Obstetrics & Gynaecology

An Evidence-based Text for MRCOG, Third Edition

David M. Luesley, Mark D. Kilby, David M. Luesley, Mark Kilby, Mark D. Kilby, David M. Luesley, Mark Kilby

• Publisher: CRC Press
• Year: 2016
• Print ISBN: 9781482233827
• eBook ISBN: 9780429586224
• Topic: Medicine
• Subtopic: Gynecology, Obstetrics & Midwifery

Modelled after the current MRCOG curriculum, the new edition of this bestselling book provides all the information a specialist registrar in obstetrics and gynaecology or senior house officer needs during training or when preparing for the MRCOG examination. Obstetrics & Gynaecology: An Evidence-based Text for MRCOG covers the latest profession

SECTION EIGHT

Reproductive Gynaecology

Chapter 68 Normal and abnormal development of the genitalia

Rebecca Deans and Sarah M Creighton

MRCOG standards

Theoretical skills

• Revise your knowledge of the embryological development of the male and female urogenital system.

• Understand the situations in which a disruption in these pathways can lead to disorders of sex development, Mullerian anomalies and Wolffian duct remnants.

• Understand the classification of Mullerian anomalies.

• Know about first-line investigations for disorders of sex development and Mullerian anomalies and treatments available in tertiary referral centres.

Practical skills

• Be able to take an appropriate history.

• Be able to initiate appropriate investigations to enable a diagnosis and/or tertiary referral

INTRODUCTION

Fetal development of the gonads, external genitalia, Müllerian ducts and Wolffian ducts can be disrupted at a variety of points, leading to a wide range of conditions with a large spectrum of clinical presentations. Disorders of sex development (DSD) occur when there is a disruption of either gonadal differentiation or fetal sex steroid production or action. Müllerian anomalies and Wolffian duct remnants occur when there is disruption of the embryological development of these systems. An understanding of embryology, as well as molecular genetics, helps us determine the biological basis of these conditions. Many of these cases present in infancy, with initial investigations and treatment performed by paediatric endocrinologists. Some will present for the first time to the gynaecologist and fertility subspecialist with primary amenorrhoea or infertility. Paediatric and urological surgeons may have initially treated others. Patients with DSDs may have coexisting medical problems and require thorough evaluation. As well as anatomical and fertility concerns for these patients, there are often many psychological issues; therefore management in a multidisciplinary team (MDT) is essential for the management of more complex cases. In some conditions, the optimal operative management is still uncertain, and there is currently debate regarding the optimal timing or need for genital surgery in patients with DSD conditions who present in childhood.

NORMAL EMBRYOLOGICAL DEVELOPMENT OF THE INTERNAL AND EXTERNAL GENITALIA

Genetic sex is determined at the moment of conception by the presence or absence of the Y chromosome, and after week 6 should guide the subsequent development of the fetus down one of two standard pathways – male or female. Until this time, development is the same in all fetuses. Primordial germ cells (the precursors of gametes) can be seen at 3 weeks in the endoderm of the yolk sac wall. During weeks 5 and 6, they migrate by amoeboid movement to the genital ridge (future gonad), an area of mesenchyme medial to the developing mesonephros and Wolffian (or mesonephric) duct. During week 6, primitive sex cords form around the germ cells in the indifferent gonad. The two Müllerian (or paramesonephric) ducts also appear lateral to the Wolffian ducts. At the same time, at the caudal end of the fetus, the cloacal membrane folds and is separated into the anterior urogenital and posterior anal parts. The urogenital section with the genital tubercle will become the future external genitalia, and by week 7 consists of a genital tubercle, urogenital membrane, urogenital folds and, more laterally, labioscrotal swellings. At the end of week 7, the urogenital membrane has degenerated and the urogenital sinus freely communicates with the amniotic fluid.

The first noticeable divergence in male and female fetuses is the differentiation of gonadal structure. The indifferent gonad has the potential for testicular or ovarian development. The presence of intact germ cells seems necessary for the ovary to develop, but this is not required for testicular development. The gonad remains undifferentiated until around 42 days. After gonadal differentiation has occurred, the presence or absence of gonadal hormone production and other fetal factors then guides the development of the Müllerian ducts, Wolffian ducts and external genitalia. Sertoli cells in the fetal testis secrete anti-Müllerian hormone (AMH – also called Müllerian inhibiting substance, MIS), leading to active regression of the Müllerian ducts. Early Leydig cells commence production of testosterone which acts through the androgen receptor on the Wolffian ducts, leading to the development of the vas deferens, seminal vesicle and epididymis. Testosterone is converted to its active metabolite dihydrotestosterone (DHT). The fetal ovaries do not secrete androgen or AMH, and therefore there is female external genital development, growth of the Müllerian ducts and spontaneous regression of the Wolffian ducts.

STANDARD MALE PATHWAY

In an XY fetus, activation of the SRY (sex-determining region of the Y chromosome) gene at the end of week 6 guides the indifferent gonad to commence development into a testis.¹ Other autosomal genes (e.g. WT1, SOX9, SF1) are also involved in this genetic cascade.² The medullary sex cord cells become Sertoli cells, surrounding the primitive germ cells. At puberty, these will become the seminiferous tubules surrounding the spermatozoa. Sertoli cells produce AMH, which acts locally to cause apoptotic regression of the adjacent Müllerian ducts from 7 weeks. The appendix testis and prostatic utricle are usually all that remain of the Müllerian ducts in the male.

At around weeks 8–10, Leydig cells appear in the testis and start to secrete testosterone. The control of testosterone production may be independent initially, then under the control of placental human chorionic gonadotrophin (hCG) through the shared leutinizing hormone/hCG receptor (LHCGR), and subsequently by 20 weeks the hypothalamic pituitary (gon-adotrope) axis becomes active and fetal leutinizing hormone (LH) production controls steroidogenesis. Testosterone acts through the androgen receptor and causes development of the Wolffian ducts into the vasa deferentia, and later the seminal vesicles and epididymides. Testosterone is also released into the circulation and undergoes peripheral conversion to its more active metabolite DHT by the enzyme 5α-reductase type 2, and acts on the target tissues of the perineum resulting in development and growth of the genital tubercle, urogenital sinus, urogenital folds and labioscrotal swellings into the glans penis, penile shaft, urethral tube and scrotum, respectively. The penis is similar in size to the clitoris at 14 weeks and, under the influence of DHT, continues growing until birth. Testicular descent is mediated by the Leydig cells under the influence of the hypothalamic pituitary (gonadotrope) axis, commences at 12 weeks, and is usually complete by week 34.

STANDARD FEMALE PATHWAY

Traditionally, ovarian development in an XX fetus has been considered a ‘default pathway’; however, emerging research indicates that a distinct set of genes are expressed in the developing ovary and required for maintaining ovarian integrity and actively opposing testicular development (DAX1, WNT4/RSPO1), termed ‘anti-testis’ genes.^{3, 4, 5} These genes, in combination with the absence of the SRY gene, cause the indifferent gonad to commence ovarian differentiation at around week 7. The sex cord cells degenerate and secondary sex cords form and surround the primordial germ cells. Between 5 and 24 weeks, rapid mitotic expansion of primordial oogonia occurs, followed by first meiotic division (8–36 weeks), and subsequently meiotic arrest as primordial follicles. The presence of ovaries is not required for regression of the Wolffian ducts, and it is the absence of local testosterone that causes their regression at 10 weeks. The paroophoron, epoophoron and Gartner’s cysts are all that may remain of the Wolffian ducts in the female. The absence of circulating testosterone also leads to an absence of peripheral DHT and directs the genital tubercle, urogenital sinus, urogenital folds and labio-scrotal swellings to develop into the clitoris, lower vagina, labia minora and labia majora, respectively.

As AMH is not produced by the fetal ovary, the Müllerian ducts continue to develop. These paired mesodermal ducts originate in week 5, lateral to the Wolffian ducts at the third to fifth thoracic segment. They are thought to be associated with the basement membrane of the Wolffian ducts and grow caudally guided by them. The cranial ends of the Müllerian ducts are independent of the Wolffian ducts and remain separate as the Fallopian tubes. At the pelvis, the Müllerian ducts cross the Wolffian ducts anteriorly to lie medially next to each other. At weeks 8–10, the pelvic Müllerian ducts have fused and subsequent breakdown of their medial walls leads to a single...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• CONTRIBUTORS
• PREFACE
• ACKNOWLEDGEMENTS
• LIST OF ABBREVIATIONS USED
• HOW TO USE THIS BOOK
• SECTION ONE INTRODUCTORY/GENERAL
• SECTION TWO ANTENATAL OBSTETRICS
• SECTION THREE FETAL CONDITIONS
• SECTION FOUR LATE PREGNANCY AND
• SECTION FIVE FIRST STAGE OF LABOUR
• SECTION SIX SECOND STAGE OF LABOUR
• SECTION SEVEN POSTPARTUM COMPLICATIONS
• SECTION EIGHT REPRODUCTIVE GYNAECOLOGY
• SECTION NINE UROGYNAECOLOGY AND SEXUAL HEALTH AND WELLBEING
• SECTION TEN LOWER GENITAL TRACT
• SECTION ELEVEN GYNAECOLOGICAL ONCOLOGY
• INDEX