor in deciding on the more appropriate sex of rearing in both the undermasculinized male and the true hermaphrodite. For correct diagnosis more thorough investigation is required. This must first be directed to confirming or refuting congenital adrenal hyperplasia since, if this is the diagnosis, the child may be a salt loser (Figure 2.6) and may die during the neonatal period or soon afterwards. Congenital adrenal hyperplasia Congenital adrenal hyperplasia is a condition which has a variety of possible causes. It is described in detail in various texts which may be consulted for those aspects of the disorder which do not directly involve the gynaecologist (Lee et al., 1977; Hughes, 1982). The condition arises because of an enzyme block which prevents complete metabolism of Cortisol and aldosterone. Figure 2.16 indicates the enzyme reaction involved in the metabolism of these two substances, and any of them may be affected. In practice, however, the commonest enzyme fault is a 21-hydroxylase deficiency which interferes with the conversion of 17-hydroxyprogesterone to 11deoxycortisone, and that of progesterone to deoxycorticosterone. The intersexual aspects of this relate to the fact that, because of the cortisol deficiency, there is little or no inhibition of the anterior pituitary, and adrenocorticotropin (ACTH) is produced in excessive amounts; ACTH then overstimulates the adrenal, which produces all that it is capable of, namely androgens which masculinize the female fetus during early pregnancy, when the external genitalia are forming. It must be emphasized, however, that the uterus, tubes and vagina are always present. Inhibition of these structures only occurs if testes are present and are producing Müllerian inhibitor; since ovaries are present which produce no Müllerian inhibitor, females with congenital adrenal hyperplasia always have a uterus,

Figure 2.6 A salt-losing child with congenital adrenal hyperplasia; wasting is evident. (From Dewhurst and Gordon, 1969, by permission) tubes and vagina and the latter always opens at some point into the lower genital tract. The salt-losing features of congenital adrenal hyperplasia are probably concerned with the degree of enzyme failure present; if this is extreme, there is virtual failure of aldosterone production with salt loss resulting; if less extreme, sufficient aldosterone may be produced to permit normal salt control. Other enzyme deficiencies which may result in somewhat similar features are 11-hydroxylase deficiency which interferes with the conversion of 11deoxycortisol to cortisol, and deoxycorticosterone to corticosterone and aldosterone. Still rarer defects include 17-hydroxylase deficiency, 3ßdehydrogenase deficiency, and lipoid hyperplasia (Pennington, 1974). Some of these conditions present with very special features, but they are, in fact, very uncommon and highly specialized in their management; if they are encountered, referral to a unit specializing in paediatric endocrinology will always be wise. The remainder of this account will

10

Intersexuality

assume that the abnormality is 21-hydroxylase deficiency, which accounts for 90% of cases. It must be stressed that in salt losers a very dangerous state of dehydration from salt and water loss may arise as early as the second week of life and rarely even during the first. The infant may vomit and lose weight rapidly while the degree of potas­ sium excess, which accompanies the condition, may cause cardiac arrest. Recent studies have allowed mapping of the 21hydroxylase gene to the region between HLA-B and HLA-DR on the short arm of chromosome 6 (Dupont, Oberfield and Smithwick, 1977; Bias, Urban and Migeon, 1981). DNA studies on chromo­ some 6 (White, New and Dupont, 1985) have demonstrated two genes for 21-hydroxylase, only one being active in adrenal steroidogenesis. The two genes lie adjacent to the genes encoding complement C4a and C4b. Prenatal diagnosis of congenital adrenal hyperplasia with 21-hydroxylase deficiency can now be made using amniotic fluid levels of 17-hydroxy~ progesterone, with HLA typing adding confirma­ tory evidence (Forrest et al., 1981). Investigations (1) Examination of a buccal smear. If this should be positive, it suggests very strongly that the karyo­ type of the infant will be female, thus making the diagnosis of congenital adrenal hyperplasia overwhelmingly likely. As soon as possible, the karyotype itself should be established, which will reveal it to be 46 XX in the genetic female. (2) Collection of a 24 h specimen of urine for assay of 17-oxosteroid excretion. During the first 7-10 days of life this investigation may present prob­ lems, since a raised level is occasionally found in normal children. After that time, if a 17oxosteroid value of >3.5 μπιο1/24 h is found, this is strongly indicative of congenital adrenal hyperplasia. (3) The intermediate products of cortisol metabol­ ism must be assayed in blood or urine. Com­ monly, pregnanetriol, which is the excretion product of 17-hydroxyprogesterone, is measured in urine or blood when raised levels indicate that there is a build-up of 17-hydroxyprogesterone which cannot be metabolized further. Alterna­ tively, or in addition, 17-hydroxyprogesterone itself may be measured in the blood. During the first 7-10 days of life, when assay of 17oxosteroids in urine does not give a reliable pointer to diagnosis, the assay of these sub­ stances is probably the best test available, since values are likely to be considerably raised over those in normal children. Pennington (1974), assaying plasma pregnanetriol in three babies with congenital adrenal hyperplasia, found

values of 4.29 μιηοΐ/ΐ in a newborn child, 2.2 μπιοΐ/ΐ at 3 days, and 1.68 μπιοΐ/ΐ at 10 days; these may be compared with a mean level of 0.26 μιηοΐ/ΐ in normal children of the same age. (4) When a child is ill and there is no time to collect a 24 h sample of urine, an indication of the diagnosis may be obtained on a single sample by measurement of the 11-oxygenation index (this is a ratio of the substances oxygenated at the C-ll position compared with those not oxygen­ ated there). A raised index points to congenital adrenal hyperplasia as the probable diagnosis. (5) In severe cases the values of sodium and potas­ sium in blood may indicate a dangerous saltlosing condition, with serum sodium reduced below 125 mEq/1 and potassium raised to 6 or 7 mEq/1. Treatment Should the diagnosis of congenital adrenal hyper­ plasia be confirmed, it must be emphasized again that the child must be reared in the female role regardless of the degree of masculinization of the external genitalia. This masculinization can always be corrected surgically; moreover, the ovaries are normal and capable of function if the condition is correctly controlled, so the infant is potentially a fertile female. The management of a newborn with congenital adrenal hyperplasia is usually a difficult task and close cooperation with the paediatrician, familiar with such cases, is strongly advised. The following is only for general guidance. The aim of treatment is to provide adequate quantities of mineralocorticoids and glucocorticoids in order to suppress pituitary ACTH function and to permit normal growth. For this purpose the super­ vision should always be directly or indirectly under the control of a paediatrician. The drug of choice may be cortisone acetate, 10-25 mg/day during early life, increasing with age to 50-100 mg (two or three times a day) in divided doses. Prednisone may be preferred, since it has a longer action and may be used twice daily in smaller quantities, 1-10 mg per day; 9a-fluorohydrocortisone will be added for salt losers. For a child who is a salt loser and in a serious condition, it is necessary to give salt intravenously. Physiological saline in 10% glucose may be used, 100 ml/kg body weight being given during a 24 h period. To correct the aldosterone deficiency, 500 μg fludrocortisone or some similar preparation every 6 h may be given. In addition, hydrocortisone in doses of 1-2 mg/kg body weight should also be given every 4-6 h, the dose being varied with the improvement of the child. Since aldosterone is short acting, intramuscular deoxycorticosterone, 1 mg/

Clinical features

day, or twice daily, should also be injected; the aldosterone may be stopped after two or three days, but the deoxycorticosterone should be continued. The addition of salt to feeds may be required, unless a 9a-fluorohydrocortisone is given instead of deoxy­ corticosterone; 9a-fluorohydrocortisone used in this manner can be given in doses of 0.05-0.1 mg/day. It is extremely important to monitor electrolytes daily, since inadequate treatment may permit crisis to occur, whereas overdosage will cause salt retention and hypertension. If the infant is not in need of such urgent measures, it may be sufficient to give half-strength physiological saline orally in quantities of 120150 ml/kg body weight/day, with the feeds. Deoxy­ corticosterone, 1 mg twice a day, should also be given. Glucocorticoid treatment as cortisone acetate, 10-25 mg/day in divided doses will also be required. Once the metabolic disorder is corrected and the anterior pituitary outpouring of ACTH is con­ trolled, attention may be paid to the correction of the external genital deformity. The child is to be raised as a girl, as already stressed, and the surgical management of the masculinized external genitalia is most important. This is fully considered with the other aspects of surgery in intersexual patients in a later section on p. 20. Subsequent treatment of a child with congenital adrenal hyperplasia requires some comment. For the most part, the child should be supervised by a paediatrician for the modification of her cortisol dosage which may be required as she grows older. Treatment should aim at sufficient anterior pituitary suppression to prevent precocious heterosexual changes and too rapid bone growth, which will lead to short stature. Oversuppression must also be avoided; this will usually be evident by the develop­ ment of a moonlike facies and general weight gain, which should always call for a check on the 17oxosteroid level in a 24 h specimen of urine. Such checks are necessary at regular intervals as an indicator of changes that may need to be made in the dosage of whatever preparation is being used. It is also important for the patient and any other medical attendant who may be involved in her care to appreciate the need for increased dosage in times of greater body stress, which would ordinarily lead to a natural increase in adrenal activity; examples of these are infective illnesses, anaesthesia, surgical procedures, etc. As puberty is reached, the gynaecologist may again be consulted if development is delayed. This may occasionally happen, especially if control of the congenital adrenal hyperplasia is indifferent. Jones and Verkauf (1971) stressed the need for the precise control of 17-oxosteroid excretion, especially in patients who do not undergo the menarche at the expected time; reduction of 17-oxosteriod excretion to the level of 20.8 μιηο1/24 h may be required

11

before periods begin. In a group of adolescents with congenital adrenal hyperplasia studied by Dewhurst (1978), 12 postmenarcheal patients showed a range of menarcheal age between 12 and 21 years with an average of 15.9 years, i.e. some 2.5 years or so above that existing in the UK at the time. Two other patients in the group were aged 15 and 18 and had not menstruated. Only three of the 12 menstruating girls had regular periods, the remainder having irregular ones with intervals of up to six months between periods. Many patients with congenital adrenal hyperplasia have been fertile, however, following correct steroid, surgical and psychiatric management. It is probable that the degree of menstrual irregularity already mentioned reflects an even greater degree of infrequent ovulation, so as the patient gets older and desires a pregnancy, induction of ovulation may need to be considered. Recently, Mulaikal, Migeon and Rock (1987) reviewed the fertility rates in 80 women with 21hydroxylase deficiency. Of 25 women with the simple virilizing form who have attemped pregnancy, 15 have achieved 25 children. In 15 with the salt-losing form, only one has conceived and some blame must be attributed to inadequate sexual function in spite of surgery, as well as more irregular menstrual cycles in the salt-losing group. The very difficult problems which may be faced when an older child reared as a boy is discovered to be a female with congenital adrenal hyperplasia are considered later.

Other androgen-induced masculinization If the investigation of a newborn, intersex child confirms a female genetic constitution (46 XX) but excludes congenital adrenal hyperplasia, the most likely explanation is that the masculinization is the result of androgens, or potential androgens having been given to the mother during early pregnancy. Androgens produced from a different source is also a possibility; examples are the coincidental presence in the mother of a masculinizing tumour such as an arrhenoblastoma (Brentnall, 1945) or maternal Cushing's syndrome (Figure 2.7). These possible sources of masculinization of the external genitalia of the newborn child must be investigated. A history of drug administration can usually be obtained if such a preparation was given. It will usually be found that the treatment, a progestogen, or, rarely, progesterone, was given for a threatened abortion or a history of abortions in previous pregnancies (Ishizuka, Kawashima and Nakanishi, 1962). The progestogens now in common use are only mildly androgenic if at all, the earlier preparations which were reported to have caused masculinization of the fetus having been withdrawn. Occasional cases due to such drug therapy may be

12

Inter sexuality

those of congenital adrenal hyperplasia with the notable exception of a salt-losing tendency which is never present. The extent of the external genital masculinization is often somewhat less than that in congenital adrenal hyperplasia (Figure 2.8), but this is not in itself a distinguishing feature in differential diagnosis; indeed profound masculinization may be associated with maternal drug therapy (Figure 2.9). Congenital adrenal hyperplasia must always be excluded by the tests already described, but if this can be done for certain and an alternative source of androgens confirmed, further investigation is unnecessary. A difficult decision faces the medical attendant when a 46 XX child with masculinized genitalia does not have congenital adrenal hyperplasia and no other androgen source can be confirmed. A possible diagnosis now is true hermaphroditism, since the most common karyotype in true hermaphroditism is 46 XX. Laparotomy and gonadal biopsy (as described later) for true hermaphrodites is therefore recommended. The management of a genetic female child with androgen-induced masculinization is similar to that for congenital adrenal hyperplasia, although no ster-

Figure 2.7 Partial masculinization of the external genitalia of a female child whose mother suffered from Cushing's syndrome

seen, however, since the condition is probably not due only to the inherent androgen potential of the preparation itself, but to this androgen potential and the patient's metabolic reaction to it taken together. The drug, danazol, a 17a-ethyltestosterone derivative, used in the treatment of endometriosis, may be administered inadvertently during early pregnancy and androgenization of the female fetus has been reported (Duck and Katayama, 1981). Maternal Cushing's syndrome, or the presence of a maternal masculinizing tumour, will probably present with distinctive clinical features which should permit their recognition. Both conditions are rarities. It must be admitted that very occasionally genetic female children with some masculinization may be born with none of the above causes, and the explanation of the masculinization remains unknown. The clinical features of these forms of masculinization do not differ to any important degree from

Figure 2.8 Masculinization of a female child due to androgenic drugs given to the mother in early pregnancy. (From Dewhurst and Gordon, 1969, by permission)

Clinical features

13

Figure 2.10 An ovotestis from a true hermaphrodite. (From Dewhurst and Gordon, 1969, by permission) other clinically except by operation and gonadal biopsy, which should be undertaken as soon as a masculinized female has been ruled out. At this time the child should only be some 2-3 weeks old; nonetheless, surgery can safely be performed. At this point in the management the position will be as follows: Known Figure 2.9 Profound masculinization of a female child caused by maternal androgen therapy during pregnancy. (From Dewhurst and Gordon, 1969, by permission)

oids are required. The condition is not progressive and normal female puberty changes including menstruation are to be expected. A newborn patient with this condition must be reared as a girl, therefore, and external genitalia reconstructive surgery carried out, as described later. The undermasculinized male and the true hermaphrodite If congenital adrenal hyperplasia and androgeninduced masculinization of the genetic female from other sources can both be excluded, the diagnosis now rests between undermasculinization of the genetic male child due to testicular failure or true hermaphroditism with testicular and ovarian tissue present. The clinical features of the two are very similar, the principal difference being that the undermasculinized male has only testicular tissue present, while the true hermaphrodite has both ovarian and testicular tissue present (Figure 2.10). Each will have ambiguous external genitalia and each will probably have Müllerian structures although a uterus is not always present. The conditions cannot with certainty be separated from each

(1) The karyotype, which may be 46 XY, 46 XX or an abnormal one. (2) The child does not have congenital adrenal hyperplasia or other androgen-induced masculinization. Unknown (1) The nature of the gonads. (2) The presence or absence of a uterus. (3) Whether the uterus, if present, communicates with the exterior. (4) If a vagina is present and, if so, at what point it opens to the exterior. The unknowns are to be investigated. In addition, an opinion must be formed as to the suitability of the external genitalia for subsequent sexual life. In deciding on the latter, it must be remembered that a vagina can be constructed surgically if none is present, or lengthened if it is short, whereas a tiny phallus can hardly ever be made large enough for sexual intercourse as a male. The procedures which may be required to resolve these doubts are: Careful examination under anaesthesia Special attention should be paid to the size of the phallus and the position of the urethra or, if this cannot be identified for certain, the urogenital sinus.

14 lntersexuality A vaginogram

The decision on rearing

A helpful procedure in some cases is to run a little radiopaque dye into the external opening and to take a series of radiographs to determine if a vagina is present, where it opens into the urogenital sinus, and if a uterus is present also (Figure 2.11).

In the case of the newborn, the decision of the sex of rearing is made on, more than anything else, the suitability of the external genitalia for sexual intercourse. The nature of the gonads is not a guide to the better gender role for the child (unless both are ovaries, a circumstance already considered above). We need to know their nature, however, for one reason only - to remove, if present, that which is inappropriate to the sex of rearing. The presence of testicular tissue alone might seem to indicate that life in the male role is better, but this is not necessarily the case. The condition of androgen insensitivity is the supreme example of this. In androgen insensitivity the external genitalia are entirely female despite normal-looking testes with normal testosterone production; but to put such a child in the male role would be folly, for how could that individual ever function sexually as a male? (See the XY female, p. 17.) It is the development of external genitalia which is paramount here. If they are judged suitable for life as a male, ovarian tissue, if present, is removed; the uterus, if present, is removed; and reconstructive surgery on the external genitalia is performed by a urologist at the appropriate time in later life. If they are judged unsuitable for life as a male but there is some masculinization present, the female role of upbringing is chosen; testicular tissue is removed and external genital reconstructive surgery is carried out as described later. If the genitalia appear, so to speak, midway between these two circumstances and capable of surgical construction to either female or male, some other criteria will have to be used. The deciding factor might be that the surgery necessary to convert to female is simpler, as it usually will be; another might be an overwhelming preference from a parent or grandparent, since continued psychological support of the child from them is so important. Whatever is decided, there is a need to remove gonadal tissue, if present, which is inappropriate for the chosen role; if this is not removed it may function at puberty and the changes it produces will be heterosexual to this chosen role, and profound psychological disturbance is likely to be produced in the patient.

Figure 2.11 A vaginogram showing the presence of a vagina (the large dye-filled shadow); the dye also enters a small uterus and fallopian tube (the same patient as illustrated in Figure 2.4). (From Dewhurst and Gordon, 1969, by permission) Gonadal biopsy It is wise to assume that the true nature of a gonad can be determined only by biopsy, as appearances can be deceptive. Probabilities are not sufficient; certainty is essential. The technique of biopsy is discussed later (p. 24). The portion removed must be carefully examined histologically. It is not recommended that a judgement on the histology of the gonads be based on a frozen section. It is better to establish the facts, take the biopsies, and conclude the operation. The decision of management can then be made after careful consideration of all the available evidence.

We will soon know, therefore: (1) If the genitalia equip the child better for life as a male or as a female. (2) If testicular tissue alone is present or if ovarian tissue is present as well. (3) The degree to which the vagina is developed and the extent of the surgery likely to be necessary to make it suitable for coitus. (4) The relationship of the external urethral orifice to the end of the phallus.

Management of the parents What is to be said to the parents of a newborn of ambiguous sex? The wisest course is something like this: 'Your child has been born with an abnormality of the external genitalia which make it impossible for us to be sure at this stage whether the child is a boy or a girl. We are quite sure your child will prove

Management of the parents to be one or the other and not something in between.' (This is not strictly true, but it should be said to relieve fear.) 'We will investigate your child at once to determine the correct sex and tell you as soon as we have done so. Meanwhile, say as little as you can to relatives, but if you must say something, tell them what I have just said to you.' The family upset will be enormous, but only a confident medical and nursing approach to the problem and the passage of time will help it. During that time, the precise intersexual state of the child must be diagnosed, and the sex of rearing and treatment decided. Once a decision on the sex of rearing is made by the medical attendant, a discussion must be held with the parents concerning the future. It is important to be as confident as possible at this time. The couple will be alarmed most of all by doubts that their child will never be one sex but will remain in some limbo of sexual frustration and uncertainty, and these doubts must be allayed. Reference has been made above to the need to reassure the parents at birth that investigation will reveal that the child is male or female and not a 'half and half, and this positive approach must be continued. The decision on rearing is simple with a masculinized female from congenital adrenal hyperplasia or other androgen source. The child is female and the parents must be given a simple explanation about why the external genitalia were masculinized, what treatment will be required to control this, the need for external genital surgery to remove evidence of maleness and re-establish femaleness, and the outlook for sexual life and fertility in the future; for all this an optimistic attitude may be adopted. For male intersexuality and true hermaphroditism, however, the decision is not as simple unless an undermasculinized male is well enough developed to be reared in that role. But if the female role is to be chosen, the approach to the parents is more difficult. It is more satisfactory to give confident advice to the parents even though this means misleading them to some extent, and to avoid disclosing the male karyotype. Indicate the following:

(1) That the child is female and that HER (and always use this pronoun from now on) degree of masculinization is due to imperfect formation of the gonad or sex gland (this is quite true). (2) That she should have the evidence of maleness removed and will thereafter be solely female. (3) That the imperfectly developed gonads do not do their work properly and will be a danger to the patient later and should also be removed. (4) That the hormone the gonads should be producing can be given near to puberty as a simple pill each day.

15

(5) That sex life can be expected to be normal. If one can convey this to the parents, a great deal will be achieved. Of course, if the uterus is absent the parents must understand that fertility is impossible; they will accept this if anxieties that they have not produced a sexual freak are relieved. The approach to the parents of a true hermaphrodite will be similar; here, however, the uterus is likely to be present and it may be possible to preserve a gonad or part of one, which may somewhat modify what needs to be said to the parents. Counselling the parents of an intersex child is one of the most difficult things a doctor has to do. Precisely what must be said will be influenced by their intelligence and scientific knowledge, their race and its culture patterns, and the severity of their own psychological reaction to the situation. Variations in approach can only be mentioned briefly; in the United States, for example, it may be difficult for medicolegal reasons to withhold any information from the parents, as one might in the United Kingdom; in the Arab world the stress on the superior position of the male may influence decisions. All that can be done here is to give general advice as outlined above. The continued psychological support of the child is essential for a satisfactory outcome. If a wise decision is made at or soon after birth, the parents' distress correctly managed, and doubts about the sex at birth never again communicated to the child, the orientation of that child to the chosen role will in most cases be good. The parents must never be allowed to choose a bisexual name such as Leslie(ey), Francis(es), or Evelyn; to do so is to put the stamp of doubt on the child for life. Once reconstruction of the external genitals has been completed and is found to be satisfactory and well healed, the genitalia should not be inspected repeatedly thereafter. To do this would only focus the child's attention on her genitalia and suggest that something is wrong. Hormone therapy will be necessary later - perhaps around the age of 10 or 11 years for a girl or later for a boy - when the child realizes he or she is not experiencing the same changes as others. A girl with a uterus but without functioning ovarian tissue will require a hormone regime similar to that given to girls with gonadal dysgenesis (see Chapter 7) oestrogens in low dosage first, with a progestagen added at a later stage. If no uterus is present, no progestogen is necessary and the oestrogens need not be given intermittently. A boy may be given methyltestosterone, 20 mg/day, which is usually sufficient. Some variation in dosage may be required to suit an individual case and, of course, an alternative preparation in equivalent dosage may be used.

16

Intersexuality

Presentation in the older child When a child or adolescent with intersexual features is seen for the first time, there are differences in approach, particularly to management, which call for separate consideration. The same diagnosis must be considered if the ambiguity of genital development has been present since birth but for some reason inadequately dealt with then. If there is no doubt about sex at birth the matter is different, since this suggests a new source of abnormal androgen formation and other possible diagnoses (see Chapter 10). In the former instance of ambiguous development evident at birth, congenital adrenal hyperplasia, if present, is unlikely to be of the salt-losing variety, or the child would have died. The diagnosis is confirmed or refuted in a similar manner to that discussed already. In a mild example of congenital adrenal hyperplasia (Figure 2.12), as such a case might well have been overlooked in this way,

measurement of the 17-oxosteroids, pregnanetriol, and the 17-hydroxyprogesterone may not give clearcut results. An ACTH stimulation test may then be helpful. Synacthen (0.25 mg) may be injected shortly after taking a sample of blood for assay of a baseline 17-hydroxyprogesterone value: 30 minutes later a further blood sample is taken for the same assay and is likely to show a rise in the level three to four times the baseline value in a patient with congenital adrenal hyperplasia. If an undermasculinized male child is being reared in the female role, there may be cause for alarm at puberty as the rudimentary testicular tissue present begins to produce a little more testosterone with phallic enlargement, deepening of the voice, or facial hair growth. True hermaphroditism may declare itself about the same time in a child being brought up in either gender roles; a 'boy' might develop breasts (Figure 2.13) or begin to menstruate through a supposed urethral orifice, or a 'girl' might experience a deep voice, hair growth and clitoral enlargement. The approach to diagnosis is similar to that already described with laparotomy and gonadal biopsy being ultimately required.

Figure 2.12 External genitalia of a female child with congenital adrenal hyperplasia whose diagnosis was made only at puberty

Figure 2.13 Breast development at puberty in a true hermaphrodite reared as a male. (From Dewhurst and Gordon, 1969, by permission)

The XY female The chief difference between the newborn and older child with intersexuality is in management. It is now of paramount importance to assess the orientation of the patient to the sex of rearing so far, since this may have a profound effect on treatment. If, for example, a female with congenital adrenal hyperplasia has been brought up for, say, 10 years as a boy and is fully adjusted to the male role, any attempt to change that child to a female may cause profound psychological confusion from which the child may never recover. A patient completely adjusted to the sex of rearing and with genitalia that are compatible with this gender role, or are at least capable of appropriate surgical improvement, should remain there, every effort being made by hormone and surgical means to underline that gender role. Thus a genetic female with congenital adrenal hyperplasia fully orientated to masculinity and virtually fully masculinized externally, should remain a boy, and have a hysterectomy and oophorectomy (since once cortisol treatment is begun, the ovaries may function and menstruation begin); later appropriate replacement therapy with testosterone can be given and testicular prostheses may be inserted into the 'scrotal' sac if desired. It may be argued that such a child would be a fertile female if successful reregistration could be achieved, while in the male role the child would always be sterile. The important words here, however, are 'if successful reregistration could be achieved': the chances of this in an older child fully adjusted to the sex of rearing are so small as to prohibit any serious consideration of this line of treatment.

17

female. Detailed accounts of this condition may be consulted for its many fascinating aspects (Wilson, 1972; Cleary et ai, 1977; Dewhurst and Spence, 1977; Wachtel, 1979; Brown and Migeon, 1986). What follows is a practical guide to understanding and management. The circumstances in which a 46 XY individual may have a female phenotype have been indicated briefly. They are: (1) Anatomical or enzymatic failure of the testes to produce androgens. (2) Failure of the tissues to respond to androgens androgen insensitivity. Anatomical failure of testicular differentiation may be seen in a 46 XY individual whose testes are represented by useless streaks of tissue (Figure 2.14); sometimes although a Y chromosome is present the karyotype is abnormal (46 X/46 XY). In the latter, the aetiology of testicular failure may be chromosomal; in the former, the fault cannot be chromosomal although it may be genetic, undetectable as yet by our methods of chromosome examination. When there is complete failure of testicular differentiation of this kind, not only are androgens not produced but neither is Müllerian inhibitor; the patient therefore has a uterus, tubes and a vagina. Since there are no androgens nor oestrogens pro-

The age of the child, say below 2-3 years, after which a sexual identity may have become firmly imprinted, and the degree to which the child when psychologically assessed may not seem to have adjusted to the sex of rearing, are two points which may indicate reregistration in the opposite sex to be the correct treatment. A very young child, say one year old, for example, brought up as a boy, yet with minimal phallic enlargement should probably be reregistered as a female and the appropriate surgery performed. The older the child and the greater the doubts about the completeness of identification with the sex of rearing, the greater the dilemma. The biggest dilemma of all is the child put into the male sex and apparently well adjusted to it, yet with such minimal masculinization that there seems little hope of sexual satisfaction after puberty. In such a case it would be best to consult with experts.

The XY female Special consideration must now be given to the apparently normal child or adolescent without any external masculinization who is found to have an XY chromosome arrangement or testes - the XY

Figure 2.14 An XY female due to anatomical testicular failure. (From Dewhurst, 1971, by permission)

18

Intersexuality

Androgen insensitivity

duced by the streak gonads there is no secondary development at puberty. These cases present, therefore, as girls with primary amenorrhoea who have no secondary sexual development. Their stature is normal or tall since increased growth of long bones is common, as the epiphysial closure is delayed. Treatment should be undertaken by replacement oestrogen therapy with added progestogen, as described for gonadal dysgenesis of which this condition is one variety. Gonadectomy is indicated once the karyotype is known, since the malignancy risk in the streaks may be in the order of 30%. (For further consideration of these matters, see Chapter 7.) Enzymatic failure of androgen synthesis (Figure 2.15) occurs at one of the various enzyme steps to testosterone formation indicated in Figure 2.16 (see Dewhurst, 1975 for review). The testes are likely to be anatomically well formed. They produce Müllerian inhibitor but little or no testosterone, so the uterus, tubes and most of the vagina are absent, but minimal lower vaginal development may arise from urogenital sinus development. The clinical features of enzymatic testicular failure vary, depending on the defect present. Secondary feminization, such as is described below for androgen insensitivity but seldom as good, may be seen if oestrogens are formed in significant amounts from androstenedione. Complete forms of enzymatic testicular failure are uncommon and some degree of external genital masculinization is usually seen. These arise in cases of inborn errors of testosterone biosynthesis with deficiency of either 20,22-desmolase, 3ß-dehydrogenase and 17a-hydroxylase. These deficiencies affect the testis and the adrenal, and the degree of sexual ambiguity depends on the deficiency. The cases then present as children with ambiguous sex and are managed as described earlier.

This condition is currently thought to be due to a structural abnormality in the androgen receptor (Kaufman et al., 1982), although the exact molecular mechanism remains obscure. Testosterone is

Figure 2.15 An XY female due to enzymatic testicular failure. (From Dewhurst, 1975, by permission)

CHOLESTEROL 20, 22-Desmolase 170C-HYDROXYPREGNENOLONE

©| DHEA

EGNEIS PREGNENOLONE

11 ■Hydroxylase ® T 18-Dehydrogenase 21-Hydroxylase * 11-DEOXYCORTICOSTERONEPROGESTERONE►CORTICOSTERONE

©

I

(T)

17, 20-Desmolase

©

Π-DEOXYCORTISOL-

©

-CORTISOL

A4-ANDROSTENEDIONE

| © | l 7 - KKetosteroid OESTRADIOL **-

©

17-,-Hydroxylase

17a-HYDROXYPROGESTERONE-

OESTRONE-*

ALDOSTERONE

| 3ß-dehydrogenase

reductase

"TESTOSTERONE

Figure 2.16 Diagrammatic representation of the enzyme steps leading to the metabolism of testosterone, cortisol and aldosterone. The numerals in circles indicate sites of enzyme activity

Androgen insertsitivity

produced in normal amounts by testes which look anatomically normal. Müllerian inhibitor is also produced normally, so again the uterus, tubes and upper vagina are absent, with some development of the lower vagina from the urogenital sinus. The classic features of this condition are well known and need to be described only briefly. The patients are apparently normal females with good - often very good - breast development (Figure 2.17), scanty or absent pubic and axillary hair, normal stature and feminine body configuration, normal vulva, shortened blind vagina, and an absent uterus and tubes; testes are to be found in the lower abdomen, groins or rarely labia majora; there is often a family history of sisters, aunts or great aunts similarly affected; inguinal herniae are often present. Variations include some degree of pubic hair growth and a longer - in some cases full length vagina especially in married women. The condition presents clinically as primary amenorrhoea in a 16-, 17-, or 18-year-old girl in the majority of instances; less often it presents in childhood when a little girl is found to have a testis in a hernial sac, or a younger sister of a known case is found to be 46 XY. The significant features of this condition are the physical ones; they are so clear-cut as to permit a

19

confident clinical diagnosis, and investigation need not be detailed. Measurement of the plasma testosterone levels will be within the normal male range in androgen insensitivity and within or only slightly above the normal female range in enzymatic failure. Follicule stimulating hormone (FSH) and luteinizing hormone (LH) values are likely to be raised in androgen insensitivity, since the hypothalamus too appears insensitive to the androgen. Other investigations are seldom necessary. Greater problems of investigation and management occur, however, when a patient is seen in childhood. If the patient already has the clinical features described the diagnosis is easy, but if the secondary feminization has not occurred, how do we know if, at puberty, there will be feminization or masculinization? The important criteria to be considered are as follows: (1) If the features of the vulva and short blind vagina are typical of those of androgen insensitivity, feminization at puberty is to be expected, especially if there is a family history of others with typical features who have feminized at that time. (2) If there is any external masculinization (Figure 2.18), then feminization at puberty cannot be

f|^ -^ f '

Figure 2.17 An XY female with typical features of androgen insensitivity

Figure 2.18 External genital masculinization of an XY child reared as a girl. Further masculinization at puberty is probable

20 Intersexuality

relied upon, masculinization being more likely. Such a case will either be partial sensitivity to androgens which are normally produced or partial production of androgens with normal tissue sensitivity; in either case masculinization is to be expected (Dewhurst, 1975). (3) If a uterus is present, a case cannot be either androgen insensitivity or enzymatic testicular failure, and is either anatomical testicular fail­ ure in which there will be no secondary develop­ ment at puberty or true hermaphroditism.

Management should be along the following lines. If the patient already has good breast development, gonadectomy should probably be performed. The degree of cancer risk in such testes is perhaps of the order of 5% or so at some time (Dewhurst, Ferreira and Gillett, 1971), a risk high enough to warrant removal. The need for removal must be carefully broached with the patient along lines similar to those discussed previously. Replacement oestrogen therapy with ethinyloestradiol, 20 μg/ day, or its natural equivalent should be given, since menopausal-type symptoms not infrequently follow. Elongation of the vagina is seldom necessary.

If the patient is a child and is thought certain to feminize at puberty, the testes should be left in situ until after that time, then dealt with as above. If, by the criteria described above, feminization at puberty is in real doubt, testicular removal in childhood with replacement oestrogen therapy at the time of puberty is advised.

Surgical considerations The various surgical procedures which might be required of a gynaecologist in the management of an intersex patient will now be considered in more detail. External genital reconstruction Only external genital reconstruction as a female will be discussed here; if the male role is chosen, a urologist, plastic surgeon, or paediatric surgeon should be involved. The commonest circumstance with which the gynaecologist will be faced is likely to be the masculinized female child with congenital adrenal hyperplasia. The abnormalities present are two-fold (Figure 2.19):

(a)

(0 Figure 2.19 Progressive stages of virilization seen in

adrenal hyperplasia

Surgical considerations 21 (1) Enlargement of the clitoris. (2) Excessive fusion of labial folds. The degree of clitoral enlargement varies but is usually sufficient to call for surgical reduction in size. Far more psychological problems arise from attempts to avoid surgery, thus leaving the child with an organ sufficiently large to be a source of great embarrassment, than physical problems associated with removal. The relationship of the opening of the urogenital sinus to the tip of the clitoris must be carefully noted; usually it is near the base on the ventral surface, although it may be further forward on the shaft or rarely at the tip. The urogenital sinus has been formed by labial fold fusion in utero which has the effect of prolonging the urethra forwards (Figure 2.19). The folds are usually thin, sometimes more substantial, and less often very thick with narrowing of the lower vagina. There are two surgical procedures to consider: (1) Reduction in the size of the clitoris. (2) Division of the labial folds to expose the vagina. Clitoral reduction is best undertaken during the neonatal period, before the child leaves the hospital. Doing the procedure then has two great advantages: (1) The parents may take the child home with no visible evidence of masculinity, so sparing them mental anguish and preventing others from knowing about the problem. (2) The control of the congenital adrenal hyperplasia is likely to be at its best following several weeks of intensive hospital investigation and treatment. Division of the labial folds, however, is best postponed until later. The tissues are very small in the newborn period, and if heavy bleeding is started deep in the urogenital sinus, it may be difficult to control; moreover, infection may result from the child's inability to control the bowel, and scarring may follow. Labial fold fusion is best omitted from the neonatal surgery, or limited to slight enlargement of the external opening. The technique of clitoral reduction will depend on the procedure chosen. In removal of the phallus, the clitoris is encircled at its base by an incision and the subcutaneous tissues reflected off the shaft to expose only the corpora cavernosa. This dissection is taken deep enough to approach the fusion of the crura. The base of the clitoris is then clamped and the organ removed. Two transfixion ligatures are applied. The deep tissues are then brought together across the stump to obliterate dead space, and the skin is closed. Bleeding is seldom troublesome; the dorsal artery and vein of the clitoris and the similar

vessels on the ventral surface are the principal ones to ligate. Other procedures have been described in an attempt to preserve the functioning glans. The blood supply of the glans may be maintained by preserving the vessels running along the ventral surface of the shaft, but the nerve supply which runs in the corpora cavernosa cannot as easily be preserved. Preservation of the glans has become fashionable in an attempt to preserve clitoral sensation. The nerves and some of the blood vessels reach the glans by running in the substance of the sheath of the corpora cavernosa. The clitoral skin is incised along its length on the dorsal surface, carefully opening the sheath of the corpora to preserve the neurovascular bundle, and shelling out the remainder of the corpora. This leaves the glans attached dorsally to skin and the nerves and blood vessels running in the anterior part of the sheath of the corpora, and ventrally to skin and further vascular supply. The corpora having been exised, the glans is then sutured onto its base. Another approach to preservation of the function of the glans has been to preserve the whole organ by bending it into ventroflexion and burying it beneath the skin. This has several disadvantages; if the organ is large, it is almost impossible to undertake this procedure without leaving a considerable deformity in that region; the acutely angled clitoris is likely to be a source of real discomfort when sexual excitement and erection occur later, so a further surgical procedure to relieve this problem may be necessary. All in all, removal seems best, especially since this has been shown in a number of patients not to inhibit orgasm in later life. Division of fused labial folds may be easy or difficult. If they are as shown in Figure 2.20, they can easily be divided by a simple posterior incision; the few stitches unite the cut edges of the incision, and the operation is over (Figure 2.20-2.21). If the thickness of the folds suggests that such a simple procedure will suffice, this may be done when the child is 3-4 years of age (before she starts school) and no further surgery may thereafter be necessary. If, on the other hand, the folds are thought to be thick and especially if they are probably narrowing the lower vagina, it is best to postpone operation until after puberty. The organs are then larger and easier to handle and the oestrogens present promote better healing. It cannot be emphasized too strongly that one must not operate on these girls until they are sexually mature. This includes physical maturation but more importantly, mental and psychological maturation. Unless prolonged effective counselling is instituted before surgery is performed, long-term results will be impaired (see Chapter 3). On several occasions it has been necessary to operate on patients whose initial procedure had been undertaken too soon, the difficulties

22

Intersexuality

(c)

Figure 2.20 Diagrammatic representation of division of fused labial folds; the clitoris has previously been amputated. (From Dewhurst and Gordon, 1969, by permission)

Figure 2.21 Division of fused labial folds to elongate the vagina in a child with congenital adrenal hyperplasia. In (a) the degree of narrowing of the introitus is evident; in (b) the divided blades of a pair of forceps spread the region of the fourchette which has been incised posteriorly; (c) after uniting the skin and epithelium of the vagina, sufficient enlargement is achieved to easily insert a broad speculum. (From Dewhurst and Gordon, 1969, by permission) not being appreciated and inadequate enlargement obtained. The procedure to be undertaken will depend on the thickness of the tissue in the fused labial folds. If this is only moderate, an operation similar to that illustrated in Figure 2.20 can be undertaken. If the folds are very thick, however, and the lower vagina contracted, a more elaborate procedure is required. This is described by Dewhurst and Gordon (1969) and is illustrated in Figure 2.22. An initial vertical

incision is made into the perineum, as shown in the figure, until the vaginal orifice is found. Once the separate urethral and vaginal openings are identified, care must be taken to carry the incision far enough up the vagina to reach the part which is of normal calibre, which is seldom more than one-third to one-half of the way up. Undercutting the perineal tissue on each side further frees the edges of the incision. A triangular flap is then raised in the region of the labia majora on each side; to preserve blood

Surgical considerations

23

(c)

Figure 2.22 (a) A marked degree of masculinization in a female with congenital adrenal hyperplasia. Posterior division of the fused labial folds during childhood failed to identify separate urethral and vaginal openings, (b) Further posterior division does identify the urethra and vagina, but the latter is so constricted in its lower part that only a sound can be introduced, (c) Diagrammatic representation of the alteration in which skin flaps are raised on each side of the introitus and laid into the posterior wall incision in the vagina, and the defects on each side are closed. (From Dewhurst and Gordon, 1969, by permission)

24

Inter sexuality

supply the height of the flap from base to apex should not be more than 1.5 times the breadth of the base. The incision in the area from which the flaps are taken is closed and the flaps themselves swung into the defect in the perineum on each side, as shown in Figure 2.22. Such a procedure is not difficult to undertake in the postmenarcheal patient, but will be far more difficult if it is unwisely attempted in the child. Masculinized females due to other androgen sources can be managed in a similar fashion. In these cases, if the degree of clitoral enlargement is small, operation on the clitoris may be omitted if it is thought that sufficient shrinkage will occur to prevent the organ from becoming a source of embarrassment in later life. Other surgical procedures Other procedures with which a gynaecologist may be faced are gonad biopsy for diagnosis, hysterectomy and oophorectomy in a true hermaphrodite being raised in the male role, and the same procedure in the rare case of a female with congenital adrenal hyperplasia who has been reared as a male and is to continue as such. Gonadal biopsy seldom causes problems. It must be remembered that if the nature of the gonad is sufficiently in doubt to call for biopsy, the organ may be an ovotestis; it is imperative to take a biopsy that is representative of the gland as a whole and not a tiny fragment of it. In addition, if part of the exposed gonad appears different from the rest, this portion must be biopsied too. Because of the importance of getting a truly satisfactory biopsy from an unknown gonad, laparoscopic biopsy is not sufficient. I have encountered, for example, only the ovarian part of an ovotestis biopsied at laparoscopy, the presence of the testicular portion becoming evident by its clinical manifestations later. Hysterectomy is only likely to provide a problem for the trained gynaecologist when the identification of the site of the cervix is difficult and the point at which the cervix enters the vagina is uncertain. Anatomical relationships in such cases may be abnormal, and if difficulty is experienced, it would be wiser to leave a portion of the cervix behind rather than cause injury to the bladder, for example. In an XY female from either androgen insensitivity or enzymatic testicular failure, consideration may have to be given to elongating the vagina, although in the former condition this is seldom necessary. A number of married patients showing androgen insensitivity will be found to have a vagina which is almost of normal length, and intercourse is entirely satisfactory. Rarely, however, this may not be the case, when the approach to treatment should be that discussed in the section on congenital absence of the vagina in Chapter 3.

Transvestism and trans-sexualism All the patients described in the earlier part of this chapter had heterosexual organs of one kind or another. Those to be discussed now do not have a physical abnormality; their intersexual features consist of their wish to behave and dress as members of the opposite sex and, in the most extreme cases, in their wish to assume that sex with the help of major plastic surgical procedures and hormone therapy. Transvestism was first described by Havelock Ellis (1920) under the heading of Eonism - the French diplomat Chevalier d'Eon de Beaumont was one of the most celebrated exponents of it, for although physically a normal male, he lived much of his life as a female. Transvestism may be defined as a deviation of personality in which the sufferer obtains gratification by wearing the clothes of the opposite role. Trans-sexualism is defined by Benjamin (1964) as the desire to change the anatomical sex. Cross-dressing is a complex phenomenon which may be the outward sign of a psychosis, or may be indulged in for homosexual gratification, or may not be associated with either of these. The classification which has been helpful is that of Roth and Ball (1964). Symptomatic

transvestism

In this condition the cross-dressing is a symptom of homosexuality or perhaps of fetishism where the desire of the patient to wear some specific article of clothing permits sexual gratification. Simple

transvestism

Here the disorder is confined to the wish to dress and behave as a member of the opposite sex. Subjects with simple transvestism describe a feeling of greater contentment and self-assurance when dressed in the clothes of the other sexual role, in contrast to frustration and anxiety which they feel when they conform to the dress of their own sex. Pronounced sexual tendencies are often lacking in this condition. Trans-sexualism Trans-sexualism is a far deeper personality disorder. The patients with it have a total conviction that they have been victims of an appalling mistake of nature and that they should properly have been members of the opposite sex. They persist in this belief despite the results of all investigations which prove otherwise. They seek only treatment which will permit them to live in the chosen role, and reject treatment designed to readjust them to their own sex. Frequently they will submit to extensive sur-

Transvestism and trans-sexualism 25 gical procedures to convert their body image to that which they wish it to be. The importance of transvestism and transsexualism in this context rises from the probability that in the majority of cases the disorder begins in childhood. The child who may be 4, 5 or 6 years of age is found to have a preference for the company of children of the opposite sex and for their games, their toys, and their clothes. Although crossdressing is a common feature, the abnormality is not only one of dress but of general behaviour, the children showing what is sometimes referred to as cross-gender behaviour. At puberty their confusion about their sexual identity becomes exaggerated and they do not readily see how they fit into the scheme of things. Many at this stage or shortly afterwards leave home, searching for their sexual identity. They drift into the company of homosexuals and sexual deviants, although seldom do they feel real satisfaction in homosexuality. Gradually the image of themselves as members of the opposite sex becomes deeply rooted in their personality, and a number of them - although how many is not certain - seek hormone therapy and surgical operation to make their body conform as closely as possible to their image of it. Trans-sexualism may be female to male, or more commonly male to female. The sufferers become repelled by their genital organs: the female will seek mastectomy and hysterectomy and perhaps even pursue the largely hopeless search for a conversion of the genitalia to the male sex; the male will also seek what is sometimes called gender reassignment surgery which involves removal of the penis and testes and the construction of an artificial vagina. What is important in the context of this book is that if this condition is curable in the ordinary sense of the word at all, it is curable in childhood. Green (1974) has written extensively on this subject. He has tried to identify those children who show significant cross-gender behaviour with a view to early diagnosis and, it is hoped, total curative treatment. It is virtually certain that by the time patients are beyond adolescence the disorder is so fixed in their personality that cure, as we understand it, by psychotherapy is out of the question. Gynaecologists may, therefore, be consulted around the time of puberty or even earlier by parents who have noticed this abnormal form of sexual behaviour in their offspring. Full examination must always be undertaken. Seldom, however, will any abnormality be disclosed, although rarely a degree of testicular hyperplasia, perhaps associated with a 47 XXY sex chromosome complement, has been reported. In the great majority of instances, however, chromosome examination shows a karyotype appropriate to the anatomical sex, and no other abnormality is to be discovered. In these

circumstances, such a patient must be taken very seriously indeed, even at an early age. Not all psychiatrists are experienced in the disorder or wish to be involved in it, so every effort should be made to find one who is knowledgeable in this highly specialized field. While there is still hope of cure in the ordinary sense of the word, this must be pursued and it is doubtful if anyone who can be regarded as sexually immature (and adolescents fall into this category) should have definitive hormone or surgical treatment to convert them to the chosen role. This subject is far too large to be treated at length here. For those wishing further information, the excellent writings of Roth and Ball (1964), Green and Money (1969) and Green (1974) may be consulted.

References BENJAMIN, H. (1964) Nature and management of transsexualism with a report on 31 operated cases. Western Journal of Surgery, 72, 105 BIAS, w. B., URBAN, M. D. and MiGEON, c. J. (1981) Intra HLA recombinations localising the 21-hydroxylase deficiency gene within the HLA complex. Human Immunology, 2, 139 BRENTNALL, C. P. A. (1945) A case of arrhenoblastoma complicating pregnancy. Journal of Obstetrics and Gynaecology of the British Empire, 52, 235 BROWN, T. R. and MIGEON, C. J. (1986) Androgen receptors in normal and abnormal male sexual differentiation. In Steroid Hormone Resistance: Mechanisms and Clinical Aspects (eds G. P Chrousos, D. L. Loriaux and M. B. Lipsett), Plenum Press, New York, pp. 227 CLEARY, R. E., CARAS, J., ROSENFELD, R. L. a n d YOUNG, P. C. M.

(1977) Endocrine and metabolic studies in a patient with male pseudohermaphroditism and true agonadism. American Journal of Obstetrics and Gynaecology, 128, 826 DEWHURST, c. J. (1971) Sex chromosome abnormalities and gynaecologist. Journal of Obstetrics and Gynaecology of the British Commonwealth, 78, 1058 DEWHURST, c. J. (1975) The aetiology and management of intersexuality. Clinical Endocrinology, 4, 625 DEWHURST, c. J. (1978) In Gynaecological Therapeutics (ed. D. F. Hawkins, Bailliere Tindall, London DEWHURST, C. J. and GORDON, R. R. (1969). The Intersexual

Disorders, Bailliere Tindall, London DEWHURST, c. J. and SPENCE, J. E. H. (1977) The XY female.

British Journal of Hospital Medicine, 17, 498 DEWHURST, C. J., FERREIRA, H. P. and GILLETT, P. G. (1971)

Gonadal malignancy in XY females. Journal of Obste­ trics and Gynaecology of the British Commonwealth, 78, 1077 DUCK, s. c. and KATAYAMA, K. P. (1981) Danazol may cause female pseudohermaphroditism. Fertility and Sterility, 35, 230

26

Inter sexuality

DUPONT, B., OBERFIELD, s. E. and SMiTHwiCK, E. M. (1977) Close genetic linkage between HLA and congenital adrenal hyperplasia. Lancet, ii, 1309 ELLIS, H. (1920) Eonism. Revolutionary Reviews of New York, 26, 3 FORREST, M. G., BETUEL, H., COUILLIN, P. a n d BOUE, A. ( 1 9 8 1 )

Prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency by steroid analysis in the amniotic fluid of mid pregnancy: comparison with HLA typing in seventeen pregnancies at risk for CAH. Pre­ natal Diagnosis, 1, 197. GREEN, R. (1974) Sexual Identity Conflict in Children and Adults, Duckworth, London GREEN, R. and MONEY, J. (1969) Transsexualism

and Sex

Reassignment, The John Hopkins Press, Baltimore HUGHES, i. A. (1982) Congenital and acquired disorders of the adrenal cortex. Clinics in Endocrinology and Meta­ bolism, 11, 89 ISHIZUKA, N., KAWASHIMA, γ. and NAKANISHI, τ. (1962) Stat­

istical observations on genital anomalies of newborns following the administration of progestagens to their mothers. Journal of the Japanese Obstetrical and Gynae­ cological Society, 9, 271 JONES, H. w. and VERKAUF, B. A. (1971) Congenital adrenal hyperplasia: age at menarche and related events at puberty. American Journal of Obstetrics and Gynecology, 109, 292 JOSSE, N. (1981) Physiology of sex differentiation in intersex child. Pediatric and Adolescent Endocrinology, 8, 1-13 KAUFMAN, M., PINSKY, L., SIMARD, L. a n d WONG, S. C. ( 1 9 8 2 )

Defective activation of androgen receptor complexes; a marker of androgen insensitivity. Molecular and Cellular Endocrinology, 25, 151 LEE, P. A., PLOTNICK, L. P., KOWARSKI, A. A. a n d MIGEON, C. J.

(1977) Congenital Adrenal Hyperplasia, University Park Press, London

Liu, H. c , KREINER, D. and ROSENWAKS, z. (1987) Anti-

Müllerian hormone. Seminars in Reproductive Endocri­ nology, 5, 283 MULAIKAL, R. M., MIGEON, c. J. and ROCK, J. A. (1987) Fertility

rates in female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. New England Journal of Medicine, 316, 178 PENNINGTON, G. w. (1974) The reproductive endocrinology of childhood and adolescence. Clinics in Obstetrics and Gynaecology, 1, 509 ROTH, M. and BALL, J. R. B. (1964) In Intersexuality in Ver­ tebrates Including Man (eds C. N. Armstrong and A. J. Marshall), Academic Press, London, p. 395 VAN NIEKERK, w. A. (1974) True Hermaphroditism: Clinical, Morphologic and Cytogenetic Aspects, Harper and Row, Hagerstown, Md WACHTEL, s. s. (1979) The genetics of intersexuality; clinical and theoretical perspectives. Obstetrics and Gynecology, 54, 671 WACHTEL, s. s. (1983) H-Y Antigen and the Biology of Sex Determination, Grune and Stratton, New York WACHTEL, s. s., OHNO, s., Koo, G. and BOYSE, Ε. (1975) Possible

role for H-Y antigen in the primary determination of sex. Nature (London), 257, 235 WACHTEL, s. s., KOO, G., BREG, R. w. et al. (1976) Serologie

detection of a Y-linked gene in XX males and XX true hermaphrodites. New England Journal of Medicine, 295, 750 WHITE, p c , NEW, M. i. and DUPONT, B. (1985) Adrenal 21-

hydroxylase cytochrome P-450 genes within the MHC class III region. Immunology Review, 87, 123 WILSON, J. D. (1972) Recent studies on the mechanism of action of testosterone. New England Journal of Medicine, 287, 1284 WOLF, u. (1981) Genetic aspects of H-Y antigen. Human Genetics, 58, 25

3 Malformations of the genital tract

Malformations of the genital tract do not all present during childhood or adolescence, and those which do present at different times. The abnormalities of the uterus alone do not become evident until the patient is pregnant; a pregnant rudimentary uterine horn, for example, may rupture with profound shock and collapse, or fusion defects of the Müllerian ducts may present with abnormalities of lie presentation and position or as a series of unsuccessful pregnancies. These lesions do not present in childhood and adolescence and will not be considered further.

Abnormalities presenting in the newborn period Malformations which become evident at birth or shortly afterwards may affect the genital tract alone or may affect it in association with an obvious urinary tract or intestinal tract anomaly. Congenital malformations are often multiple, and it should be remembered that although a malformation of the genital tract seems to be an isolated lesion, there may be renal tract abnormalities too which may not be recognizable unless an intravenous pyelogram is undertaken. Patients with ambiguous sexual development make up a special group, which was discussed in Chapter 2. Hydrocolpos This condition in the newborn is the counterpart of haematocolpos which presents about the time of puberty. An imperforate membrane situated in the region of the hymen obstructs the lower vagina and allows vaginal and cervical secretions to collect therein. The membrane is often referred to as an

imperforate hymen, although this is not strictly correct; the hymen can usually be detected as a separate structure applied very closely to the external aspect of the obstructing membrane. This membrane is called a transverse vaginal septum and it results from failure of fusion of the urogenital sinus and the downgrowth of the vaginal plate from the Müllerian structures. It may be assumed that the majority of newborn children with such an imperforate vagina do not have symptoms related to it at that time and the abnormality only becomes evident at puberty; the quantity of vaginal secretions in such patients is presumably insufficient to cause symptoms, and unless the vagina is very carefully inspected no fault will be recognized. When a large quantity of fluid collects, however, there may be difficulty in emptying the bladder, as the distended vagina fills the pelvis, and the child may be fretful and clearly in discomfort. The physical signs then are a lower abdominal cystic swelling (Figure 3.1) (the distended bladder perched upon a vagina full of fluid) and a bulging membrane at the introitus (Figure 3.2); if a rectal examination is done with a little finger, a cystic swelling in front of the rectum will be noted (Figure 3.3). The bulging membrane at the vulva does not have the bluish discolouration of the membrane in haematocolpos, since the retained fluid is milkywhite in colour; if, as very rarely happens, there is a short length of uncanalized vagina instead of a membrane, there will be no bulge at all and the diagnosis may rest on the combination of the lower abdominal swelling, the cystic mass felt at a higher level on rectal examination, and the imperf orate vaginal orifice. Diagnosis is the most difficult and important aspect of hydrocolpos. The literature contains many examples of errors in diagnosis leading to laparotomy 27

28

Malformations of the genital tract

Figure 3.1 Lower abdominal distension in a patient with haematocolpos. The lower abdominal swelling in hydrocolpos is identical Distended vagina and uterus

Figure 3.3 Illustration of vaginal and uterine distension in hydrocolpos, haematocolpos and haematometra

Figure 3.2 Bulging membrane at the introitus in a newborn with hydrocolpos. (From Dewhurst, 1968, by permission) or even hysterectomy, perhaps with fatal results. The most common mistake, of course, is to believe the swelling to be an ovarian cyst which can occur in the newborn, although rarely. These mistakes occur for many reasons; the examiner either is unaware that the condition of hydrocolpos exists, or does not examine the vulva, or is misled by the size of the abdominal swelling which can be very large (Figure 3.4). All masses in infants should be examined by ultrasound to identify the organ involved so that appropriate treatment can be planned. Treatment is simple in most cases. The intact membrane is incised and the retained fluid released. The redundant portions of the membrane may be snipped away, and the procedure is over. Greater difficulty may be encountered if the obstruction is a good deal more extensive than a thin membrane. In such a case the dissection will be more hazardous

Figure 3.4 Enormous abdominal swelling in an 8-day-old child with hydrocolpos. (From Dewhurst, 1968, by permission) and great care must be taken to avoid the bladder and rectum. Once the fluid is reached it is best to attempt to enlarge the opening if this can safely be accomplished, since it will have a very strong tendency to contract, and if infection is introduced before the vagina has discharged all its fluid, a serious and difficult problem may arise. The origin of the fluid cannot entirely be

Abnormalities presenting in the newborn period

o

15 mm : 6 weeks

or

* (a)

(b)

or

(c)

(d)

Full development

Figure 3.5 On the left, three stages of normal development of the female genital organs are indicated by white arrows. The black arrows indicate various developmental abnormalities: (a) cloaca; (b) cloaca with hydrocolpos; (c) persistent urogenital sinus; (d) persistent urogenital sinus with double uterus and vagina. (From Dewhurst, 1978, by permission)

explained. It is presumably a mixture of the physiological vaginal discharge, which is formed at this time as a result of passive hormone stimulation across the placenta, and the mucus of cervical glands. Presumably only in exceptional cases in which the outpouring of vaginal discharge is large in amount do symptoms occur in the neonatal period. If they do not arise then, it is very uncommon for them to appear until menstrual blood collects at puberty. Hydrocolpos is usually an isolated abnormality with no special inherited tendency. It is reported, however, in different members of the same family in the Amish sect (McKusick, 1964), and it is probably due to a rare autosomal recessive gene (McKusick, Weiboecher and Gragg, 1968). Occasionally gynaecological opinion may be sought for a young child without symptoms who, on routine examination, is believed to have an imperforate vagina. Most such patients have labial

adhesions which can easily be distinguished by their characteristic appearance, if care is taken (see Figure 4.8). Less often the vagina will be imperforate and the problem will be in determining whether this is due to a membrane, or short length of absent vagina, or a complete absence. Clinically the distinction cannot easily be made, since the main distinguishing feature - a collection of blood in the pelvis - has not yet made its appearance. If the uterus is present, blood will begin to collect at puberty, but not before; if the uterus is not present, as is usually the case with the absent vagina, no blood will collect. The diagnosis is better postponed until puberty although ultrasound demonstration of a uterus can be helpful in reassuring the parents. It may be prudent to warn the parents of the possibility of a haematocolpos and its symptoms, if the vagina cannot be found with certainty, but great care must be taken when giving the explanation as immense long-term anxiety may be generated.

29

30

Malformations of the genital tract

Ectopic anal opening During the early development of the vagina and bowel, the cloaca is divided by a longitudinal septum into the urogenital part anteriorly and a rectal part posteriorly. At that time (15 mm: 6 weeks) the intestinal opening lies adjacent to the urogenital opening, and as development proceeds, the anus migrates posteriorly and is separated from the vagina by the perineum (Figure 3.5). This stage of separation is sometimes incomplete; the bowel may open onto the perineum in front of its normal site, or at the fourchette immediately alongside the introitus, or into the lower vagina. In all these cases it passes through the levator sling, and effective sphincteric control of the bowel is generally achieved if correct treatment is instituted. More serious abnormalities exist with the bowel opening into the upper vagina above the levator muscles; no sphincteric control of this orifice exists, and the faeces pass freely into the upper vagina. In extreme cases the cloaca persists as a common cavity into which the bladder, genital tract and bowel open (Figures 3.5 and 3.6). Cloacae and high rectovaginal fistulae present very serious lesions. The cooperation of an expert paediatric surgeon is essential, since the most pressing problems lie with him. Colostomy is likely to be the first step but the particular circumstances of the case will, of course, influence treatment. There is no need for immediate gynaecological treatment, although even if the child does well, difficult problems may arise at puberty. Openings of the bowel into the lower vagina or onto the perineum at any point may or may not require major surgery. One important point in such a case is that the actual bowel opening is almost always contracted (Figure 3.7). Unless this is dealt with appropriately, there will soon be chronic retention of faecal matter in the rectum and lower colon; the solid faecal matter may be retained and the fluid faeces from a higher level may be evacuated past it with difficulties in control as a result. Sooner or later the rectal reflex will be lost. The construction of the anal opening may be enlarged by dilation or by the Denis Brown 'cutback' procedure; an incision is made from the midpoint of the bowel opening posteriorly to enlarge the opening and allow free egress of faeces (Figure 3.8). The degree of sphincteric control which exists when this is done is usually sufficient to permit a normal life with possibly slight soiling when faeces are fluid. Most paediatric surgeons prefer a 'pull-through' procedure, with the bowel dissected off the vagina and brought through the perineal tissues at the normal position. Injury to the sphincteric mechanisms must be avoided when this is done. For an anus that opens at any point outside the vagina, operation will usually be unnecessary and a dilatation or cutback procedure will be adequate.

(b)

Figure 3.6 (a) A newborn child with a cloaca. There is excessive fusion of labial folds restricting the single opening to one which merely receives a fine probe. Note the absence of the anus, (b) A diagrammatic representation of the findings in the child illustrated in (a). Note the associated sacral agenesis. (From Dewhurst, 1968, by permission)

Abnormalities presenting in the newborn period

31

Figure 3.7 An ectopic anus opening at the fourchette Note the constricted anal opening. (From Dewhurst, 1968, by permission)

The gynaecologist's involvement will be minimal in most such cases but his experience and advice may be helpful on occasions; a good cooperative relationship with a paediatric surgeon will give fruitful results. Later, of course, as the immediate problem is solved and the girl grows up, attention may be required to the vagina which may be narrow to some extent at the point at which the bowel originally entered. Whether this narrowing will need treatment at all will, of course, depend on the likelihood of its causing dyspareunia; if this seems probable, a surgical enlargement may be required. This should not be attempted until well after puberty and in practice, not until the girl has a sexual partner if possible. The procedures likely to be helpful are not always easy and a mould may need to be worn for weeks or months to prevent contraction from recurring. Thus, any attempt to correct these anomalies without a patient who is well informed, mature intellectually and well motivated is doomed to failure. The principles to be used in approaching such a case are similar to those employed in all forms of vaginal construction or of absence of part of the vagina with blood retained at a higher level (see pp. 35-43). The constricted area can be incised laterally on one or both sides to obtain an organ of normal calibre; once haemostasis is controlled, a firm mould of suitable size should be inserted, sewn into place,

Figure 3.8 A patient in whom an ectopic anus opening at the fourchette has been enlarged by a cutback in infancy. She has excellent anal control and worn for approximately 2-3 months. This allows epithelialization and minimizes later constriction. Meanwhile the patient is kept on a combined oral contraceptive to prevent menstruation. It is difficult to give precise advice in cases such as these. If the problem does not seem straightforward, referral to a specialist with the particular expertise would be wise. It is important to remember that the first attempt gives the best results and the necessity for recurrent surgery will lead to increasing frustration for the patient and the surgeon. These patients have deep psychological problems and the possibility of a normal sex life is paramount to their self-esteem. They are not the type of case where a surgeon should operate without experience. These abnormalities are considered in more detail by Stephens (1963) and Dewhurst (1968).

32

Malformations of the genital tract

Bladder exstrophy and related lesions Most variants of bladder exstrophy are serious lesions with the likelihood of one or more major surgical procedures being required. The problems are again predominantly those of the paediatric surgeon or urologist, but there are gynaecological associations for which an opinion may be sought. The gynaecological aspects of this interesting abnormality are discussed more fully by Jones (1973), Stanton (1974) and Dewhurst (1978). In complete exstrophy, the anterior wall of the lower abdomen and the anterior wall of the bladder and urethra are deficient. The posterior bladder wall with its trigone and ureteric orifices is clearly seen (Figure 3.9); this is tender, and the child cries and winces when it is touched. The clitoris is bifid, each half being folded over a small red spot of erectile tissue. The superior ramus of the pubis on each side is grossly deficient and the bone ends can easily be felt widely separated from each other (Figure 3.13). In some cases an exomphalos is also present. The gynaecological abnormalities present at birth include anterior displacement of the vagina which may lie about level with the bifid clitoris. The vaginal orifice may be normal, but not infrequently it shows a remarkable degree of constriction, as though the surrounding skin and mesoderm had attempted to grow forwards to close the anterior

Figure 3.9 An example of gross bladder exstrophy in a newborn. The two catheters are placed in the ureters and the two probes in the lower part of the photograph indicate widely separate vaginas. (From Dewhurst, 1963, by permission)

Figure 3.10 A pubertal girl whose bladder exstrophy has been repaired during childhood. Note the greatly constricted vaginal opening which is lying in an anterior situation. (From Dewhurst, 1968, by permission)

wall defect, and all but closed the vagina instead (Figure 3.10). A sound or probe can usually be inserted quite easily to identify the orifice but constriction may be so marked that only with great difficulty and under anaesthesia can an opening be found and a tiny probe inserted. The opening can be enlarged by a midline posterior incision (Figure 3.11) but care should be taken not to enlarge the opening too much, since to do so will predispose to a further gynaecological fault - genital prolapse which sometimes occurs at a very early age in patients with bladder exstrophy (Figure 3.12). It has been reported a number of times in the teens and early twenties. The large defect in the bony pelvis in front (Figure 3.13) associated with a similar defect in the anterior portion of the levator ani muscle is probably responsible for this. Treatment may be very difficult. Success may be possible with a procedure in which the abdomen is opened, and the posterior aspect of the cervix fastened to the periosteum of the sacrum by means of an intervening bridge of Ivalon sponge or porcine skin in which firm fibrosis quickly occurs (a sacrocolpopexy). The absence of the usual supporting structures from the anterior part of the pelvis makes the customary form of pelvic floor repair inappropriate.

Abnormalities presenting in the newborn period

wJW'mk ' , ■'■',■ '

Figure 3.11 The introitus has been enlarged by a posterior incision to reveal a vagina of normal capacity. Note the tendency for the anterior vaginal wall to bulge, indicating the subsequent risk of prolapse. This enlargement is probably greater than was necessary

Figure 3.12 Marked degree of prolapse with the cervb outside the body in a 13-year-old girl born with a bladder exstrophy. Deformity of the anus also present at birth can be noted. (From Dewhurst et al., 1980, by permission)

33

Figure 3.13 X-ray of a patient with a bladder exstrophy showing the gross defect in the anterior part of the bony pelvis Minor cases of exstrophy with less bladder uncovered may be seen, but the gynaecological associations are similar. Sometimes the defect is limited to the urethra, the roof being absent and the condition being one of epispadias in the female (Figure 3.14). The least abnormality of all is the bifid clitoris with an intact urethra (Figure 3.15). Clearly, close cooperation will again be required with a paediatric surgeon or urologist. In some cases reconstruction of the bladder and urethra may be possible with acceptable urinary control. If this closure is anatomically unsuccessful but urethra control is not achieved, it is possible that a urethroplasty type of

Figure 3.14 A minor degree of bladder exstrophy in a newborn. This amounts to epispadias. (From Dewhurst, 1968, by permission)

34

Malformations of the genital tract

Figure 3.15 Bifid clitoris in a newborn who has no urethral abnormality. (From Dewhurst, 1968, by permission) procedure might be considered, but caution should be exercised here. If only the lower portion of the urethra is affected, the upper sphincteric part being intact, the decision to intervene will depend on the degree of urinary control that exists already. If this is for the most part adequate for everyday life, the temptation to operate should be resisted since there is a chance that it might make matters worse. If the degree of urethral control is not acceptable, an attempt to close the lower urethra may be appropriate. An inverted U-shaped incision around the margins of the exposed floor of the urethra is then made, the edges freed, and the tube of urethra formed in a manner similar to that used for the refashioning of the urethra destroyed by childbirth (Moir, 1961). The skin layer may be closed over this again to complete this part of the procedure. A reconstruction of the urethral tube may be quite inadequate to give urethral control, however, and it might be necessary to consider suburethral plastic repair in a manner similar to that used for stress incontinence. Needless to say, such procedures are not easy and if an expert gynaecologist or urologist is available, referral is preferable. Moreover, the older the child, the easier the operation will be, so procrastination as long as possible is advisable. Reduplication of the urethra A bizarre type of abnormality has from time to time been reported involving duplication of the urethra (see Dewhurst, 1978 for review). There is external evidence of maleness (Figure 3.16), and the prominent phallus contains a narrow urethra in its substance; in addition, a second urethra opens in more

Figure 3.16 (a) External appearances in a newborn with a duplication of the urethra and a cloaca, (b) The appearances are illustrated diagrammatically. (From Dewhurst, 1978, by permission) or less the normal position. Other abnormalities too may be associated such as a persistent cloaca. Urinary retention has been a common feature of reported cases, dilatation of the 'normal' urethra often being required; similarly, reflux is a possible complication. Many affected children have died early, but those reported more recently who have not had serious associated anomalies have done well. It is not easy to give general advice on such rare cases but removal of the phallus with its second urethra will usually be required. If there is an associated bowel fault, colostomy may be required at first with perhaps a perineal pull-through opera-

Abnormalities presenting in the pubertal patient

35

tion later. If the child does well, an operation to permit a normal sex life will ultimately be required.

Abnormalities presenting in the pubertai patient Haematocolpos This condition in its typical form is neither serious nor difficult to manage; in its atypical form it can cause considerable problems in diagnosis and treatment. Typically haematocolpos occurs in the 14-16-yearold girl who has good secondary sexual development but has not menstruated. She complains of intermittent lower abdominal pain which is sometimes regular and monthly but more often irregular in time and duration. The pain is due to the accumulation in the vagina of menstrual blood at each period, and since periods are seldom regular at this age, pains are usually equally irregular. The vagina can accommodate a large quantity of blood and it seems probable that little collects in the uterus as haematometra until somewhat later. The next symptom to appear is difficulty in emptying the bladder as more and more blood distends the vagina, culminating in an episode of acute retention of urine, if the patient is not seen before this occurs. The physical signs are similar to those already described for hydrocolpos - a lower abdominal cystic swelling (Figure 3.1), a similar cystic swelling felt anteriorly on rectal examination (Figure 3.3), and a tense bulging bluish membrane at the introitus (Figure 3.17). The diagnosis is generally straightforward, and treatment is equally easy; the membrane is incised (Figure 3.17) and the redundant parts of it excised, and nothing else need be done. Swabbing out the vagina or irrigating it with fluid, or examining the depths of it with the finger are neither necessary nor desirable. They can do little good and may introduce infection. Once treatment is complete, the retained blood drains away in a few days and nothing else need be done. An intravenous pyelogram is desirable later to exclude a malformation of the renal tract which is not an uncommon association. The subsequent menstrual history and fertility are usually normal in such an uncomplicated case. Complicated haematocolpos Complex cases of haematocolpos occur which give rise to a great many more problems. Absence of a part of the vagina with blood retained above this portion will give rise to similar symptoms, but the physical signs will not be exactly the same. The bulging membrane will be absent, although it is usually possible to detect that the introitus is

36

Malformations of the genital tract

Figure 3.18 Haematocolpos associated with (a) lower transverse vaginal septum, and (b) upper transverse vaginal septum

imperforate. Upon rectal examination, the cystic collection of blood may be found at a higher level than previously (Figure 3.18). In general, the more vagina absent, the higher the cystic swelling felt per rectum, but the determination of the amount of vagina missing is one of the most difficult aspects of such a case. Transverse vaginal septae These cases are due to a transverse vaginal septum which may be high, mid or low. The majority occur at the junction of the middle and upper two-thirds of the vagina (Rock et al., 1982). Prior to any attempt at therapy, the amount of vagina present must be determined, either clinically or with the aid of ultrasound. An intravenous pyelogram should always be performed as the incidence of renal abnormalities is 15% for major anomalies, e.g. single pelvic kidney. Many surgically minded gynaecologists reading this may think it excessively cautious. It is not. Dissecting blindly from below is not

easy and may result in the dissection entering the rectum before the retained blood is reached and the risk of a recto-vaginal fistula. In general, the greater the absence of the vagina, the more difficult the case becomes surgically, and success may be hampered by the presence of endometriosis (Rodeck, Craft and Dewhurst, 1975; San Fillipo et al., 1986) and concurrent haematosalpinges. In cases where the transverse vaginal septum is in the lower and middle thirds of the vagina, and the upper part of the vagina has been well defined, the dissection may be from below, through a transverse incision in the blind vagina. After the initial incision across the region of the posterior aspect of the introitus, most of the dissection along the track of the absent vagina can be done bluntly with the fingers. The technique of doing this blunt dissection along the line of the Müllerian ducts on each side of a midline septum which lies between them and which is usually detectable quite easily, has been reported on favourably by Sheares (I960). The upper vagina is usually then incised and the retained black menstrual blood is released. The vaginal septum is excised with scissors and the upper and lower parts of the vagina are reanastomosed with 2-0 chromic catgut. This procedure is only practicable if the absent portion of the vagina is 2-3 cm, or the risk of contracture is too great and the constriction may be very difficult to treat subsequently. For cases where the transverse septum is high, or the lower part of the vagina is absent and the distance from the introitus great, a different approach is necessary. The approach is abdominal and perineal and the abdomen is opened through a Pfannenstiel incision. A space is created between the rectum and the bladder and urethra as described above and the blood is drained, getting as large a calibre as possible to the new vagina. Nothing more is done for about one week, the blood merely being allowed to drain away. Then after this interval the patient is anaesthetized again and a further procedure is undertaken to enlarge the vaginal tract to its former size, since some contraction will already have occurred. A solid mould of dental stent or other plastic material is then chosen of appropriate size to fit the vagina snugly but on no account tightly. If this can be hollow, so much the better, since menstruation may occur while the mould is being worn, despite the precaution of keeping the patient on a combined oral contraceptive all the time. The mould is sewn in place and left in situ for 3-4 months. If too large a mould is chosen, there may be pressure on the bladder base and on the urethra or rectum, and avascular necrosis may lead to fistula formation. If the mould is too narrow, an adequate calibre of vagina may not be obtained. If it is too short, contraction may still occur below it, squeezing

Abnormalities presenting in the pubertal patient

it up into the upper part where it will achieve nothing. If the correct size is chosen for the individual patient, epithelialization occurs from above and below with, it is hoped, little tendency to contract thereafter. The mould may be removed after this time and if good epithelialization has occurred throughout, nothing more need be done. The patient may wear the mould for a while at night and pass it occasionally by day, but if there is no contraction evident at two follow-up visits, this practice may cease. The prospects for fertility after these procedures are difficult to assess. In patients with imperforate hymen, the fertility potential is probably normal, but the cases of transverse vaginal septae are not so lucky. They tend to present later, and the incidence of endometriosis and adhesions is much greater, impairing their fertility. Rock et al. (1982) reports an overall pregnancy rate of 47% but all cases of lower third obstruction conceived, 43% of middle third, and only 25% of upper third cases. Thus, prompt diagnosis and treatment may preserve reproductive capacity in these patients. Congenital absence of the cervix This is an extremely rare but interesting anomaly. The literature contains a total of 54 cases, summarized by Regan and Dewhurst (1985), Färber (1986), and Edmonds, Drew and Dewhurst (1989). The presenting symptoms are of primary amenorrhoea and cyclical abdominal pain in the presence of a functional uterus. There is congenital absence of the vagina in 50% of cases and other anomalies in 22%, thus almost 75% of cases have multiple abnormalities. The primary aim of treatment is relief of symptoms and preservation of any fertile potential. The condition is rare, and little surgical expertise has developed in the management of these cases; of 50 cases with a functioning uterus, 14 cases had primary hysterectomy and in the remaining cases, where an attempt to establish a communication was made, long-term follow up is only available in 21 cases. Eleven patients required a hysterectomy due to subsequent cervical occlusion although there are two cases of pregnancy (Zarou et aL, 1973; Singh and Devi, 1983) delivered by caesarian section. Although the chances of success would seem small, one feels obliged to try, especially if the amount of damage to the fallopian tubes makes pregnancy a possibility. Given normal fallopian tubes and an otherwise clear pelvis, an attempt to create a new vagina connected to the uterus may be made as follows. The dissection of the vagina is made up to the region of the cervix as previously described. The uterus is then opened by vertical incision in the lower part. A blunt probe or sound is then introduced into the

37

uterine cavity downwards towards the cervix and manoeuvred through the solid cervical tissue into the vault of the newly constructed vagina. A plastic catheter of sufficient length must now be carried down through this channel so that it enters the vagina, the balloon end of the catheter being, of course, inside the uterine cavity. A hollow mould is then covered with amnion or a split thickness skin graft and threaded up the catheter so that the mould lies snugly in the vagina as described above. The mould and catheter are left in place for as long as possible (up to three months). Infection is the problem, since organisms can easily gain access to the uterus and the pelvis. These cases are so rare that management should only be in a centre where experience in the management of congenital abnormalities is extensive. If the procedure fails, only hysterectomy is left.

Disorders of lateral fusion As the two Müllerian ducts fuse, a single vagina, cervix and uterus usually results. However, if this is incomplete, then a double uterus is created, and a double cervix. The vagina is usually double also but a variety of anomalies are associated. Septae

vagina

Here a duplication of the vagina is asymptomatic unless there is dyspareunia due to narrowing of the vagina. This necessitates surgical removal of the septum and as this is usually rather thick, care must be taken to ensure adequate pedicles and good haemostasis. It is not usually necessary to excise the complete septum as the tissue retracts and leaves a narrow ridge which is of no consequence. Complete imperforate unilateral

vagina

Here, there is outflow obstruction of menstrual flow, which collects in the blind vagina (Figure 3.19). The diagnosis is made when there is regular menstruation, severe dysmenorrhoea and examination reveals a cystic swelling, bulging into the side of the patent vagina. This condition can be treated by incising the septum between the two vaginas to allow one to drain into the other. Unless a large enough opening is made in the septum, however, there is a real risk that it will contract again with further retention of blood and perhaps infected matter. Once the septum is incised, the outpouring of blood will so obscure the field that it may be difficult to safely excise the redundant parts of the septum. Suction and lavage should be used to wash away the retained blood and mucus, and the septum removed.

38

Malformations of the genital tract

Figure 3.20 External genital appearance in a patient with congenital absence of the vagina

Figure 3.19 (a) Haematocolpos and (b) haematometra in an imperforate half of a double genital tract Reproductive performance is only fair with a double uterus and problems with recurrent pregnancy wastage and interuterine growth retardation mean a successful outcome in only about 60% of cases (Rock and Jones, 1977; Buttram and Gibbons, 1979). Congenital absence of the vagina This condition usually exists with congenital absence of the uterus or a rudimentary solid uterus, or uterine horns which lie laterally on the pelvic sidewall, although the ovaries are normal. It is commonly referred to as the Mayer-RokitanskyKuster-Hauser syndrome (or shortened to the Rokitansky syndrome) after the first four papers to describe the anomaly (Mayer, 1829; Rokitansky, 1838; Küster, 1910; Hauser, Keller and Koller, 1961). It is an abnormality which often presents in adolescence, although treatment should only rarely

be undertaken before later adolescence and never during childhood. The malformation usually comes to light when a pubescent girl with good secondary sexual development fails to menstruate. As outlined previously, this combination of features commonly suggests an anatomical cause for primary amenorrhoea; one such case is haematocolpos as just discussed, another congenital absence of the vagina. The latter is distinguished from the former by the absence of any symptom or sign suggesting that blood is collecting in the pelvis, i.e. no pain at intervals suggesting cryptomenorrhoea, and no palpable mass on rectal examination. The area where the vaginal introitus should be shows no opening, but the vulva is otherwise normal (Figure 3.20); there is a slightly rugose appearance to the skin over the surface of the normal introitus. The condition must be distinguished from two others - labial adhesions and androgen insensitivity; in the latter, the vulva, vaginal introitus and hymen usually appear normal but the vagina is, in fact, short and blind. Such a very short vagina can sometimes be mistaken for an absent one in an otherwise normal female. In androgen insensitivity, however, the pubic hair is usually absent or very scanty - an important distinguishing feature. Should there be the slightest doubt, the chromosomal constitution of the patient should be established which will be 46 XY in androgen insensitivity

Abnormalities presenting in the pubertal patient

Figure 3.21 Intravenous pyelogram indicating a single pelvic kidney in a patient with congenital absence of the vagina. (From Dewhurst, 1976, by permission) and 46 XX in congenital absence of the vagina. If there is doubt about the presence or absence of the uterus or of a collection of blood in the pelvis, an ultrasound examination should dispel it. Investiga­ tion should include an intravenous pyelogram to exclude or confirm an associated malformation in the urinary tract (Figure 3.21). The association of congenital absence of the va­ gina with other anomalies must be remembered. Some 40% of patients have some urinary tract abnormality, although only 15% have major defects such as a single kidney or a pelvic kidney. Skeletal abnormalities also occur in about 12% of cases and are mainly associated with the vertebral column. Fusion of L5 to the sacrum or six lumbar vertebrae, absence and fusion of cervical vertebrae and rarely abnormalities of the hands. The clinical management of these cases is divided into two stages, psychological counselling and therapy. Psychological

problems

The response to the information given that the vagina is absent is generally devastating and profound. The reaction is both by the patient and the parents and varies considerably with the age of the girl. The most comprehensive study of these

problems has been published by Poland and Evans (1985). These girls are frightened and confused and most express feelings of rejection and 'feeling like a freak'. They feel isolated and lonely and do not feel anyone can understand how they feel. The concern about sexual activity and fertility is obvious, but they feel 'no man will want me' and the thought of childlessness is very depressing and the most diffi­ cult aspect that they have to accept. They often ask 'Why did this happen to me?' 'Am I a real woman?' 'What can be done to help me?' The gynaecologist must be gentle and caring in answering these impor­ tant questions in a sympathetic manner, but with great honesty. Most mothers feel guilty and worry that they have done something during pregnancy to result in the abnormality. They are much more demanding that surgery be performed immediately to 'put the prob­ lem right'. The pressure can be very considerable and the gynaecologist must not slip into the easy folly of keeping the mother happy by treating the problem too soon. There are few patients who would be classified as developing a psychiatric problem, although thoughts of suicide because they feel 'worthless' are not uncommon. If necessary, psychiatric referral should be sought. It is important for the health care team to under­ stand the psychological and psychosexual problems these patients have and to be able to offer adequate support. We feel it is very important to admit patients in groups for counselling to dispel the feeling of Ί thought I was the only person in the world with this problem'. Meeting other patients, both at the same stage of treatment and those who are in mid therapy and post therapy, is vital in the battle to regain the loss of self-esteem. The time when therapy should start is very diffi­ cult to assess. In general, those patients aged 17 years do less well. When the health care team in consultation with the patient with or without her parents, feel the time is right gives probably the best guide, but the presence of a boyfriend is the key to success. If the patient is motivated through a desire to achieve sex with a caring partner, her ability to dedicate herself to the arduous task of dilators and/or surgery and the inevitable slow progress to the end result, will be much greater. She will require endless support and encouragement from a well trained team of personnel to achieve her aims and so we recommend referral to a major centre if this is not locally available. These patients find travelling to the centre for treatment a worthwhile hurdle to overcome, and we have had very few patients who have found it difficult. After treatment, long-term follow-up through self-help support groups seems to be very useful. As the patients mature, the questions which concern them change and a forum for open discussion with

39

40

Malformations of the genital tract

V ?^#M'

Figure 3.23 Dilator of the variety used for graduated dilatation in patients with congenital absence of the vagina Figure 3.22 The same patient as illustrated in Figure 3.20 indicating the extent to which the region of the absent vagina can be indented with the finger

other women with similar problems and the health care team has proved invaluable. The sexual experience which patients find after therapy is important. Most are very frightened that they may be hurt or damage their new vagina. This may lead to male anxiety and premature ejaculation. The reassurance of the dilator and its size as well as counselling with the partner in general will overcome these difficulties. It is important to note that in studies done in which men who had had previous partners were asked to comment on the artificial vagina, most found no difference. Most couples find that lubricants, e.g. KY Jelly, are very helpful. The loss of the ability to have a child is one which is never resolved and although most women marry and some adopt children, they often feel anger and resentment at their inability to reproduce, as they equally regret not menstruating.

Therapy The management of these cases is usually by a non-surgical method initially, and then, if necessary, a surgical approach. The technique of non-surgical treatment of the absent vagina is that originally described by Frank (1938). The principle of the method is that the region which the vagina should occupy is a potential space filled with comparatively loose connective tissue which is capable of considerable indentation (Figure 3.22). If the examining finger is pressed gently but firmly into this potential space, as shown in the figure, the capacity for indentation can readily be demonstrated.

The first step is to tell the patient that she is going to help with her own treatment and, if successful, which it has every chance of being, she may avoid an operation altogether. This is a powerful argument to win her cooperation. The second step is to show the patient the dilators to be used. These may be of a variety illustrated in Figure 3.23 or similar ones made of the same or different material. They are better in graduated sizes so that she can begin with a small one and gradually increase as progress is made. These girls have never explored their anatomy and it is very important to explain her features and to show her using a mirror. Until she understands the purpose and the site of the new vagina, and also the normality of her external genitalia, she will not cooperate or be successful with any technique, especially Frank's manoeuvre. By using the medial aspect of the closed fist and illustrating the mode by which pressure will deepen the penetration, she will gradually understand the manipulation. The use of diagrams and models of female anatomy are also very useful and important. The tip of the dilator is then placed against the introitus to show the girl where it must go; then it is removed and she must replace it herself at the correct site. When she has correctly placed it, firm pressure, but of course not to the point of pain, is exerted by her for approximately 10 min in the first instance. She may do this twice a day. Gradually the dilator will go further and further in. The duration of pressure may be increased to 15 and then to 30 min; she may lie in bed while one hand keeps the dilator pressed in place, or in some instances the patient finds it easier to site the tip of the dilator in the correct place and then sit on the dilator and control the pressure by gently lowering herself onto the dilator. Ingram (1981) has suggested the use of a modified bicycle seat, with the dilator on the seat, with encouraging results. With encouragement from all - mother, family physician and gynaecologist - she will see a notice-

Abnormalities presenting in the pubertal patient

41

number of operative techniques have been devised. There are two methods which are used nowadays; a vaginoplasty using various types of tissue to line the neovaginal space, e.g. skin or amnion, and the Williams' vulvovaginoplasty. The choice of operation depends on the case, and although preference is to create a vaginal space in the anatomically correct site, some cases of congenital adrenal hyperplasia make this almost impossible and the Williams' technique is invaluable under these circumstances.

Williams'

Figure 3.24 Vagina constructed by Franck's procedure into which a Sim's speculum can be fully inserted able improvement in 1-2 months, and a vagina 7-8 cm or more in length may be the result after 3-4 months. Figure 3.24, which shows a Sim's speculum inserted to its full length into a patient treated in this way, indicates what is possible. With coitus, of course, greater lengths still may be achieved. We believe that the initiation of therapy should be done as an inpatient and instruction and counselling be performed by experienced and understanding personnel. The role of a female member of the team in these circumstances is in our opinion vital, as a need to relate to a woman helps patient understanding and trust. The patients usually spend about five days in hospital initially, and then are seen at weekly intervals as outpatients. If the progress is not satisfactory, or the patient is having psychological problems, then they are readmitted for further counselling. No patients undergo vaginoplasty until at least six months of counselling and instruction on the use of dilators has been completed. Only then, if this technique has failed, will surgery be considered. This treatment does not always succeed - no treatment ever does! The results of the Frank technique have been variously reported, but about 80% of patients will achieve a satisfactory result. These figures emphasize the importance of not pursuing a surgical approach as an initial therapy but reserving it for those cases where the non-surgical therapy has to be abandoned. Under these circumstances, a

vulvovaginoplasty

This simple procedure was first described by Williams in 1964. The surgical technique is described in Figure 3.25. The initial U-shaped incision is made 4 cm lateral to the midline and it is carried anterior to the urethra in front while the transverse portion of the U transverses the perineum a short distance in front of the anus. The incision is deepened to open tissue planes and free the edges. The tissue is loose in the area and the dissection is not difficult. Haemostasis is secured and an indwelling catheter is put into the bladder. The inner skin edges are sewn up from behind forwards, as shown in Figure 3.25, the knots in the catgut being placed within the vaginal pouch. Once the inner layer of suture is in place, a few loose deep stitches may be inserted across the posterior aspect of the wound to obliterate the dead space, although these must not constrict the new vagina. The outer skin edge is then closed and the operation is over. The indwelling catheter is kept in place for 6-7 days. During this time it must be kept strapped forwards over the lower abdomen so that it does not drag backwards and break down the suture line. When the catheter is removed after about seven days, no further postoperative procedures are required. The new vagina is, of course, a pouch made from the labia, and on completion usually accommodates 1.5-2 fingers quite easily for 3-4 inches of its length. Its angle is not that of a normal vagina, of course, but with continued intercourse the high perineum is depressed and the apex of the vagina becomes further indented by the penis so that a more physiological angle is soon achieved. Capraro and Capraro (1972), recognizing that the procedure permits excellent natural dilation of the potential space where the vagina should be, report good results with a shorter Williams' procedure without taking the incision forward of the urethra. There are scarcely any immediate surgical risks to this simple procedure. Amongst possible later complications, a breakdown of the entire area on one occasion has been observed (Feroze, Dewhurst and Welply, 1975) and a growth of hair in the vagina on another; a few patients are aware of a little pooling

42

Malformations of the genital tract

Figure 3.25 (a) Initial incision for the performance of a Williams' vulvovaginoplasty. (The anterior limbs of this incision are more medial than is desirable.) (b) After freeing and undercutting the deeper tissues the inner skin layer is being brought together to form a tube which will be the new vagina, (c) Suturing the inner skin layer has almost been completed, (d) The outer skin layer has been brought together over the inner and two fingers are inserted into the introitus of the new vagina. A satisfactory functional result occurred in this case

Abnormalities presenting in the pubertal patient

of urine in the vagina after micturition but this is not troublesome as it is easily squeezed out. Two final observations may be made concerning this simple procedure. If the labia minora are prominent, they may fill the new vagina when the inner incision is closed, turning them into its cavity. If this is thought likely to be a problem, the labia may be removed flush with the skin of the vulva, the incision closed, and the operation proceeded with as above without any disadvantage. The second point to be made is that once the vagina is constructed by this method it appears to have little if any tendency to contract if not used for some years - this is in contrast to the strong tendency of contraction in the skin graft procedure described below. A successful functional result can be achieved in the majority of cases, but there is little doubt that the formation of the pouch distorts the anatomy and this is psychologically unsatisfactory for the majority of patients. The external genitalia are usually normal and the anomaly of the absent vagina is 'not seen'. By altering the normal anatomy, a visual and tactile reminder of their abnormality exists which is unacceptable to most women.

Mclndoe vaginoplasty This technique was first reported by Mclndoe and Bannister (1938) and the first series reported by Mclndoe in 1950. The principle was to use a single, large, split-thickness, skin graft around a solid rubber mould to line the neovaginal space and create a new vagina. Counsellor and Flor (1957) modified the Mclndoe technique and advocated the use of a soft foam rubber mould and this is the method most widely used today. The patient is placed in the lithotomy position and the labia separated. A transverse incision is made in the vaginal dimple and the neovaginal space is created by digital exploration, making sure that the movement is in a lateral direction. The dissection should be continued until the peritoneum is reached, although a large area must not be exposed or there is a risk of enterocoele formation. Attention to haemostasis is fundamental to the success of the graft. A foam rubber mould is then created to fit the new vaginal space, and this is covered with a condom. A split-thickness skin graft, about 0.05 mm thick is cut from the buttock, about 10 cm wide and sufficiently long to be twice the length of the vagina. The graft is then fashioned to form a tube with interrupted sutures of non-reactive material and placed upon the mould so that the exterior surface of the skin is against the condom. The mould is then pushed into place and it is held in place by transverse sutures across the labia, and a suprapubic

43

catheter inserted to allow bladder drainage without urethral pressure. The patients are mobilized on day 2, and seven days after the initial surgery the patient returns to the operating theatre and the mould is removed, the new vagina irrigated and a new mould created. The suprapubic catheter is removed. The patients are then taught to insert the soft mould daily and at night for two weeks, and then they use dilators to prevent contraction of the neovagina. The complications of the technique are fistula formation and failure of the graft to 'take'. These are rare problems, and the graft site on the buttock usually heals well. The results of the technique give excellent functional success (90%) and anatomical success in 80% (Jackson, 1965; Färber and Mitchell, 1978; Rock, Reeves and Retto, 1983).

Amnion

vaginoplasty

A technique favoured by us is the use of amnion to line the neovagina instead of skin. This technique negates the necessity of a donor skin site and the results have been equally good (Dhall, 1984; Morton and Dewhurst, 1986). The use of dilators is introduced at an earlier stage than with skin grafting as the risk of contraction seems to be higher. As time proceeds, the new vaginal epithelium undergoes stratification and glycogen storage occurs. The changes seen in the vaginal mucosa in the normal menstrual cycle are also reflected in the neovagina. All these patients require long-term follow-up with appropriate psychosexual and psychological counselling. Failure to deliver this very important health care makes the non-surgical and surgical therapies a waste of time and effort on the part of the gynaecologist and the patient. More elaborate procedures such as that in which the new vagina is lined by the peritoneum of the pouch of Douglas are unnecessarily complex for the management of the condition and more satisfactorily dealt with by simpler means. To sum up, the approach to the problem of the absent vagina in adolescents should be: (1) Correct diagnosis of the condition. (2) Elimination of the possible presence of a functioning uterus and a renal tract anomaly. (3) Discussion of the implications fully with parents and with the patient, and the use of counselling. (4) Treatment by Frank's method when the patient is emotionally prepared. (5) If (4) is unsuccessful, performance of a vaginoplasty or, rarely, the Williams' vulvovaginoplasty.

44

Malformations of the genital tract

References BUTTRAM, v. s. and GIBBONS, W. E. (1979) Miillerian anoma­ lies: a proposed classification. Fertility and Sterility, 32, 40 CAPRARO, v. j . and CAPRARO, E. J. (1972) Creation of a

neovagina. Obstetrics and Gynecology, 39, 544 COUNSELLOR, V. S. and FLOR, F. S. (1957) Congenital absence of the vagina. Surgical Clinics of North America, 37, 1107 DEWHURST, c. J. (1963) Gynaecological Disorders of Infants and Children, Bailliere Tindall, London DEWHURST, c. J. (1968) Congenital malformation of the genital tract in childhood. Journal of Obstetrics and Gynaecology of the British Commonwealth, IS, 377 DEWHURST, c. J. (1972) Surgical treatment of genital tract malformations. Transactions of the College of Medicine of South Africa, 16, 39 DEWHURST, c. J. (ed.) (1976) Integrated Obstetrics and Gynaecology for Postgraduates, 2nd edn, Blackwell Scientific Publications, Oxford DEWHURST, c. J. (1978) Congenital malformations of the lower urinary tract. In Clinics in Obstetrics and Gynae­ cology: Gynaecological Urology, Vol. 5 (ed. S. L. Stanton), Saunders, Eastbourne, p. 51 DEWHURST, SIR JOHN, TOPLIS, P. J. and SHEPHERD, J. H. (1980)

Ivalon sponge hysterosacropexy for genital prolapse in patients with bladder exstrophy. British Journal of Obstetrics and Gynaecology, 87, 67 DHALL, K. (1984) Amnion graft for treatment of congenital absence of the vagina. British Journal of Obstetrics and Gynaecology, 91, 279 EDMONDS, D. κ., DREW, N. c. and DEWHURST, c. J. (1989) Use of

a uterovaginal fistula in the management of cervical atresia. Adolescent and Pediatric Gynecology (in press) FARBER, M. (1986) Congenital atresia of the uterine cervix. Seminars in Reproductive Endocrinology, 4, 33 FARBER, M. and MITCHELL, G. w. (1978) Surgery for congenital absence of vagina. Obstetrics and Gynecology, 51, 365 FEROZE, R. M., DEWHURST, c. J. and WELPLY, G. (1975) Vagino-

plasty at the Chelsea Hospital for Women: a comparison of two techniques. British Journal of Obstetrics and Gynaecology, 82, 536 FRANK, R. T. (1938) The formation of an artificial vagina without operation. American Journal of Obstetrics and Gynecology, 35, 1053 HAUSER, G. A., KELLER, M. and

KOLLER, τ.

(1961)

Das

Rokitansky-Kuster syndrome: uterus bipartitus solidus rudimentarius cum vagina solida. Gynaecologia, 151, 111 INGRAM,J. (1981) The bicycle seat stool in the treatment of vaginal agenesis and stenosis. American Journal of Obstetrics and Gynecology, 140, 867 JACKSON, i. (1965) The artificial vagina. Journal of Obstetrics and Gynaecology of the British Commonwealth, 72, 336 JONES, H. w. (1973) An anomaly of the external genitalia in female patients with exstrophy of the bladder. American Journal of Obstetrics and Gynecology, 17, 748 KUSTER, H. (1910) Uterus bipartitus solidus rudimentarius

cum vagina solida. Zeitschrift für Geburtshilfe und Gynäkologie, 67, 692 MAYER (1829) Über vordoppelungen des uterus und ihre arten, nebst bemerkungen über hasenscharte und Wolfsrachen. Journal Chirurgica Augenheilk, 13, 525 MCINDOE, A. (1950) Treatment of congenital absence and obliterative conditions of the vagina. British Journal of Plastic Surgery, 2, 254 MCINDOE, A. H. and BANNISTER, J. B. (1938) An operation for

the cure of congenital absence of the vagina. Journal of Obstetrics and Gynaecology of the British Empire, 45, 490 MCKUSICK, v. A. (1964) Approaches and methods in human genetics. American Journal of Obstetrics and Gyne­ cology, 90, 1014 McKUSICK, V. A., WEIBOECHER, R. G. a n d GRAGG, G. W. ( 1 9 6 8 )

Recessive inheritance of a congenital malformation syndrome. Journal of the American Medical Association, 204, 113 MOIR (1961) The Vesico-Vaginal Fistula, Bailliere, Tindall and Cox, London MORTON, K. E. and DEWHURST, C. J. (1986) Human amnion in the treatment of vaginal malformations. British Journal of Obstetrics and Gynaecology, 93, 50 POLAND, M. L. and EVANS, T. N. (1985) Psychological aspects of vaginal agenesis. Journal of Reproductive Medicine, 30, 340 REGAN, L. and DEWHURST, c. J. χ985) Atresia of the cervix. Pediatric and Adolescent Jynecology, 3, 83 ROCK, J. A. and JONES, H. W. (1977) The clinical management of the double uterus. Fertility and Sterility, 28, 798 ROCK, J. A., REEVES, L. A. and RETTO, H. (1983) Success follow­ ing vaginal creation for Miillerian agenesis. Fertility and Sterility, 39, 809 ROCK, J. A., ZACUR, H. A., DLUGI, A. M., JONES, H. W. a n d TELINDA,

R. w. (1982) Pregnancy success following surgical correc­ tion of imperforate hymen and complete transverse vaginal septum. Obstetrics and Gynecology, 59, 448 RODECK, C , CRAFT, I. L. and DEWHURST, C. J. (1975) Genital

tract obstruction and endometriosis. International Journal of Gynaecology and Obstetrics, 13, 197 ROKITANSKY (1838) Über die sogenannten Verdoppelungen des uterus. Medica Jahrbuch Oesterreich Staat, 26, 36 SAN FILLIPO, J. S., WAKIM, N. G., SCHIKLER, K. N. a n d YUSSMAN, M.

A. (1986) Endometriosis in association with uterine anomaly. American Journal of Obstetrics and Gyne­ cology, 154, 39 SHEARES, B. H. (1960) Congenital atresia of the vagina: a new technique for tunnelling the space between bladder and rectum and construction of the new vagina by a modified Wharton technique. Journal of Obstetrics and Gynaecology of the British Empire, 67, 24 SINGH, J. and DEVI, Y. L. (1983) Pregnancy following surgical correction of non fused Miillerian bulbs and absent vagina. Obstetrics and Gynecology, 61, 267 STANTON, s. L. (1974) Gynecologic complications of epispadias and bladder exstrophy. American Journal of Obstetrics and Gynecology, 119, 749 STEPHENS, F. D. (1963) Congenital Malformations of the

References Rectum, Anus and Genito-Urinary Tracts, Churchill, Livingstone, Edinburgh WILLIAMS, E. A. (1964) Congenital absence of the vagina: a simple operation for its relief. Journal of Obstetrics and Gynaecology of the British Commonwealth, 71, 511

45

ZAROU,G.S.,ESPOSITO,J. M.andzAROu.D M. (1973) Pregnancy following the surgical correction of congenital absence of the cervix. International Journal of Gynecology and Obstetrics, 11, 143-147

4 Vulvovaginitis and other vulval lesions

Vulvovaginitis This condition is probably the only gynaecological disorder of childhood which may be thought of as common. Capraro (1974), Huffman (1977) and Altchek (1984) have given good general accounts of it. Aetiology Its commonest cause is a growth of organisms of low virulence in a vagina which, as yet, lacks the protective acid secretion of later life. The epithelium of the vagina of the newborn is many layers thick, the cells being rich in glycogen (Figure 4.1). The reaction is acidic, as this glycogen is acted upon by lactogenic bacilli. Within a few weeks, however, the epithelium shrinks to only a few layers thick, and the glycogen has disappeared (Figure 4.2). The pH of the vagina rises and the organ loses its natural acid protection. Along with these vaginal changes, and an important part of the causation of vaginitis in children, is the greater ease with which organisms can be introduced into the vagina at that age. The vaginal opening is less protected by fat and the anus is anatomically close to the introitus, while children's tendency to slide around on the floor or in the sand gives a greater chance of tiny particles of foreign matter and organisms with them being introduced to set up an infective reaction. Infection with a specific organism sometimes occurs, of course; the earlier the patient is seen in the illness and the less the condition is modified by prior treatment, the more often is such an organism to be found. The presence of an infected lesion elsewhere on the body - otitis media, tonsillitis, etc. - is sometimes associated with the same organism 46

Figure 4.1 A histological section showing the appearance of a vagina in a newborn. Note the many layers of squamous epithelium filled with glycogen. Stain: haematoxylin and eosin. (From Dewhurst, 1963, by permission) being responsible for vaginal discharge. Gonorrhoea too must always be considered. Another cause of vaginitis is a pinworm infestation. Pinworms inhabit the lower bowel and spread onto the perineum and into the vagina, setting up an irritative discharge or introducing infective organisms as well. Foreign bodies, it must be admitted, can also cause vulvovaginitis, but much less often than many gynaecologists believe. If the foreign body is present, the discharge is likely to be foul-smelling and blood-stained, and this diagnosis should always be suspected if the discharge has these characterstics. A rare cause giving rise to persistent discharge and perhaps soreness of the vulva is an ectopic

Vulvovaginitis 47

vaginal epithelium has now become and there is no glycogen present. Stain: haematoxylin and eosin. (From Dewhurst, 1963, by permission) ureter which intermittently discharges a small amount of urine into the vagina or alongside the introitus. Such an opening may be very difficult to identify and the patients may receive incorrect treatment for years before it is properly diagnosed. Infections with Trichomonas vaginalis and Can­ dida albicans, so common in older women, are only rarely seen in children. The former may, of course, appear around puberty or afterwards in girls who are sexually active. The latter may be seen in diabetic children or in children receiving repeated antibiotic therapy for any reason. A physiological discharge develops at puberty a short time before menstruation starts and is sometimes complained of by the patient or her mother who believes it to be abnormal. All of these are causes of vaginal discharge which may secondarily cause vulvitis. It must be remembered that vulval afflictions alone may cause soreness independent of any vaginal discharge. These are described later.

of the day may be represented as a discharge. It is pertinent to determine if the discharge is stained with blood and should, if necessary, be established by direct questioning. It is also wise to enquire about antibiotic therapy and about any infections the child may have had elsewhere in the body. A most important point to establish is what treatment - prescribed by a doctor or undertaken independently by the mother - has been used. Vulval soreness can easily be worsened by subjecting the affected skin to any source of irritation such as bathing it with antiseptic solutions, the wearing of wool or even nylon pants, and leaving wet nappies in place for too long. A chemical or irritative vulvitis can thus be superimposed on whatever condition was originally present. Inspection of the vulva will usually distinguish the more important from the less important. Vulval soreness perhaps spreading laterally to the thighs and backwards to the anus may be present (Figure 4.3), or there may be little or nothing to see despite complaints. Parting the labia allows the introitus to be inspected, and the lower part of the vagina posteriorly can often be seen too. The discharge may be immediately evident; if it is not, a rectal examination should be made and the discharge, if

Examination and investigation A careful history must always be taken from the child with vulvovaginitis and from her mother. In particular, it must be ascertained if the child is merely aware of the presence of a discharge or if it makes her sore, and if so, when and to what extent. Some mothers unquestionably magnify the severity of the discharge; it is often then described in colourful, even lurid, language which should alert the doctor. Other meticulous and fastidious mothers are upset by a suggestion of 'uncleanliness' - even a little yellow staining on the child's pants at the end

Figure 4.3 Vulval and perianal soreness in a child with vulvovaginitis as a result of a vaginal discharge

48

Vulvovaginitis and other vulval lesions

present, 'milked' down to the introitus. If there is no discharge but evidence of vulvitis is present, the patient should be managed as outlined below under 'Vulvitis'. Some attempt should usually be made to obtain a specimen or specimens for bacteriological examination. If a child has apparently suffered many recurrences, and has received a wide variety of treatments, bacteriological study is unlikely to be helpful, and if she is at all difficult this step may be omitted. A cotton wool-tipped swab is often difficult to insert and withdraw from the vagina in a small child without causing pain, and the following technique described by Capraro (1974) is recommended. A piece of plastic tubing about 5 cm long is attached to the tip of an ordinary medicine dropper. It is sterilized and kept in a sterile container or wrapper until used. When required, the tubing is gently inserted through the hymen. Secretion can be sucked up by the medicine dropper which is then detached and a cotton wool-tipped applicator or platinum loop inserted down the plastic tube which is kept in place until all the necessary specimens have been taken. If pinworms are suspected, the mother should be asked to examine the child's perineum when the girl is asleep late at night; this can usually be done without waking her and the pinworms may easily be seen. A sticky tape (sellotape) test may also help. A piece of sticky tape is placed sticky side down onto the anus. The tape is then removed and pressed onto a slide. After further removal, the fragments adhering to the slide are treated with toluene which clears everything but the adult worms and the eggs, which may be seen under a low power microscope. The place of examination under anaesthesia is very limited; it is seldom indicated but often performed. If there is a blood-stained or foul-smelling discharge, examination under anaesthesia is mandatory. In other circumstances it may be considered only in a protracted case which has resisted all treatment. Inspection of the vagina in a small child is not easy and a variety of specula have been developed to permit it. A Capraro speculum (Capraro, 1974) or the Huffman speculum (Huffman, 1968) are helpful; an air cystoscope has been used; an infant McGill laryngoscope may give good results, but the best is a CO2 hysteroscope, which allows full view. What is important is that a good view be obtained so that there is no doubt about the presence or absence of foreign matter, be it solid or vegetable.

Treatment There is no shortcut to the cure for vulvovaginitis. It requires care and attention to detail - and often tactful handling of the mother as well.

If a specific organism is found, it may be treated with an antibiotic to which this organism is sensitive and cure is likely. If no specific organism is present, which is usually the case, a course of antibiotics is less likely to help, although it is often tried; provided it is not given repeatedly, there is no harm in this. For the majority of patients with a discharge due to low-grade bacterial infection, the most satisfactory treatment is local oestrogens. These need not be put into the vagina - indeed it is better not to do so for fear that this will cause pain or injury - but may be used as an oestrogen cream (Dienoestrol cream 0.01%) applied to the vulva. The child's mother or an older child herself, may do this; gentleness is necessary when the cream is being applied. This treatment increases the natural vaginal protection, allows the infection to be overcome and shows mother and child that the infection can be cured. It is imperative to combine this treatment, however, with indoctrination of the mother of the correct care of her daughter's vulva. It is wise to be very specific. The mother must be told to wash the child gently, using a good unscented soap, at least daily or if necessary, more often; cheap harsh soaps can irritate. The vulva must then be gently dried with a soft towel. A little bland cream (e.g. E45) can be applied. The child is best dressed in fairly loosefitting cotton pants, nylon and wool being discarded. Underclothes are changed frequently and at least every day. Only a good soap is used in the bathwater. Bubble baths should be avoided. They may not irritate if all the bubbles are rinsed away, but unless the child showers afterwards, this does not happen. In particular, antiseptics should never be put into contact with the skin. A good washing powder must be used for washing the child's underclothes and several rinses are necessary to make sure that all the tiny soap flakes are washed away. It is important to explain the necessity of good vulval hygiene after bowel action. The child should be taught to wipe from the front to the back, and if necessary, gentle washing to ensure adequate cleaning. The perineum must be properly dry after micturition and bowel action to protect the vulval skin. This approach usually succeeds. Oestrogen cream should not be used for more than 2-3 weeks at any one time and longer than this is seldom required. There may be recurrences which can be similarly dealt with but if attention is paid to vulval hygiene as described above, they will probably be few and far between. A doctor very much needs the cooperation of a sensible mother who will do what she is told when the condition can be overcome. Finally, mention may be made of a few specific entities. Gonococcal infections are fortunately found less often than formerly. They are best treated with penicillin or ampicillin in appropriate

Vulvitis dose for age. Benzylpenicillin may be given sixhourly for 24 h or a single injection may be given instead. For patients who are penicillin sensitive, doxycycline and other antibiotics may also be effective. Other members of the family should, of course, be investigated, since it is from one of them that the infection has probably been acquired, and sexual abuse must be considered. A pinworm infestation will usually respond to mebendazole (Vermox). A single dose of 100 mg is very effective in children over two years. Other effective preparations exist such as piperazine citrate given for seven days in doses according to age: up to 2 years, 50-75 mg/kg; 2-4 years, 750 mg; 5-12 years, 1.5 g; over 12 years, 2 g. Whatever is used, a repeat course of treatment 2-3 weeks later is desirable. The difficult problem of an ectopic ureter is really a paediatric surgical one for which cooperation with an appropriate colleague will be wise. An intravenous pyelogram may indicate an upper renal tract deformity which may suggest an ectopic ureter if it does not, in fact, demonstrate it. A careful search for the ectopic opening must be made, since it may be difficult to find; the opening may be situated in the vagina, vestibule, urethra, or bladder, although in the latter site it is unlikely to present in this way. Its treatment, of course, is surgical and a urologist or paediatric surgeon should be consulted.

Vulvitis Aetiology Vulval soreness may arise independently of irritation from a vaginal discharge. Various skin diseases may be present in this manner during childhood, e.g. eczema, psoriasis, erythema multiforme. They then require management in a similar manner to the disease present elsewhere. One particular condition requires special consideration - lichen sclerosis. Lichen

sclerosis

Lichen sclerosis of the vulva is a disorder usually found in postmenopausal women but it sometimes presents during childhood. The appearances are similar to the disease seen in later life. Macroscopically, an early case will show ivory-white discrete, flat papules which in later cases may be found to coalesce into large plaques. Central dark or even horny spots may be seen; these result from the extreme keratosis plugging the skin follicles. During the course of the disease, shrinkage may be evident in the skin folds around the clitoris or on each side of the labia minora. The whole vulva may show a patchy or diffuse atrophic white appearance (Figure 4.4) which closely resembles the leukoplakia' of previous gynaecological authors.

49

Figure 4.4 Lichen sclerosis of the vulva and the perianal region of a child aged three years Microscopically the features of lichen sclerosis are predominantly hypoplastic ones, with the exception of the hyperkeratosis of the surface which is a notable feature. Beneath this the epithelium is thin and the rete pegs are flattened (Figure 4.5); beneath this again there is a whitish decollagenized area of featureless tissue, in the deepest parts of which a band of round-cell infiltration can be seen. It is important to understand that the same condition may occur on other parts of the body surface as well; 75% of affected children have anogenital lesions, and 42% have extragenital lesions. It usually occurs in children under the age of seven years and resolves spontaneously at puberty (Clark and Müller, 1967). The cause is unknown although 20-30% of patients have an autoimmune disorder (Harrington and Dunsmore, 1981), and HLA typing has supported this theory with sharing of HLA-As31 (Holt and Dorke, 1985). Positive immunofluorescence for C3, fibrin and IgM has been shown in involved areas in 75% of cases (Dickie, Home and Sutherland, 1982). Examination and investigation In the management of a child thus affected, or indeed one with any vulval skin-irritative lesion, it is important to undress the child completely and examine all the body surface. Other affected areas may be found and their appearance, unaffected by

50

Vulvovaginitis and other vulval lesions

Figure 4.5 Histological appearances of lichen sclerosis. Note the hyperkeratosis and the flattened epithelium beneath which there is a whitish featureless zone with some round-cell infiltration at a deeper layer still. Stain: haematoxylin and eosin the special features of the skin of the vulva, may be more typical and permit precise diagnosis. The appearance of lichen sclerosis is usually easily recognized if one is aware of the possibility of the disorder affecting a young girl. Biopsy, which is so important in the postmenopausal patient, is unnecessary here.

Figure 4.6 Marked secondary infection in vulval lichen sclerosis in a four-year-old child

Treatment Great attention to the detail of vulval hygiene is as important here as in vulvitis secondary to an irritative vaginal discharge. The same advice should be given. If the area has been scratched a good deal and is secondarily infected (Figure 4.6), an antibiotic cream may be used until this infection is overcome; then application should be stopped. Topical steroids are not usually necessary but may be given in moderate strength for short periods of time in difficult cases. With care and a meticulous practice of vulval hygiene the condition can usually be kept in check until puberty, when spontaneous cure is to be expected. It is almost unknown to encounter lichen sclerosus of the vulva during the reproductive period, and it must be concluded that a great majority of, if not all, cases regress at that time, and that a lack of endogenous oestrogen is a predisposing factor in the aetiology of the disorder.

Other vulval disorders Condylomata acuminata These are soft, pink, papillomatous lesions which are found in the anogenital region. They may be quite small, or rapidly enlarge to become warty

lesions. Secondary infection may cause pain or discharge. The cause is thought to be the human papilloma virus (HPV), types 6, 11, 16 and 18 (Singer, Campion and McCance, 1985). It was previously an uncommon condition in childhood, but the incidence is rising. The association of HPV with cervical carcinoma in adults makes its appearance in children worrying. Transmission may be by sexual or nonsexual contact and incubation periods of nine months may be necessary. Treatment is usually topical, with applications of podophyllum 15% in 95% spirit to smaller lesions. Patients must be advised to wash the treated area after 6 h to avoid local irritation. Applications may be required on several occasions to eradicate the problem. Larger lesions (greater than 5 mm) may need treatment with cryosurgery, but if the tumour is very large, or cryosurgery is inappropriate, then the lesion may be surgically removed, or evaporated with the CO2 laser. This has the advantage of reducing the amount of scarring. Any child presenting with condylomata acuminata must be considered as victims of sexual abuse and investigated appropriately.

Other vulval disorders 51

Labial adhesions The condition of labial adhesions is a trivial one which in itself scarcely deserves special consideration. It is important, however, for one reason only - the frequency with which it is mistaken for congenital absence of the vagina. Tremendous parental anxiety is then created which is entirely unnecessary, as the condition is an insignificant one responding well to the simplest of treatment. Capraro and Greenberg (1972) have reviewed it well. The physical signs are easily recognized. The labia minora stick together in the midline usually from behind forwards until only a tiny opening is left anteriorly through which urine is passed (Figure 4.7). Similar adhesions sometimes bind down the clitoris, and it may be difficult to distinguish an opening at all. The vulva is flat and no normal tissues beyond the clitoris are evident. A translucent vertical line in the midline, where the adhesions are thinnest, can usually be seen (Figure 4.8). It must be stressed that these appearances are quite different from those of congenital absence of the vagina. In this latter malformation there is no vaginal orifice but the vulva is in other respects normal; the urethra

can be easily identified and the area where the introitus should be shows irregular rugae which are easily recognized. There is no real similarity in the clinical features if careful inspection is carried out, but the two diagnoses may well be confused if only a casual inspection is made. The symptoms associated with labial adhesions are either mild or absent. The child may complain of a little (but seldom more) discomfort as she passes urine; often the adhesions are apparently symptomless. The aetiology is not known precisely but must be concerned with the low oestrogen status of the child; such adhesions are never seen during the reproductive era, although they may be recognized in an older woman. They are never seen at birth and it is difficult to accept other accounts that they may be congenital. The labia minora may, of course, fuse in utero as a manifestation of androgenization, but such a fusion is not capable of simple separation, as are adhesions, and the two conditions are different. Treatment is extremely simple. If the adhesions are very thin they can be induced to separate spontaneously by the application of a little oestrogen cream by the child's mother to the line of the

Hm f

v

·.*·>;

Figure 4.7 Firm labial adhesions in a young girl (cf. Figure 4.9)

Figure 4.8 Comparatively early labial adhesions in a young girl. Note the translucent vertical line in the centre where the adhesions are forming

52

Vulvovaginitis and other vulval lesions

adhesion every night for approximately two weeks. It is generally not advisable to continue the applica­ tion of cream for longer, since this may provoke pigmentation in the area. If after two weeks they have not separated, they will be at least much thinner than formerly. The separation may then be completed by gently pressing the tip of a blunt probe through the exact midline at two or three points and joining up these 'buttonholes' by gentle strokes of the probe. Very little discomfort is usually caused. It is important to show the mother the normal vagina beneath to convince her that all is well (Figure 4.9), especially if she has already been alarmed by a previous diagnosis of congenital absence of the vagina. Some claim that the application of the cream does not have a specific reaction; however, Aribarg (1975) showed it to be far more effective than a simple cream which had scarcely any action at all. Recurrences are common and the mother should be warned to inspect the vulva at intervals to ensure that the adhesions are not reforming. If they seem to be doing so, a little lateral pressure with the thumbs on each side of the introitus should be sufficient to separate early ones and a little cream can then be applied. Constantly recurring adhesions are prob­ ably best left until the girl starts to produce her own oestrogen at puberty, when they can be expected to separate spontaneously.

Prolapse of the urethra Prolapse of the urethral mucosa during childhood is not a common condition but is likely to be seen fairly regularly by anyone concerned in paediatric gynaecology. It is usually noticed for the first time after an episode of crying or coughing, or perhaps constipation. Rarely is injury a factor. Attention may be drawn to it first because of painless bleeding, or discomfort in passing urine, or simply a vulval pain. Careful examination of the vulva reveals the circular prolapse at the external urethral orifice (Figure 4.10). The colour is reddish or reddish-blue, or even black in some circumstances. Sometimes the amount of prolapsed mucosa combined with the oedema present causes the whole mass to cover the vulva almost completely, when it may be difficult to identify its precise nature. The mass is soft or at the most fleshy, and never firm and indurated as some tumours are. If there is difficulty in reaching the diagnosis, examination under anaesthesia may be necessary, when it should be possible to identify the nature of the swelling and the urethral orifice in the centre of it. Superficially the tumour may resemble the mesodermal mixed tumour (botyroid sarcoma) and very careful examination including vaginoscopy will be necessary to make this distinction. Periurethral cysts or abscesses, papillomata, and condy-

ψ7·

Figure 4.9 Showing the normal vulva and vaginal appear­ ances in a child illustrated in Figure 4.7 once the ad­ hesions had been separated by a probe. (From Dewhurst, 1968, by permission)

Figure 4.10 Circular prolapse of the urethra in a young girl

Other vulval disorders

lomata may also be mistaken for the prolapse. Should there be doubt, biopsy will be necessary, although this seldom is the case. The aetiology of the condition is not well understood. A large percentage of patients appear to be black girls, but what factor causes this predisposition is unknown. The condition is more common in childhood, showing a peak incidence between the ages of five and nine years, and therefore oestrogen lack may be a factor; urethral prolapse is certainly uncommon in women of childbearing age although it may be seen in postmenopausal women. Not all cases require surgical treatment, although it is carried out on the majority. The application of saline compresses to the tumour may reduce oedema and may allow the prolapse to be replaced inside the urethra. If this can be brought about and the catheter can be left in the bladder for several days, the tumour may not recur. Should there be recurrence or should replacement inside the urethra not have been possible, surgery will be indicated. The most effective method appears to be excising the redundant mucosa and suturing the cut edges of it to the skin with fine catgut. Again, a catheter will be left in the bladder for 2-3 days postoperatively to avoid problems which the child may have in passing urine. A simple method which has sometimes been used is the insertion of a Foley catheter into the bladder and tying a constricting ligature around the base of the lesion. After a few days the mucosa sloughs away with very little bleeding, and healing is complete in some 10 days. Cauterization has been used but is not recommended. There are very few long-term complications unless extensive cauterization has been performed. The condition has been reviewed by Capraro, Bayonet-Rivera and Magoss (1970) and Klaus and Stein (1973).

53

occasionally a hood of skin forms above or even across the front of the urethra. Infibulation is literally the fastening together of the labia with a fibula or clasp. The labia minor were originally pinned to each other with thorns, although doubtless other materials are now used. As a result, the vaginal introitus is obscured to a greater or lesser extent (Figure 4.11), leaving an orifice anteriorly or posteriorly, or at both sites (Figure 4.12). The procedures are usually carried out sometime before puberty, the precise age being determined by local practice. Damage may, of course, be inflicted on the urethra or vagina during performance of the circumcision and deep, firm scarring may result, especially if there has been infection. Once healing has been completed, however, there may be no symptoms until intercourse is attempted or during delivery, when intervention may be required to divide the contracted tissues to permit the child to be born (Figure 4.13); anterior episiotomy is sometimes required. If a physician unfamiliar with this condition encounters circumcision in a daughter or wife of a diplomat or businessman from one of the countries practising it, his immediate reaction may be to undertake a 'decircumcising' procedure. It must be

Female circumcision A considerable deformity of the vulva may result from the practice of female circumcision. This practice has, in former years, been restricted largely to the north-eastern part of the African continent particularly Sudan, Egypt, Ethiopia, and Somalia although it has been performed elsewhere in Africa and even outside it. Now with the increasing prevalence of air travel, circumcised females are not uncommonly seen in other countries, and some account of the condition seems appropriate. Broadly speaking there are two forms of circumcision - Pharaonic circumcision and infibulation. In the former, part of the clitoris is removed in ritual fashion - usually by an older woman of the village, sometimes by a midwife, and even, it must be said, occasionally by a doctor. During the healing process the patient may be kept with her legs bound closely together for a week or more, possibly causing extensive scarring in the anterior part of the vulva;

Figure 4.11 Infibulation in a Sudanese woman. Note no operation has been performed on the clitoris, but the labia minora have been fixed together

54

Vulvovaginitis and other vulval lesions

Figure 4.12 Another case of infibulation u n d e r s t o o d , however, that t h e reaction of t h e patient or of her parents or husband t o t h e circumcision may b e quite different from that of the doctor discovering it for t h e first time. T h e practice is steeped in national, tribal a n d religious associations. N o o n e knows when it began. It is certainly p r e M o h a m m e d a n (the p r o p h e t neither c o n d o n e d n o r decried it), and it probably goes back into a past so r e m o t e that n o o n e can now identify its origin. T o people in other countries it m a y a p p e a r inexplicable that it is performed at all, b u t to those of whose heritage it is a part, it h a s d e e p psychological associations. N o t wishing it u n d o n e , t h e patient and her parents or husband are likely to ask for t h e vulva to b e reconstituted in its circumcised form after, for example, a confinement. T h o s e wishing further information should consult Laycock (1950), Mustafa (1966) a n d Shandall (1967).

References

adhesions in children. British Journal of Obstetrics and Gynaecology, 82, 424 CAPRARO, v. J. (1974) Vulvovaginitis and other local lesions of the vulva. Clinics in Obstetrics and Gynaecology, 1(3), 533 CAPRARO, v. J. and GREENBERG, H. (1972) Adhesions of the

labia minora: a study of 50 patients. Obstetrics and Gynecology, 39, 65 CAPRARO, V. J., BAYONET-RIVERA, N. p. and MAGOSS, i. (1970)

Vulvar tumour in children due to prolapse of urethral mucosa. American Journal of Obstetrics and Gyne­ cology, 108, 572 CLARK, j . A. and MULLER, s. A. (1967) Lichen sclerosus et atrophicus in children. Archives of Dermatology, 95, 476 DEWHURST, c. J. (1963) Gynaecological Disorders of Infants and Children, Bailliere Tindall, London DEWHURST, c. J. (1968) Congenital malformations of the genital tract in childhood. Journal of Obstetrics and Gynaecology of the British Commonwealth, 75, 377 DICKIE, R. J., HORNE, c. w. and SUTHERLAND, H. w. (1982) Direct

guidance of localised immunological damage in vulvar lichen sclerosus et atrophicus. Journal of Clinical Patho­ logy, 35, 1395 HARRINGTON, c. J. and DUNSMORE, i. R. (1981) An investiga-

ALTCHEK, A. (1984) Pediatric vulvovaginitis. Journal of Reproductive Medicine, 29, 359 ARIBARG, A. (1975) Topical oestrogen therapy for labial

tion into the incidence of autoimmune disease with lichen sclerosus et atrophicus. British Journal of Derma­ tology, 104, 563

References HOLT, p. J. A. and DORKE, C. (1985) HLA antigens in lichen sclerosus et atrophicus. Clinical and Experimental Der­ matology, 10, 132 HUFFMAN, J. w. (1968) The Gynecology of Childhood and Adolescence, Saunders, Philadelphia HUFFMAN, J.W. (1977) Premenarchal vulvovaginitis. Clinical Obstetrics and Gynecology, 20(3), 581 KLAUS, H. and STEIN, R. T. (1973) Urethral prolapse in young girls. Pediatrics, 52, 645 LAYCOCK, H. T. (1950) Surgical aspects of female circum-

55

cision in Somaliland. East African Medical Journal, 27, 445 MUSTAFA, A. z. (1966) Female circumcision and infibulation in the Sudan. Journal of Obstetrics and Gynaecology of the British Commonwealth, 73, 302 SHANDALL, A. A. (1967) Circumcision and infibulation of females. Sudan Medical Journal, 5, 178 SINGER, A., CAMPION, M. J. and MCCANCE, D. J. (1985) Human

papilloma virus. British Journal of Hospital Medicine, 34, 104-108

5 Normal puberty

The Oxford English Dictionary defines puberty as the state of being functionally capable of procreation. The term is generally used in a more comprehensive sense, however, to refer to the whole of the period of time during which secondary sexual characteristics are being developed, menstruation begins, and the psychosexual outlook of the patient changes; it is this wider sense that will be considered here.

Physical changes of puberty The most important fact about the physical changes of puberty is their variability. They vary in the age of onset from one girl to another; they vary in the time taken for their full development; and to a certain extent, they vary in the order of their appearance. It must be emphasized at this point that it is a mistake for the clinician to expect puberty changes to conform to a definite pattern; the limits of variation are so wide that two girls of the same age might both be normal, although one has no sign of puberty while the other is already menstruating. Five physical features of puberty will first be considered. These are breast growth, pubic hair growth, axillary hair growth, growth in height and menstruation. The final feature is the establishment of ovulation. Breast growth Tanner (1962) has divided breast growth into five stages (Figure 5.1): Stage 1: Infantile stage with no development whatever.

Figure 5.1 The five stages of breast development aecording to the Tanner scale. (From Tanner, 1962, by permission)

Physical changes of puberty Stage 2: Development of breast bud as a small mound beneath an enlarged areola. Stage 3: The breast and areola are enlarged still further to resemble a small adult breast with a continuous rounded contour. Stage 4: The nipple and areola are enlarged even more to produce a secondary projection above the contour of the remainder of the breast (Figure 5.2). Stage 5: Normal adult breast with smooth rounded contours, the secondary mound of stage 4 having been assimilated into the whole breast form (Figure 5.3). Stage 4 of breast development may never appear at all, since some children seem to pass directly from

IT

stages 3 to 5. On the other hand, some girls show persistence of stage 4 until the first pregnancy or sometimes even later. The range of ages at which each stage of breast development was reached in British girls is shown in Figure 5.4, which is adapted from Marshall and Tanner (1969). The considerable variation which may occur is evident in this figure. Most other studies have shown similar results. In general, it might be said that the first sign of breast development may appear from about the age of nine years onwards, and it is quite uncommon for no breast development to be evident by the age of 13 years. One girl may have mature breasts by the time she is 12 years old, and another not until she is perhaps 19 or 20 years old. One aspect of breast growth in a pubertal girl has not received as much attention as it might; this is inequality in breast size. During early growth one breast quite often enlarges quicker than the other. This inequality disappears as growth proceeds and it seldom calls for treatment beyond reassurance. The risk is that in the very early stages when only one breast may be showing enlargement, unwise surgical intervention in an attempt to biopsy what is believed to be a possible tumour might result in the removal of the whole breast bud on one side with ultimately very serious cosmetic results (Capraro and Dewhurst, 1975; Dewhurst, 1981).

Stage 2 Stage 3 Breast Stage 4

Figure 5.2 Lateral view of the breast to show a somewhat pronounced stage 4

^Stage 5|Stage 2

Pubic hair

Stage 3 Stage 4 Stage 5

Menarche

8

10

12

14

16

18

20

Age in years

Figure 5.3 View of the breast of another adolescent to show stage 5

57

Figure 5.4 Graph indicating the range and means of the ages at which various stages of breast, pubic hair and menses are achieved

58

Normal puberty

Pubic hair growth

Growth in height

Pubic hair development is also described in five stages (Figure 5.5):

Growth in children is very interesting. The child grows at different rates at different times, and one child will grow faster or slower and to a different final height than another. But if children's growth is measured accurately during childhood, it will be seen that there is an initial period of rapid growth which stabilizes to a reasonably constant level about the age of 1-2 years (Figure 5.6). Growth continues at this rate until there is a growth spurt about the time of puberty. This period of accelerated growth may result in an increase in height of 6-11 cm/year, which may be almost twice as much as the rate of growth prior to that time. The time when the child is growing fastest of all is known as peak height velocity, after which growth rapidly declines and finally stops. The effect of the growth spurt is better shown by plotting growth velocity in cm/year against the age (Figure 5.7), when it will be seen that the rapid increase in the speed of growth occurs until peak height velocity is reached which is followed by decline. It must be understood that this growth spurt occurs at different times in different children and may produce marked discrepancies in size, and can be a cause of great parental and child anxiety. Marshall and Tanner (1969) found that most adole­ scent girls reached their maximum growth rate between their tenth and fourteenth birthdays, although some lay outside these limits; the mean age of peak height velocity was 12.14 years. If a girl undergoes an adolescent spurt at an early age, she will temporarily be significantly taller

Stage 1: No true pubic hair present at all. Stage 2: A little sparse hair showing pigmentation appears first on the labia and then in the midline on the mons pubis. Stage 3: The hair spreads sparsely over the symphysis pubis and is darker in colour and more coarse. Stage 4: The hair has the adult appearance but does not cover the entire triangle in most adults. The upper lateral corners of the triangle still require to be filled in. Stage 5: The hair now assumes the typical triangular distribution of the adult female. Hair may also be evident on the medial aspects of the thighs. The range of ages at which the various stages of pubic hair growth are evident in British girls is shown in Figure 5.4. It will be seen that there is a close similarity between the ages at which the stages of pubic hair growth and breast growth appear in girls in general, although there may be individual variations which will be referred to later.

170 -

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—— ——._.£

150

_

*-> ω

70

Axillary hair growth Axillary hair growth is only described in three stages, stage 1 being the infantile stage, stage two being when some hair is present but growth is not yet complete, and stage 3 being the fully developed stage.

YYY

YYYy WY

- 1

90

-

■YY>/

~

2cu 11°

Figure 5.5 Stages 2-5 of pubic hair development in the female. (From Marshall, 1974, by permission)

/ Y'///''

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9ZJ

9075. SO. __2E 10

"* -

w

-

- / y 1/

-Ψ II

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501 0

2

4

6

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1

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8 10 12 Age (yr)

1

1

14

L— L

16

~ 18

Figure 5.6 Graph illustrating stature of girls at different ages - note growth spurt at puberty. (After Marshall, 1974)

Physical changes of puberty

I

0

i

i

2

i

i

4

I

I

6

I

1

I

J

I

I

8 10 12 Age (yr)

l_J2

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18

Figure 5.7 Graph illustrating the velocity of growth of girls at different ages - the effect of growth spurt is easily seen. (After Marshall, 1974) than others; such a girl, however, stops growing sooner and is likely to be caught up by those who experience a growth spurt at a later time. Menstruation The menarche The average age of the menarche in the UK is 13 years, and Marshall (1974) reports that 95% of the population will have the menarche between their eleventh and fifteenth birthdays. In other countries with similar social conditions, the age range of the menarche is similar, being slightly lower than 13 years in the USA. There are many differences in various populations which will be discussed presently. During the last century there has been a steady decline in the menarcheal age (Tanner, 1962). Girls are now menstruating on the average a year earlier than did their mothers. In Norway and in the UK this trend appears to have stopped, although it may still be continuing in other countries. The explanation usually accepted for the decline in menarcheal age in some countries is that it is due to improvements in the standard of living with better nutrition, hygiene, etc., rather than an apparent racial effect. There may, nonetheless, be small racial factors just as there are small genetic factors involved. There is a close similarity between the menarcheal age of twins living in the same environmental conditions; monozygotic twins menstruate more closely together than do dizygotic twins who in turn menstruate more closely together than sisters. Interrelationships in pubertal changes The order of events in the appearance of these changes at puberty follows a very loose pattern to

59

which there are many exceptions. Some 50% of girls will show the following pattern: first breast development which coincides closely with the onset of the growth spurt; next is pubic hair development, followed by axillary hair development, followed by menstruation. The remaining 50% will show one or other variation, however. Thus as reported some years ago (Dewhurst, 1969) in a group of London schoolgirls, 38% showed menstruation before pubic hair appeared, 8% menstruated before axillary hair appeared, 2.6% showed pubic hair growth before breast development, and the same percentage showed axillary hair development before breast development. The menarche usually appears when breasts are in stage 4, but as many as 25% of girls may menstruate at an earlier breast stage, while a small percentage will not have menstruated even though their breasts are fully developed. The menarche usually occurs after peak height velocity; thus growth in height is small after this has occurred. An interesting relationship exists between skeletal maturity and the various features of puberty. Bone age may be estimated by taking radiographs of the hand and wrist and comparing the appearances with the atlas produced by Greulich and Pyle (1959); alternatively the revised Tanner/Whitehouse method (Tanner et al., 1975) may be used in which a score is given to each bone in the hand and wrist. There is little relationship between the child's bone age and the onset of puberty, although there is a much closer relationship between bone age and the menarche. At the menarche the majority of girls have a skeletal age between 13 and 14 years; it is uncommon for the menarche to occur before bone age 12.5 years or after 14.5 years. This relationship to bone age is very useful in girls suspected of constitutional delay in puberty. If chronological age is, for example, 16 years yet the bone age is 12.5, which is not infrequent, menstruation would not be expected and we may safely wait for it. If, however, the bone age is also 16, the child should have menstruated and there is clearly an abnormality present. The further parameter which is apparently related to the onset of menstruation and to other signs of secondary sexual development is weight. Frisch and Revelle (1969, 1970) reported that the mean weight of girls at the time of the initiation of the growth spurt was 30 kg, the mean weight at peak height velocity was 39 kg, and at the menarche 47 g. These weights did not differ significantly in early and latematuring girls. However, others have disputed this view and it is less likely that the menarche is initiated by attaining a certain weight, but associated with it (Johnston, Roche and Schell 1975; Marshall, 1978). Although it is difficult to prove the direct association of body weight with the onset of puberty, the relationship is probably seen in percentage of body fat. Some 17% of body weight as fat is the

60

Normal puberty

minimum required for menstruation, the average being 20- 24% (Frisch and McArthur, 1974).

Characteristics of early menstrual cycles The menstrual cycles which follow closely after the menarche are much less regular than they will be in later life. Some girls, it is true, show a reasonable degree of regularity almost immediately but others may show intervals of four, five or six months between periods during their first five cycles, while intervals of two or three months between periods is not uncommon between cycles 5-10 (Dewhurst, Cowell and Barrie-Lorna, 1971). The length be­ tween cycles gradually declines, although reason­ able regularity may not be achieved for one or two years following the menarche. The duration of the menstrual periods is also variable but less so than the cycle length. The flow lasted from 3-7 days in 88% of cycles, with an average of five days. Precise information on the onset of ovulation is difficult to obtain. Vollmann (1977) found 45% of ovulatory cycles by 1-2 years after menarche, and 97% by 11-12 years postmenarche. Very early menstrual cycles are usually anovulatory, and so dysmenorrhoea often post-dates menarche. Similar findings were reported by Matsumoto, Ishizuka and Takenaka (1981) who also demonstrated that the early luteal phases are short and associated with poor function of the corpus luteum.

Endocrine changes at puberty The physical changes described occur as a result of hormonal changes. In the prepubertal state, gonadotrophin levels are low, although the changes soon after birth are interesting. The levels of FSH and LH rise in the first three months of life to reach pubertal levels, the FSH remaining elevated for 2-Λ years, whereas the LH level becomes basal after 4-6 months (Grumbach, Grave and Mayer, 1975). The levels then remain low until pubertal changes begin as a result of the gradual rise in FSH, peaking at menarche. LH levels remain basal until mid-puberty and do not reach their peak until after menarche (Pennington, 1974). The release of FSH and LH tends to occur at night in early puberty, and as menarche approaches so the level of release be­ comes equal day and night (Lee, Plotnick and Migeon, 1978). The control of gonadotrophin production from the pituitary is mediated through hypothalamic release of luteinizing hormone releasing hormone (LHRH) (Schalley, Akimura and Kastin, 1971; Knobil, 1980). The prepubertal state is one of LHRH insufficiency and in early puberty a high

amplitude pulsatile release of LHRH, especially at night, leads to nocturnal release of FSH and some LH. The frequency is approximately two-hourly and as puberty advances an increase in pulse amplitude rather than frequency during the daytime leads to a rise in FSH and LH release (Penny, Olambiwonnu and Frasier, 1977). This maturation of the hypothalamus is also associated with increased growth hormone secretion and the resultant pubertal growth acceleration (Tanner, 1981). The ovarian response to the gradual increase in FSH is the increase in circulating oestradiol-17ß, and the initiation of breast growth. The excretion of oestrogen in longitudinal studies shows that the level remains low until about the age of eight, and a gradual slow rise occurs until it reaches 1 μ ^ 24 h when secondary sexual development may com­ mence. The pattern thereafter is one of sporadic increases and falls, until menarche when levels of the adult are reached (Brown, Harrison and Smith, 1978). Histological examination of ovarian function prepubertally shows follicular activity from fetal life onwards (Peters, Byskov and Grinster, 1981). Simi­ lar findings have been published using ultrasound assessment (Stanhope et al., 1985) and from age 8.5 years a number of follicles develop giving a multicystic appearance. It seems that this is a normal response to gonadotrophins prior to the develop­ ment of the dominant follicle, and continues for some years and well after menarche when the release of the midcycle LH surge commences. The changing amount of androgen production and early puberty is interesting. The secretion of dehydroepiandrosterone (DHEA) and DHEA sul­ phate begins at age 4-6 years and continues to rise until age 12 (Parker et al., 1978; Apter, Pakarinen and Hammond, 1979). Androstenedione production is less than DHEA. It is likely that this production of androgens is responsible for the initiation of pubic hair growth as it parallels it (Tanner, 1981). Testo­ sterone is of less importance in girls than boys where it is associated with pubic hair growth. Although DHEA and DHEA sulphate seem the prime in­ stigators of pubic hair growth, some circulating oestrogen is also necessary. Control of the onset of puberty There is still no consensus of opinion to hypothesize as to the mechanism of initiation of puberty. The hypothalamus is probably functioning throughout fetal and prepubertal life, as the early secretion of FSH and LH substantiates. However, why the de­ creased release of LHRH, both initially in ampli­ tude and then frequency, occurs is unexplained. Presumably, a higher centre neuroendocrine control is the explanation, although the site is unknown. The pineal has been suggested, but data are rather

Endocrine changes at puberty scanty and m e a s u r e m e n t of pineal function remains indirect. T h e role of oestrogen is interesting. T h e hypothalamus is very sensitive to low levels of oestrogen which inhibit its function. C o n t e , G r u m b a c h a n d Kaplan (1972) and Kelch et al (1972) d e m o n s t r a t e d this p h e n o m e n o n in different ways, using oestrogen administration and measuring t h e decrease in gonadotrophin release. This was possible with very low amounts of oestrogen and so it would seem that t h e hypothalamus is inhibited at a very sensitive level. T h e changes in F S H release at age 4 m a y come about because of androgen secretion and peripheral conversion t o oestrogen ( H o p p e r a n d Y e n , 1975; D u c h a r m e et al., 1976; Parker et al., 1978). This cannot b e t h e complete explanation because, as T a n n e r (1981) points o u t , girls with Addison's syndrome undergo normal puberty without adrenal changes. T h e role of body weight h a s already been discussed a n d t h e 1 7 % body fat association with puberty would seem t o b e important. O t h e r higher centres such as t h e limbic centre have been suggested as having a role t o play, a n d certainly animal data would support this theory (Steger, 1976). H o w e v e r , our understanding of t h e initiation of puberty is at best elementary. A full review of this subject has been published by Dewhurst (1984) and should b e consulted.

References AFTER, D., PAKARINEN, A. and HAMMOND, G L. (1979) Adreno-

cortical function in puberty. Ada Paediatrica Scandinavica, 68, 599 BROWN, J B., HARRISON, p. and SMITH, M A. (1978) Oestrogen

and pregnanediol excretion through childhood, menarche and first ovulation. Journal of Biosocial Science, Supplement, 5, 43 CAPRARO, v. J. and DEWHURST, C. J. (1975) Breast disorders in childhood and adolescence. Clinical Obstetrics and Gynecology, 18, 25 CONTE, F., GRUMBACH, M. M. and KAPLAN, S L. (1972) Variations

in plasma LH and FSH with age in 35 patients with XO gonadal dysgenesis. Pediatric Research, 6, 353 DEWHURST, C J. (1969) Variations in physical signs in pubertal girls. Journal of Obstetrics and Gynaecology of the British Commonwealth, 76, 831 DEWHURST, C. J. (1981). Breast disorders in children and adolescents. Pediatric Clinics of North America, 28, 287 DEWHURST, c. J. (1984). Female Puberty and its Abnormali­ ties, Churchill Livingstone, Edinburgh DEWHURST, C. J., COWELL, C. A. and BARRIE-LORNA, C. (1971).

The regularity of early menstrual cycles. Journal of Obstetrics and Gynaecology of the British Common­ wealth, 78, 1093

61

steroids in human pubertal development. Journal of Clinical Endocrinology and Metabolism, 42, 468 FRISCH, R. E. and MCARTHUR, J. w. (1974) Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance of onset. Science, 185, 949 FRISCH, R. E. and REVELLE, R. (1969) Variation in body weights and the age of adolescent growth spurt among Latin American and Asian populations in relation to calorie supplies. Human Biology, 71, 185 FRISCH, R. E and REVELLE, R. (1970) Height and weight menarche and a hypothesis of critical body weights and adolescent events. Science, 169, 397 GREULICH, W. W. and PYLE, s. I. (1959) Radiographic Atlas of Skeletal Development of the Hand and Wrist, 2nd edn, Stanford University Press, Stanford, California GRUMBACH, M. M., GRAVE, G. D. and MAYER, F. E. (1975) The

Control of the Onset of Puberty, Wiley, New York HOPPER, R. B. and YEN, s. s. c. (1975) Circulating concentra­ tions of DHEA and DHEAS during puberty. Journal of Clinical Endocrinology and Metabolism, 40, 458 JOHNSTON, F. E., ROCHE, A. F. and SCHELL (1975) Critical weight

at menarche: critique of a hypothesis. American Journal of Diseases of Children, 129, 19 KELCH, R. P., CONTE, F. A., KAPLAN, S. L. a n d GRUMBACH, M. M.

(1972) Evidence for the episodic secretion of LH and decreasing sensitivity of the hypothalamic-pituitary 'gonadostat' in adolescent patients with gonadal dys­ genesis. Pediatric Research, 6, 349 KNOBIL, E. (1980) The neuroendocrine control of the mens­ trual cycle. Recent Progress in Hormone Research, 36, 53 LEE, p. A., PLOTNICK, L. p. and MIGEON, c. J. (1978) Integrated

concentrations of FSH and puberty. Journal of Clinical Endocrinology and Metabolism, 46, 488 MARSHALL, w. A. (1974) Growth and secondary sexual development and related disorders. Clinics in Obstetrics and Gynaecology, 1(3), 593 MARSHALL, w. A. (1978) The relationship of puberty to other maturation indicators and body composition in man. Journal of Reproduction and Fertility, 52, 437 MARSHALL, w. A and TANNER, J. M. (1969) Variations in the

pattern of pubertal changes in girls. Archives of Disease in Childhood, 44, 291 MATSUMOTO, s., ISHIZUKA, J. and TAKENAKA, γ. (1981) Basal

body temperature findings in girls aged 18 and 19 years. Japanese Journal of Adolescent Medicine, 4, 17 PARKER, L. N , SACK, J., FISHER, D. A. and ODELL, w D. (1978) The

adrenarche; prolactin, gonadotrophins, adrenal androgens and cortisol. Journal of Clinical Endocrinology and Metabolism, 46, 396 PENNINGTON, G. w. (1974) The reproductive endocrinology of childhood and adolescence. Clinics in Obstetrics and Gynaecology, 1(3), 509 PENNY, R , OLAMBIWONNU, N. o. and FRASIER, s. D. (1977) Episo­

dic fluctuations of serum gonadotrophins in pre- and postpubertal girls. Journal of Clinical Endocrinology and Metabolism, 45, 307

DUCHARME, J. R., FOREST, M. G , de PERETTI, E , SEMPE, M.COLLU, R.

PETERS, H., BYSKOV, A. G. and GRINSTER, J. (1981) The develop­

and BERTRAND.J. (1976) Plasma adrenal and gonadal sex

ment of the ovary during childhood in health and

62

Normal puberty

disease. In Functional Morphology of the Human Ovary (ed. J. R. T. Coutts), MTP Press, Lancaster, pp. 26 SCHALLEY, A. v., AKiMURA, A and KASTIN, A. J. (1971) Gonadotrophin releasing hormone: one polypeptide regulates secretion of luteinising and follicle stimulating hormone. Science, 173, 1036

TANNER, j . M. (1962) Growth at Adolescence, 2nd edn, Blackwell Scientific, Oxford TANNER, j . M. (1981) Endocrinology of puberty. In Clinical Paediatric Endocrinology (ed. C. G. D. Brook), Blackwell Scientific, Oxford, p. 207

STANHOPE, R., ADAMS, J , JACOBS, H. S. a n d BROOK, C. G. D. ( 1 9 8 5 )

B. s. (1975) Equations for the prediction of adult height from height and skeletal maturity at ages 4 to 16. Archives of Disease in Childhood, 50, 14 VOLLMAN, R. F. (1977) The Menstrual Cycle, Vol. 7, Saunders, Philadelphia

Ovarian ultrasound assessment in normal children, idiopathic precocious puberty and during low dose GnRH therapy for hypogonadotrophic hypogonadism. Archives of Disease in Childhood, 60, 116 SIEGER, A. (1976) In Sexual Maturity (eds G. S. E. Hafez and J. J. Peluso), Ann Arbor Science, Ann Arbor, Michigan, p. 57

TANNER, J. M., WHITEHOUSE, R. H., MARSHALL, w. A and CARTER,

6 Precocious puberty

The clinical features of puberty sometimes make their appearance in a very young subject. The age before which the term 'precocious puberty' may be applied, however, is variously described by different authors. In this account the appearance of any of the physical signs of secondary sexual development before the age of eight years or of menstruation before the age of ten years will be regarded as precocious.

Aetiology The cause of precocious puberty is interesting in that the disorder is most often found when there is no abnormality at all to be detected but merely an unusually early awakening of the hypothalamic/ pituitary activity. We do not know why this happens and we are still obliged to label such cases 'constitutional precocious puberty'. In series by Huffman, Dewhurst and Capraro (1981) and Rayner (1981) between 75 and 80% of precocious puberty was constitutional in type. Apart from these, in which no cause for precocity can be found, there is a group of cases in which the activity of the hypothalamus and pituitary is apparently awakened early by a variety of intracranial lesions, e.g. meningitis, encephalitis, a ventricular hamartoma, or a pineal or other tumour. Again beyond speculating that such lesions stimulate the hypothalamus into earlier activity than usual, we do not really understand how the changes come about; the association of precocious puberty changes with pineal tumours which destroy the gland has already been mentioned and it may be that an inhibitory effect of the gland on hypothalamic activity is destroyed, or the tumour may produce a stimulatory factor, initiating hypothalamic activity. One particularly interesting condition giving rise to precocious

puberty and to other abnormalities as well is the McCune-Albright syndrome. This is a disorder in which widespread cystic bony changes (polyostotic fibrous dysplasia) are associated with dysfunction of various endocrine glands, notably the hypothalamus and pituitary: a further association is the occurrence of areas of light-brown skin pigmentation known as cafe-au-lait spots. Mention may also be made of other possible causes. These include neurofibromatosis, an adrenal tumour, or hypothyroidism (Table 6.1). The most important gynaecological lesion which may be encountered as a cause of precocious puberty is a feminizing ovarian tumour - usually a granulosa cell tumour. This variety of tumour produces significant quantities of oestrogen which cause secondary sexual development and menstruation; it will be seen, however, that the mechanism of production of these changes is different from the Table 6.1 (1) (2)

(3) (4) (5) (6)

Aetiology of precocious puberty in girls

Constitutional Neurological: cerebral tumours hydrocephalus cysts meningitis encephalitis polyostotic fibrous dysplasia neurofibromatosis Ovarian tumours Adrenal neoplasms Gonadotrophin secreting tumours: chorion-epithelioma hepatoblastoma Others: hypothyroidism exogenous oestrogens 63

64

Precocious puberty

other conditions causing precocious puberty. Constitutional precocious puberty, cerebral precocious puberty, and the McCune-Albright syndrome all produce their secondary sexual effects and menstruation by the early development of hypothalamic/ pituitary activity which stimulates the ovary to produce oestrogens; in precocious puberty due to a granulosa cell tumour there is no abnormal activity at the hypothalamic/pituitary level, but merely an increased production of oestrogens from the tumour itself. Sometimes, in an attempt to distinguish these varieties from each other, we restrict the term 'precocious puberty' to those cases in which changes are of hypothalamic/pituitary origin, those associated with an ovarian tumour being labelled 'precocious sexual development' or 'precocious pseudopuberty'. A different kind of gynaecological lesion may be very rarely seen - a chorio-carcinoma - which by its secretion of gonadotrophins stimulates ovarian activity.

Clinical features Since a variety of causes can give rise to precocious puberty, there are differences in the clinical picture in these various types of cases. Constitutional precocious puberty (Figure 6.1) is characterized merely by the very early development of secondary sexual

characteristics and by menstruation without any other striking features. Broadly speaking, the signs of puberty appear in their customary order, with menstruation becoming evident after several other signs have preceded it. Less commonly, vaginal bleeding may occur at an earlier stage but it is quite rare for it to be a first sign. This is in contrast to the McCune-Albright syndrome in which vaginal bleeding is often the first manifestation of the abnormality. Growth in height is an obvious feature of most patients with constitutional precocious puberty, a girl being a good deal taller than others of her same chronological age; indeed a combination of this increased stature with obvious secondary sexual development gives the patient the appearance of being much older than she really is. An X-ray will show the bone age to be considerably advanced (Figure 6.2). Most cases of cerebral precocious puberty show a similar pattern to this, and no easy distinction can be made on clinical grounds. If there is a chronic neurological fault, e.g. hydrocephalus, or mental retardation from previous encephalitis, these features will be evident too. In the majority of cases, however, a cerebral cause for precocity should be excluded by investigation. Precocious puberty associated with the McCuneAlbright syndrome tends to give a different picture. A characteristic feature is the tendency for vaginal bleeding to occur at a much earlier stage in the disease, perhaps as the first sign of abnormality. In a series of cases reviewed by Heller, Savage and Dewhurst (1978), vaginal bleeding was the first sign of abnormality in seven out of nine patients with

L H /

$

"i *· wt 1 Figure 6.1 A child aged seven years with constitutional precocious puberty. Note the increased height for age

Figure 6.2 Advanced bone age in the child shown in Figure 6.1. On the left is shown the normal radiological appearances of the hand and wrist at the age of 13. On the right is shown the X-ray of the patient in Figure 6.1

Clin ica I fea tu res

65

McCune-Albright syndrome, whereas in 15 cases of constitutional precocious puberty it was noticed to be the first sign of abnormality only once. The other clinical features which may suggest this particular form of precocious puberty are the presence of cafe-au-lait spots on the body surface (Figure 6.3) and the tendency to fractures. The former usually affect the neck, face, back and shoulders and they may be evident at birth, although the other features of puberty may be delayed for some years. A tendency to fractures can be very serious and may be a more important feature regarding treatment than the pubertal changes. As far as the gynaecologist or paediatric surgeon is concerned, an important aspect of precocious puberty of hypothalamic/pituitary origin is the possibility that a sizeable ovarian cyst may form as a result of the premature stimulation of the ovary. Such cysts are follicular in variety. Although the majority are small, some may attain a sufficient size to be felt per rectum or even per abdomen (Figure 6.4). Such a swelling is a difficult clinical feature to assess, since it may be a follicular cyst which is the result of the premature ovarian stimulation or an Figure 6.4 Precocious puberty in a young girl. This child had a large lower abdominal swelling which at operation was shown to be bilateral follicular cysts, the result of premature ovarian stimulation and not the cause of the condition. (From Dewhurst, 1963, by permission)

Figure 6.3 A large cafe-au-lait spot in a child with precocious puberty as a result of the McCune-Albright syndrome

ovarian neoplasm which is the cause of the precocious sexual changes. The approach to such a case is discussed below when treatment is considered. Precocious puberty due to an ovarian feminizing tumour is a far less common condition than is usually suspected; all the above varieties of hypothalamic/pituitary precocity are much more frequently seen. Nonetheless, the possibility must be considered in any child showing precocious sexual changes such as we are discussing. In a patient with a feminizing tumour there may be differences in the clinical picture in that bleeding may occur earlier than is usual with cerebral or constitutional precocious puberty, but this is not a particularly helpful feature; the same may be said about bone growth which is usually less advanced than in constitutional or cerebral precocity. The most striking feature suggesting an ovarian feminizing tumour is, of course, the palpation of the pelvic swelling. Granulosa cell tumours or other feminizing tumours causing precocious puberty are usually sufficiently large to be palpated per abdomen, but a smaller tumour palpable only per rectum may be sufficiently hormonally active to produce secondary development. Very rarely an adrenal tumour may present with feminization, although heterosexual development is far more common.

66

Precocious puberty

Another possible cause of secondary sexual development and vaginal bleeding in a young girl is the accidental ingestion of an oestrogenic preparation. The child may find her mother's supply of combined oral contraceptive and take some with consequences which may alarm the parents and the medical attendant if the fact of her taking them remains unknown. Very rarely from contact with such oestrogen preparations, children have appeared to absorb sufficient hormone to produce precocious changes; this anomalous source of stimulation should be kept in mind.

Investigation Investigation is necessary in all children showing precocious sexual changes, to exclude the possibility of a serious cause demanding early treatment. Hormone assay should be undertaken but may be less helpful than in theory. It has already been mentioned that follicle stimulating hormone (FSH), luteinizing hormone (LH), oestrogens and androgens are all detectable from a very early age, and the range of normal is wide. The detection of FSH and LH alone in blood or urine does not distinguish between varieties of precocious puberty, therefore, since these hormones would be detectable in a child with a granulosa cell tumour although the level is likely to be low. Precocious puberty of constitutional or cerebral origin, being associated with unusually early increased hypothalamic/pituitary activity, should demonstrate somewhat raised FSH and LH levels; provided several assays are performed, this finding is likely to be substantiated, but if only one assay is undertaken a low value may well be found if it is taken at a time of reduced FSH and LH activity in the hypothalamic/pituitary cycle. The use of pelvic ultrasound has proved invaluable in diagnosis and monitoring of treatment in precocious puberty. The diagnosis of precocious puberty may be confirmed by enlargement of the uterus and characteristic ovarian changes with a multicystic appearance (Stanhope et al., 1985). This constitutional picture differentiates these patients from those with pseudopuberty when the ovaries will either be inactive, or the presence of a solid/ cystic tumour (granulosa cell tumour) can be seen. The presence of follicular cysts may also be identified and the use of serial ultrasound during therapy will negate the need for invasive procedures. Saenz de Rodriguez and Toro-Sola (1982) detected 61 cases with ovarian cysts, and operated on 32 of these; 31 were follicular benign cysts and the other was a fibroma. It is probable that all these operations could have been avoided and serial ultrasound to monitor response will eradicate the necessity. Bone age should be established by one of the methods mentioned in Chapter 5. It is generally

considerably advanced in constitutional and cerebral precocious puberty (Figure 6.2), perhaps less so in the presence of a feminizing tumour. A wide survey of the bony skeleton including the long bones, for evidence of the McCune-Albright syndrome, must be undertaken. An X-ray of the skull may show abnormalities of the sella turcica, suprasella calcification, or rarely in the McCune-Albright syndrome, bony lesions in the base of the skull. Further investigations may depend on the age of the child, the other clinical features and the results of investigations thus far. What must be decided in particular is if further cerebral investigation is to be undertaken. In an older child with probable features on a skull X-ray, there is probably no further need for investigation. The younger the child, however, the greater the likelihood of an intracranial lesion. If the clinical findings suggest an intracranial lesion, a CT scan should be performed to locate the presence of a tumour, the discovery of which will necessitate referral to a neurosurgical unit.

Management The management of most children with precocious puberty does not involve the gynaecologist to any significant extent. In the minority of cases, however, he has an important part to play. This will particularly be the case when a pelvic swelling has been palpated and an opinion is sought about its nature and treatment. In all cases an ultrasound scan should be performed and the findings will normally differentiate a simple follicular cyst from a solid/cystic tumour. The latter requires a laparotomy to remove the granulosa cell tumour. The granulosa cell tumour is of different appearance. It is predominantly a solid tumour, although there may be cystic areas in its substance. It is normally a very vascular growth with large vessels evident on its external surface. Normal ovarian tissue cannot easily be identified at any point. Ovarian tumours of this kind are usually unilateral. If the tumour is sectioned its cut surface shows solid and cystic areas with evidence of haemorrhage at various points. These appearances are quite unlike the smooth, thin cystic lining and serous contents of a follicular cyst. If the swelling is a feminizing tumour, unilateral salpingo-oophorectomy is probably the treatment of choice. Granulosa cell tumours are usually benign, although a minority are malignant. Unless there are clear signs of malignancy with spread to nearby organs, the procedure should be confined to unilateral salpingo-oophorectomy, the other ovary being carefully inspected and even, if there is doubt, divided longitudinally for observation of its deeper parts to exclude a second tumour. If there is obvious

Isolated manifestations of precocious sexual development malignancy there will be little alternative to total hysterectomy and bilaterial salpingo-oophorectomy with possible radiotherapy treatment later if re­ quired. The parents must be warned of the possibil­ ity of this radical surgery before operation is under­ taken and their permission for it must be obtained. If the ultrasound findings suggest a follicular cyst, the progress should be followed by serial measure­ ments at 2-4-weekly intervals whilst the patient is receiving medical therapy. If, in spite of this treat­ ment, the cyst fails to regress, it must be surgically removed. Ovarian cystectomy (see Figure 11.20) should be employed with conservation of as much ovarian tissue as possible. Even bilateral cysts may easily and safely be dealt with in this way and the majority of the child's ovary conserved. The remaining management of a patient with precocious puberty is usually the responsibility of the paediatrician; it concerns the possibility of inhi­ biting the precocious hypothalamic activity, and the emotional and psychological management of the child and parents. For some years attempts have been made to inhibit hypothalamic activity and halt the precocious puberty changes by giving medroxyprogesterone acetate (Provera) in doses of 100-200 mg i.m. every 2-4 weeks. This treatment may cause regression of some of the sexual changes and cessation of menstruation. It is less successful, however, in inhibiting bone growth. The advanced bone growth associated with precocious puberty causes the girl to be initially much taller than her classmates, but the early fusion of her epiphyses results in her ultimate stature being shorter than that of most girls undergoing puberty at the right time. Medroxyprogesterone acetate therapy has com­ paratively little effect on bone growth, and ultimate short stature may nevertheless be a result. There are disadvantages too to this therapy which may cause suppression of adrenocortical activity; later, when the drug is stopped, hypothalamic/pituitary activity may remain depressed for a time. Whether this variety of suppression is to be employed, however, is not an easy choice. This decision may be influenced by the age of the patient - the younger she is the more desirable is suppression - the adjustment of the child and parents to the early puberty, and the degree of supervision which can be exercised. Sexual assaults have occurred on young children with precocious puberty, with pregnancy resulting. If medroxy­ progesterone acetate is used, cooperation with the paediatric endocrinologist is important. An alternative to medroxyprogesterone acetate suppression is treatment with cyproterone acetate, a drug with antiandrogenic and antigonadotropic pro­ perties. It has been used successfully in the treat­ ment of hirsutism (see Chapter 10) and appears to be superior to medroxyprogesterone acetate in the treatment of children with precocious puberty. Kauli

et al. (1976) reported its use in 29 children of whom 23 were girls. Two dosage schedules were used: 70-150 mg/m2/day by mouth, and 107-230 mg/m2 every 2-4 weeks by injection. The simpler oral treatment proved more efficacious. Kauli and col­ leagues noticed suppression of the signs of puberty and some effect on bone growth in height; the latter was evident only in children with a bone age of less than 11 years, however, an effect noted also by Bossi, Zurbrugg and Joss (1973) and Werder et al. (1974). There are a number of side effects from treatment with cyproterone acetate which limit its use, the most significant of which is adrenal suppres­ sion (Savage and Swift, 1981). The mainstay of treatment nowadays is the use of LHRH analogues. The basis of this treatment is the ability to suppress hypothalamic/pituitary function, and thereby arrest or regress the clinical signs of puberty. A number of analogues have been used: (D-Trp )-LHRH has been administered parenterally (Comite, Cutler and River, 1981; Laron et al., 1981) and (D-Ser 6 )-LHRH can be given intranasally, 200 μg t.d.s. or (D-Ser 10 )-UHRH m a y be­ come a useful depot preparation. Roger, Chaussain and Raynaud (1984) have reported the successful use of (D-Trp 6 )-LHRH by monthly injection. There are no data as yet to suggest any improvement in growth prognosis in these patients. The use of monthly depot preparations allows pubertal devel­ opment to be temporarily arrested until the child reaches an appropriate age for normal pubertal development to occur. An important aspect of the management of a child with precocious puberty is social management. There are often behavioural problems and edu­ cational problems since an affected child is likely to be taken as older and more mature than she really is. The joint cooperation of the teachers, social workers, family doctor and, above all, the parents, is of immense importance if a successful outcome is to be achieved. The long-term outlook for these girls is very good (Muran, Dewhurst and Grant, 1983).

Isolated manifestations of precocious sexual development From time to time a young girl may be seen with only one manifestation of precocious sexual devel­ opment. This may be pubic hair only (premature pubarche or adrenarche), breast development only (precocious thelarche, Figure 6.5), or menstruation only (precocious menarche, Figure 6.6). The aetiology of such changes is not properly understood. It is usually supposed that they repre­ sent unusual sensitivity of one end organ to the very low levels of circulating oestrogens (and in case of premature pubarche, androgens) in a young girl. Their importance lies in the fact that they may be

67

68

Precocious puberty

Figure 6.5 Precocious thelarche in a young child. (Courtesy of Dr John Huffman)

the first manifestation of true precocious puberty or even of the oestrogenic activity of a feminizing ovarian tumour. Full examination and investigation are therefore essential before the condition can be accepted as one without special danger which requires no treatment. Hormone assay will usually demonstrate all levels to be appropriate for the chronological age of the child; bone age will similarly correspond to chronological age in most cases. Occasionally the physical signs are transient, breast development, for example, showing regression at least for the time (Figure 6.7). Sometimes one breast only is involved, when there is a real risk of unwise surgery being undertaken to biopsy a supposed tumour. Capraro et al. (1971) have reviewed this matter fully. Of these isolated manifestations of secondary sexual development the most difficult to assess and the most potentially serious is vaginal bleeding. A patient with vaginal bleeding during childhood may have: (1) A malignant (or rarely benign) genital tract tumour. (2) A vaginal foreign body. (3) Precocious puberty of any aetiology. (4) Precocious menarche as here defined. (5) Other vulval or vaginal lesions, e.g. prolapsed urethra, lichen sclerosus or trauma.

Figure 6.6 A child aged 1.5 years who has been having periodic 'menstruations' for many months at more or less regular intervals. Note the absence of secondary sexual development. No other cause for the vaginal bleeding could be recognized. (From Heller, Dewhurst and Grant, 1979, by permission) Heller, Savage and Dewhurst (1978) in a review of 51 cases of vaginal bleeding in childhood found the causes shown in Table 6.2. It is imperative to exclude a malignant vaginal or cervical growth, and examination under anaesthesia must always be undertaken at an early stage. At this examination care must be taken to exclude an ovarian tumour. Since bleeding may occur as the first manifestation Table 6.2 Causes of vaginal bleeding in 51 children. (From Heller, Savage and Dewhurst, 1978)

Constitutional precocious puberty McCune-Albright syndrome Precocious menarche Cerebral precocious puberty Vaginal or cervical tumour Trauma Vaginitis Vaginal prolapse

Number

Percentage

15 9 8 5 6 4 3 1

29 17 16 10 12 8 6 2

References 69

Figure 6.7 Four photographs illustrating the fluctuation in breast size in premature thelarche. (a) April 1973; (b) August 1973; (c) October 1974; (d) December 1974 of the McCune-Albright syndrome or rarely of the other forms of precocious puberty, an X-ray of the long bones should be performed and a pelvic ultrasound carried out. An exogenous source of oestrogens to which the child may have had access should be sought. If there is any possibility that bleeding may be urinary, cystoscopy could be performed at the time of examination under anaesthesia and a midstream sample of urine should be examined. Only when all other causes have been excluded and the bleeding is period-like, although not necessarily regular, can it be accepted as being due to premature menarche. Even then, since this condition is little understood, careful follow-up is essential. Relatively few reports of the condition appear in the literature. These have been reviewed by Heller, Dewhurst and Grant (1979). Such isolated manifestations of puberty do not require treatment.

References BOSSI, E., ZURBRUGG, R. p. and JOSS, E. E. (1973) Improvement

of adult height prognosis in precocious puberty by cyproterone acetate. Acta Paediatrica Scandinavica, 62, 405 CAPRARO, V. J., BAYONET-RIVERA, N. P., ACETO, T. and

MacGiLLivRAY, M. (1971) Premature thelarche. Obstetrical and Gynaecological Survey, 26, 2

COMITE, F., CUTLER, G. B. and

RIVER, J. (1981) Short

term treatment of idiopathic precocious puberty with a long acting agonist of luteinising hormone releasing hormone. New England Journal of Medicine, 305, 1546-1550 DEWHURST, c. J. (1963) Gynaecological Disorders of Infants and Children, Bailliere Tindall, London HELLER, M. E., SAVAGE, M. o. and DEWHURST, J. (1978) Vaginal

bleeding in childhood: a review of 51 patients. British

70

Precocious puberty

Journal of Obstetrics and Gynaecology, 85, 721

fic, Oxford, p. 224

HELLER, M. E., DEWHURST, J. and GRANT, D. B. (1979) Premature

ROGER, M., CHAUSSAIN, J. L. and RAYNAUD, F. (1984) Treatment

menarche without other evidence of precocious puberty. Archives of Disease in Childhood, 54, 472

of male and female precocious puberty by monthly injections of a continuous release preparation of D-Trp LHRH. Pediatric Research, 18, 1209

HUFFMAN, j . w., DEWHURST, J. and CAPRARO, v. j . (1981) The

Gynaecology of Childhood and Adolescence, Saunders, Philadelphia KAULI, R., PERTZELAN, A., PRAGER-LEWIN, R., GRUNEBAUM, M. a n d

LARON, Z. (1976) Cyproterone acetate in treatment of precocious puberty. Archives of Disease in Childhood, 51, 202 LARON, Z., KAULI, R., BEN-ZEEV, Z., COMARU-SCHALLY, A. M. a n d

SCHALLY, A. v. (1981) D-Trp2 analogue of luteinising hormone releasing hormone in combination with cyproterone acetate to treat precocious puberty. Lancet, i, 955 MURAN, D., DEWHURST., J. and GRANT, D. B. (1983) Premature

menarche - a follow-up study. Archives of Disease in Childhood, 58, 142 RAYNER, P. H. w. (1981) Early puberty. In Clinical Paediatric Endocrinology (ed. C. G. D. Brook), Blackwell Scienti-

SAENZ DE RODRIGUEZ, c. A. and TORO-SOLA. (1982) Anabolic

steroids in meat and premature thelarche. Lancet, i, 1300 SAVAGE, D. c. L. and SWIFT, p. G. F. (1981) The effect of

cyproterone acetate on adrenocortical function in children with precocious puberty. Archives of Disease in Childhood, 56, 218 STANHOPE, R., ADAMS, J , JACOBS, H. s. and BROOK, c. G. D. (1985)

Ovarian ultrasound assessment in normal children, idiopathic precocious puberty and low dose pulsatile GnRH therapy in hypogonadotrophic hypogonadism. Archives of Disease in Childhood, 60, 116 WERDER, E. A., MURSET, G., ZACHMANN, M., BROOK, C. G. D. a n d

PRADER, A. (1974) The treatment of precocious puberty with cyproterone acetate. Pediatric Research, 8, 248

7 Delayed puberty

The concept of delayed puberty is somewhat unfamiliar to gynaecologists and yet it is a far more appropriate term than the commonly used 'primary amenorrhoea'. Primary amenorrhoea focuses attention merely on one of the physical features of puberty, whereas delayed puberty implies interference with the general process of sexual maturation. The close relationship already described between the signs of secondary sexual development and menstruation makes it important to consider them together if a proper understanding of an individual case is to be achieved. A simple example shows the wisdom of thinking in terms of puberty delay and not in terms of primary amenorrhoea. If a patient aged 15 years comes for consultation because she has not yet menstruated this is not necessarily abnormal, since the normal range of the age of the menarche is some 10-16 years. If that patient has no sign of secondary sexual development, however, this is abnormal and demands further investigation. A further important point is that when failure to menstruate is considered in relation to the degree of development of the other secondary sexual characteristics, the probable diagnosis usually becomes evident as follows:

/ / secondary sexual development is good apart from the amenorrhoea, the diagnosis is likely to be an anatomical fault in the uterus or vagina such as: (1) imperforate vagina; (2) absent vagina; and if these can be excluded, a third diagnosis must be considered: (3) resistant ovary syndrome.

/ / secondary sexual development is poor or absent, there is likely to be an endocrine cause for the failure to develop: (1) constitutional delay in the appearance of puberty changes (the late developer); (2) primary gonadal failure (gonadal dysgenesis); (3) hypothalamic/pituitary failure of rhythmic follicle stimulating hormone (FSH) and luteinizing hormone (LH) production. If secondary sexual development is heterosexual, the diagnosis may be: (1) (2) (3) (4) (5)

one of the forms of XY female; congenital adrenal hyperplasia; an adrenal tumour; masculinizing ovarian tumour; Cushing's syndrome.

Clinical investigation When a patient who has never menstruated is brought for examination therefore, very careful inspection must be undertaken to identify the clinical features which may clearly indicate the correct diagnosis. Particular attention must be paid to: (1) (2) (3) (4)

Age. Height. Weight. The presence or absence of somatic features such as neck webbing, short metatarsals, etc. suggesting gonadal dysgenesis. (5) The degree of secondary sexual development. (6) The presence or absence of intermittent lower abdominal pain, suggesting haematocolpos. (7) The presence or absence of any heterosexual 71

72

(8) (9) (10) (11)

Delayed puberty

feature such as deep voice, abnormal hair growth, enlarged clitoris, etc. The normality or abnormality of the vulva. The patency of the introitus. The bulging of the intact membrane of the introitus if not patent. The palpation of a cystic swelling in the pelvis on rectal examination, again suggesting haematocolpos.

Secondary sexual development otherwise good The conditions to be considered here are: (1) Haematocolpos (see Chapter 3). (2) Congenital absence of a vagina (see Chapter 3). (3) Resistant ovary syndrome. Resistant ovary syndrome This is a rare syndrome with several bizarre features. It was first reported by Jones and de Moraes-Ruehsen (1969), and other reports by Starup, Sele and Hendriksen (1971), Van Campenhout, Vauclair and Maraghi (1972), Dewhurst, de Koos and Ferreira (1975), Koninckx and Brosens (1977) and Evers and Rolland (1981) have appeared since. Briefly, the patient with some degree of secondary sexual development but with primary amenorrhoea is found to have FSH and LH levels raised to the menopausal range; despite this finding, the ovaries contain numerous ova, some in various stages of development, although advanced follicular growth and evidence of ovulation are very rare. Attempts to stimulate ovulation by administration of human menopausal gonadotrophin (HMG) or human pituitary gonadotrophin (HPG) with human chorionic gonadotrophin (HCG) have met with little success, despite the use of high doses. The condition is not fully understood although it may be a gonadotrophin receptor abnormality. In the present context its importance lies in the probability that the patient who has never menstruated and is found to have postmenopausal levels of FSH and LH may be thought to have undergone a premature menopause, and a hopeless prognosis for childbearing may be given, whereas in the resistant ovary syndrome childbearing, although reduced in likelihood, may be a possibility. Repeatedly raised FSH and LH values can only signify ovarian failure if there are clearcut clinical and cytogenetic features of gonadal dysgenesis; if these are absent, laparoscopy and ovarian biopsy must be undertaken. An adolescent with the resistant ovary syndrome will probably need no treatment at all until such time as she wishes to become pregnant; ovulation induction can then be attempted, although it may

not succeed. Background oestrogen production may be inadequate to maintain the state of the vagina and protect against osteoporosis, and replacement hormone therapy will probably be wise.

Secondary sexual development poor or absent Such a patient may be an example of: (1) Constitutional delay in the onset of puberty (the late developer). (2) Gonadal dysgenesis. (3) Hypothalamic/pituitary failure of adequate gonadotrophic production. The late developer It is usually possible to distinguish the latedeveloping adolescent who, given time, would develop normally from the other two conditions in this group, provided attention is paid to several clinical points. Late developers are often familial. A history of a late start to menstruation in mother or sisters should always be sought and if found is a useful pointer to diagnosis. This is not invariable, however, and a negative family history of late menarche does not exclude late development in the patient. Careful attention must be paid to the relationship between the age, the degree of secondary sexual development present, the time of its first appearance and its progress since, the height and weight, and the presence or absence of any serious intercurrent disease. One or two examples will indicate the type of patient seen and the probable diagnosis. A 16-yearold girl of short stature with no secondary sexual development at all is highly likely to be an example of gonadal dysgenesis; on the other hand, a girl also aged 16 whose first signs of breast development occurred 1-2 years earlier, and whose growth spurt seems now to be getting well under way, is possibly a late developer who need not be investigated intensively. An adolescent with a serious chronic disease or other intestinal absorption disorder (Figure 7.1) may suffer constitutional delay in sexual maturation as a result; improvement in the general disease may coincide with a spurt of growth, secondary sexual development and menstruation. The relationship of weight to pubertal changes has been commented on already, and such an association may explain delay in the completion of puberty in some patients in a similar manner to the way in which it may be associated with secondary amenorrhoea. The early development of anorexia nervosa may halt the process of sexual maturation before the stage of menstruation has been reached.

Secondary sexual development poor or absent

73

*

:t... W 1 Figure 7.1 Stunting of growth and genital infantilism in a 15-year-old girl who had suffered from coeliac disease for several years The effect is hypothalamic in origin and requires the weight changes to precede the menarche for primary amenorrhoea to be the result; secondary amenorrhoea from this cause is very much more common. Similarly, a profound emotional disturbance of the variety commonly associated with secondary amenorrhoea may, if it occurs before the menarche, produce primary amenorrhoea. Careful attention to all these points is necessary in evaluating the possible late-developing adolescent. One of the most valuable investigations is the bone age. If the bone age (Figure 7.2b) is less than the chronological age and below the normal upper limit for menstruation of 14.5 years, this suggests simple delay in maturation, permitting us to wait and see, at least for a while. If the bone age is more than 14.5 years, menstruation should have begun, and investigations along the lines described later in this chapter should be undertaken. Gonadal dysgenesis 'Gonadal dysgenesis' is a term which may be used in a narrow or broad sense. A gonad is dysgenetic if it is imperfectly formed, and since there are an infinite

Figure 7.2 (a) External appearance of an 18-year-old girl who is a late developer. Breasts have been growing steadily for the last two years and the pubic hair has reached stage 3; menses have not yet begun, but it is thought that they are imminent since, as seen in (fr), the bone age of the patient on the right is comparable with the standard appearances at bone age 13 seen on the left number of degrees of imperfection which may affect either testes or ovaries, gonadal dysgenesis can be an exceedingly broad term indeed. It is certainly unhelpful to consider it in such a fashion, but it is equally inappropriate to restrict it to the type of

74

Delayed puberty

person with all the features of Turner's syndrome and gonads which are useless streaks of tissue. Gonadal dysgenesis as a clinical entity is a spectrum of conditions and the clinical features within the spectrum may vary with the degree of gonadal differentiation; this is in turn related to the presence or absence of a sex chromosome abnormality, and if there is such an abnormality, the nature of it. Aetiology Gonadal dysgenesis is a condition frequently associated with the presence of a sex chromosome anomaly in the afflicted person. The commonest finding is a missing sex chromosome, the patient having only one X and a karyotype which is referred to as 45 X. Cells with only a Y chromosome present are non-viable and this karyotype is never encountered. Some patients with gonadal dysgenesis, however, have a different fault from the 45 X one, and some have none at all. A patient with gonadal dysgenesis may have a mosaic karyotype. Mosaicism is the presence in an individual of two or more cell lines with different chromosomal complement derived from the same zygote; it is to be distinguished from the less common chimerism in which two cell lines are present, derived from different zygotes. The commonest mosaic patterns to encounter are probably the 45 X/46 XX and 45 X/46 XY. In these cases one cell line is normal but mosaicism may occur with both cell lines abnormal as in the 45 X/47 XXX; alternatively, three cell lines may be present as in 45 X/46 XX/47 XXX. Sometimes the chromosomal abnormality present is a structural abnormality of the chromosome, part of it being deleted. The deletion may affect the long arm (46 XXq-) or the short arm (46 XXp-). Deletion may arise in a different way, as in the formation of an isochromosome. Here a chromosome divides transversely instead of longitudinally, so instead of there being two identical chromosomes following division, we have one representing two short arms and one representing two long arms. The important thing to remember is that if the chromosome representing two long arms is involved in fertilization, the material present on the short arm is missing, and vice versa. Rarely, if a break occurs in each arm of a chromosome, the two ends unite as a ring 46 XXr. It must also be stressed that quite often mosaicism and an abnormal chromosome coexist, i.e. 45 X/46 XXq-. Some patients with gonadal dysgenesis do not have a chromosome fault at all but have a normal female 46 XX or male 46 XY karyotype, at least as far as present methods of chromosome analysis are concerned. Such patients show clear differences in clinical features from those demonstrated by patients with a chromosome fault present.

The manner in which these chromosome faults occur will be mentioned only briefly; more detailed descriptions of this and other cytogenetic matters can be found in works by Dewhurst (1971), Simpson (1976), Tho and McDonough (1981) and McDonough (1987). Loss of an X or Y chromosome to give rise to a 45 X karyotype is due to the process of nondisjunction arising during one or other division of meiosis (Figure 7.3). Mosaicism may be due to the same abnormality affecting the first cleavage division of the zygote when the two cell lines will be abnormal - 45 X/47 XXX (Figure 7.4) - or affecting a slightly later division when a normal cell line will exist as well. Mosaicism may also occur as a result of anaphase lag; in this phenomenon during anaphase, as the chromosomes are returning down the nuclear spindle, one lags behind sufficiently to be excluded when the nuclear membrane closes (Figure 7.5); this may result in a 45 X/46 XX mosaic or a 45 X/46 XY one. Other more bizarre chromosome abnormalities do not require separate consideration in a work of this kind. (a) Primary oocyte

1st meiotic division (reduction division)

1st polar body (22 + X) 2nd meiotic division )2nd polar body (22 + X) x / " ~ Ootid (ovum) Zygotes XX or XY

4

+ \

Primary oocyte

XX j

1st polar body 22A + XX

2nd polar body 22Aonly Sperm 22A + X Zygote 45 X

Figure 7.3 id) Normal oogenesis; a single X chromosome enters the secondary oocyte and the first polar body, and a single X enters the ovum and the second polar body. (b) Non-disjunction of the first meiotic division; both X chromosomes enter the first polar body, and none enters the secondary oocyte. As a result the X chromosome obtained from the sperm is the only one present and the zygote has a 45 X karyotype

Secondary sexual development poor or absent

(a)

(b)

Figure 7.4 Mosaicism as a result of non-disjunction affecting (a) the first cleavage division, or (b) the second cleavage division. In the former there are two abnormal cell lines; in the latter there are three cell lines, two abnormal and one normal

Figure 7.5 Mosaicism resulting from anaphase lag. One cell line is normal and one abnormal

Clinical

Figure 7.6 A patient showing the typical features of the extreme form of gonadal dysgenesis often known as Turner's syndrome. (From Dewhurst, 1963, by permission)

features

To understand the clinical features of gonadal dysgenesis, it is best to consider first a classic case associated with a 45 X karyotype - what has in the past been known as Turner's syndrome (Figure 7.6). Such patients are of short stature (seldom above 145 cm tall and usually far less), absent secondary sexual development, a wide carrying angle of the arms, a webbed neck, a broad chest with widely spaced nipples, and primary amenorrhoea. They may have associated features such as colour blindness, coarctation of the aorta, short metatarsals (Figure 7.7), etc. Their gonads are useless streaks of tissue which histologically bear a resemblance to ovarian stroma but ova are absent. The work of Singh and Carr (1966) on 45 X fetuses indicates that there is initially a normal number of germ cells but an accelerated atresia during later intrauterine life leads to the streak ovary. The uterus, tubes and

Figure 7.7 The metatarsal shortening in a patient with gonadal dysgenesis

75

76

Delayed puberty

vagina are present and the vulva is normal but infantile. It is important to understand that this combination of features is due to the loss of different genetic material carried out on the same sex chromosome. There are clinical features which are due to the failure of gonadal development - the absence of secondary sexual development and primary amenorrhoea - and features due to lack of genetic material important to growth - short stature, in particular. These patients are not short because they have gonadal dysgenesis but because they have lost growth potential by lacking important chromosomal material. This point is best illustrated by studying patients with a gonadal dysgenesis who have lost no genetic material but whose karyotype is 46 XX or 46 XY. This condition is best called pure gonadal dys­ genesis, since the only features present relate to gonadal dysgenesis, and none relates to growth failure. Such patients (Figure 7.8), although showing absent secondary sexual development and primary amenorrhoea, are of normal height for their genetic constitution. Whether they have a 46 XY or 46 XX karyotype does not affect their phenotype,

Figure 7.8 A patient with pure gonadal dysgenesis and a 46 XY karyotype. (From Dewhurst, 1971, by permission)

which remains female since no androgens are produced to cause masculinization and no Müllerian inhibitor to prevent the uterus, vagina and tubes from forming. When mosaicism or an abnormal sex chromosome, or both, are the cause of the dysgenesis, clinical features may vary (Dewhurst and Lucas, 1971). Taking mosaicism first, the manner in which variations occur may be thought of as follows. If there is an overwhelming preponderance of 45 X cells - say 99% compared with 1% of 46 XX ones the patient will resemble a case of Turner's syndrome just described. If the proportions are reversed - 99% 46 XX, 1% 45 X - the patient may be normal or virtually normal. If the proportions are fairly equal, the clinical features may depend on the distribution of normal and abnormal cells in the early embryo; should the genital ridge be largely developed from 46 XX cells, for example, ovarian differentiation may be virtually normal, or if from 45 X cells the gonads would be streak-like. The presence of a normal cell line will, however, allow for the possibility of a degree of ovarian differentiation which may give rise to minimal secondary sexual development without menstruation (Figure 7.9), to a greater degree of secondary development still with irregular menstruation (Figure 7.10), or to normal secondary sexual development and regular menstruation (Figure 7.11). Some 11-12% of patients exhibit some degree of oestrogenic activity (Simpson, 1976; McDonough etal., 1977) and a few, albeit rarely, have conceived, although the outcome is usually a mosaic or an X deletion infant (Dewhurst, 1978; Muram and Jolly, 1982). Height may be similarly variable (Figure 7.12), although it is less easy to decide precisely how this might happen. If, however, a group of 45 X patients is compared for height with a group of mosaic and abnormal chromosome patients, and they in turn with a group of pure gonadal dysgenesis patients, the difference in height relating to karyotype can clearly be seen (Table 7.1). The clinical picture in a patient with an abnormal chromosome is also variable and variation is now related to part of the chromosome lost. Much has yet to be learned about the function of the genetic material carried on different parts of the sex chromosome, and we cannot precisely relate differences in the clinical picture with the part of the chromosome that is missing. It is usually supposed that material carried on the short arm is related to growth, and material set close to the centromere is associated with gonadal differentiation, but there are clinical exceptions which do not fit into this generalization (Figure 7.13). The close study of the relationship between a part of the chromosome lost and the incidence of menstruation in patients with a deletion but without mosaicism presents anomalies not easily explained

Secondary sexual development poor or absent

Figure 7.9 A patient with 45 X/46 XX gonadal dysgenesis. Her stature is short but there has been some spontaneous secondary sexual development, although there has been no menstruation

Table 7.1

77

Figure 7.10 A patient with 45 X/46 XX karyotype. Her stature is short and she has normal secondary sexual development and she menstruates from time to time; note the marked neck webbing

Gonadal dysgenesis: stature related to karyotype

Karyotype

Stature (cm)

Karyotype

Stature (cm)

Karyotype

Stature (cm)

Karyotype

Stature (cm)

45 X

133.75 135.0 137.5 138.75 140.0 140.0 140.5 141.75 142.5 145.0 145.0

X/XXqi X/XY X/XY X/XX X/XX X/XX X/XY XXqi X/XX X/XY XXqX/XXqi X/XY X/XY X/XX

135.0 136.25 137.5 138.75 138.75 140.0 140.5 140.5 142.5 142.5 145.5 150.0 151.25 155.0 157.5

46 X X

148.75 155.0 157.5 160.0 162.5

46 X Y

165.0 167.5 170.0 170.0 170.0 177.5

169.5

170.0 172.5

78

Delayed puberty

ft

Figure 7.11 A patient with normal secondary development and regular menstruation despite having 45 XI 46 XX karyotype

(Table 7.2). We do not understand, for example, why long or short arm deletion should not be more often associated with sufficient ovarian differentiation to permit menstruation, if indeed the material in the region of the centromere is that related to gonadal differentiation. Nor is it clear why an isochromosome in which paracentric material is lost is not always associated with amenorrhoea. The explanation of these anomalies must be awaited. An important practical point is that clinical variations related to stature and secondary sexual development may occur in the presence of an abnormal chromosome just as they can in a patient with mosaicism. Table 7.2 Menstruation in association with X deletion in non-mosaic patients Abnormality

Number

Deletion of short arm Deletion of long arm Isochromosome of short arm Isochromosome of long arm

17 20 5 24

Menstruation 6 3 0 1

Figure 7.12 A patient with a mosaic karyotype who shows clear evidence of gonadal dysgenesis, although her stature is greater than usual

A very significant clinical variation is sometimes seen in patients with a Y chromosome present. When such patients have no testicular differentiation whatsoever, their gonads will be useless streaks and they will demonstrate the typical features associated with dysgenetic gonads; whether they are tall or short, of course, relates to whether or not genetic material has been lost. But if there is a degree of testicular differentiation, there may be a similar degree of external genital masculinization causing doubts about the individual's sex (Figure 7.14). Some such patients exhibit what has been called mixed gonadal dysgenesis (Davidoff and Federman, 1973) - an inappropriate term. In mixed gonadal dysgenesis one gonad is a streak and the other a rudimentary testis, and some masculinization is usually evident. The condition merely represents a greater degree of interference with the development of one gonad than with the other, and is readily understandable in terms of the variable distribution of normal and abnormal cells during embryogenesis as postulated above. The term

Secondary sexual development poor or absent 79

Figure 7.13 A patient with 46 XXq- karyotype. Despite the deletion of the long arm of her X chromosome she is short of stature. Her secondary sexual development, however, is normal and she has menstruated fairly regularly for some years 'mixed' implies that the gonads are fundamentally different from each other, which is not so. It must also be mentioned that gonadal dysgenesis may be recognizable during childhood. The manner of presentation is variable. In the first few months of life there may be unexplained oedema of hands and feet (Figure 7.15), loose folds of skin at the neck (Figure 7.16) and unusual facies (Figure 7.17). In older children the oedema usually disappears but may rarely persist; the main feature of the growing child is shortness of stature, which should always focus attention on the possibility of a sex chromosome anomaly of the varieties associated with gonadal dysgenesis.

first be performed. If this shows a karyotype commonly associated with gonadal dysgenesis and there are no discordant features, further investigation is unnecessary although it is frequently undertaken. If it is felt appropriate to do anything further, the simplest and most satisfactory test is to measure FSH and LH which, being raised to menopausal levels, will confirm the gonadal failure. Laparoscopy is an unnecessary surgical procedure. An LHRH test will seldom be necessary; if it is undertaken it will show raised baseline FSH and LH levels and a further rise in both following the LHRH injection. If there are atypical clinical features such as those already described, or if there is no chromosomal abnormality, diagnosis may not be quite so straightforward. Atypical clinical features with mosaicism or an abnormal chromosome raises the possibility of gonadal differentiation, and it may be advisable to determine if this is present. FSH levels raised to the menopausal range would tend to confirm gonadal failure, as would an exaggerated LHRH test; normal ones would be compatible with a degree of normal ovarian formation. Laparoscopy and ovarian biopsy are usually undertaken in such a circumstance to permit a detailed histological study of the gonad itself, noting the presence and number of primary follicles and their degree of development if any. If this test fails to give clear information, perhaps because of technical problems in the laparoscopy or failure to get a representative biopsy, stimulation of the gonad with HPG or HMG and measurement of the oestrogenic response should permit an assessment of the capability of the ovary to respond to gonadotrophic stimulation; an LHRH test may be employed, but is less likely to be helpful. If there is sexual infantilism but there are no growth features, the diagnosis to be suspected is, of course, pure gonadal dysgenesis. If chromosomal analysis reveals a 46 XY karyotype and there is no evidence of masculinization, the gonads may be regarded as streaks and dealt with as described below. If the karyotype is 46 XX, however, it will not be possible clinically to distinguish pure gonadal dysgenesis from a failure of the hypothalamus and pituitary to produce FSH and LH in the proper amounts. Assay of these hormones will, of course, make the distinction; in the former they will be raised to menopausal levels and in the latter they will be low or perhaps within the very wide range of normal (see below). Different LHRH test results would also be found.

Investigation Investigation of a possible case of gonadal dysgenesis may be extremely simple or more complex, depending on the typical or atypical clinical features present. If the patient has typical clinical features of gonadal dysgenesis, chromosome analysis should

Treatment Treatment in gonadal dysgenesis resolves itself mainly into two important physical considerations the need for hormone replacement therapy and for surgical removal of the rudimentary gonads; in

80

Delayed puberty

(a) (b) Figure 7.14 (a) Minimal clitoral enlargement and minimal fusion of genital folds in a patient with a 45 X/46 XY karyotype whose other features were consistent with those of gonadal dysgenesis. (b) Greater clitoral enlargement and further fusion of genital folds in another patient with 45 X/46 XY karyotype. (Part (b) from Dewhurst, 1971, by permission)

V :Ä

addition the very important psychological aspects must constantly be kept in mind. Hormone treatment is very important in patients with gonadal dysgenesis. It is psychologically devastating for an adolescent to be both short in stature and to lack secondary sexual development; we cannot do much to help the former but we can do a great deal to help the latter. Hormone therapy aims to produce breast growth which will have an important effect on the patient's morale. It is not necessary to give high doses of oestrogen to achieve this; indeed high doses are a disadvantage because of their effect on the endometrium. It is usual to use this simple routine:

Pr

511

Figure 7.15 Unexplained oedema of feet in an infant with 45 X karyotype. (From Dewhurst and Gordon, 1969, by permission)

Ethinyloestradiol, 10 μg/day, during days 1-24 of each calendar month for 3-4 months. Then ethinyloestradiol, 20 μg/day, during days 1-24 of each calendar month for a further six months or so. Then ethinyloestradiol, 20 μg/day during days 1-24 and norethisterone, 5 mg/day, during days 19-24 for the next three years.

Secondary sexual development poor or absent

Figure 7.16 Loose folds of skin at the neck in an infant with a 45 X karyotype.

Figure 7.17 Unusual fades and pronounced epicanthic folds in an infant with a 45 X karyotype. (From Dewhurst, 1969, by permission)

81

Following the regime, the normal gradual increase in oestrogen of adolescence occurs, menstruation usually not occurring until after the addition of progestogens. The choice of long-term hormone replacement therapy is between the oral contraceptive pill, natural oestrogens or oestrogen patches. The oral contraceptive is probably not advisable, in spite of its simplicity of use, because of the concern over the metabolic and cardiovascular problems related to changes in high density lipoproteins (HDL) and cholesterol. Natural oestrogens with progestogens for ten days, e.g. oestradiol valerate 1 or 2 mg with norgestrel 0.25-0.5 mg (Cyclo-Progynova) or conju­ gated equine oestrogens, 0.625 mg or 1.25 mg plus norgestrel 150 μg (Prempak-C) probably have less effect on HDL and are preferable in the long term. The newer mode of delivery of oestrogen is percutaneously. Estroderm patches (CIBA) containing 50 μg or 100 μg of oestradiol-17ß are applied to the skin of the lower body and changed every three days. This mode of delivery avoids the transport of oestrogen through the portal system to the liver where its effect on HDL and cholesterol is presumed to occur. Progestogens are still administered orally for ten days to oppose the oestrogen and induce a monthly withdrawal bleed. An important consideration in some patients with gonadal dysgenesis is the possible need for operation to remove streak or rudimentary gonads due to their raised cancer potential. In some patients there is undoubtedly a raised risk of malignancy, but this is only present in patients with a Y chromosome in their karyotype (see reviews by Fathalla, Rashad and Kerr, 1966; Barr et al., 1967; Dewhurst, 1971). In these patients the risk of gonadal malignancy may be of the order of 30% or so at some time in the patient's life - a level certainly high enough to call for prophylactic gonadectomy; by contrast patients without a Y chromosome present, whatever their karyotype may otherwise be, do not have a raised risk of gonadal malignancy and surgery is not indicated. Chiefly two varieties of malignancy are present: the gonadoblastoma and the dysgerminoma (further discussed in Chapter 11). The former is a most interesting growth illustrated in Figures 7.18 and 7.20; it is composed of supporting cells of the germ cells. The dysgerminoma (Figure 7.20) is actually a germ cell tumour and is a metastasizing malignant growth much more serious than a gonadoblastoma which, although spreading locally throughout the pelvis, does not appear to metastasize. The tumours sometimes coexist in the same gonad, as indeed they did in the patient shown in Figure 7.19. Some gonadoblastomas are only recognized histologically after the rudimentary gonads have been removed; the presence of such small histological foci indicates

82

Delayed puberty

'üiS^K^

^ρ-^βα * Ä ; " * · · ^ ^ * *r **&,

■Jfr&iA

Figure 7.18 Histological appearance of a gonadoblastoma which is illustrated in Figure 7.20. Stain: haematoxylin and eosin

Figure 7.19 External appearance of a 45 X/46 XY Indian patient. Her degree of breast development strongly indicated the likelihood of a gonadoblastoma being present in one gonad. The appearances found are shown in Figure 7.20

Figure 7.20 Pelvic findings in the patient illustrated in Figure 7.19. On the left a distinct tumour in one gonad is evident, and on the right a somewhat smaller tumour in the other gonad. Both tumours showed a mixture of gonadoblastoma (illustrated in Figure 7.18) and dysgerminoma the possibility of increased growth later and makes it clear that laparoscopy and visualization of the streaks is not adequate management for a patient with gonadal dysgenesis and a Y chromosome present. The fact that a streak looks entirely innocent at one time does not preclude the possibility of a small tumour in the substance of a streak beginning to spread at a later time. The association of the gonadoblastoma with a Y chromosome accounts for the fact that several patients with such a tumour reported in the literature have shown some degree of masculinization. Rarely, however, the gonadoblastoma appears to be oestrogen-producing and causes some female secondary development (Figure 7.19). This may cause clinical confusion, since feminization in association with the presence of a Y chromosome is not easy to explain. Secondary feminization in a 46 XY female may, of course, occur in androgen insensitivity or less often in association with a defect of testosterone biosynthesis, but in these conditions the uterus is absent; in anatomical testicular failure there is no secondary sexual development at all, as in most patients with gonadal dysgenesis. The combination of gonadal dysgenesis, a Y chromosome and secondary feminization can only mean the presence of a gonadoblastoma in the gonadal streak. Rarely in patients with gonadal dysgenesis consideration must be given to performing a surgical procedure on the external genitalia. This is particularly so if enlargement of the clitoris, perhaps with fusion of the labio-scrotal folds, is present with a Y chromosome, and if there is minimal testicular differentiation as in Figure 7.14. Such cases may be

Secondary sexual development poor or absent managed in a similar manner to that discussed under Surgical considerations in Chapter 2. In patients with gonadal dysgenesis and no Y chromosome, surgical enlargement of the vagina is hardly ever required. The vagina is, of course, very narrow, especially at the introitus before exogenous oestrogens have been given, and the tissues are markedly oestrogen deficient. Once adequate oestrogenization has been achieved by the type of hormone therapy described above, the vagina becomes as capable of natural enlargement as that of a normal woman. The psychological management of the patient with gonadal dysgenesis must never be neglected. At some time, of course, the patient must be given the unpalatable knowledge that she will be infertile. How and when this information is imparted will depend on the individual physician and his relation­ ship with the patient. It will generally be wise to concentrate on what can be done and most of all to convey to the patient that she can live a normal sex life. Emphasis on this last point will do much to increase the patient's acceptance of her condition.

Hypothalamic/pituitary lesion Many patients with gonadal dysgenesis have suf­ ficiently distinctive features for a firm diagnosis to be made on clinical grounds alone; patients with hypothalamic/pituitary causes for primary amenorrhoea can usually be diagnosed only after fuller investigation. There are a number of possible anatomical lesions in the hypothalamic/pituitary area which may account for a primary failure to menstruate. These include craniopharyngiomas, gliomas and various pituitary tumours. Several other rare conditions may be encountered such as the olfactogenital syndrome, pituitary dwarfism associated with various tropic hormone deficiencies including that of growth hor­ mone, and the Laurence-Moon-Biedl syndrome in which hypogonadism, obesity, polydactyly, retinitis pigmentosa, and mental retardation are in evidence. Sexual maturation may also be greatly delayed if there has been a marked disorder in earlier life, such as congenital heart disease, malnutrition, or a malabsorption syndrome (Figure 7.1). More com­ mon than any of these, however, is a functional failure of gonadotrophic production by the anterior pituitary in the absence of any clearcut recognizable cause. The clinical examination of a patient with a possible hypothalamic/pituitary lesion for her failure of sexual maturation will include a search for visual field defects, acromegalic changes, the signs of Cushing's syndrome, mental retardation, sleepiness and diabetes insipidus. It is wise to test the sense of smell, since anosmia is often found in the little

83

understood olfactogenital syndrome (Mroueh and Kase, 1968). Although these features should be borne in mind, they will seldom be encountered and usually no characteristic clinical features are evident, and the patient merely demonstrates absent secondary sexual development and primary amenorrhoea. The patient will generally be of average height or perhaps even taller, and in this sense will resemble the patient with pure gonadal dysge­ nesis from whom she can be distinguished only by cytogenetic and hormonal studies. Other investigations which are desirable include a visual field scan, an X-ray of the skull with special reference to the sella turcica, thyroid tests, and FSH and LH assay preferably on several occasions. In some circumstances growth hormone assay may be appropriate, especially if dwarfism is a feature and no chromosomal fault has been discovered; such cases are often recognized in early childhood as soon as stunting of growth becomes evident. If a serious anatomical lesion has been ruled out and if low levels of FSH and LH suggest primary failure of gonadotrophin production by the hypothalamus or pituitary, further investigations should be undertaken to try to determine which of the two is at fault and if the ovary is indeed capable of function if adequately stimulated. The former may be investi­ gated by the LHRH test (Nakano et al., 1977). In this test 100-200 μg i.v. LHRH are injected into the subject. The values for FSH reach a maximum after 30-45 min, when they are approximately twice the baseline level; by 2 h the level returns to normal. LH values also reach a maximum after 30-45 min, but they are some 6-8 times the baseline figure and they are still raised after 2 h. Patients with hypothalamic failure of LHRH production show a pat­ tern of response (Figure 7.21a) closely similar to that of normal women (Figure 7.21/?). Patients with a pituitary failure of LH and FSH production show no rise in either FSH or LH levels. Patients with 100

100

80

80

60

60

5 40

D 40

20

20

60

20 (a)

0

60

20 (b)

Figure 7.21 LHRH stimulation test comparing (a) hypothalamic failure with (b) normally menstruating women

84

Delayed puberty

primary ovarian failure show a greatly exaggerated response; baseline F S H a n d L H values a r e , of course, raised to ' m e n o p a u s a F levels, and a m a r k e d rise is evident following L H R H injection. It should be mentioned that t h e response of normal patients differs at different times during t h e menstrual cycle. In general, t h e response during t h e late follicular phase is greater than that in t h e early follicular phase and greatest of all a r o u n d t h e time of ovulation. A n increased pituitary response is also found in the luteal phase. It is n o t , however, envisaged that this test will play a routine part in the work-up of a patient with pathological a m e n o r r h o e a . In patients with gonadal dysgenesis, for example, t h e diagnosis can b e m a d e for certain by simpler means and there would b e n o necessity for L H R H testing. If a distinction is necessary between a possible hypothalamic o r pituitary cause for failure to m e n s t r u a t e , the L H R H test might well b e of advantage. T o complete t h e investigation t h e effect of exogenous gonadotrophin on t h e urinary oestrogen excretion can be tested, a n d p e r h a p s laparoscopy and gonadal biopsy u n d e r t a k e n to confirm that t h e ovaries appear normal and contain primary follicles. A three- to four-fold rise in t h e oestrogen output should follow t h e injection of 150 i.u. H M G , so confirming ovarian capacity to respond normally. Once investigation is complete and the diagnosis of a functional failure of gonadotrophin production has been reached, appropriate oestrogen replacement therapy should b e u n d e r t a k e n along lines similar to that described for patients with gonadal dysgenesis. W h e n the patient is older and desires a pregnancy, induction of ovulation with H P G or H M G with H C G may b e u n d e r t a k e n . F u r t h e r consideration of this matter does n o t come within t h e scope of this work.

Heterosexual puberty changes Male-type puberty changes may a p p e a r in a patient being reared in t h e female role in a variety of circumstances. T h e patient may b e o n e of the forms of X Y female already discussed in C h a p t e r 2 or she may have congenital adrenal hyperplasia becoming m o r e evident, or even evident for the first time, at puberty. Although u n c o m m o n , these a r e perhaps the most likely conditions to present at puberty in this way. O t h e r possibilities which must b e considered are the presence of an ovarian masculinizing t u m o u r , an adrenal a d e n o m a o r carcinoma o r a pituitary lesion giving rise to t h e features of Cushing's syndrome. F o r these lesions t o produce the features of heterosexual puberty, however, t h e coincidence of their onset with the age of puberty is necessary.

References BARR, M. L., CARR, D. H., PLUNKETT, E. R., SOLTAN, H. C. a n d WIENS,

R. G. (1967) Male pseudohermaphroditism and pure gonadal dysgenesis in sisters. American Journal of Obstetrics and Gynecology, 99, 1047 DAVIDOFF, F. and FEDERMAN, D. D. (1973) Mixed gonadal dysgenesis. Pediatrics, 52, 725 DEWHURST, c. J. (1963) Gynaecological Disorders of Infants and Children, Bailliere Tindall, London DEWHURST, c. J. (1971) Sex chromosome abnormalities and the gynaecologist. Journal of Obstetrics and Gynae­ cology of the British Commonwealth, 78, 1058 DEWHURST, c. J. and CORDON, R. R. (1969) The Intersexual

Disorders, Bailliere Tindall, London DEWHURST, C. J. and LUCAS, M. (1971) Gonadal dysgenesis and chromosome mosaicism. British Journal of Hospital Medicine, 11, 807 DEWHURST, C J., DE KOOS, E B. and FERREIRA, H. P. (1975) The

resistant ovary syndrome. British Journal of Obstetrics and Gynaecology, 82, 341 DEWHURST, J. (1978) Fertility in 47 XXX and 45 X patients. Journal of Medical Genetics, 15, 132 EVERS, J. L. H. and ROLLAND, R. (1981) The gonadotrophin

resistant ovary syndrome: a curable disease? Clinical Endocrinology, 14, 99 FATHALLA, M. F., RASHAD, M. N. and KERR, M. G. (1966) The

relationship between ovarian tumours and intersex states with special reference to the dysgerminoma and arrhenoblastoma. Journal of Obstetrics and Gynae­ cology of the British Commonwealth, 73, 812 JONES,

G. s.

and

DE MORAES-RUEHSEN,

M.

(1969)

A

new syndrome of amenorrhoea in association with hypergonadotropism and apparently normal ovarian follicular apparatus. American Journal of Obstetrics and Gynecology, 104, 597 KONINCKX, p. R. and BROSENS, I. A. (1977) The gonadotrophin

resistant ovary syndrome as a cause of secondary amenorrhoea and infertility. Fertility and Sterility, 28, 926 MCDONOUGH, P. G. (1987) Disorders of gonadal differentiation and sex chromosome anomalies. Seminars in Repro­ ductive Endocrinology, 5, 221 McDONOUGH, P. G., BYRD, J. R., THO, P. T. a n d MAHESH, V. B.

(1977) Phenotypic and cytogenetic findings in eighty-two patients with ovarian failure - changing trends. Fertility and Sterility, 28, 638 MROUEH, A. and KASE, N. (1968) Olfactory-genital dysplasia. American Journal of Obstetrics and Gynecology, 100, 525 MURAM, D. and JOLLY, E. E. (1982) Pregnancy and gonadal dysgenesis. Journal of Obstetrics and Gynaecology, 3, 87 NAKANO, R., HASHIBA, N., KOTSUJI, F. and TOJO, s. (1977) A

schematic approach to the work-up of amenorrhoea. Fertility and Sterility, 28, 229 SIMPSON, J. L. (1976) Disorders of Sexual Differentiation: Etiology and Clinical Delineation, Academic Press, New York

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histology of XO human embryos and fetuses. Anato­ mical Record, 155, 369

THO, p. T. and MCDONOUGH, P. G. (1981) Gonadal dysgenesis and its variants. In Pediatric Clinics of North America, vol. 28 (ed. C. A. Cowell), Saunders, Philadelphia, p. 309

STARUP, J., SELE, v. and HENDRIKSEN, B. (1971) Amenorrhoea

VAN CAMPENHOUT, J., VAUCLAIR, R. and MARAGHI, K. (1972)

associated with increased production of gonadotropins and a morphologically normal ovarian apparatus. Ada Endocrinologica, 66, 248

Gonadotrophin resistant ovaries in primary amenorrhoea. Obstetrics and Gynecology, 40, 6

SINGH, R. P. and CARR, D. H. (1966). The anatomy

and

8 Menstrual disorders in the adolescent

Excessive menstrual bleeding Excessive menstrual bleeding in the pubertal girl is an abnormality which causes concern to the mother and sometimes to the doctor. Its problems arise more from the emotional reaction that these features produce in the parents, and through them in the girl herself, than the actual physical features present. It has already been mentioned that soon after the menarche menstrual periods are seldom as regular as they will probably be a little while later when some kind of rhythm has become established. This irregularity usually takes the form of infrequent periods rather than more frequent ones, but toofrequent periods undoubtedly do occur and cause some alarm in the family thereby. The parental distress and domestic upheaval arising from a very heavy menstrual period or an unusually long one in such a young subject can easily be misunderstood and it is not surprising that such girls are often brought for advice in circumstances of some anxiety. The normal physiological control of menstruation has been discussed in Chapter 5. It will only be referred to in outline here. In the normal menstrual cycle, pulsatile release of FSH from the anterior pituitary stimulates follicular recruitment and subsequent follicular growth. Of several recruited follicles, one becomes dominant and matures. Oestradiol-17ß is produced which sensitizes the hypothalamus and pituitary and eventually, when the follicle is mature, LH is released which induces changes in the follicle leading to follicle rupture and oocyte release. The luteinization of the follicle produces the corpus luteum which produces large quantities of progesterone. Oestradiol is responsible for the proliferation of the endometrium (Figure 8.1) and progesterone for the secretory changes 86

Figure 8.1 Histological appearance of the endometrium in the proliferative phase. Stain: haematoxylin and eosin (Figure 8.2). As the corpus luteum undergoes luteolysis, the progesterone level falls and the endometrium cannot be maintained and thus this is shed as menstruation, and the cycle repeats itself. In the adolescent the pattern is very different until the ovulatory cycle is established. Although 50% of cycles during the first years of menstruation are anovulatory, most adolescents do not develop menstrual problems (Altchek, 1977). In those girls with problems, they are generally associated with inappropriate maturation of the hypothalamus and persistent anovulation with elevated levels of LH.

Excessive menstrual bleeding 87 This hypothalamic disorder of LHRH release produces a polycystic ovary type syndrome with infrequent episodes of heavy bleeding. Ultrasound of the ovaries will reveal typical appearances (Figure 8.3). These infrequent periods allow prolonged exposure of the endometrium to unopposed oestrogen and a hyperplasia which may lead to irregular shedding and irregular bleeding. It is worthy of mention that sometimes slight bleeding which accompanies ovulation in some patients may be the basis of a girl's complaint that she is having frequent periods. There may be a fall in oestrogen production immediately after ovulation; levels then quickly rise again. This fall sometimes causes brief endometrial breakdown and vaginal bleeding until the rise in oestrogen again puts an end to the loss; it seldom lasts longer than a few hours to a day. The problem of excessive bleeding in adolescence is rarely so severe that it requires urgent treatment. In the study of Claessens and Cowell (1981), a nine-year review suggested 19% had a primary coagulation disorder, e.g. idiopathic thrombocytopenia. Our experience would not substantiate these findings of so high a coagulopathy incidence.

Clinical approach

Figure 8.2 Histological appearance of the endometrium in the secretory phase. Stain: haematoxylin and eosin

When the patient is seen with the symptom of excessive menstrual loss, the approach must be above all a confident reassuring one. There is a strong tendency for spontaneous cure to occur, given the opportunity to do so. The history must

Figure 8.3 Ultrasound appearance of the ovary in polycystic ovarian disease. Note the small black areas in the ovary which reflect the cystic structure

88

Menstrual disorders in the adolescent

first be taken. This is far easier to say than to do and it is commonplace for such a history to be graph­ ically described in emotional terms; the length of the loss, its severity, the appearance of sanitary towels, the fluctuations of the flow, the effect on the girl perhaps the drama of being put into the medical room at school and much more, may be revealed. Reference to what the mother herself was like when she began menstruating and how different the situa­ tion is in her daughter is frequently made. It is uncommon for a clear history of when the period began and when it ended to be available. Persistent questioning to uncover the facts from the fancy is usually required. Examination is important. For one thing, the opportunity to examine the girl away from her mother will permit her own account of the loss to be obtained and in many cases it may be less alarming. On examination one needs to know if the general health of the girl is good. Are there obvious signs of anaemia? Is there any suggestion of a general dis­ order contributing to the problem? (There seldom is, but the examination should be performed none­ theless.) Is there any abdominal swelling? What does the vulva look like? Does the hymen look normal and intact? Is there any abnormality on rectal examination? If bleeding is in progress, how heavy does it appear? What is the blood picture? The gynaecological examination of such a young patient is not easy, but sufficient information for our purposes can usually be obtained. The practical problem which arises is whether the girl should be examined in the presence of her mother or not. Our view is loosely based on the philosophy that if the patient is a child, the mother should be present, and if she is an adolescent, examination is performed alone. There are circumstances when such a rule is incorrect, and the doctor must decide in the case of each patient, but examination of the adolescent is much easier without the mother. Inspection of the vulva is seldom objected to. If the hymen appears intact, as it usually will, a bimanual rectal examin­ ation should be performed, since to attempt a vaginal examination on a frightened young patient is usually unwise. There will seldom be any abnormal physical signs in the pelvis if one is dealing with a case of dysfunctional uterine bleeding. Inspection may occasionally reveal a large hymenal opening, perhaps with some damage, when an abortion must be suspected. The use of a pelvic ultrasound is invaluable in both assessing pathology but more importantly in showing mother and patient normality as an aid to reassurance. Great care must be taken by the ultrasonographer or the doctor in commenting on the findings as it is easy to alarm using medical terms, e.g. cyst. The use of ultrasound has decreased the necessity for pelvic examination per rectum in these girls as pathology is rare.

The blood picture should be established but further investigation is seldom required. If the patient is not anaemic and there are no abnormal physical signs, and it is judged that the degree of bleeding is somewhat less than has been repre­ sented, treatment should first be by a confident simple explanation to mother and child of the phy­ siology of early menstrual periods. They must be told about the tendency to arrhythmic bleeding at the beginning of menstrual life, informed that no serious fault has been found, assured of the strong tendency to spontaneous cure which, it may be added, is so much to be preferred to hormone therapy at this stage. A prescription for iron will do no harm and may do good. An early appointment must be given for a follow-up consultation. Mean­ while a simple calendar is given to the patient who is told to mark off precisely when her periods start and stop and to bring it back with her for future visits. When this objective record is examined by the doctor and patient on subsequent occasions, it will often be found that the frequency of periods and their duration are less alarming than was previously thought. The majority of girls with pubertal menorrhagia require no further treatment. They do not always recover instantly, of course, but over a few months of careful supervision and confident assurance, most will make sufficient progress to indicate clearly that recovery is taking place. In the minority, more will need to be done. If there is already some anaemia or if the extent of the loss is judged to be genuinely heavy, and dysfunc­ tional bleeding is the diagnosis, hormone therapy to control it should be used. Bleeding may be con­ trolled by prescribing oestrogens alone, progestogens alone, or both concurrently or consecutively. Oestrogens alone are not recommended because of the endometrial proliferation they cause and the heavy loss that is apt to occur when they are stopped: progestogens alone are generally effective unless the patient's background oestrogen produc­ tion is very low when breakthrough bleeding may occur. Combined oestrogen/progestogen therapy, as in the combined oral contraceptive, is preferred. A combined oral contraceptive containing 30 μg oestrogen with a progestogen should be given as one tablet, three times per day, until bleeding stops: one tablet per day may then be continued for a further two weeks and stopped to allow the patient to have a withdrawal 'period'. A further course of combined oral contraceptive can then be prescribed using a 30 μg oestrogen/progestogen combination. Such treatment should be undertaken only for some three months, when the girl should be observed for a while without treatment. It is important to give the natural tendency to recover every opportunity to do so, and the continuation of hormone therapy will interfere with this. One occasionally sees girls who

Excessive menstrual bleeding have been treated with hormones too early in their menstrual lives, treatment then being continued for some years in order to regulate menstruation. This is to be avoided if at all possible as the maturation process of the hypothalamus may be interfered with and when therapy is stopped the re-establishment of the process will still occur. Exceptionally a blood dyscrasia such as idiopathic thrombocytopenic purpura or Von Willebrand's disease may be discovered with pubertal menorrhagia. These cases are extremely rare and even when they occur, they do not conform to a pattern. Cooperation with a haematological department in an attempt to control loss by hormones and haematinics will always be worthwhile before any form of surgery is contemplated. When is curettage indicated and is surgery of a more major kind ever required? Curettage has a very small part to play in the management of adolescent menorrhagia. It has already been made clear that most patients recover with no treatment at all or minimal treatment combined with reassurance. Most of the remainder respond to hormone therapy of limited duration. There remain, however, a very small number of patients who do not improve sufficiently with the approach outlined above to be able to maintain reasonably regular periods with a normal loss of their own accord. Dilation and curettage may be indicated in these once the medical treatment advised is clearly not being successful; this will seldom be sooner than six months from the beginning of treatment, but if heavy menstrual loss is continuing for this time or longer, curettage should be carried out. Should there be any reason to suspect endometrial disease, of course, curettage may be indicated sooner. Tuberculosis is one condition which may be found in association with adolescent menorrhagia. In the UK, the USA and in most developed countries, however, there will be remarkably few occasions on which one need suspect tuberculosis, but in some countries where the disorder is still prevalent, endometrial tuberculosis is more likely; somewhat sooner intervention may then be wise (Sutherland, 1980). In most cases in which curettage is performed, the histology of the endometrium is likely to show proliferative changes with no evidence of ovulation. Prolonged adolescent menorrhagia is nearly always anovulatory in origin and the classic symptoms may present in some patients: 7-8 weeks or more may pass between periods which are prolonged for 2-3 weeks or more when they occur. The condition is caused by failure of ovulation and persistence of the graafian follicle, whose continued high oestrogen output causes an increased growth of endometrium with a proliferative pattern; when this endometrium does break down from an ultimate fall in oestrogen production from the follicle, the loss is prolonged. It is here that the only serious risk of adolescent

89

menorrhagia lies. Endometrial overstimulation with oestrogens unopposed by a progestogen can produce cystic glandular hyperplasia illustrated in Figure 8.4, which is accepted by many - even most - gynaecologists as probably predisposing to endometrial cancer sooner or later. It is certainly true that a few young patients have developed carcinoma of the endometrium in association with prolonged anovular menstruation of this kind. It is doubtful if any case can be said to have arisen in adolescence, although Southam and Richert (1966) reported four cases aged 23, 29, 30 and 33 years with endometrium carcinoma occurring in these circumstances. Although this disease may not reach a malignant stage during adolescence, however, the changes which lead to it exist in the younger patient, and as a general rule it may be said that anovular bleeding persisting over several years should be taken seriously. If the original endometrial histology shows cystic glandular hyperplasia there may be no need for immediate therapy, but if there is no spontaneous recovery and no modification of the cycle to suggest that ovulation is occurring, therapy with a progestogen must be considered. Norethisterone, 5-10 mg/ day given between days 5 and 25 of the menstrual cycle, is likely to lead to regular withdrawal bleeding from a progestational endometrium. This treatment may be persisted with for a time and then stopped in the hope that natural cure may have occurred. If there is a reversion to previous anovulatory cycle patterns with no evidence of ovulation on basal body temperature records, norethisterone should be given again. After a year or so of this treatment, repeat curettage will be indicated towards the end of

Figure 8.4 Histological appearance of the endometrium in cystic glandular hyperplasia. Stain: haematoxylin and eosin

90

Menstrual disorders in the adolescent

the ten days of the progestogen therapy to examine the endometrium. A combined oral contraceptive may be used instead of this regime by a patient not wishing to become pregnant, since ovulation may occur spontaneously at any time which the norethisterone therapy given from day 14 will not inhibit. Whichever is preferred, ovulation induction may be appropriate later when a pregnancy is desired. A word of warning should be given, however, about treating infrequent periods in this way. As mentioned later when oligomenorrhoea and secondary amenorrhoea are considered, the use of a combined oral contraceptive in this fashion may result in prolonged hypothalamic suppression with resulting post-pill amenorrhoea for several years.

Dysmenorrhoea Dysmenorrhoea is as emotional a condition in some adolescents as is excessive menstrual bleeding, and requires a similar approach to management of parent and child. Primary dysmenorrhoea is described as pain beginning on the first day of menstruation. In fact the first few periods are usually pain-free, since they are anovulatory periods which are painless. Not until ovulation begins a variable time later does so-called primary dysmenorrhoea usually arise. When pains do start, the severity, time of onset and duration will be variable. The patient may experience a heavy pelvic dragging sensation preceding the actual period; alternatively, when the period starts the pain may be colicky in nature or it may sometimes be of this type before the flow and relieved by it. This is known as secondary dysmenorrhoea and is usually associated with pelvic pathology. Such pain commonly lasts for a few hours and seldom longer than a day. The aetiology of dysmenorrhoea involves endocrine, myometrial factors and prostaglandins. The cycles are ovulatory and Akerlund, Stromberg and Gorsling (1979) suggested the release of vasopressin and disturbed myometrial action as possible aetiological factors. There is no evidence that cervical stenosis is responsible for primary dysmenorrhoea (Ylikorkala and Dawood, 1978). There is little doubt that elevated uterine prostaglandin production is the main cause of primary dysmenorrhoea. These patients have elevated uterine basal tone, elevated active intrauterine pressure, increased frequency of contractions and incoordinate uterine activity (Ylikorkala and Dawood, 1978). The management of such a problem involves taking a very accurate history from the patient herself and, if she is a young adolescent, also from her mother. It has already been mentioned that the emotional element in menstrual pain can be strong and it may indeed be that the mother is its source.

Dickens (1974) pointed out the serious problem of the conditioning of a daughter by the mother to expect pain associated with periods and the resulting problem of fear. If one is seeing a patient for the first time it may not be easy to assess the maternal influence, but gradually as a patient is seen more often this may become more clear. Examination generally reveals scarcely any fault. As already indicated, when considering excessive bleeding, a pelvic examination may have to be a bimanual rectal one if the patient is virgo intacta and very young and anxious. With the more frequent use of internal sanitary protection and a more open sexual outlook, a one-finger vaginal examination is sometimes possible without discomfort either physical or mental, especially in a somewhat older patient. Ultrasound has provided us with a useful examination modality, and it is frequently used to exclude pelvic pathology. The approach to treatment must begin with educating both the patient and her parents concerning the physiology of menstruation so that they can understand what is happening and perhaps correct any outdated fallacies which they may still retain. It is in dealing with problems of this kind that good doctors truly demonstrate their skill. It is difficult to give clear guidance as to how one should manage such a situation if it is felt that there are pronounced emotional overtones, but gradually with a confident manner and simple explanations, patients can begin to view menstruation as a physiological process. Once this explanation has been undertaken, simple analgesics such as paracetamol or soluble aspirin should be prescribed for pain relief, and in the first instance nothing stronger is advisable. Should this not succeed the drugs of choice are prostaglandin synthetase inhibitors. There are five groups: (1) (2) (3) (4) (5)

Benzoic acid derivatives (aspirin). Butyrophenones (phenylbutazone). Indoleacetic acid derivatives (indomethacin). Fenamates (mefenamic acid, flufenamic acid). Arylpropionic acid derivatives (ibuprofen, ketoprofen, naproxen).

As phenylbutazone and indomethacin have a high incidence of side effects, the drugs of choice are mefenamic acid, 250-500 mg three times daily, ibuprofen 400 mg four times daily, or naproxen sodium 250 mg four times daily. These drugs have been shown to relieve dysmenorrhoea in over 70% of patients. An approach of this kind is likely to be helpful in many patients but some will continue to have sufficiently bad pain to interfere with their schooling or their work, and more effective control is desirable. The best line of treatment then will be to inhibit ovulation with a combined oral contraceptive used in the same manner as for contraception. Provided previous periods have been comparatively regular,

Secondary amenorrhoea

there is no objection to the use of the combined oral contraceptive in this way. Treatment is almost always successful unless there is a strong psychosomatic component to the disorder. Failure to respond to this medical therapy necessitates a laparoscopy to exclude pelvic disease such as endometriosis or pelvic inflammatory disease. If this is normal, referral to a psychologist or psychiatrist must be considered.

Secondary amenorrhoea Oligomenorrhoea A relatively common complaint of the adolescent is the occurrence of infrequent periods which from time to time may be absent for six months or more, when the term 'secondary amenorrhoea' may reasonably be applied. Failure to menstruate for several months may be physiological or pathological. It is physiological, of course, during pregnancy but also during the first year or so of menstrual life when, in some girls, very infrequent periods are experienced. Beyond emphasizing the fact that any patient examined with such a complaint may be pregnant, this possibility will not be considered further. During the first year or so of menstrual life, menstrual irregularity is particularly common and need be a matter of no real concern. As time goes by, however, the intervals between periods should become shorter until after a period of time varying between months and 1-2 years, some kind of rhythm will become established. When a young adolescent with a history of infrequent periods is brought for advice, therefore, these facts must be borne in mind. It is important to examine the patient carefully, of course, to exclude a gross fault but in most instances none will be found. Spontaneous improvement is to be expected in most cases and unless there are specific features calling for concern, such as hirsutism or galactorrhoea, the patient may be given reassurance and seen again after a period of six months or so. However, if the periods of amenorrhoea increase or regularity, once established, is followed by amenorrhoea, further examination should be undertaken and appropriate treatment carried out.

Aetiology Secondary amenorrhoea may be concerned with lesions at hypothalamic/pituitary level, at ovarian level, at adrenal level, and, in theory at least, at uterine level. Hypothalamic/pituitary lesions are by far the most common, with lesions at ovarian level and adrenal level occasionally encountered. The extent to which local uterine lesions may cause secondary amenorrhoea is debatable; in the UK

91

they are very uncommon causes indeed, but in other countries they appear to occur more frequently. Hypothalamic/pituitary lesions are bracketed together since they are closely associated; hypothalamic lesions are much more common than pituitary ones, although either may give rise to secondary amenorrhoea. The pulsatile production of follicle stimulating hormone (FSH) and luteinizing hormone (LH) is easily disturbed in some patients by a wide variety of causes. Emotional stress of one kind or another is easily the most common of these; stress factors include anxiety about examinations, unhappiness from domestic discord, an uncongenial job away from home in a different town or country, grief from a family bereavement, etc. A particularly important cause is weight loss, especially acute weight loss which results from a crash diet in which the patient may lose 15-20 lb in a relatively short period of time. Weight loss appears to have a direct relationship with hypothalamic activity but it seldom exists as a single factor, since in most patients with pronounced weight loss there is a strong emotional element present as well. The most extreme form of this disorder, of course, is anorexia nervosa in which there may be almost total refusal to eat with profound weight loss. Weight gain may also have an association with secondary amenorrhoea but this is not seen so frequently. A common cause of secondary amenorrhoea appears to be the combined oral contraceptive pill, since a number of patients stopping the pill do not begin menstruating again for some months or even for some years. It is debatable if the pill is the sole factor concerned, and many clinicians believe that suppression caused by the pill is merely another factor which exists in a patient already susceptible to hypothalamic suppression or in whom another hypothalamic/pituitary lesion is present. For example, when patients who have previously suffered from oligomenorrhoea are put onto a combined oral contraceptive, they may menstruate regularly while taking the pill, but there is an increased likelihood of prolonged amenorrhoea when the treatment is stopped; moreover, the presence of a physical lesion such as a tumour in the region of the hypothalamus must always be considered in patients with secondary amenorrhoea, even though an apparent cause such as stopping the pill is present. Tumours of this region or tumours of the pituitary itself are, however, rare compared with the very common functional causes which have just been outlined, but they cannot be forgotten. Lesions at the ovarian level occur much less frequently than hypothalamic and pituitary ones. Premature ovarian failure giving rise to an early menopause even during adolescence is sometimes observed in patients with gonadal dysgenesis as discussed later. Rarely patients with a 47 XXX karyotype may be encountered, and they appear to

92

Menstrual disorders in the adolescent

have an increased tendency to secondary amenorrhoea, although what the precise relationship is between this and the karyotype is not yet clear. Such patients seldom have clinical features which permit them to be recognized for what they are, and they may be discovered only when chromosome analysis is undertaken. Polycystic ovarian disease is one of the conditions which may be encountered in patients with oligomenorrhoea rather more frequently than in patients with frank secondary amenorrhoea, although six months or more sometimes go by between periods; in such patients investigation similar to that discussed below will be appropriate. Very rarely an androgen-producing ovarian tumour (arrhenoblastoma, masculinovoblastoma, theca cell tumour) may present as a cause of secondary amenorrhoea with virilizing changes (see Chapter 11 for further discussion of these disorders). Adrenal lesions such as congenital adrenal hyperplasia, or Cushing's syndrome secondary to a pituitary or hypothalamic lesion or due to an innocent or malignant adrenal tumour, are rare causes of secondary amenorrhoea associated with masculinization which must be borne in mind. Similarly, thyroid disorders may be associated with secondary amenorrhoea, although this is uncommon. The local uterine lesions which may be encountered are traumatic amenorrhoea associated with the formation of adhesions within the uterine cavity (Asherman's syndrome) and certain pelvic infections. Asherman's syndrome is said to result from frequent and vigorous curettage which causes profound endometrial destruction and permits adhesions to form. Widespread infection of the pelvic organs with tuberculosis is extremely rare in most well-developed countries, although it may be seen more frequently elsewhere; it may then be seen in association with secondary amenorrhoea. Clinical features A clear indication of the diagnosis will often be obtained if a careful history is taken from a patient with secondary amenorrhoea. One or other of the various emotional causes mentioned may easily be elicited which will suggest hypothalamic suppression as the likely cause. Another symptom focusing attention on a lesion at hypothalamic/pituitary level is the presence of galactorrhoea. This feature may be concerned with a pituitary adenoma or it may be functional in association with secondary amenorrhoea following combined oral contraceptive administration. Virilization should always suggest an ovarian or adrenal androgen-producing lesion. In most patients examination will not show abnormal findings, since functional hypothalamic suppression is by far the commonest condition likely to be encountered. In others short stature and

indifferent secondary sexual development will point to a diagnosis of gonadal dysgenesis with some ovarian differentiation; polycystic ovaries may be palpated on vaginal examination, or there may be a degree of hirsutism or obesity which would also suggest this diagnosis. Various investigations may be necessary in a patient with secondary amenorrhoea. In patients likely to have functional hypothalamic suppression, a relatively simple screen may be undertaken in which FSH, LH and prolactin are measured and the pituitary fossa is X-rayed. FSH and LH assays are only of limited value if carried out on a single occasion, and if necessary they should be repeated. Their main value is that if they are found within the very wide range of normal, as they nearly always will be, this excludes premature ovarian failure and at least indicates a favourable prognosis and suggests that fertility will later be possible following ovulation induction if recovery has not occurred spontaneously by that time. If very high levels of gonadotrophin are recognized, this will suggest a premature menopause. If there are clear signs of gonadal dysgenesis, then several raised values of this kind may be taken to indicate that a premature menopause has occurred, but if there are no such confirmatory clinical features the diagnosis may be the resistant ovary syndrome, and laparoscopy and ovarian biopsy will be indicated to put the matter beyond doubt. In the investigation of patients with secondary amenorrhoea, the LHRH test described previously would probably play a relatively small part. For example, in a patient giving a clearcut history of hypothalamic suppression by a combined oral contraceptive or domestic or other disharmony, and with LH and FSH values compatible with this diagnosis, it would seem an unnecessary step to undertake an LHRH test; these patients usually recover spontaneously or, failing that, generally respond to induction^ of ovulation with clomiphene. If their capacity to respond to ovulation induction is in question, or if there is a possibility of a premature menopause, LHRH testing may be appropriate. If either galactorrhoea or hirsutism is present, more detailed investigations should be carried out. It has been recognized in recent years that galactorrhoea with raised prolactin levels is a more common and important aspect of secondary amenorrhoea than was previously thought. Any patient with secondary amenorrhoea should be specifically examined to see if fluid can be expressed from the breasts, and the blood prolactin levels should be assayed. Pathological galactorrhoea has a number of causes; it may be the result of drug therapy with phenothiazines or be concerned with 'post-pill' amenorrhoea, or it may be present if there is an adenoma of the pituitary producing raised prolactin values; it can occur postpartum or it may be as-

References 93 sociated with primary hypothyroidism. Close en­ quiry should always be made about a possible drug history. Plasma prolactin levels should be measured on several occasions. If two consecutive prolactin levels are above 1000 mmol/1, then a pituitary adenoma must be suspected and CT scan of the pituitary fossa should be performed. The value of X-rays is limited as only destructive bony changes can be detected. If hirsutism and secondary amenorrhoea are pres­ ent together, a search must be made for a possible excessive production of androgens. Investigation of such a case is dealt with in Chapter 10. The administration of norethisterone 10 mg/day for five days is sometimes advocated as a means of distinguishing between secondary amenorrhoea of little significance and a more important abnormality requiring full investigation. In the latter, it is said that there will be no bleeding if the drug is stopped after five days, since background oestrogen levels are not sufficiently high; in the former, with good background oestrogen levels, bleeding takes place.

Treatment Hypothalamic

suppression

It must be stated that the adolescent with this condition requires to be handled gently and with sympathy, for this is a very disturbing symptom for her. It will be wise, first of all, to give an explana­ tion, appropriate to her level of understanding, of what menstruation is and how it can so easily be suppressed by a variety of everyday events. She should be made to understand that her failure to menstruate is doing her no harm; even now some people hold very strange views about this matter. She should be told that there is a strong tendency for spontaneous recovery especially if the precipitating cause, whatever it may be, can be in some way corrected. Enquiry into dietary habits will always be wise, and she should be urged to eat correctly. She must understand that she may well be able to have a child without any treatment at all if she improves spontaneously, but if this does not happen she may be treated then by induction of ovulation, with every chance of success. It is to be expected that two-thirds to three-quarters of patients with hypo­ thalamic suppression of this kind will undergo a spontaneous recovery after some time. Most patients will accept advice of this kind. Some may need proof by demonstrating that they can be made to menstruate if necessary by adminis­ tering ethinyloestradiol 10 μg daily for 21 days with norethisterone 5 mg daily for days 12-21 which will produce a withdrawal bleed.

Secondary amenorrhoea hirsutism

associated

with

The management will be appropriate to the cause as discussed in Chapter 10. Galactorrhoea

and raised prolactin

level

Management will depend on whether or not a pituitary adenoma or other physical lesion of the pituitary/hypothalamic area has been discovered. If it has, neurosurgical advice and treatment will be required if it has not already been obtained; further consideration of this is not within the scope of this book. If no such physical lesion has been identified, treatment may be undertaken with bromocryptine with every likelihood of success. Bromocryptine is a dopamine agonist, and its administration raises dopamine levels in the brain. Dopamine is a prolactin inhibitory factor and its elevation will decrease prolactin secretion by the posterior pituitary to normal. Concomitant return of hypothalamic release of LHRH to normal will result in the reestablishment of the normal menstrual cycle. Bromocryptine, given in doses of 2.5 mg once or twice per day, has a rapid effect on most patients with secondary amenorrhoea and galactorrhoea. Galactorrhoea is quickly reduced and ceases approximately within a month; the patient may also menstruate during this time, and ovulation is usually established in the following cycle. There have been several excellent reviews of prolactin secretion and the use of bromocryptine in the secondary amenorrhoea/galactorrhoea syndrome which may be con­ sulted (Franks et ai, 1977; Jacobs, 1980; Thorner et al., 1980). See also Chapter 9. The majority of patients who wish a pregnancy, achieve one quite soon. By the same token, if the patient does not wish to become pregnant but is at the risk of pregnancy, some form of contraception should be practised. One of the mechanical methods is then recommended, since the combined oral contraceptive is likely to exaggerate the degree of the hypothalamic suppression which led to her disorder.

References AKERLUND, M., STROMBERG, P. a n d GORSLING, M. D.

(1979)

Primary dysmenorrhoea and vasopressin. British Journal of Obstetrics and Gynaecology, 86, 484-486 ALTCHEK, A. (1977) Dysfunctional uterine bleeding in adole­ scence. Clinics in Obstetrics and Gynaecology, 20, 633-645 CLAESSENS, E. A. and COWELL, c. A. (1981) Dysfunctional

uterine bleeding in adolescents. In Pediatric Clinics of

94

Menstrual disorders in the adolescent

North America (ed. C. A. Cowell), Saunders, Philadel­ phia, p. 369 DICKENS, A. (1974) Excessive menstrual bleeding and dysmenorrhoea. In Clinics in Obstetrics and Gynaecology, 17, 655 FRANKS, S., JACOBS, H. S., HULL, M. G. R., STEELE, S. J. a n d

NABARRO, J. D. N. (1977) Management of hyperprolactinaemic amenorrhoea. British Journal of Obstetrics and Gynaecology, 84, 241 JACOBS, H. s. (1980) Management of prolactin secreting pituitary tumours. In Progress in Obstetrics and Gynae­ cology, Vol. 1 (ed. J. W. Studd), Churchill Livingstone, Edinburgh, p. 263 SOUTHAM, A. L. and RiCHERT, R. M. (1966) The prognosis for adolescents with menstrual abnormalities. American

Journal of Obstetrics and Gynecology, 94, 637 SUTHERLAND, A. M. (1980) Surgical treatment of tuberculosis of the female genital tract. British Journal of Obstetrics and Gynaecology, 87, 610 THORNER, M. O., EVANS, W. S., McLEOD, R. M. et al.

(1980)

Hyperprolactinaemia: current concepts of management including medical therapy with bromocryptine. In Ergot Compounds and Brain Function - Neuroendocrine and Neuropsychiatric Aspects (eds M. O. Thorner, D. B. Calne, A. Lieverman and G. Goldstein), Raven Press, New York, p. 165 YLIKORKALA, o. and DAWOOD, M. γ. (1978) New concepts in

dysmenorrhoea. American Journal of Obstetrics and Gynecology, 130, 833

9 Breast lesions and abnormalities of stature

Breast lesions The breast and several of its abnormalities are relevant to the practice of gynaecology even in those countries where breast disease as such is usually the province of a general surgeon. Adolescent breast disorders and the gynaecologist have been reviewed by Capraro and Dewhurst (1975). In particular, modifications to the physiological response of the breast may call for gynaecological opinion. It has already been emphasized in Chapter 1 that there is temporary breast enlargement in most mature male and female newborns; the degree of enlargement is usually slight and its duration short. More rarely, sufficient enlargement to cause concern may be evident (see Figure 1.1) and the mother may be somewhat disturbed if there is also a small amount of discharge from the nipple. It must be stressed that these changes are the result of passive hormone stimulation across the placenta and they can therefore be regarded as physiological; treatment is unnecessary and indeed inadvisable, since any undue handling of the breast may cause bruising, infection and persistence of the enlargement for longer than would otherwise be the case. In the prepubertal child breast enlargement may be noted in association with precocious puberty from any of its causes, or the breast growth may be the only manifestation of a puberty change in the disorder known as premature thelarche. In this condition, which seems likely to be due to unusual sensitivity to the very low levels of circulating hormones in childhood, the breast enlargement is usually small in amount and nipple growth is often poor. The condition may be transient (see Figure 6.7) or may fluctuate in degree; sometimes it is unilateral. It must be fully investigated, of course, to eliminate the various causes of precocious puberty

- especially those such as a feminizing tumour which calls for specific treatment - but if no cause is found and the diagnosis of premature thelarche is reached, no treatment is required beyond complete assurance of the parents and child. Capraro (Capraro and Dewhurst, 1975) has stressed the real risk that in such a case, should only one breast be predominantly involved, a surgical opinion may be sought and biopsy undertaken in the belief that the swelling may be a tumour. This will result in most, if not all, of the developing breast bud on one side being removed with almost complete failure of that breast to grow at puberty (Figure 9.1). Tumours of the breast have been reported in childhood (McDivitt and Stewart, 1966) but are a very rare occurrence. Great caution must be exercised when considering breast biopsy in these circumstances. At puberty a number of variations in breast growth may be evident. Here again, breast inequality in size is common during development and the overwhelming majority of patients will find that as development proceeds, the breasts will become virtually of equal size (breasts are scarcely ever precisely equal if accurately measured, but inequality can seldom be discerned otherwise). Rarely clinical inequality persists (Figure 9.2) and can be a cause of disturbance in the adolescent. Here it is important to explain to the girl that should the irregularity persist when growth is complete, a plastic surgical procedure can be undertaken to equalize the breasts. This should not be undertaken unless breast growth and linear growth have stopped, however; otherwise, if growth is still proceeding, breast inequality may reappear later as one breast continues to grow. The patient must understand, however, that something effective can be done for her when the time comes. Whether this is enlargement of the smaller or reduction of the larger 95

96

Breast lesions and abnormalities of stature

Figure 9.1 Failure of the right breast to develop at puberty in a girl whose breast bud was removed at a biopsy procedure during childhood. (From Capraro and Dewhurst, 1975, by permission)

Figure 9.2 Breast irregularity in an adolescent. The abnormality has persisted in this form for two years. (From Capraro and Dewhurst, 1975, by permission)

breast will depend on the actual size of the large breast in relation to the patient's height and build. This and other technical aspects of breast cosmetic surgery are considered by Horrman and Massiha (1975). Pronounced hypoplasia (Figure 9.3), or hyperplasia or deformity (Figure 9.4) can all cause psychological disturbance not only in the adole­ scent, but even later in the adult. Moderate hypoplasia may concern a patient at first, although as she adjusts to her body image she may decide against treatment. In some such cases slight benefit may be noted if the patient is given a combined oral contraceptive; at least this treatment is worth trying. If the hypoplasia is due to oestrogen deficiency as in gonadal dysgenesis or certain XY females, of course, treatment with replacement hormone

Figure 9.3 Breast hypoplasia causing considerable psychological disturbance in an adolescent girl

therapy can usually give satisfactory results. It is better to commence with low oestrogen doses (ethinyloestradiol, 10-20 μg/day) and increase beyond 20 μg if the response is indifferent. Seldom has there been a poor response to treatment of this kind, but poor responses have been seen to larger doses given ab initio (Figure 9.5). Should the breast response to hormone therapy be indifferent, an augmentation mammoplasty should be considered if, after mature thought, the patient wishes it (Figure 9.6). The response to hormone therapy in patients whose poor breast growth is the result of oestrogen

Breast lesions

97

improvement and should psychological disturbance persist due to 'organ inferiority', augmentation mammoplasty is recommended (Figure 9.6). Deformities of the breast are unlikely to respond to hormone therapy and cosmetic surgery should be considered.

Figure 9.6 Augmentation mammoplasty carried out on the patient seen in Figure 9.5

Figure 9.4 Marked hypoplasia with an ugly deformity of both breasts. (From Capraro and Dewhurst, 1975, by permission)

Breast hyperplasia may also be a cause of concern to the adolescent. Even moderate hyperplasia such as that seen in Figure 9.7 may be enough to disturb the girl and make her unwilling to join in games or go swimming, etc. Here reduction in breast size may achieve an excellent result. Breast hyperplasia may be unilateral when it must be decided whether this is an abnormal response of one breast or is due to a tumour (Figure 9.8). The tumour most likely to be found in these cases is the juvenile-type fibroadenoma (Ashikari, Farrow and O'Hara, 1971; Capraro and Dewhurst, 1975). It is much softer in consistency than the adult type of fibroadenoma and grows much more rapidly. In only a few months the breast may become almost twice its original size.

Figure 9.5 Indifferent breast development in an XY female whose testes were removed at childhood. She was treated with large doses of oestrogens at puberty despite which her breast growth has been indifferent (cf. Figure 9.6) deficiency is significantly better than that in normally menstruating women with breast hypoplasia. In the latter patients it must be assumed that the hypoplasia is mainly concerned with relative end-organ insensitivity to oestrogen or to imperfect development of the primitive breast structures. Treatment with a combined oral contraceptive may, as already stated, produce some improvement in the latter, but this improvement is usually slight. Should such a patient find that the response to combined oral contraceptive does not give her sufficient

Figure 9.7 Hypertrophy of the breasts in an adolescent. The abnormality has caused some psychological stress

98

Breast lesions and abnormalities of stature

Figure 9.8 Soft fibroadenoma in the breast of an adolescent. The area of the tumour has been outlined. (From Capraro and Dewhurst, 1975, by permission) Clinical detection of the tumour may nonetheless be difficult, since the softness of the growth makes it similar in consistency to the surrounding breast tissue. The increased blood supply to that breast, however, is usually detectable. Removal of the tumour is indicated, care being taken to make the breasts of equal size if at all possible. The tumour is always benign. Galactorrhoea This is rare in adolescents but may occur in association with secondary amenorrhoea. It is usually due to increased prolactin secretion or, rarely, cystic glandular hyperplasia of the breast (see Chapter 8). Prolactin is produced by the anterior pituitary, under the control of dopamine. Dopamine is a direct inhibitor of prolactin release and it is depressed in the puerperium allowing lactation to occur. In inappropriate galactorrhoea there is usually a microadenoma or, less commonly, a macrotumour in the pituitary. Some drugs cause galactorrhoea, e.g. phenothiazines, reserpine, tricyclic antidepressants, oral contraceptive pill. A full history and examination is performed, although there is rarely anything to find except the galactorrhoea. Visual fields should be tested as a significant pituitary tumour may press on the optic chiasma. A skull X-ray may demonstrate a double pituitary fossa, but a CT scan is considerably more accurate. Blood should be taken to measure the prolactin level, and also to exclude thyroid disease, also associated with hyperprolactinaemia. Two

levels of prolactin in excess of 1000 mmol/1 may be diagnostic of a pituitary lesion in 40% of cases (Jacobs, 1980), and prolactin will be an excellent tumour marker. The drug of choice in treating this condition is bromocryptine, a dopamine agonist which inhibits prolactin secretion. Bromocryptine not only reduces prolactin secretion and synthesis, but it also diminishes DNA synthesis and reduces mitotic activity leading to tumour shrinkage. Bromocryptine is prescribed beginning with 2.5 mg daily for seven days and then 5 mg daily thereafter. This initial starting dose of 2.5 mg is to minimize the problem of early side effects, i.e. nausea, vomiting, headache, lethargy and some postural hypertension. After a few days these side effects disappear and the dose is increased. After six weeks prolactin levels are repeated and the dose increased until prolactin levels are normal. Therapy is continued for one year and then stopped. After six weeks the prolactin level is repeated and, if normal, the patient should be seen annually for review. If the level remains elevated then treatment is continued for a further year. Any patient with a macroadenoma should be followed with serial CT scans to monitor tumour regression. Rarely, tumours are unresponsive and surgery may be required. Extensive reviews on the subject are available (Franks, Jacobs and Hull, 1977; Bergh, Nillius and Wide, 1978; Jacobs, 1980; Pepperall and O'Herlihy, 1985).

Stature and the gynaecologist Stature is related to a number of gynaecological disorders as indicated in this chapter and in Chapter 5. Short stature in a child may be concerned with the fact that the girl's growth spurt has not yet occurred; thus when her height is compared with that of a number of her classmates whose spurt appeared somewhat earlier, she is considerably shorter. This is not an abnormality and when her growth accelerates as she too enters puberty, she is likely to make up the lost ground; by this time the earlier maturers will have either passed peak height velocity and their growth will be slowing down, or may have stopped altogether. Short stature may, however, be a manifestation of a sex chromosome abnormality as already discussed, or it may be concerned with several other general medical conditions. The child may, for example, have achondroplasia or one of its variants; here there will be anomalies of face, trunk and limbs which should strongly suggest the correct diagnosis. There are a number of rare syndromes which may be recognizable in the appearance of the child which are also associated with short stature, and if there is a suspicion of these, a consultation with a geneticist

Stature and the gynaecologist 99 will be wise. Growth may also be inhibited by adrenal, pulmonary or circulatory disorders and these symptoms require investigation in possible cases. Here, cooperation with a paediatrician or a department interested in growth will be helpful. Marshall (1974) suggests that if these various conditions can be excluded, the remaining causes of short stature may be considered under four headings:

Correction of the underlying fault in a number of the conditions referred to will improve growth and may result in the child achieving normal height. For inherited failure of growth potential, however, as in a patient with a sex chromosome anomaly or one with very short parents, little specific treatment is possible.

(1) (2) (3) (4)

Excessive growth of a child may be a manifestation of an abnormality or may be due to an inherited tendency to tallness from her parents. Rare patho­ logical lesions such as giantism, Marian's syndrome, and excessive growth hormone production should be considered but will seldom be encountered. Tallness is sometimes associated with sex chromosome trisomy (Figure 9.9), which can easily be detected by establishing the karyotype in the peripheral blood. Most tall girls, however, are normal apart from their stature, and it is social attitudes which play a major role in deciding what is an acceptable body image. It is important to predict the final height as described by Tanner et al. (1975) and after discus­ sion, advise on therapy. The mean height for UK children is 165 cm, but the 97th centile is 179 cm and, thus, many children may be reassured of their normality and that being tall is not necessarily a handicap. The principle of treatment is to use oestrogen to accelerate puberty and induce epiphyseal closure, especially of the long bones. The largest experience of this problem has been published by Wettenhall (1981). Large doses of oestrogen are necessary, given continuously, and progestogens are given intermittently to ensure a withdrawal bleed at monthly intervals. Wettenhall (1981) recommends ethinyloestradiol, 150 μg daily, and after two months norethisterone, 10 mg daily, for four days every month. Other oestrogens have been used, e.g. stilboestrol (Crawford, 1978), conjugated oestro­ gens (Schoen et al., 1973) and oestradiol valerate (Whitelaw, 1967), but in the opinion of Wettenhall (1981) they are less effective. The therapy is best started before menarche since this is when growth is most rapid and the potential growth of final height at its greatest. It is not essential to limit treatment to premenarcheal girls as growth continues, albeit more slowly, for three years following menarche. The expected reduction of the predicted final height is 3.5-7.3 cm, with a mean of 4.6 cm, if started before bone age 13 (Marshall, 1974) although a reduction of up to 9 cm is possible in rare cases. There are possible disadvantages to this therapy which concern the gynaecologist. Pubertal changes occur more rapidly and an increase in vaginal discharge and pigmentation of the nipple and areola may occur. The breasts may be very tender and

Extreme variants of the normal. Chromosomal disorders. Environmental disorders. Endocrine disorders.

Stature is related to growth potential; tall parents tend to have tall children and short parents have short children. Such short parents will generally show a bone age somewhat behind their chrono­ logical age so that their inherited shortness is exag­ gerated by late development. Usually such subjects achieve final height just within the normal range. Chromosomal disorders have already been dis­ cussed (Chapter 7). Environmental factors may affect the ultimate height of a child. Babies who suffer from growth retardation in utero may not recover growth lost then and they may become small children and small adults. It is important in such cases to establish birth weight and to plot growth carefully during the childhood period. Marshall (1974) suggests that psychosocial factors may rarely inhibit growth, and moving such a child to another environment may be helpful. Undernutrition of sufficient degree to stunt growth is rare in developed countries but may be more important in less welldeveloped ones. Marshall groups endocrine causes under four headings: (1) Iatrogenic: inhibition of growth may occur in some children treated with steroids for asthma, skin lesions, etc. (2) Growth hormone deficiency: this may be partial or complete; a defect may be isolated or associa­ ted with other trophic hormone defects. Growth hormone defect may be idiopathic or associated with an intracranial lesion requiring full investi­ gation. Idiopathic growth hormone deficiency is rare in girls, and the diagnosis should not be accepted unless complete investigation has been performed. Human growth hormone treatment is now available for such patients. (3) Hypothyroidism: such patients treated with thyroxine will increase their growth rate and probably reach a normal final height. (4) Disorders of the pituitary/adrenal axis such as congenital adrenal hyperplasia or adrenal insufficiency.

Tall girls

100

Breast lesions and abnormalities of stature who is overweight between ages 10 and 13 has a 6.3 times greater chance of being an obese adult (Abraham, Collins and Nordsieck, 1970). Family factors are the most important in the development of obesity, including modelling, food and exercise availability, stimulus and reinforcement control (Epstein, 1986). The inclusion of parents is essential in the treatment process if success in childhood weight control is to be achieved. The programme for treatment should include: (1) a diet that will produce weight loss but is easy to adhere to; (2) an exercise programme; and (3) training for the parents including alterations in their eating habits if they are also obese. The traffic light diet is the most widely used which identifies foods which must not be eaten (RED), those which can be eaten readily (GREEN) and those to eat with caution (AMBER). Successful therapy takes time and effort and the child and parents require repeated encouragement, but longterm follow-up has shown excellent results. Further reading on the subject may be provided by Epstein, Wing and Valoski (1985) and Brownwell and Foreyt (1986).

References ABRAHAM, s., COLLINS, c. and NORDSIECK, M. (1970) Relation-

Figure 9.9 Tall stature in a young adolescent with a 47 XXX karyotype. Her height is 6 ft 4 in. (From Dewhurst, 1971, by permission) overall weight gain is common. Menstrual irregularity is also frequent, although no change in the regime is recommended by Wettenhall (1981), reassurance being all that is needed. The long-term concerns include fertility although Wettenhall (1981) reports no problems in conceiving in treated patients compared to controls. No cases of post-treatment genital tract cancer have been reported and no problem with subsequent menstruation has been encountered. Obesity The gynaecologist is occasionally asked for an opinion on childhood obesity, as many parents believe the cause to be hormonal. A synopsis for management advice is, therefore, given although referral to an appropriate centre is advised. Obese children are more likely to become obese adults than are thinner children, and children with obese parents are more likely to be overweight. A child

ship of child weight status to morbidity in adults. Public Health Report, 86, 273 ASHIKARI, R., FARROW, J. s. and O'HARA, J. (1971) Fibro-

adenomas in the breast of juveniles. Surgery, Gynecology and Obstetrics, 132, 259 BERGH, T., NILLIUS, s. J. and WIDE, L. (1978) Hyperpro-

lactinaemic amenorrhoea - results of treatment with bromocryptine. Acta Endocrinologica, 88 (Suppl. 216), 147 BROWNWELL, K. D. and FOREYT, J. P. (eds) (1986) Eating

Disorders, Basic Books, New York CAPRARO, v. J. and DEWHURST, C. J. (1975) Breast disorders in childhood and adolescence. Clinical Obstetrics and Gynecology, 18, 25 CRAWFORD, J. D. (1978) Treatment of tall girls with estrogen. Pediatrics, 62 (Suppl.), 1189 DEWHURST, c. j . (1971) Sex chromosome abnormalities and the gynaecologist. Journal of Obstetrics and Gynae­ cology of the British Commonwealth, 78, 1058 EPSTEIN, L. H. (1986) The treatment of childhood obesity. In Eating Disorders (eds K. D. Brownwell and J. P. Foreyt), Basic Books, New York EPSTEIN, L. H., WING, R. R. and VALOSKI, A. (1985) Childhood

obesity. Pediatric Clinics of North America, 32, 363 FRANKS, s, JACOBS, H. s. and HULL, M. G. R. (1977) Management

of hyperprolactinaemic amenorrhoea. British Journal of

References Obstetrics and Gynaecology, 84, 241 HORRMAN, G. w. and MASSIHA, H. (1975) Cosmetic surgery of the breast. Clinical Obstetrics and Gynecology, 18, 253 JACOBS, H. s. (1980) Management of prolactin secreting tumours. In Progress in Obstetrics and Gynaecology, Vol. 1 (ed. J. W. W. Studd), Churchill Livingstone, Edinburgh, p. 263 MARSHALL, w. A. (1974) Interrelationships of skeletal maturation, sexual development and somatic growth in man. Annals of Human Biology, 1, 29 MCDIVITT, R. W. and STEWART, F. W. (1966) Breast carcinoma in children. Journal of the American Medical Association, 195, 388 PEPPERALL, R. J. and O'HERLIHY . (1985) Induction of ovu-

lation with bromocryptine. In Clinical Reproductive Endocrinology (ed. R. P. Sherman), Churchill Living-

101

stone, Edinburgh, p. 508 SCHOEN, E. J., SOLOMAN, I. L., WARNER, O. a n d WINGERD, J. ( 1 9 7 3 )

Estrogen treatment of tall girls. American Journal of Diseases of Children, 125, 71 TANNER, J. M., WHITEHOUSE, R. H., MARSHALL, W. A. a n d CARTER,

B. s. (1975) Prediction of adult height from height, bone age, and occurrence of menarche, at ages 4 to 16 with allowance for midparent height. Archives of Diseases in Childhood, 50, 14 WETTENHALL, H. N. B. (1981) The tall child. In Clinical Paediatric Endocrinology (ed. C. G. D. Brook), Blackwell Scientific, Oxford, p. 138 WHITELAW, M. J. (1967) Experience of treatment of excessive height in girls with cyclical estradiol valerate: a ten year study. Acta Endocrinologica, 54, 473

10 Hirsutism and virilism

Hirsutism Hirsutism is not a common complaint in the adolescent, but when present is a most disturbing one. In some young girls it is associated with acne which may be as troublesome as, or even more than, the abnormal hair growth. It is most important to distinguish hirsutism from virilism. The former is concerned only with an excessive growth of hair, and may or may not be concerned with an increased production of androgens; the latter is always concerned with abnormal androgen production - perhaps to very high levels; several serious conditions may give rise to it. Some of the different conditions which may cause virilism, e.g. congenital adrenal hyperplasia or one of the varieties of the XY female, have been referred to already and will not be reconsidered. Other causes are discussed later in the chapter. In patients referred with hirsutism, idiopathic hirsutism and polycystic ovarian syndrome account for 95% of cases, idiopathic being predominant. In idiopathic hirsuitism there are two aspects of the endocrine system to consider: circulating androgens and the end-organ, the pilosebaceous unit. Age and familial tendencies may play a significant role, but if hair growth is increased, elevated levels of testosterone and/or androstenedione will be found. This reflects an increased production rate, and it is believed this is primarily ovarian in origin, although some will be from peripheral conversion (Kirschner, Zuckner and Jesperson, 1976). Sex hormone binding globulin (SHBG) binds 78% of androgens and albumin binds 20%; thus only 1-2% is free in the circulation. Testosterone is converted in peripheral tissues to dihydrotestosterone (DHT) by 5areductase which affects cellular function. The pilosebaceous unit consists of the hair follicle 102

and the sebaceous gland. The hair root metabolism in hirsutism shows increased 5a-reductase activity and thus increased local production of DHT. Sebaceous glands are also androgen-dependent and in idiopathic hirsutism sebum production is increased by at least two-fold. Acne vulgaris is not necessarily androgen-related although there may be some increase in 5a-reductase activity. The primary problem is excessive keratinization which leads to retention of sebum. The upper part of the duct becomes colonized by staphylococci and the well known sequelae result. Polycystic ovarian disease (PCO) is a spectrum of disorders which seem to originate from inappropriate ovarian function. Although it is familial, genetic evidence is still inconclusive but some patients may have 3ß-ol-dehydrogenase deficiency (Lorber, McKenna and Rabinowicz, 1978). The ovary is usually enlarged with a thickened tunica albuginea and the cortex is filled with antral follicles at different stages of atresia. The local endocrine abnormality seems to be a failure of aromatization of androgens to oestrogen, and there are elevated levels of androstenedione and testosterone in the follicular fluid and in plasma. The activity of aromatase is FSH-dependent and its lack of activity may be due to either depressed pituitary output of FSH or the failure of FSH to reach the granulosa cells due to the thickening of the basal lamina of the follicle. Of interest is the observation that granulosa cells from PCO follicles, when exposed to FSH in culture, function normally with regard to aromatase activity (Erickson et al., 1979). Why the stromal thickening occurs is more difficult to explain, although androgens promote theca fibroblast activity. Sclerocystic ovaries are also found in patients with congenital adrenal hyperplasia, probably due to the elevated levels of androgens.

Hirsutism

The circulating androgen is peripherally converted to oestrogen which creates a constantly elevated oestrogen environment at the level of the hypothalamus and pituitary. This leads to a substantially increased amplitude and/or frequency of LHRH pulses (Wentz, Jones and Sapp, 1976; Baird et al., 1977) and the subsequent familiar disordered FSH/ LH secretion. The FSH level is depressed below normal levels and the LH is significantly higher and there is a strong correlation between the LH level and androgen production (Duignan et ai, 1975). This abnormality of hypothalamo-pituitary-ovarian function results in a pattern of anovulatory oligomenorrhoea and hyperandrogenism (Figure 10.1). Further detailed reviews of PCO may be found by referring to Chang (1984) and Goldzieher and di Zerega (1985). Other rare causes presenting to the gynaecologist are congenital adrenal hyperplasia, Cushing's syndrome and carcinoma of the adrenal. Increased hair growth may occur following nerve injury (Maroulis, 1981).

(Ovarian thecal stimulation

( LMRH amplitude and frequency ' 1 Follicular maturation

] \ 1SHBG

I

Jfree androgen

i

Hirsutism

Figure 10.1 Pathophysiology of polycystic ovarian disease. (After Rebar, 1984)

Clinical features A careful history of the hirsute patient should be taken. When was the abnormal hair growth noticed? Is it increasing? How extensive is it? What effect is it having on the patient's social life? Is menstruation normal? Is there any other important clinical feature? Is the patient receiving drug therapy for any other condition? What does the patient do to attempt to get rid of the excess hair? How often does she do this? How long does she spend doing it? Special enquiry should always be made about the effect that hair growth has on the patient's social

103

life. There are two components to hirsutism: the actual abnormal growth of hair and the patient's reaction to it. In some instances a young patient with an annoying degree of hair may be adjusted to it and may allow it to interfere to a minimal degree, if at all, in her daily life; in other circumstances an emotionally unstable patient may develop a degree of concern and introspection about her imagined disfigurement which is not in reality very marked. The patient's response to her disease is very important. Examination must detect the presence or absence of signs of virilism and determine the extent of the abnormal hair growth. The signs of virilism are enlargement of the clitoris, temporal recession of hair, loss of subcutaneous fat on the limbs, atrophy of the breasts, and deepening of the voice. The extent of abnormal hair growth may be assesed in several ways and some attempt at objective measurement has much to commend it. Ferriman and Gallwey (1961) assessed hair growth by dividing the body into 11 areas and giving a score between 0 and 4 to each area. A count of up to 10 is regarded as being within normal limits, although many normal patients have a count far lower than this (Figure 10.2 and Table 10.1). Only terminal hair is scored, vellus hair being ignored. The patient should be weighed and her height noted, and the Ponderal index (weight in kg/height in m 2 ) calculated. Caucasian women have a value of 19-24 representing the 5th-95th centile. On pelvic examination particular attention should be paid to the size of the ovaries. Polycystic ovaries are usually enlarged to a slight or moderate extent, although in plump adolescents it may be far from easy to detect this. Failure to detect enlargement does not exclude polycystic ovarian disease which will remain the probable diagnosis if hirsutism is associated with oligomenorrhoea. It is unlikely that there will be any other abnormal physical signs. In patients with PCO, ultrasound scanning of the pelvis will show classical changes as seen in Figure 8.3. The appropriate investigations will depend on the clinical severity of the case. Androgen levels should be measured both as plasma testosterone and androstenedione. In patients with PCO, values are likely to lie in the zone where male and female levels overlap; in patients with idiopathic hirsutism they will be within the normal female range. Single values give little information, and if it is considered important to ensure that androgens are significantly raised, assays should be performed on several occasions. FSH and LH assays should also be undertaken, again on more than one occasion. Relatively raised LH values are commonly seen but are not always evident. Plasma 17-hydroxyprogesterone levels should be performed as adrenal hyperplasia may only present post-puberty. The level of sex hormone binding globulin (SHBG) is also useful in

104

Hirsutism and virilism

__ /

1

1\

- 1 ^ 8

NJ-.-.O

I \

Jl'-

\

4

7

\ 1 Ί

11

TOTAL

HORMONAL (1-9)

Figure 10.2 Ferriman and Gallwey scoring chart. The brackets in the posterior view scoring indicate that the score has been included in the anterior view score and should not be included again. (After Ferriman and Gallwey, 1961)

diagnosis, depression with an associated elevated plasma androstenedione level being an indication of idiopathic hirsutism in the absence of an androgensecreting tumour. In most adolescents with hirsutism alone it is doubtful if further tests are necessary if the above have not given alarming results. Should diagnosis remain in doubt, however, especially if one of the serious causes of virilism (to be discussed later) is suspected, further studies may be required. Thus, the possibility that a persistently large ovary may contain a masculinizing tumour will be seen on ultrasound and a laparotomy may need to be undertaken. Only exceptionally will these pro­ cedures be necessary in the kind of adolescent we are considering. A suspicion of an adrenal tumour or Cushing's syndrome may suggest the need for adrenal suppres­ sion tests with dexamethasone, plasma cortisone assessment over a 24 h period, and radiological studies (described later). It is important to undertake investigations in this way in order to reassure the patient of her relative normality in the majority of cases. Nearly all patients are convinced they are hormonally ab­ normal and have masculinizing tendencies. Caring explanation of their endocrine results is most reassuring.

Treatment Until recently truly effective treatment for hirsutism due to polycystic ovarian disease or to idiopathic causes has not been available. In mild cases, standard means of removing hair usually suffice; depilatory creams, plucking, bleaching, waxing, electrolysis and even shaving have been employed at some time by many patients, and some can keep the condition sufficiently at bay by one or other of these means. Shaving should be avoided if possible, and if it has been necessary, the case is probably sufficiently severe for alternative treatment. All patients who are overweight must be encour­ aged to lose weight and dramatic improvement in the symptoms can be achieved in this way. Cosmetic methods of controlling excessive hair are often sufficient. These include bleaching, depila­ tory creams, waxing, cutting, plucking, shaving and electrolysis. Electrolysis is the only method which will permanently remove the hairs and it must be remembered that plucking and waxing of facial hair which distort the hair follicle, result in increasing coarseness of the subsequent hairs, which makes any future electrolysis difficult and prolonged. Waxing of the limbs is a commonly used technique which provides a good cosmetic result. Bleaching, depila­ tory creams and cutting are temporary and local means of cosmetic control and do not worsen the

Hirsutism Table 10.1 Scoring system for hirsute areas. Ferriman and Gallwey (1961)

After

Site

Grade

Definition

Upper lip

1 2 3

A few hairs at outer margin A small moustache at outer margin A moustache extending halfway from outer margin A moustache extending to mid-line

4 Chin

1 2 3,4

A few scattered hairs Scattered hairs with small concen­ trations Complete cover, light and heavy

4

Circumareolar hairs With mid-line hair in addition Fusion of these areas, with threequarter cover Complete cover

Upper back

1 2 3,4

A few scattered hairs Rather more, still scattered Complete cover, light and heavy

Lower back

1 2 3 4

A sacral tuft of hair With some lateral extension Three-quarter cover Complete cover

Upper abdomen

1 2 3,4

A few mid-line hairs Rather more, still mid-line Half and full cover

Lower abdomen

1 2 3 4

A few mid-line hairs A mid-line streak of hair A mid-line band of hair An inverted V-shaped growth

Arm

1

Chest

1 2 3

3,4

Sparse growth affecting not more than a quarter of the limb surface More than this cover still in­ complete Complete cover, light and heavy

Thigh

1,2,3,4

As for arm

Forearm

1,2,3,4

Complete cover of dorsal surface: two grades of light and two of heavy

Leg

1,2,3,4

As for arm

2

Grade 0 at all sites indicates absence of terminal hair

condition. The previously described negative effect of shaving has never been substantiated and in those women in whom severe hirsutism fails to respond to medical therapy, it may remain the only effective method of control. Inhibition of ovarian activity and thus of the source of excessive androgen production with the combined oral contraceptive has been tried. This method has resulted in mild to moderate improve­ ment in some patients, but it is seldom sufficiently helpful and in many patients is disappointing. Surg­ ery to carry out bilateral wedge resection of the

105

ovaries is never indicated in an adolescent since it has comparatively little effect on hair growth. The most effective therapy to date is undoubtedly the anti-androgen drug cyproterone acetate. This preparation has progestational as well as antiandrogen properties. Its latter effects come from its competition with androgens at the receptor; it is thus interfering with androgen utilization rather than production. It has been reported to be contraindicated in patients with liver disease, but in the absence of a liver disorder it can be given for 2-3 years without ill effects. Side effects include lassi­ tude which is not usually severe enough to call for interruption of treatment which is otherwise effec­ tive. The 'reversed sequential regime' of Hammerstein (1975) is employed. Cyproterone acetate is given in doses of 50 mg twice daily between days 5 and 14 of the menstrual cycle; ethinyloestradiol is given in doses of 30-50 μg/day between days 5 and 25 of the cycle. Ovulation suppression is most important, since feminization of the male rat fetuses has been reported when cyproterone acetate has been given during pregnancy to the rat mothers. Significant improvement has been observed in 65-80% of patients thus treated (Hammerstein, 1973; Braendle et al., 1974; Underhill and Dewhurst, 1979; Fräser et al., 1983). Hair becomes finer and less pigmented as well as growing more slowly (Figure 10.2 and Table 10.1). Hair scores show an overall decline. The use of low dose regimes, e.g. 2 mg cyproterone acetate and 30 μg ethinyloestradiol (Dianette, Schering) are less effective, although in mild and moderate hirsutism improvement can be achieved in about 50% of cases (Moltz, Meckies and Hammerstein, unpublished work). It is important to emphasize to the patient that there will be little improvement for at least six months because of the physiological length of the hair cycle. The success of therapy depends on a number of factors. The longer the hirsutism has existed, the slower and less completely it regresses. The localization is also important, and the thoracic region responds best, followed by the lower abdo­ men, the face and the limbs. Excessive hair growth on the calves is often resistant to therapy, but may be due to hypertrichosis which is not androgendependent. Excessive facial hair is often the only worrisome symptom which persists after therapy and continued use of mechanical measures will be required although less frequently. Seborrhoea and acne associated with hirsutism respond extremely well on both high and low dose therapy (Figures 10.3-10.5). For acne alone, however, often as­ sociated with a less severe degree of hirsutism, treatment with long-term antibiotics such as the tetracyclines has given promising results. Local skin applications with a drying effect containing salicylic

106

Hirsutism and virilism

Figure 10.3 (a) A marked degree of peri-areola hirsutism in an adolescent before treatment with cyproterone acetate. (b) Showing the marked improvement following eight months of treatment with cyproterone acetate

Figure 10.4 (a) Pronounced hirsutism on the chin of a 30-year-old Spanish patient, (b) Showing marked improvement following nine months of treatment with cyproterone acetate acid, sulphur and resorcinol have also been helpful. period of use. It is inadvisable to use prolonged high Unfortunately, not all patients respond and the dose therapy as the progestational effects are 30-50 reason for the failure is not yet clear. Moreover, times the normal state. Once the treatment has been recurrence after treatment is stopped is very comeffective, a good therapeutic approach is to transfer mon as the drug has no sustained effect beyond the to long-term low dose regimes, reintroducing the

Virilism

107

(a)

Figure 10.5 (a) Marked acne in an adolescent, (b) Significant improvement in acne following nine months of treatment with cyproterone acetate high dose for short periods of time if the hirsutism returns significantly. What should the place of this treatment be in the adolescent? It is probably best kept for the more severely affected person who has tried local or alternative methods without being able to keep the hair growth in check. Liver function tests are a necessary preliminary, and careful objective assessment of the degree of hirsutism using some scoring system is recommended before such treatment is used so that the result can be carefully evaluated.

striae. The presence of an abdominal mass may be evident in a patient with a masculinizing ovarian tumour. The most important disorders giving rise to virilism are:

Virilism

In the adolescent, adrenal hyperplasia and the XY female are the most likely disorders to be encountered. Puberty is particularly the time when masculine features of these conditions will probably become more evident when testicular activity in the XY female and adrenal androgen activity in the patient with congenital adrenal hyperplasia are increased. Both conditions are usually evident at birth if careful examination is conducted; sometimes, however, the abnormal physical features are not pronounced and are overlooked until they become more marked at puberty. Clitoral enlargement then becomes more pronounced (Figure 10.6) and the voice deepens, symptoms likely to have a serious effect on the child unless investigated and dealt with expeditiously. In the case of congenital adrenal hyperplasia, it seems possible that in some patients

This condition is more severe than hirsutism. It is always due to excessive androgen production and the abnormalities causing it are all serious - even life-threatening. The clinical features have been briefly indicated. There are defeminizing features, e.g. secondary amenorrhoea, loss of subcutaneous fat, and breast atrophy, and positive masculine features, e.g. deepening of the voice, temporal recession of hair, clitoral enlargement and abnormal hair growth. Special clinical features associated with a particular cause may be evident in individual patients. Patients with Cushing's syndrome, for example, may show obesity, especially in the shoulder girdle and face, hypertension and the presence of subcutaneous

(1) (2) (3) (4) (5) (6)

Congenital adrenal hyperplasia. Varieties of XY female. A masculinizing ovarian tumour. A masculinizing adrenal tumour. Cushing's syndrome. Rarely, polycystic ovarian disease.

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Hirsutism and virilism

with a minimal enzyme defect the genitalia at birth may be within normal limits, and only when there is greater enlargement of the clitoris about the time of puberty it is possible to recognize that an abnormality exists. These conditions will not be considered further here and the rest of this account will be devoted to the remaining conditions - a masculinizing ovarian tumour, an adrenal tumour, Cushing's syndrome, and (briefly) polycystic ovarian disease; all are rare in the adolescent. The patient with features suggesting any of these conditions must have a very careful clinical examination to establish the presence of temporal hair recession, the presence of excess body hair, clitoral enlargement (Figure 10.7a and 6), loss of subcutaneous fat from the limbs, the presence of cutaneous striae, the patient's bodily configuration, the blood pressure, and the presence of a pelvic tumour. Palpation of the kidneys is necessary to detect significant downward displacement of one, which may indicate an adrenal tumour. If excessive fusion of the labial folds is noted (see Figure 2.28), this means that excess androgen activity in utero had been taking place, thus ruling out the acquired conditions such as androgen-producing tumours and Cushing's syndrome.

Figure 10.6 Significant clitoral enlargement which has increased at puberty in a 12-year-old child with a 46 XY karyotype who is being reared as a girl

Figure 10.7 (a) Pronounced facial hirsutism and temporal recession of hair in a woman with a hilar cell tumour. (b) Clitoral enlargement in the patient illustrated in (a)

Virilism Further investigations of a case of virilism involves the measurement of: (1) (2) (3) (4) (5) (6)

17-Hydroxyprogesterone. Cortisol (assayed in morning and evening). Testosterone. ACTH. Androstenedione. Dehydroepiandrosterone (DHEA).

It must be stressed that there is a great difference in the biological activity of the various androgens produced in the body, the relationship of the DHEA:androstenedione:testosterone being 1:2:10. Moreover, conversion of weak androgens to testosterone occurs more readily in the ovary than in the adrenal which produces predominantly DHEA and androstenedione. In the direct measurement of cortisol it is important to realize that there is a significant circadian rhythm and the level must be assayed morning and evening. In our own laboratories the normal range of values is 150-600 nmol/1 with, of course, higher values being obtained in the morning blood sample. In addition to the estimation of cortisol, adrenocorticotrophin (ACTH) assay is important in distinguishing between the various possible conditions giving rise to Cushing's syndrome. Testosterone can and should be measured directly in patients with virilism. The measurement of androstenedione and DHEA gives valuable information as well. The distinction between the various causes of virilism is undertaken by these tests in association with suppression of adrenal activity by dexamethasone, examination under anaesthesia, laparoscopy, intravenous pyelography and ultrasound.

Androgen-producing tumours The most likely virilizing ovarian tumour to be encountered is the androblastoma; other possibilities are the lipoid cell tumours and the adrenal rest tumours. The androblastoma was formerly called the arrhenoblastoma. It is composed of Sertoli or Leydig cells or their precursors. These tumours may well be differentiated and composed of only Sertoli cells, only Leydig cells, or both. Sometimes only moderate differentiation is evident when both cell types are usually present (Figure 10.8). In other cases differentiation is minimal when the cells resemble undifferentiated gonadal stroma within which a few Sertoli or Leydig cells may be recognized. In welldifferentiated cases, the appearances are those of testicular-like tubules lined with Sertoli cells; instead there may be a collection of Leydig cells arranged in clumps, or in mixed well-differentiated tumours there may be tubules lined by Sertoli cells

109

but separated from each other by stroma containing some Leydig cells. Other masculinizing tumours form a difficult histological group to assess. They include the lipoid cell tumours and the adrenal rest tumour; specialized texts such as those by Fox and Langley (1976) or Novak and Woodruff (1974) should be consulted for further details. Careful examination per vaginam should disclose the presence of a palpable ovarian tumour, but such tumours are sometimes of small size and if the other features of the case support this diagnosis, ultrasound or laparoscopy may well be indicated. Plasma levels of testosterone will be raised but adrenal activity is normal, so if a dexamethasone suppression test is employed (see below) normal suppression is to be expected. Treatment is, of course, by operation and removal of the tumour by salpingo-oophorectomy as 25% are malignant. Conservative surgery should be at-

Figure 10.8 Histological appearances of an androblastoma. The cells present are chiefly Sertoli cells, although Leydig cells can also be recognized. Stain: haematoxylin and eosin tempted in the adolescent if a tumour appears circumscribed and there is no suggestion of extension beyond the boundaries of the ovaries. If there is no such evidence, there is little alternative to total hysterectomy and bilateral salpingo-oophorectomy.

Adrenal tumours These tumours produce various clinical features, including virilism (as described above) or Cushing's syndrome with obesity, moon face, hypertension, cutaneous striae, etc. (Figure 10.9). Plasma cortisol levels are elevated as is the ACTH level. As a rule, such levels exceed those seen in congenital adrenal hyperplasia.

110

Hirsutism and virilism

A dexamethasone suppression test is very useful in distinguishing between the various possible causes of raised cortisol. In this test a 24 h urinary sample is collected on the day before the test for the baseline value; dexamethasone, 0.5 mg four times a day, is given for the next three days; blood is collected daily and cortisol should be suppressed to low levels in congenital adrenal hyperplasia, but in the presence of an adrenal tumour no suppression will be obtained. If suppression has not been achieved with this dose, a test may be repeated giving 2 mg four times a day for three days. Some slight suppression may be obtained in the presence of an adrenal tumour but never to any significant extent. Further management is transferred to the appropriate endocrine/surgical units. Cushing's syndrome This disorder may be due to various causes. As already indicated, the features may be associated with the presence of an ovarian carcinoma or adenoma, or they may be concerned with a primary pituitary fault overstimulating adrenocortical activity.

The features of Cushing's syndrome are due to an excess production of cortisol and androgens. A useful scheme of investigation is outlined in Figure 10.10. The clinical presentation of Cushing's syndrome may be somewhat different in children from that in the adult. Short stature may be a striking feature, although the precise mechanism of its production is uncertain; the growth delay in association with obesity may give the clue to diagnosis. McArthur et al. (1972) point out that diagnostic tests also may be less helpful in children; for example, there may be suppression with low doses of dexamethasone which is not seen in the adult. The absence of circadian rhythm of cortisol production is one of the most significant findings. Treatment involves the removal of an adrenal tumour if such is present, hypophysectomy if a pituitary adenoma is the cause of the condition, or bilateral subtotal adrenalectomy if excess pituitary production of ACTH in the absence of a tumour has stimulated adrenal overactivity.

Elevated corticosteroids Loss of diurnal rhythm

Dexamethasone suppression test

No suppression

/ Normal ACTH

\

Ectopic ACTH syndrome

Suppression

\ Low ACTH

\

Adrenal tumour

\ Elevated ACTH

\ Cushing's syndrome

Figure 10.10 Investigation of suspected Cushing's syndrome

Polycystic ovarian disease Rarely polycystic ovarian disease may be associated with sufficient androgen production to cause virilization instead of simple hirsutism.

References BAIRD, D. T., CORKER, C. S., DAVIDSON, D. W., HUNTER, W. M., MICHIE, E. A. and VAN LOOK, P. F. A. (1977) Pituitary-ovarian

relationships in polycystic ovarian disease. Journal of Clinical Endocrinology and Metabolism, 45, 798 BRAENDLE, W., BOESS, H., BRECKWOLDT, M., LEVEN, C. a n d

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