Primary excretory duct

In stage 11 embryos of approximately 14 somites, the primary excretory duct can be seen as a solid rod of cells in the dorsal part of the nephrogenic cord. Its cranial end is about the level of the ninth somite and its caudal tip merges with the undifferentiated mesenchyme of the cord. It differentiates before any nephric tubules, and when the latter appear it is at first unconnected with them. In older embryos the duct has lengthened and its caudal end becomes detached from the nephrogenic cord to lie immediately beneath the ectoderm. From this level it grows caudally, independent of the nephrogenic mesenchyme, and then curves ventrally to reach the wall of the cloaca. It becomes canalized progressively from its caudal end to form a true duct, which opens into the cloaca in embryos at stage 12 (Fig. 78.1C). Clearly, up to this stage the name ‘duct’ is scarcely appropriate.

Mesonephric duct

Once mesonephric nephrons connect to the primary excretory duct it is renamed the mesonephric duct. This runs caudally in the lateral part of the nephric ridge, and at the caudal end of the ridge it projects into the cavity of the coelom in the substance of a mesonephric fold (Fig. 78.3). As the mesonephric ducts from each side approach the urogenital sinus the two mesonephric folds fuse, between the bladder ventrally and the rectum dorsally, forming a transverse partition across the cavity of the pelvis, which is somewhat inappropriately called the genital cord (Fig. 78.3). In the male the peritoneal fossa between the bladder and the genital cord becomes obliterated, but it persists in the female as the uterovesical pouch. In the male the mesonephric duct itself becomes the canal of the epididymis, vas deferens and ejaculatory duct (p. 1317).

Urogenital sinus

The primitive hindgut ends in a cloacal region. This is connected ventrally with a blind-ending diverticulum, the allantois, which is intimately related to the development of the caudal portion of the urinary system. The enteric and allantoic portions of the hindgut are separated by the proliferation of the urorectal septum, a partition of mesenchyme and endoderm in the angle of the junction of hindgut and allantois (Fig. 78.4; see Fig. 78.7). The endodermal epithelium beneath the mesenchyme of the urorectal septum approaches but does not fuse with the cloacal membrane: it effectively divides the membrane into anal (dorsal) and urogenital (ventral) membranes, and the cloacal region into dorsal and ventral portions. The dorsal portion of the cloacal region is the putative rectum. The ventral portion can be further divided into: a cranial vesicourethral canal, continuous above with the allantoic duct; a middle, narrow channel, the pelvic portion; and a caudal, deep, phallic section, which is closed externally by the urogenital membrane. The second and third parts together constitute the urogenital sinus.

Fig. 78.4 The division of the hindgut into urinary and enteric parts. Left ventrolateral view of the intraembryonic coelom and corresponding midsagittal sections. A, Early cloaca. B, Proliferation of urorectal septum. C, Complete separation of urethra and anal canal, and position of perineal body.

Fig. 78.7 A, The caudal end of a human embryo, 4 weeks, showing the left lateral aspects of the spinal cord, notochord and endodermal cloaca. B, The endodermal cloaca of a human embryo, near the end of the fifth week. Part of the left wall of the cloaca, including the left mesonephric duct, has been removed, together with the adjoining portions of the walls of the developing bladder and rectum. A piece of the ectoderm around the cloacal membrane has been left in situ. A wire is shown passing along the right mesonephric duct into the cloaca. C, The caudal end of a human embryo, 5 weeks, showing the endodermal cloaca. D, The caudal end of a human embryo, 6 weeks. The cloaca is becoming divided by the urorectal septum. E, The caudal end of a female human fetus, 8½–9 weeks, from the left-hand side showing structures in and near the median plane. The cloaca is now completely divided into urogenital and intestinal segments. F, Part of the vesicourethral portion of the endodermal cloaca of a female human fetus, 8½–9 weeks. The sinus tubercle is the elevation on the posterior wall of the urogenital sinus, caused by the fusion with the paramesonephric ducts.

Endocrine development of the kidney

The kidney functions not only as an excretory organ, but also as an endocrine organ, secreting hormones that are concerned with renal haemodynamics. Before birth homeostasis is controlled by the placenta. The fetal kidney produces amniotic fluid. The kidneys of premature babies of less than 36 weeks are immature. They contain incompletely differentiated cortical nephrons, which compromise their ability to maintain homeostasis. Problems of immaturity are further compounded by the effects of hypoxia and asphyxia, which modify renal hormones.

Renal hormones include the renin–angiotensin system, renal prosta-glandins, the kallikrein–kinin system, and renal dopamine. Renin is found in the smooth muscle cells of arterioles, interlobular arteries and branches of the renal artery, and has also been described in the distal convoluted tubule cells. Kallikrein has been demonstrated in rat fetal kidney, and prostaglandins have been demonstrated in the renal medulla and renal tubule. Renal dopamine is produced (mainly) by the enzymatic conversion of L-dopa to dopamine in the early segments of the proximal convoluted tubule, and is also sourced locally from dopaminergic nerves. Other renal hormones include an antihypertensive lipid, which is produced in the interstitial cells of the renal medulla, and, possibly, histamine and serotonin. Growth factors produced by human embryonic kidney cells include erythropoietin and interleukin β (which stimulate megakaryocyte maturation) and transforming growth factor-β.

Ascent of the kidney

The metanephric kidney is initially sacral. As the ureteric outgrowth lengthens, it becomes positioned more and more cranially. The metanephric pelvis lies on a level with the second lumbar vertebra when the embryo reaches a length of about 13 mm. During this period the ascending kidney receives its blood supply sequentially from arteries in its immediate neighbourhood, i.e. the middle sacral and common iliac arteries. The definitive renal artery is not recognizable until the beginning of the third month. It arises from the most caudal of the three suprarenal arteries, all of which represent persistent mesonephric or lateral splanchnic arteries. Additional renal arteries are relatively common, and may enter at the hilum or at the upper or lower pole of the gland – they also represent persistent mesonephric arteries.

Ureter

The wall of the early ureter is initially highly permeable. Its lumen later becomes obliterated and is subsequently recanalized. Both of these processes begin in intermediate portions of the ureter and proceed cranially and caudally. Recanalization is not associated with metanephric function, but perhaps reflects the rapid elongation of the ureter as the embryo grows. Two fusiform enlargements appear at the lumbar and pelvic levels of the ureter at 5 and 9 months respectively (the pelvic enlargement is inconstant). As a result the ureter shows a constriction at its proximal end (pelviureteric region) and another as it crosses the pelvic brim. A third narrowing is always present at its distal end and is related to the growth of the bladder wall.

At first the distal end of the ureter is connected to the dorsomedial aspect of the mesonephric duct, but, as a result of differential growth, this connection comes to lie lateral to the duct.

Urinary bladder

The urinary bladder develops from the cranial vesicourethral canal, which is continuous above with the allantoic duct (Figs 78.4, 78.6, 78.7). The mesonephric ducts open into the urogenital sinus early in development. The ureters develop as branches of the mesonephric ducts, which attain their own access to the developing bladder, and their orifices open separately into the bladder on the lateral side of the opening of the mesonephric ducts. Later the two orifices become separated still further and, although the ureter retains its point of entry into the bladder, the mesonephric duct opens into that part of the urogenital sinus that subsequently becomes the prostatic urethra (Fig. 78.6). The triangular region of absorption of the mesonephric ducts contributes to the trigone of the bladder and dorsal wall of the proximal half of the prostatic urethra, i.e. as far as the opening of the prostatic utricle and ejaculatory ducts, or its female homologue, the whole female urethral dorsal wall. The remainder of the vesicourethral canal forms the body of the bladder and urethra, and its apex is prolonged to the umbilicus as a narrow canal, the urachus.

The fetal bladder can be identified by ultrasound examination at 9–11 weeks’ gestation and the absence of a bladder image is considered abnormal at 13 weeks or later.

Uterus and uterine tubes

In the female the mesonephric duct is vestigial. Cranially it becomes the longitudinal duct of the epoöphoron, while caudally it is referred to as Gartner’s duct (Table 78.1). The cranial part of the paramesonephric ducts forms the uterine tubes, and the original coelomic invagination remains as the pelvic opening of the tube. The fimbriae become defined as the cranial end of the mesonephros degenerates. The caudal vertical parts of the two ducts fuse with each other to form the uterovaginal primordium (Figs 78.7, 78.13, 78.14; see Fig. 78.19). This gives rise to the lower part of the uterus and, as it enlarges, it takes in the horizontal parts to form the fundus and most of the body of the adult uterus. A constriction between the body of the uterus and the cervix can be found at 9 weeks. The stroma of the endometrium and the uterine musculature develop from the surrounding mesenchyme of the genital cord.

Table 78.1 Homologies of the parts of the urogenital system in male and female.

Fig. 78.14 Relative movements of the gonads and associated tubes. A, Gonads and mesonephros move caudally, and the metanephros ascends. B, Posterior view of the mesonephric ducts (ureters) and the fused paramesonephric ducts (uterovaginal canal) in the female. For earlier development, see Fig. 78.3.

(Redrawn from Tuchmann-Duplessis H, Haegel P 1972 Illustrated Human Embryology, Vol 2 Organogenesis. London: Chapman and Hall. With kind permission of Springer Science+Business Media.)

Failure of fusion of the two paramesonephric ducts can lead to a range of anomalies summarized in Fig. 78.15. These fusions can also contribute to anomalies of vaginal development.

Fig. 78.15 Uterovaginal malformations.

(Redrawn from Tuchmann-Duplessis H, Haegel P 1972 Illustrated Human Embryology, Vol 2 Organogenesis. London: Chapman and Hall. With kind permission of Springer Science+Business Media.)

At birth the uterus is 2.5–5 cm long (average 3.5 cm), 2 cm wide between the uterine tubes, and a little over 1 cm thick (Fig. 78.9; see Figs 14.4, 14.5). The body of the uterus is smaller than the uterine cervix, which forms two-thirds or more of the length. The isthmus between the body and the cervix is absent. The fetal female reproductive tract is affected by maternal hormones and undergoes some enlargement in the fetus. The endocervical glands are active before birth and the cervical canal is usually filled with mucus. The uterus is relatively large at birth, and subsequently involutes to about one-third of its length and more than half of its weight; it does not regain its neonatal size and weight until puberty. The uterine tubes are relatively short and wide.

The position of the uterus in the pelvic cavity depends to a great extent on the state of the bladder anteriorly and the rectum posteriorly. If the bladder contains only a small amount of urine the uterus may be anteverted but it is often in a direct line with the vagina (Fig. 78.9; see Fig. 78.19).

Vagina

At approximately 60 mm crown rump (CR) length an epithelial proliferation, the sinuvaginal bulb, arises from the dorsal wall of the urogenital sinus in the region of the sinus tubercle (Figs 78.7F, 78.14B),. Its origin marks the site of the future hymen. The proliferation gradually extends cranially as a solid anteroposteriorly flattened plate inside the tubular condensation of the uterovaginal primordium, which will eventually become the fibromuscular vaginal wall. The caudal tip of the paramesonephric duct epithelium recedes until, at about 140 mm (CR), its junction with the epithelial proliferation lies in the cervical canal.

Starting from its caudal end, and gradually extending cranially through its whole extent, the solid plate formed by the sinus proliferation enlarges into a cylindrical structure. Thereafter the central cells desquamate to establish the vaginal lumen. The extent to which mesonephric and paramesonephric ducts contribute directly to the formation of the vagina is controversial. As the upper end of the vaginal plate enlarges it grows up to embrace the cervix, and then is excavated to produce the vaginal fornices. Anomalies of paramesonephric duct fusion can produce related vaginal anomalies (Fig. 78.15). The urogenital sinus undergoes relative shortening craniocaudally to form the vestibule, which opens on the surface through the cleft between the genital folds. The lower end of the vaginal plate grows caudally so that in 109 mm embryos the vaginal rudiment approaches the vestibule. In fetuses of 162 mm the vaginal lumen is complete except at the cephalic end where the fornices are still solid; they are hollow by 170 mm. At approximately half way through gestation (180 mm) the genital canal is continuous with the exterior. During the later months of fetal life the vaginal epithelium is greatly hypertrophied, apparently under the influence of maternal hormones, but after birth it assumes the inactive form of childhood.

In the neonate, the vagina is 2.5–3.5 cm long and 1.5 cm wide at the fornices, and the uterine cervix extends into the vagina for about 1 cm. The posterior vaginal wall is longer than the anterior wall, giving the vagina a distinct curve (Fig. 78.9; see Fig. 78.19 and Fig. 14.5). The cavity is filled with longitudinal columns covered with a thick layer of cornified, stratified squamous epithelium. These cells slough off after birth when the effect exerted by maternal hormones is removed.

The orifice of the vagina is surrounded by a thick elliptical ring of connective tissue, the hymen (Fig. 78.9). During childhood the hymen becomes a membranous fold along the posterior margin of the vaginal lumen. Should the fold form a complete diaphragm across the vaginal lumen it is termed an imperforate hymenal membrane.

Reproductive ducts in the male

In the male, most of the paramesonephric ducts atrophy (Fig. 78.13) under the influence of anti-Müllerian hormone (AMH), which is released into the mesonephric duct by the Sertoli cells of the testis. Vestigial structures are therefore most likely to persist cranially and/or caudally, at the limits of the local exocrine effects of AMH. A vestige of the cranial end of the duct persists as the appendix testis (Fig. 78.13; see Fig. 78.19, Table 78.1). The fused caudal ends of the two ducts are connected to the wall of the urogenital sinus by a solid utricular cord of cells, which soon merges with a proliferation of sinus epithelium, the sinu-utricular cord. The latter is similar to, but less extensive than, the sinus proliferation in the female. The proliferating epithelium is claimed to be an intermingling of the endoderm of the urogenital sinus with the lining epithelia of the mesonephric and paramesonephric ducts, which have extended on to the surface of the sinus tubercle. As the sinu-utricular cord grows, so the utricular cord recedes from the tubercle. In the second half of fetal life the composite cord acquires a lumen and becomes dilated to form the prostatic utricle, the lining of which consists of hyperplastic stratified squamous epithelium (Fig. 78.13; see Fig. 78.19). The sinus tubercle becomes the colliculus seminalis.

The main reproductive ducts in the male are derived from the mesonephric ducts; the latter persist under the action of androgens that are probably secreted down the ducts themselves, and are subsumed into the male reproductive system as the metanephric kidney develops. The mesonephric duct gives rise to the canal of the epididymis, vas deferens and ejaculatory duct. The seminal vesicle and the ampulla of the vas deferens appear as a common swelling at the end of the mesonephric duct during the end of the third and into the fourth month. Their appearance coincides with degeneration of the paramesonephric ducts, although no causal relation between the two events has been established. Separation into two rudiments occurs at about 125 mm crown–heel length. The seminal vesicle elongates, its duct is delineated and hollow diverticula bud from its wall. About the sixth month (300 mm crown–heel length) the growth rate of both vesicle and ampulla is greatly increased. Figure 78.10 shows the position of the ampulla of the vas deferens in the neonate, possibly in response to increased secretion of prolactin by the fetal or maternal hypophysis, or to the effects of placental hormones. The tubules of the prostate show a similar increase of growth rate at this time.

Testis

Most studies support the hypothesis that the seminiferous tubules are formed from cords of epithelial cells derived from the proliferating coelomic epithelium (Figs 78.13, 78.16). The cords lengthen, partly by addition from the coelomic epithelium, and encroach on the medulla, where they unite with a network of cells derived from the mesonephric mesenchyme destined to become the rete testis. Primordial germ cells are incorporated into the cords, which later become enlarged and canalized to form the seminiferous tubules. The cells derived from the surface of the early gonad form the supporting Sertoli cells. The latter proliferate throughout development and perhaps into childhood; when they stop dividing they mature and cannot be reactivated. Each Sertoli cell can only support a fixed number of germ cells during their development into spermatozoa, i.e. the number of Sertoli cells produced at this time determines the maximal limit of sperm output. Because the germ cells make up the bulk of the adult testis, the number of Sertoli cells is a major determinant of the size to which the testes will grow (factors which impair the process of spermatogenesis, resulting in the loss of germ cells, will also affect testicular size). Variation in Sertoli cell number is probably the most important factor in accounting for the enormous variation in sperm counts between individual men, whether fertile or infertile. Indeed, the available data for adult men indicate that Sertoli cell numbers vary across a fifty-fold range. Although some of this variation may result from attrition of Sertoli cell numbers because of ageing, the major differences in Sertoli cell numbers will have been determined by events in fetal and/or childhood life.

The interstitial cells of the testis are derived from mesenchyme and possibly also from coelomic epithelial cells that do not become incorporated into the tubules. Among other cell lines they form the embryonic and fetal cells of Leydig, which secrete testosterone and insulin-like factor 3 (Insl3). A later migration of mesenchyme beneath the coelomic epithelium forms the tunica albuginea of the testis.

The cords of the rete testis become connected to the glomerular capsules in the persisting part of the mesonephros. Ultimately they become connected to the mesonephric duct by the five to twelve most cranial persisting mesonephric tubules. These become exceedingly convoluted and form the lobules of the head of the epididymis. The mesonephric duct, which was the primitive ‘ureter’ of the mesonephros, becomes the canal of the epididymis and the vas deferens of the testis. The seminiferous tubules do not acquire lumina until the seventh month; the tubules of the testicular rete become canalized somewhat earlier.

Disorders of development of the testis and reproductive tract in the male fetus seem to be increasing in incidence. Testicular maldescent (cryptorchidism) and hypospadias appear to have doubled or trebled in incidence in the last 30–50 years, while testicular cancer has increased by an even greater margin and is now the commonest cancer of young men. Although testicular cancer is primarily a disease of young men (95% of cases affect 15- to 45-year-old males) it is now established that this age-incidence reflects activation of premalignant carcinoma-in-situ (CIS) cells, which are present at birth and which almost certainly arise during fetal life. It has been suggested that CIS cells are primordial germ cells that have failed to develop normally. Abnormalities of development of the testis and reproductive tract (e.g. gonadal dysgenesis, cryptorchidism, small testes) are important risk factors for the development of testicular cancer. However, the most dramatic change that appears to have occurred in the relatively recent past is a fall in sperm counts of around 40–50% (1% per year over the last 50 years). Although this dramatic decrease is obviously manifest only in adulthood, as is the case with testicular cancer, it is thought that it may reflect impaired testicular development during fetal or childhood life.

Ovary

The ovary closely resembles the testis early in development, except that its characteristically female features are slower to differentiate (Figs 78.13, 78.16). Few, if any, of the epithelial cords invade the medulla. The majority remain in the cortex, where they may be joined by a second proliferation from the coelomic epithelium overlying the gonad. In histological sections of ovaries from the third and subsequent months, the epithelial cords appear as clusters of cells, which may contain primitive germ cells, separated by fine septa of undifferentiated mesenchyme. An ovarian rete condenses in the medullary mesenchyme and some of its cords may join mesonephric glomeruli. The medulla subsequently regresses, and connective tissue and blood vessels from this region invade the cortex to form the ovarian stroma. During this invasion the clusters of epithelial cortical cells break into individual groups of supporting cells (now identified as granulosa cells), which surround the primordial germ cells (now identified as primary oocytes) that have entered the prophase of the first meiotic division. Primary oocytes are derived from a mitotic division of the primordial germ cells (naked oogonia). Their epithelial capsules consist of flattened pregranulosa cells derived from proliferations of coelomic epithelium. The ovary now has its full complement of primary oocytes. The majority undergo atresia, a hormonally controlled apoptotic process, but the remainder resume development after puberty, when they complete the first meiotic division shortly before ovulation (p. 1296). The granulosa cells at this time enlarge and multiply to form the stratum granulosum; as they do so, they become surrounded by thecal cells, which differentiate from the stroma.

Only the middle part of the gonadal ridge produces the ovary. Its cranial part is sterile and becomes the suspensory ligament of the ovary (infundibulopelvic fold of peritoneum). Its caudal region, also sterile, is incorporated into the ovarian ligament.

Sex determination in the embryo

It was believed that the gonads were indifferent or ambisexual until the arrival of the primordial germ cells in the gonadal ridge, at which point the sex of the embryo was ‘turned on’ by the presence of the male or female germ cells. It now seems that the germ cells may be essentially irrelevant to testis determination; embryos in which the genital ridges are devoid of germ cells may still have morphologically normal testis development. It is not clear if the germ cells are necessary for ovarian determination. They are required for the proper organization and differentiation of the ovary, and their absence results in the development of ‘streak gonads’, where only lines of follicular cells can be seen, as in Turner’s syndrome.

The processes of sex determination and differentiation involve interacting pathways of gene activity, which lead to the total patterning of the embryo as either male or female.

In the current, generally accepted model of sex determination in humans, the female pathway is considered to be the default pathway. According to this model, the Y chromosome of a male embryo diverts development into the testicular pathway, and the resulting changes that convert an indifferent gonad to a testis produce a range of local and widely acting hormones, which collectively generate all the secondary sexual characteristics.

The possession of a Y chromosome is usually associated with a male developmental pathway. Deletion mapping of the Y chromosome in a class of XX males arising from abnormal X:Y interchange at meiosis showed that the male-determining region of the chromosome was a conserved sequence located near its tip, termed the testis-determining factor (TDF). This sequence contains a gene that is regarded by some as the ‘master switch’ that programmes the direction of sexual development, the so-called SRY gene (sex-determining region on Y chromosome). It is believed to be genetically and functionally equivalent to the TDF. The SRY gene acts initially within the epithelial cords of cells derived from the coelomic epithelium of the ambisexual gonad. These cells can potentially differentiate into either Sertoli or granulosa cells (the supporting cells for the germ cells in the testis and ovary respectively). Studies indicate that SRY initiates testis formation from the indifferent gonad by directing the development of supporting-cell precursors as Sertoli rather than granulosa cells (Albrecht & Eicher 2001). Gene expression is seen first in cells designated as pre-Sertoli located centrally in the developing gonad and then later in the cranial and caudal poles. Once the developmental pathway of Sertoli cells is directed this influences the differentiation of the other cell types in the testicular pathway, so that Leydig cells appear later, and the connective tissue becomes organized into a male pattern. The germ cells are also affected by this environment. When they arrive they become enclosed within the Sertoli cells and enter mitotic arrest (which is characteristic of spermatogenesis), instead of entering meiosis and meiotic arrest (which characterizes oogenesis). Thus the development of male characteristics follows the expression of SRY, and female characteristics develop in its absence.

The possession of a Y chromosome expressing SRY may, therefore, underlie the switch to development of the male phenotype, by initiating Sertoli cell differentiation. An alternative view is that the possession of SRY accelerates the development of the gonads in XY embryos generally, so that testes are larger and more advanced than ovaries of the same age. Male human fetuses are generally bigger than females from 12 weeks’ gestation; indeed males are already slightly ahead of females at six weeks’ gestation, just prior to testicular differentiation. It has been suggested that this difference in the growth rate is encoded in the sex chromosomes. Once gonadal development has started, the difference in size between testes and ovaries becomes proportionately much greater than the overall size difference between XY and XX fetuses. (Interestingly, the right gonad develops slightly ahead of the left, an observation which may be correlated with the finding that testes are more often on the right side, and ovaries on the left, in hermaphrodites.)

Subsequent development of the male phenotype requires fetal secretion of both testosterone and anti-Müllerian hormone (AMH), (also called Müllerian inhibiting substance or MIS), and the development of the appropriate cytoplasmic testosterone-binding protein. Sertoli cells synthesize AMH, which causes the regression of the Müllerian ducts, and Leydig cells produce testosterone, which promotes the development of the mesonephric ducts, sets into process the development of male external genitalia, and sensitizes other tissues to testosterone. Absence of the testosterone-binding protein in the complete androgen insensitivity syndrome (CAIS) results in XY individuals who have testes and degenerated Müllerian ducts, but cannot respond to the circulating testosterone produced by their testes: they therefore develop female secondary sexual characteristics.

Although fetuses of either sex are exposed to maternal hormones, the accelerated development of the testis at early embryological stages ensures arrest of meiosis of the germ cells, and the production of hormones that masculinize the male embryo before the development of the reproductive tract and ovaries of the female. The range of intersex conditions, of phenotypic sex that is not correlated to genotype, and the effect of multiple X chromosomes in males, suggests that the male developmental pathway involves many testis determining genes, whereas only a single X chromosome determines the female default pathway. Once testicular differentiation and male hormone secretion have begun, other Y-chromosomal genes are required to maintain spermatogenesis and complete spermiogenesis. The consequences of impairment of oogenesis by other chromosomal abnormalities are much less severe than the impairment of spermatogenesis.

Descent of the testis

The mechanism of testicular descent is not completely understood, and to some extent remains controversial. Recent evidence suggests that it involves two phases, transabdominal and inguinoscrotal, that are regulated by distinct morphological and endocrine factors.

Transabdominal phase

Each testis initially lies on the dorsal abdominal wall. As it enlarges, its cranial end degenerates and the remaining organ therefore occupies a more caudal position. It is attached to the mesonephric fold by the mesorchium (the mesogenitale of the undifferentiated gonad), a peritoneal fold that contains the testicular vessels and nerves and a quantity of undifferentiated mesenchyme. It also acquires a secondary attachment to the ventral abdominal wall, which has a considerable influence on its subsequent movements. At the point where the mesonephric fold bends medially to form the genital cord (Fig. 78.3), it becomes connected to the lower part of the ventral abdominal wall by an inguinal fold of peritoneum. The mesenchymal cells occupying the core of the inguinal fold condense as another cord, the gubernaculum (Figs 78.3, 78.13, 78.17). This extends from the inguinal abdominal wall, at the site of the future inguinal canal, through the inguinal fold and the mesorchium to the caudal pole of the testis. The future inguinal canal is formed around it by the differentiating muscles of the abdominal wall. At the end of the second month the caudal part of the ventral abdominal wall is horizontal but, after the return of the intestine to the peritoneal cavity, it grows in length and becomes progressively more vertical. As the umbilical artery runs ventrally from the dorsal to the ventral wall, it pulls up a falciform peritoneal fold, which forms the medial boundary of a peritoneal fossa, the saccus vaginalis or lateral inguinal fossa, into which the testis projects. This lower end of the fossa protrudes down the inguinal canal, within the ventrosuperior aspect of the gubernaculum, as the processus vaginalis (Fig. 78.17; see Fig. 78.19).

Fig. 78.17 The descent of the testis. The testis is retroperitoneal throughout development, A. It is held in apposition to the deep inguinal ring from the fourth month and descends into the scrotum surrounded by the processus vaginalis during the seventh month, after which time the proximal part of the processus vaginalis obliterates. The layers of the distal processus vaginalis which remain around the testis form the tunica vaginalis, B–D.

(Redrawn from Tuchmann-Duplessis H, Haegel P 1972 Illustrated Human Embryology, Vol 2 Organogenesis. London: Chapman and Hall. With kind permission of Springer Science+Business Media.)

Up to about 10 weeks the gubernaculum in male and female embryos is the same, but then production of insulin-like factor 3 (Insl3) from the Leydig cells stimulates enlargement (known as the ‘swelling reaction’) of the gubernaculum in males. This serves to anchor the fetal testis near the future inguinal canal as the abdominal cavity enlarges between 10 and 15 weeks. By comparison, the gubernaculum in females remains thin and subsequently develops into the round ligament (see below). The cranial attachment of the urogenital ridge, known as the cranial suspensory ligament, regresses in males under the action of androgens.

Descent of the ovary

The relative movements of the ovary are less extensive than those of the testis and are not hormonally regulated. Like the testis, the ovary ultimately reaches a lower level than it occupies in the early months of fetal life, but it does not leave the pelvis to enter the inguinal canal, except in certain anomalies. The ovary is connected to the medial aspect of the mesonephric fold by the mesovarium (homologous with the mesorchium), and to the ventral abdominal wall by the inguinal fold (Figs 78.13, 78.18). A mesenchymatous gubernaculum develops in this fold but, as it traverses the mesonephric fold, it acquires an additional attachment to the lateral margin of the uterus near the entrance of the uterine tube. Its lower part, caudal to this uterine attachment, becomes the round ligament of the uterus and the part cranial to this becomes the ovarian ligament. Collectively these structures are homologous with the gubernaculum testis in the male (Figs 78.17–78.19). This new uterine attachment may be correlated with the restricted ovarian descent. At first the ovary is attached to the medial side of the mesonephric fold but, in accordance with the manner in which the two mesonephric folds form the genital cord, it is finally connected to the posterior layer of the broad ligament of the uterus (Figs 78.3, 78.13, 78.14B). The gubernacula thus develop in the female, unlike the male, as bilateral fibrous bands or ligaments in the absence of Insl3. They do not extend into the labia majora, but end in the connective tissue just external to the external ring of the inguinal canal, because, in the absence of androgens, there is no migratory phase analogous to inguinoscrotal migration in the male. The saccus vaginalis is present in the female. Its prolongation into the inguinal canal (sometimes termed the canal of Nuck) is normally completely obliterated, but may remain patent and form the sac of a potential indirect inguinal hernia.

Fig. 78.18 Descent of the ovary. A, Early developing left ovary and uterine tube. B, Start of posterior movement of ovary. C, Left ovary in definitive posterior position. D, Sagittal section of the ligaments associated with the ovary viewed from a left lateral position.

(Redrawn from Tuchmann-Duplessis H, Haegel P 1972 Illustrated Human Embryology, Vol 2 Organogenesis. London: Chapman and Hall. With kind permission of Springer Science+Business Media.)

In the neonate the ovaries lie in the lower part of the iliac fossae. The long axis of the ovary is almost vertical. It becomes temporarily horizontal during descent, but regains the vertical when it reaches the ovarian fossa. The ovaries complete their descent into the ovarian fossae in early childhood. Thus, at birth the ovary and the lateral end of the corresponding uterine tube lie above the pelvic brim. They do not sink into the lesser pelvis until the latter enlarges sufficiently to contain both of them and the other pelvic viscera, including the bladder. The combined weight of the ovaries at birth is 0.3 g, which is relatively large, and much larger than the combined weight of the testes (Fig. 78.9; see Fig. 14.4). The ovaries double in weight during the first 6 postnatal weeks. They bear surface furrows, which disappear during the second and third postnatal months. All of the primary oocytes for the reproductive life of a female are present in her ovaries by the end of the first trimester of pregnancy. Of the 7,000,000 primary oocytes estimated to be present at the fifth month of gestation, 1,000,000 remain at birth, 40,000 by puberty, and only 400 are ovulated during reproductive life.

Pelvic floor

The pelvic floor consists of the ligamentous supports of the cervix, and the pelvic and urogenital diaphragms, and constitutes another partition that traverses the body cavity. Little is known about pelvic floor development in the human. The striated muscle is derived from the dermomyotomes in a similar manner to the muscles of the ventrolateral body wall. Puborectalis appears in 20–30 mm embryos, following opening of the anal membrane, and striated muscle fibres can be seen at 15 weeks. The smooth muscle of the urethral sphincter is also present at this time.

Urethra

The urethra is derived from endoderm, as are the prostate gland and vagina (both outgrowths of the lower urogenital sinus), and the other small glandular structures that develop around the caudal body orifices.

In the male, the prostatic urethra proximal to the orifice of the prostatic utricle is derived from the vesicourethral part of the cloaca and the incorporated caudal ends of the mesonephric ducts. The remainder of the prostatic part, the membranous part, and probably the part within the bulb, are all derived from the urogenital sinus. The anterior urethra, as far as the glans, is formed by canalisation of the urethral plate (see below). Secondary ingrowth of mesenchyme fuses the genital folds over the urethra (Fig. 78.20). The short section within the glans may be formed from ectoderm, which invaginates into the glans.

In the female, the urethra is derived entirely from the vesicourethral region of the cloaca, including the dorsal region derived from the mesonephric ducts. It is homologous with the part of the prostatic urethra proximal to the orifices of the prostatic utricle and the ejaculatory ducts. The region of the early urethra remains open to form the vestibule into which the definitive urethra and vagina open (Fig. 78.20). It is believed that these regions are invaded by ectoderm because they are innervated by somatic nerves.

Urethral defects caused by anomalous development are not uncommon in the male. In epispadias the urethra opens on the dorsal aspect of the penis at its junction with the anterior abdominal wall. This anomaly is considered to be a less severe form of exstrophy of the bladder. In the simplest form of hypospadias related to incomplete canalisation of the urethral plate, the urethra may open on the ventral (perineal) aspect of the penis at the base of the glans, and the part of the urethra that is normally within the glans is absent. In more severe cases the genital folds fail to fuse, and the urethra opens on the ventral aspect of a malformed penis just in front of the scrotum. A still greater degree of this malformation is accompanied by failure of the genital swellings to unite with each other. In these cases the scrotum is divided and, since the testes are also frequently undescended, the resemblance to the labia majora is very striking, leading to genital ambiguity. In such cases it is important to determine at the earliest time not only the chromosomal status of the infant but also the internal anatomy and state of development of the internal genital tract. Sex assignment and rearing will depend on these factors.

The urethral sphincter first forms as a mesenchymal condensation around the urethra in 12–15 mm (stage 18) embryos, after division of the cloaca. The mesenchyme proliferates and becomes defined at the bladder neck in 31 mm embryos, and along the anterior part of the urethra by 69 mm. The muscle fibres differentiate after 15 weeks’ development, at which time both smooth and striated fibres are present. In females there is continuity between the smooth muscle of the urethral wall and of the bladder. In males the muscle fibres are less abundant because of the local development of the prostate. Striated muscle fibres form around the smooth muscle initially in the anterior wall of the urethra and later encircle the smooth muscle layer. The origin of the striated muscle is not known: it could be derived from the myogenic cells that give rise to puborectalis. The smooth and striated components of the urethral sphincter are closely related, but there is no mixing of fibres as occurs in the anorectal sphincter.

Prostate gland

The prostate gland arises during the third month from interactions between the urogenital sinus mesenchyme and the endoderm of the proximal part of the urethra. Early outgrowths, some 14 to 20 in number, arise from the endoderm around the whole circumference of the tube, but mainly on its lateral aspects and excluding the dorsal wall above the utricular plate. They give rise to the outer glandular zone of the prostate. Later outgrowths from the dorsal wall above the mesonephric ducts arise from the epithelium of mixed urogenital, mesonephric and possibly paramesonephric, origin that covers the cranial end of the sinus tubercle. They produce the internal zone of glandular tissue. The outgrowths, which are at first solid, branch, become tubular and invade the surrounding mesenchyme. The latter differentiates into smooth muscle, associated blood and lymphatic vessels and connective tissue and is invaded by autonomic nerves.

Similar outgrowths occur in the female but remain rudimentary in the absence of androgenic stimulation. The urethral glands correspond to the mucosal glands around the upper part of the prostatic urethra, and the para-urethral glands correspond to the true prostatic glands of the external zone.

The bulbourethral glands in the male, and the greater vestibular glands in the female, arise as diverticula from the epithelial lining of the urogenital sinus.

External genitalia

Patterning of the external genitalia may be achieved by mechanisms similar to those that pattern the face and limb. In the cranial region neural crest mesenchyme makes an important contribution to the organization of the pharyngeal arches and the regions around the upper sphincters. Neural crest also arises from the tail-bud region, specifically from a population of cells termed the caudoneural hinge, which share the same molecular markers as the primitive node. The neural tube at this level is derived from a mesenchymal/epithelial transformation of caudoneural-hinge cells, which form a cylinder. Neural crest cells delaminate from the dorsal surface of the cylinder in a rostrocaudal direction. It is not known whether neuronal neural crest arising from secondary neurulation processes contributes to the caudal interface between endoderm and ectoderm.

The external genitalia, like the gonads, pass through an indifferent state before distinguishing sexual characters appear (Fig. 78.20). From stage 13, primordia of the external genitalia, composed of underlying proliferating mesenchyme covered with ectoderm, arise around the cloacal membrane, between the primitive umbilical cord and the caudal limit of the embryo. During stage 15 the cloacal membrane is divided by the urorectal septum into a cranial urogenital membrane and a caudal anal membrane (Figs 78.4, 78.14). Local ectodermal/mesenchymal interactions give rise to the anal sphincter, which will develop even without the presence of the anal canal. A surface elevation, the genital tubercle, appears at the cranial end of the urogenital membrane and two lateral ridges, the genital or urethral folds, form each side of the membrane (Fig. 78.20). The genital tubercle forms a distinct primordium, which will become the glans of either the penis or the clitoris. Elongation of the genital folds and urogenital membrane produces a primitive phallus. As this structure grows it is described as having a cranial surface analogous to the dorsum of the penis, and a caudal surface analogous to the perineal surface of both sexes. The urogenital sinus, contiguous with the internal aspect of the urogenital membrane, becomes attenuated within the elongating phallus forming the primitive urethra. The urogenital membrane breaks down at about stage 19, allowing communication of ectoderm and endoderm at the edges of the disrupted membrane and continuity of the urogenital sinus with the amniotic cavity. Urine can escape from the urinary tract from this time. The endodermal layer of the attenuated distal portion of the urogenital sinus, which is now displayed on the caudal aspect of the phallus, is termed the urethral plate. As mesenchyme proliferates within the genital folds, the urethral plate sinks into the body of the phallus forming a primary urethral groove. The genital folds meet proximally in a transverse ridge immediately ventral to the anal membrane.

While these changes are in progress two labioscrotal (genital) swellings appear, one on each side of the base of the phallus, and extend caudally, separated from the genital folds by distinct grooves (Figs 78.20, 78.21).

Fig. 78.21 Scanning electron micrographs of early human external genitalia. A, Indifferent stage in a human embryo estimated as 42 postovulatory days. B, A human female embryo at 12 weeks’ development. The genital folds are not fused. C, A human male embryo at 12 weeks. Fusion of the genital folds has occurred.

(Photographs by P Collins.)

As a general rule, epithelium, which can be touched easily and has a somatic innervation, is derived from ectoderm. In the buccal cavity and pharynx the ectoderm/endoderm zone is towards the posterior third of the tongue – touch here usually elicits the gag reflex. In the anal canal the outer portion, distal to the anal valves, is derived from ectoderm and has a somatic innervation, whereas the epithelium proximal to the valves is derived from endoderm and has an autonomic innervation.

Homologies of the parts of the urogenital system are shown in Table 78.1.