DEVELOPMENT OF THE GENITOURINARY SYSTEM

The genitourinary system begins to take form from intermediate mesoderm in the third week of gestation. At this point, the embryo is a bilaminar disk composed of external ectoderm and internal endoderm. The longitudinal growth of the embryo begins to exceed its transverse growth, such that the resulting tension induces folding of the cranial and caudal ends toward one another around the umbilical stalk. This folding brings the cloacal membrane (a bilaminar membrane in the caudal portion of the embryo, distal to the allantois) ventrally. The endoderm-lined yolk sac dilates, and the cloaca forms.

The cloaca ultimately is divided into the anterior urogenital sinus and the posterior rectum (Fig. 1-1), although the mechanism is debated. It was once believed that urorectal folds on either side of the midline grew caudomedially to fuse with the cloacal membrane and divide the cloacal membrane into the urogenital sinus and the dorsal rectum by week 7. Subsequent regression of the tail then rotated the urogenital sinus and rectum dorsally. Some investigators^3,⁴ have suggested that the urorectal septum may not exist or may not fuse with the cloacal membrane.

Figure 1-1 Development of the lower urinary tract. At 4 weeks, the cloaca is divided by a septum into an anterior urogenital sinus and posterior rectum. The mesonephric duct already joins the anterior portion of the cloaca, and the ureteral bud has started to develop at the bend of the mesonephric duct as it turns forward and medially to join the urogenital sinus. At 6 weeks, the urorectal septum progressively separates the urogenital sinus anteriorly from the rectum posteriorly. By week 7, the separation is complete, and the ureter and the mesonephric duct acquire separate openings in the urogenital sinus. After the 12th week, the ureter starts its upward and lateral movement as the mesonephric duct moves downward and medially. Tissue absorbed in between forms the trigone.

The development of the urinary tracts and portions of the genital system is induced by the mesonephric and paramesonephric (müllerian) ducts. Both ductal systems grow toward the urogenital sinus; the mesonephric ducts grow medially, whereas the müllerian ducts have already fused into a single midline structure. Fusion of the wolffian ducts with the cloaca occurs by the middle of the fourth week (day 24). The junction of the müllerian ducts and the urogenital sinus is a central embryologic location called Müller’s tubercle. The mesonephric ducts bend laterally; at this bend, a ureteric bud forms. The portion of the mesonephric duct between the urogenital sinus and the ureteric bud is called the common nephric duct, and by day 33, it is absorbed into the urogenital sinus, providing an island of mesoderm in the otherwise endoderm-based urogenital sinus (Fig. 1-2). This mesodermal island expands laterally to become the trigone of the bladder. The location of the ureteric bud relative to the urogenital sinus determines whether the ureteral orifices will be orthotopic; a ureteric bud that originates on a short, common nephric duct will be incorporated sooner into the bladder, with resultant lateral displacement of the ureteral orifices. The intramural ureteral tunnel predisposes to vesicoureteral reflux. Conversely, ureteric buds that are located a great distance from the urogenital sinus will be incorporated into the urogenital sinus later and may be associated with ectopic drainage into surrounding structures.

Figure 1-2 The lower end of the mesonephric duct as it joins the anterior division of the cloaca. Notice that the common nephric duct is progressively absorbed into the urogenital sinus. By week 7, the ureter and the mesonephric duct have separate openings, and rotation takes place. The ureter moves upward and laterally, and the mesonephric duct moves downward and medially, expanding the absorbed tissue to form the trigonal structure.

The ureteric bud continues to grow craniolaterally while the mesonephric duct (distal to the bifurcation of the common nephric duct into the mesonephric duct and ureteric bud) grows caudomedially. The ureter undergoes a process of obstruction during the sixth week (37 to 40 days) and then is recanalized from the central portion to the cranial and caudal limits. Incomplete recanalization at either end may account for obstruction at the ureteropelvic junction or at the ureterovesical junction, where a thin transient membrane (i.e., Chwalla’s membrane) may fail to dissolve. The cuboidal epithelium of the immature ureter evolves to a lining of transitional cells by 14 weeks.⁵

The urogenital sinus expands caudally to form the bladder and gives rise to the posterior urethra in males or the entire urethra and distal third of the vagina in females. The cranial portion of the urogenital sinus tapers during the third month of gestation so that the allantois forms the urachus and the saccular bladder remains in place. The intramural bladder wall develops throughout the remainder of gestation, with collagen formation beginning in the lamina propria and with subsequent intercalation between intramural muscle fibers. Intramural muscle fibers form as perivesical splanchnic mesoderm matures after induction by epithelial-mesenchymal interactions. Compliance of the fetal bladder increases over time in human fetuses and in animal models.^6,⁷ Koo and colleagues⁷ showed a decreasing ratio of type 3 to type 1 collagen in the fetal bovine bladder; the changing ratios of perivesical collagen and muscle likely account for at least a portion of this evolution.

Renal and Ureteral Development

The renal excretory unit is the result of a complex developmental process influenced by reciprocal induction of mesenchyme and the ureteric bud and by many molecular events. The kidney develops in three stages. The first is the pronephros, which arises late in the third week in the cranial portion of the embryo. Pronephric tubules develop cranially and extend caudally, but they degenerate quickly, and the pronephros is obliterated by the start of the fifth week. By day 24, mesonephric ducts are present at the ninth and tenth somites. These ducts grow caudally to the cloacal membrane by day 28, fuse in the midline, and eventually form the bladder. Caudal canalization and then cranial canalization follows. The mesonephros, unlike its predecessor, is able to accomplish limited excretory function for the growing embryo. Mesonephric tubules along the medial nephrogenic cords form and dissolve, sequentially disappearing by the fourth month of development to leave only remnants. Some tubules develop lumens and vesicles and twist into an S shape, in which the lateral portion becomes the mesonephric duct and the medial portion surrounds capillaries originating in the aorta and forms a primitive renal corpuscle. Cranially, the tubules form efferent ductules. The mesonephric ducts give rise to the epididymis and vas deferens, and in females, remnants persist as the paroöphoron and epoöphoron, which are vestigial mesosalpingeal structures.

The metanephros gives rise to the fetal kidney. It forms in the sacral region as the ureteric buds arise from the mesonephric ducts. As the ureteric buds grow cranially, they encounter metanephric mesenchyme on about day 28. After the ureteric bud contacts the mesenchyme, release of many factors culminates in reciprocal induction of growth factors governing the development of the metanephric system. The ureteric bud divides repeatedly between weeks 6 and 32 of development, ultimately giving rise to the collecting system: the collecting ducts, calyces, renal pelvis, and ureter. The metanephric mesenchyme gives rise to the parenchymal portions of the kidney that perform filtration and clearance: the glomeruli, proximal and distal tubules, and loop of Henle. Because of the lengthy period during which branching of the ureteral bud occurs, the growth of the metanephric mesenchyme that will give rise to renal parenchyma is not uniform; nephrons at the juxtamedullary region are formed earlier and mature sooner than nephrons in more peripheral locations. Nephrons undergo four defined stages of development in the human. Stage I occurs when the metanephric mesenchyme is fully discrete from the ureteral bud. Stage II begins when the S-shaped nephron connects with the ureteral bud. In stage III, an ovoid structure emerges, and in stage IV, a round glomerulus is seen. Most nephrons in humans are stage IV at birth, although maturation is completed fully in the early postnatal period.⁵

As the kidneys grow, their location in the embryo becomes progressively more cranial; this is likely caused by active growth of the kidney parenchyma and by increased differential growth of the caudal portion of the embryo. As a result, the kidneys ascend from their initial pelvic location to the upper retroperitoneum. As renal ascent proceeds, new blood vessels are generated cranially, and the more caudal blood vessels break down. In postnatal patients with renal ectopia, the renal blood supply is typically anomalous because angiogenesis is arrested when renal ascent ceases. The possibility of an aberrant blood supply should be considered in any patient with renal ectopia.

Formation of the Urogenital Sinus and External Genitalia

With dissolution of the tail and further development of the lower abdominal wall, the cloaca returns to a more dorsal position, and mesodermal proliferation in the fifth week forms genital tubercles. These tubercles ultimately fuse in the midline to form the phallus or clitoris. The urogenital sinus remains at the base of the tubercles; the folds of the urogenital sinus ultimately fuse in the male to form the penile urethra and widen in the female to form the vaginal vestibule and the discrete labia minora. The endodermally derived urethral groove develops from the urogenital sinus in the sixth week, and the urethral plate (a deepening of this groove) forms shortly thereafter. Male and female embryos remain morphologically identical until approximately 12 weeks’ gestation.

Abnormalities of the Urogenital Sinus

Bladder exstrophy occurs in approximately 1 of 30,000 births and is seven times more likely in children conceived through in vitro fertilization.⁸ This disorder is characterized by early rupture of the cloacal membrane, which is sometimes related to an intrinsic defect in the membrane. It is more common in males than in females by a ratio of approximately 2:1 to 6:1,⁹ and it is related to epispadias and to cloacal exstrophy. The latter condition is also associated with early rupture of the cloacal membrane, although it occurs much less commonly (1 in 200,000 to 400,000 births¹⁰). Although no genes associated with either condition have been definitively identified, the risk of bladder exstrophy is substantially greater with an affected relative (1 in 275) or an affected parent (1 in 70).⁹ Mesenchymal ingrowth between the ecto-dermal and endodermal layers of the cloacal membrane ultimately results in formation of the lower anterior abdominal wall and division of the cloaca into the anterior urogenital sinus and posterior rectum. Both disorders are associated with malformations of other organ systems, including the limbs, lower anterior abdominal wall, pelvic girdle, and in the case of cloacal exstrophy, the hindgut. Management of these conditions remains challenging.

Gonadal Development

Development of the testes and ovaries is initiated in the fifth week of gestation, when germ cells from the yolk sac migrate to the posterior body wall, inducing formation of the urogenital ridge medial to the mesonephros (Fig. 1-3). Invasion of the adjacent mesenchyme in the sixth week creates a primitive gonad with epithelium and blastema; the latter is formed from loosened epithelial cells. Persistent growth of the germinal epithelium into the adjacent mesenchyme forms cords that ultimately branch many times and form seminiferous tubules.

Figure 1-3 The undifferentiated sexual structures early in embryonic life (eighth week) grow and differentiate into female or male forms. The representative segments and their future course (depending on sexual differentiation) are illustrated.

(From Tanagho EA: Embryology of the genitourinary system. In Tanagho EA, McAninch JW [eds]: General Urology, 14th ed. Norwalk, CT, Appleton & Lange, 1995.)

Initially, all embryos have the potential to become male or female; the development of internal or external genitalia is an event influenced by genetic, endocrine, and paracrine factors. SRY, a gene on the short arm of the Y chromosome, induces formation of the Sertoli and Leydig cells. It also induces secretion of anti-müllerian hormone (AMH), formerly called müllerian-inhibiting substance (MIS), which induces regression of the müllerian system between 8 and 10 weeks’ gestation.⁵

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