35 D. Keith Edmonds1,2 1 Imperial College London, London, UK 2 Queen Charlotte’s and Chelsea Hospital, London, UK Sexual differentiation and its control are vital to the continuation of our species, and for every gynaecologist an understanding of the development of the genital tract is clearly important. Our knowledge of this process has greatly increased in recent years and with it an appreciation of normal and abnormal sexual development. Following fertilization the normal embryo contains 46 chromosomes, including 22 autosomes derived from each parent. The basis of mammalian development is that a 46XY embryo will develop as a male and a 46XX embryo as a female. However, it is the presence or absence of the Y chromosome which determines whether the undifferentiated gonad becomes a testis or an ovary. Although the sequence of genes required for differentiation of the gonads and development of the genital tract remains to be clearly defined, sex determination equates to gonadal development. This is then followed by a second process known as sex differentiation. Studies of the genetic control of gonadal development are based on animal data. The Y chromosome contains a region known as SRY (sex‐determining region of the Y chromosome) and it has been shown that the testis‐determining factor is on chromosome Yp11.31. In males this gene triggers testis formation from the undifferentiated gonad [1] but SRY is only one member of a family of genes that exist within the homeobox known as HMG. These genes, known as SOX genes, act in combination to differentiate the gonad to a testis. Mutations of SRY cause pure gonadal dysgenesis or hermaphroditism. Ovarian development is also dependent on genes on the short arm of the X chromosome, although the exact mechanism by which these genes invoke ovarian development remains to be defined. Ovarian differentiation seems to be determined by the presence of two X chromosomes and the ovarian determinant is located on the short arm of the X chromosome; this was discovered by observing that the absence of the short arm results in ovarian agenesis [2]. At present, it is believed that DAX1 is the gene which determines that the bipotential gonad will become an ovary. Other autosomal loci are certainly involved in ovarian development and development of the Wolffian and Müllerian structures is also under genetic control; this is thought to be a polygenic multifactorial inheritance, although autosomal recessive genes may also be involved [3]. The influence of the differentiated gonad on the development of other genital organs is thus fundamental and the presence of a testis will lead to male genital organ development and its absence means the individual will develop female genital organs whether ovaries are present or not. Most embryological accounts agree on the principles of genital tract development, although some different views are held on the development of the vagina. The genital organs and those of the urinary tract arise in the intermediate mesoderm on either side of the root of the mesentery beneath the epithelium of the coelom. The pronephros, a few transient excretory tubules in the cervical region, appears first but quickly degenerates. The duct, which begins in association with the pronephros, persists and extends caudally to open at the cloaca, connecting as it does so with some of the tubules of the mesonephros shortly to appear. The duct is called the mesonephric (Wolffian) duct. The mesonephros itself, the second primitive kidney, develops as a swelling bulging into the dorsal wall of the coelom of the thoracic and upper lumbar regions. The mesonephros in the male persists in part as the excretory portion of the male genital system; in the female only a few vestiges survive (Fig. 35.1). The genital ridge in which the gonad of each sex is to develop is visible as a swelling on the medial aspect of the mesonephros; the paramesonephric (Müllerian) duct from which much of the female genital tract will develop forms as an ingrowth of the coelomic epithelium on its lateral aspect; the ingrowth forms a groove and then a tube and sinks below the surface. Fig. 35.1 Diagrammatic representation of genital tract development: (a) indifferent stage; (b) female development; (c) male development. The two paramesonephric ducts extend caudally until they reach the urogenital sinus at about 9 weeks’ gestation. It is important to remember that there is fusion between the caudal tip of the Müllerian and Wolffian ducts during this time The blind ends project into the posterior wall of the sinus to become the Müllerian tubercle (Fig. 35.2). At the beginning of the third month the Müllerian and Wolffian ducts and mesonephric tubules are all present and capable of development. From this point onwards in the female there is degeneration of the Wolffian system and marked growth of the Müllerian system. In the male the opposite occurs as a result of production of anti‐Müllerian hormone by the fetal testis. The lower ends of the Müllerian ducts come together in the midline, fuse and develop into the uterus and the cervix. The cephalic ends of the duct remain separate to form the fallopian tubes. The thick muscular walls of the uterus and cervix develop from proliferation of mesenchyme around the fused portion of the ducts. Fig. 35.2 Paired paramesonephric ducts protruding into the urogenital sinus as the Müllerian tubercle at 9 weeks of intrauterine life. At the point where the paramesonephric ducts protrude their solid tips into the dorsal wall of the urogenital sinus as the Müllerian tubercle, there is marked growth of tissue from which the vagina will form, known as the vaginal plate. This plate grows in all dimensions, greatly increasing the distance between the cervix and the urogenital sinus, and later the central cells of this plate break down to form the vaginal lumen. The complete canalization of the vagina does not usually occur until around weeks 20–24 of pregnancy and failure of complete canalization may lead to a variety of septa, which cause outflow tract obstruction in later years. The embryological development of the vagina has been the subject of debate for many years, but current molecular studies show that the whole vagina is derived from the paramesonephric duct. The primitive cloaca becomes divided by a transverse septum into an anterior urogenital portion and a posterior rectal portion. The urogenital portion of the cloacal membrane breaks down shortly after division is complete and this urogenital sinus develops into three portions (Fig. 35.3). There is an external expanded phallic part, a deeper narrow pelvic part between it and the region of the Müllerian tubercle, and a vesico‐urethral part connected superiorly to the allantois. Externally in this region the genital tubercle forms a conical projection around the anterior part of the cloacal membrane. Two pairs of swellings, a medial part (genital folds) and a lateral pair (genital swellings), are then formed by proliferation of mesoderm around the end of the urogenital sinus. Development up to this time (10 weeks’ gestation) is the same in the male and the female. Differentiation then occurs. The bladder and urethra form from the vesico‐urethral portion of the urogenital sinus, and the vestibule from the pelvic and phallic portions. The genital tubercle enlarges only slightly and becomes the clitoris. The genital folds become the labia minora and the genital swellings enlarge to become the labia majora. In the male greater enlargement of the genital tubercle forms the penis and the genital folds fuse over a deep groove formed between them to become the penile part of the male urethra. The genital swellings enlarge, fuse and form the scrotum. Fig. 35.3 Diagrammatic representation of lower genital tract development: (a) indifferent stage; (b) female development; (c) male development. The final stage of development of the clitoris or penis and the formation of the anterior surface of the bladder and anterior abdominal wall up to the umbilicus is the result of the growth of mesoderm, extending ventrally around the body wall on each side to unite in the midline anteriorly. The primitive gonad appears in embryos at around 5 weeks’ gestation. At this time coelomic epithelium develops on the medial aspect of the urogenital ridge and following proliferation leads to the establishment of the gonadal ridge. Epithelial cords then grow into the mesenchyme (primary sex cords) and the gonad now possesses an outer cortex and an inner medulla. In embryos with an XX complement, the cortex differentiates to become the ovary and the medulla regresses. The primordial germ cells develop by the fourth week in the endodermal cells of the yolk sac and during the fifth week they migrate along the dorsal mesentery of the hindgut to the gonadal ridges, eventually becoming incorporated into the mesenchyme and the primary sex cords by the end of the sixth gestational week. The differentiation of the testis is evident at about 7 weeks by the disappearance of germ cells from the peripheral zone and gradual differentiation of remaining cells into fibroblasts, which form the tunica albuginea. The deeper parts of the sex cords give rise to the rete testis and the seminiferous and straight tubules. The first indication that the gonad will become an ovary is failure of these testicular changes to appear. The sex cords below the epithelium develop extensively with many primitive germ cells evident in this active cellular zone (Fig. 35.4). The epithelial cells in this layer are known as pre‐granulosa cells. The active growth phase then follows, involving the pre‐granulosa cells and germ cells, which are now very much reduced in size. This proliferation greatly enlarges the bulk of the gonad and the next stage (by 20 weeks onwards) shows the primitive germ cells, now known as oocytes, becoming surrounded by a ring of pre‐granulosa cells; stromal cells develop from the ovarian mesenchyme later, surround the pre‐granulosa cells and become known as granulosa cells and follicle formation is complete (Fig. 35.5). An interesting feature of the formation of follicles and the development of stroma is the disintegration of those oocytes which do not succeed in encircling themselves with a capsule of pre‐granulosa cells. Fig. 35.4 Detail of immature ovary showing small epithelial cells (pre‐granulosa cells) and larger germ cells. Fig. 35.5 A later ovary (31 weeks) showing a well‐formed primary follicle (top left) and a germ cell (centre right) which is not yet completely surrounded by granulosa cells. The number of oocytes is greatest during intrauterine life and thereafter declines. Baker [4] found that the total population of germ cells rose from 600 000 at 2 months to a peak of 7 million at 5 months. At birth the number falls to 2 million, of which half are atretic. After 28 weeks or so of intrauterine life, follicular development can be seen at various stages and various sizes of follicles are also seen (Fig. 35.6). Fig. 35.6 Numerous primary follicles and one showing early development in the ovary of a child stillborn at 38 weeks. Disorders of sexual development (DSD) have been reclassified by Hughes [5] and this has now been adopted as the best way of classifying these disorders (Table 35.1). Table 35.1 Classification of disorders of sexual development (DSD). This group of disorders includes Turner’s syndrome (46XO), which is the most important in this group of disorders and the most common. Patients with Turner’s syndrome have gonads that contain no oocytes and merely fibrous tissue and as a result of this they have no secondary sexual development (see Chapter 38). This group of disorders is divided into three groups. The gynaecologist may occasionally come across a case of ovotesticular DSD where both ovarian and testicular tissue exist within the same individual. These patients are rare in Europe and the USA but are notably more common in South Africa. They present with varying degrees of sexual ambiguity, with maleness predominating in some patients while female changes are more apparent in others. In the majority the uterus and vagina are present and the karyotype is usually normal female (46XX); in the largest series reported, Van Niekerk [6] found that 58% of cases had a normal karyotype, 13% had 46XX/XY, 11% had 46XY and 6% had 46XY/47XXY, with other mosaics accounting for 10%. Gonadal differentiation is interesting in that the commonest combination of ovotestis is for an ovotestis to be on one side and an ovary on the other, with a testis on one side and an ovary on the other being almost as frequent. Ovotestes can be bilateral or combined with a testis but this is much rarer. Diagnosis of true ovotesticular DSD can only be made after gonadal biopsy, and sex of rearing should be determined on the functional capability of the external genitalia after which inappropriate organs should be removed. In some cases it may be possible to identify the ovarian and testicular portions of an ovotestis for certain and to remove only that part that is unwanted. If this is not possible, both must be removed and then the patient needs to be brought up in the gender role for whichever is appropriate and hormone replacement therapy instituted at puberty. In group B1 (see Table 35.1), the most commonly seen, though rare, is 5α‐reductase deficiency. These patients are genetic males who show ambiguous genitalia at birth and at puberty begin to virilize like normal males. This results in penile enlargement, increased facial hair and muscular hypertrophy but breast development does not occur. The phallus is rather small and a perineal urethral orifice is present. The disorder of androgen synthesis relates to deficiency of 5α‐reductase, the enzyme responsible for the conversion of testosterone to dihydrotestosterone, which results in virilization of the external genitalia during embryogenesis. Testosterone is unable to induce virilization during fetal life but at puberty androgen receptors become sensitive to circulating levels of testosterone and therefore a degree of virilization can occur. Management of these patients after puberty can be difficult as they themselves may find sexual orientation difficult and may wish to change their gender role but they must be fully assessed before any permanent decisions are made. In these conditions the individual has a chromosome complement of 46XY but an absence of functional androgen receptors. This is known as complete androgen insensitivity syndrome and during fetal life female external genitalia develop, but as the testis produces Müllerian inhibitor the internal structures of the Müllerian duct regress. However, the Wolffian duct cannot develop as it also lacks androgen receptors. These individuals usually present at puberty with failure of menstruation. They are shown to have bilateral testes and a blind‐ending vagina and they may well feminize at puberty as testicular production of oestrogen induces breast growth. Absence of the androgen receptor means that pubic hair and axillary hair growth is sparse and the diagnosis is often easy to make clinically. The testes are usually normal in size and located either in the abdomen or the inguinal canal and can present as inguinal hernias. These sometimes present in childhood when the diagnosis is made on surgical excision of the mass. Height is slightly increased compared with normal women. Testicular neoplasia is increased though very rare under the age of 30. It is therefore perfectly acceptable to leave the gonads in situ until pubertal development has been completed and then to remove them. Partial androgen insensitivity occurs when the androgen receptor has a mutation and has partial function. At puberty therefore individuals feminize as do patients with complete androgen insensitivity but as they have some function in the androgen receptor, their external genitalia change, with phallic enlargement and partial labioscrotal fusion. Again, bilateral testes are present within the abdominal cavity or the inguinal canal and there are normal circulating levels of testosterone equivalent to a male. At birth phallic enlargement may already be present due to incomplete virilization and the intersex state at birth needs to be assessed and the sex of rearing determined.
Normal and Abnormal Development of the Genital Tract
Development of the genital organs
Uterus and fallopian tubes
Vagina
External genitalia
Gonads
Disorders of sexual development
Sex chromosome DSD
46XY DSD
46XX DSD
Sex chromosome disorders
46XY
Disorders of gonadal (testicular) development
Disorders of androgen synthesis
Androgen insensitivity syndromes
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
