Development of the indifferent gonad

The gonads develop from the intermediate mesoderm that is situated in the paired longitudinal urogenital ridges, the more medial part of these ridges being the gonadal ridges. In the sixth week primordial germ cells migrate from the wall of the yolk sac via the dorsal mesentery of the hindgut to occupy the gonadal ridges. The arrival of these cells induces the cells in the ridges to form primitive sex cords (derived from the mesonephros and overlying coelomic epithelium) (Fig. 9.1A). At this stage the gonad is indifferent or uncommitted (Fig. 9.2), and consists of an outer cortex and an inner medulla. During the next week the male and female gonads begin to differentiate (Fig. 9.1B-D). If germ cells fail to migrate to the gonadal ridges the gonads do not develop.

Fig. 9.1 Formation of gonads during the fifth week. The migration of primordial germ cells to the gonadal ridges is shown in (A). (B) Indifferent stage at 7 weeks. (C) Male genital system in a newborn. (D) Female genital system in a newborn.

Fig. 9.2 Indifferent genital system at 6 weeks.

Development of the testis (Fig. 9.3)

The sex-determining gene in the Y chromosome produces a protein (testis-determining factor) that promotes the development of a testis: the primitive sex cords proliferate and penetrate into the medulla to form the testicular cords. Some of those cells differentiate into Sertoli cells, whilst the remainder become incorporated into seminiferous tubules. The latter are solid cylinders until after puberty at which time they canalize. The testicular cords anastomose to form the rete testis, which becomes continuous with 15–20 persisting mesonephric tubules, the ductuli efferentes. The testis-determining factor also induces differentiation of gonadal mesenchymal cells into the interstitial Leydig cells.

Fig. 9.3 Development of the testis and male genital ducts.

Development of the ovary (Fig. 9.4)

In embryos where no testis-determining factor is produced the primitive sex cords extend into the medulla of the gonad, degenerate and form a vascular stroma, resulting in an ovary. The surface epithelium of the female gonad, unlike that of the male, gives rise to second generation cortical cords. In the fourth month these cords invest the primordial germ cells to form the ovarian follicles.

Fig. 9.4 Differentiation of the indifferent gonad into an ovary.

Genital ducts

Initially, two pairs of genital ducts arise in both male and female: the mesonephric and paramesonephric ducts (Fig. 9.1B–D).

In the male, the mesonephric duct loses its urinary function once the mesonephros is superseded by the metanephros. The mesonephric duct becomes the ductus deferens and the epididymis (the main genital ducts in the male), opening into the urogenital sinus (the anterior part of the cloaca) (Fig. 9.1). The secretion of testosterone by the interstitial Leydig cells from week 8 stimulates the mesonephric ducts to differentiate into their adult derivatives. Each seminal vesicle buds out from the distal mesonephric duct. The prostate arises as a bud from the urethra (Fig. 9.5). The regression of the paramesonephric ducts in the male is stimulated by the anti-mullerian hormone, secreted by the Sertoli cells. The old name for the paramesonephric duct was mullerian duct; the old name for the mesonephric duct was wolffian duct.

Fig. 9.5 Development of the accessory glands of the male genital system at 10 weeks (A) and 12 weeks (B).

In the female, the mesonephric duct is not involved in genital duct formation. In the absence of anti-mullerian hormone and testosterone the mesonephric ducts regress in the female. The paramesonephric duct system arises as a pair of longitudinal invaginations (Figs 9.1 and 9.2) of the coelomic epithelium that overlies the urogenital ridges. The two ducts lie mainly lateral to the mesonephric ducts, though they cross the mesonephric ducts before entering the urogenital sinus. At their cranial ends the paramesonephric ducts open into the future peritoneal cavity as the future fimbriae of the uterine tubes. The caudal ends of the ducts meet in the midline and fuse to form the uterovaginal canal, from which the uterus and upper part of the vagina arises. The canal fuses with the sinuvaginal bulb, a swelling on the urogenital sinus (Fig. 9.6). As the paramesonephric ducts fuse in the midline they bring together two peritoneal folds, thus forming the right and left broad ligaments. The upper part of the vagina forms from the fused paramesonephric ducts. The lower part of the vagina arises from the urogenital sinus, from the sinuvaginal bulb or later the vaginal plate, initially as a solid tube, later canalizing to form the vaginal lumen (Fig. 9.6).

Fig. 9.6 Formation of the uterus and vagina at 9 weeks (A) and 10 weeks (B).

Descent of the testis and development of the inguinal canal

In both sexes the descent of the gonad to its adult position is by the guidance of the fibrous strand called the gubernaculum. The descent is towards the labioscrotal swellings (that form either the labia majora or the scrotum) (Fig. 9.7). In the female the descent of the gonad is as far as the pelvic cavity, on the posterior aspect of the broad ligament. The part of the gubernaculum remaining between the ovary and the uterus is the ovarian ligament; the part between the uterus and the labia is the round ligament of the uterus. Subsequently in the male, an outpouching of the future peritoneum of the coelomic cavity protrudes into the labioscrotal swellings, into the space created by the gubernaculum. This outpouching is known as the processus vaginalis, and it precedes the future testis into the scrotum (Fig. 9.7). As the processus vaginalis pushes through the three layers of the abdominal wall it forms the inguinal canal, which is actually a series of slits or apertures in the aponeuroses of the inferomedial parts of the anterolateral abdominal wall musculature.

Fig. 9.7 Descent of the testis at 7 weeks (A), 13 weeks (B), 24 weeks (C) and in a newborn (D).

The testes descend from their initial position high on the future posterior abdominal wall and remain in the vicinity of the deep inguinal rings until about the seventh month of intra-uterine life. The second phase of migration proceeds from then until about the ninth month, and is hormone-dependent.

The factors related to the descent of the testis include, firstly, the elongation of the trunk of the fetus, and secondly an increase in intra-abdominal pressure arising because of the increasing size of intra-abdominal organs and the regression of the extra-abdominal part of the gubernaculum. As a consequence of the initial development of the testis high on the future posterior abdominal wall, the testis acquires its blood supply from the abdominal aorta, close to the origin of the renal arteries. Thus, the blood supply also migrates inferiorly, resulting in long, thin testicular arteries which pass through the inguinal canals.

External genitalia

At the earliest stages there is no difference in the form of the external genitalia between the two sexes. At the fifth week a cloacal fold forms on either side of the cloacal membrane and these two folds meet in the midline, anteriorly, as the genital tubercle. Subsequently, and lying lateral to the cloacal folds, the genital swellings form (Fig. 9.8). The latter give rise to the labia majora in the female or to the scrotum in the male. Thus, the genital swellings fuse in the male but not in the female.

Fig. 9.8 Formation of external genitalia.

Clinical box

Sexual differentiation defects

The chromosomal complement of 46XX or 46XY is essential for normal sex determination of the embryo. In females, the absence of one X chromosome in Turner’s syndrome (45X0) will lead to degeneration of the ovaries. An extra X chromosome in a male embryo, with a karyotype of 47XXY, results in small testes and other physical malformations.

Abnormal levels of sex hormones at the final stages of sexual differentiation may lead to the intersex conditions of pseudohermaphroditism. Genetic females with male external genitalia due to over-production of androgens by fetal adrenal glands are called female pseudohermaphrodytes, and genetic males with inadequate virilization of external genitalia are called male pseudohermaphrodytes. True hermaphrodytes possess both ovarian and tesicular tissue.

Uterine duplication and vaginal malformation

Failure of the paired paramesonephric ducts to fuse will result in varying degrees of uterine duplication, including a bicornuate uterus resembling the common non-primate mammalian pattern. Incomplete formation of the sinuvaginal bulbs may result in vaginal atresia or duplication.

Herniae and undescended testes (cryptorchidism)

If the processus vaginalis remains in continuity with the peritoneal cavity (normally this connection is lost within the first year of life), then a congenital indirect hernia may develop. If the obliteration of the connection is incomplete with fluid-filled cystic structures remaining these are termed hydrocoeles, and may become inflamed or infected. Such structures may occur anywhere along the length of the spermatic cord, or be related to the testes themselves in the layer known as the tunica vaginalis, which is the persisting part of the original processus vaginalis. The abnormalities of the processus vaginalis are shown in Figure 9.9.

Fig. 9.9 Abnormal development of the processus vaginalis. (A) Congenital inguinal hernia; note the intestinal loops in the hernial sac. (B) Hydrocoele of the testis; note the open communication of the processus vaginalis with the peritoneal cavity.

Undescended testes pose a problem because they are located in the abdomen where the higher temperature is incompatible with normal spermatogenesis. The affected testis may lodge anywhere in the normal path of descent, but this is usually within the inguinal canal.

Abnormalities of the urethra and urinary bladder

Failure of the fusion of the urethral folds results in hypospadias, in which the urethra is open on its inferior aspect, either partly or fully. In the much rarer condition epispadias the urethral meatus is located on the dorsal surface of the penis. This latter condition is associated with exstrophy of the urinary bladder. This is where the interior of the bladder wall is open, due to failure of the closure of the abdominal wall.

The urorectal septum divides the anteriorly placed urogenital sinus from the anorectal canal. In doing so it divides the cloacal membrane into an anterior urogenital membrane and a posterior anal membrane. The urogenital membrane breaks down and the phallic urethra is therefore in an open groove flanked by the urethral folds. The posterior part of the urogenital membrane becomes the anal membrane.

The genital tubercle elongates under hormonal influence to form the penis. The urethral folds are pulled anteriorly to unite by the end of the third month, forming the penile urethra. In females, the genital tubercle forms the clitoris, and the urethral folds remain separate to form the labia minora (Fig. 9.8).

Summary box

The genital system develops from gonadal ridges which are medial parts of the urogenital ridges.

Primordial germ cells from the yolk sac migrate into the gonadal ridges in week 6, forming the primitive sex cords.

A product of the sex-determining gene in the Y chromosome induces formation of a testis; lack of such a protein results in ovary formation.

Two pairs of genital ducts form initially: the mesonephric and the paramesonephric ducts.

In the male the mesonephric duct becomes the ductus deferens and epididymis.

The seminal vesicles bud off the distal mesonephric duct and the prostate buds off the urethra.

In the female the mesonephric duct almost completely regresses and the uterus, uterine tubes and upper part of the vagina develop from the paramesonephric duct.

The caudal ends of the paired paramesonephric ducts fuse as the uterovaginal canal.

The lower part of the vagina arises from the sinuvaginal bulb or vaginal plate, from the urogenital sinus.

The testes and ovaries descend from their original site to their adult position following the path of the fibrous strand, the gubernaculum.

The external genitalia begin as cloacal folds in week 5 on either side of the cloacal membrane.

The urorectal septum fuses with the cloacal membrane to divide it into an anterior urogenital membrane and a posterior anal membrane.

The cloacal folds meet anteromedially to form the genital tubercle.

On each side of the cloacal folds genital swellings form which give rise to the labia majora or scrotum.

The genital tubercle elongates to form the penis in the male, or it forms the clitoris in the female.

The urethral folds are pulled anteriorly uniting to form the urethra.