Phenotypic Sex Differentiation
Unlike the bipotential gonads and external genitalia, the male and female internal genitalia arise from separate duct systems (Fig. 6.1). Development of these structures occurs in parallel and in close physical proximity with the developing urinary system. Both begin to occur at about 4 embryonic (6 menstrual) weeks. The primordial kidney (mesonephros) is composed of tubules and a duct known as the mes- onephric or Wolffian duct. The Wolffian duct grows out from the tubules toward the urogenital sinus. The mesonephric tubules make contact with the primitive sex cords just as the gonad begins to differentiate. Simultaneously, an inpocketing of the coelomic epithelium near the lateral edge of the mesonephric ridge forms the paramesonephric or Müllerian duct. As kidney development proceeds (metanephric stage), the mesonephric structures will become totally incorporated into the reproductive tract and lose their urinary function. The Wolffian and Müllerian ducts are primordia for the internal organs of reproduction in the male and female, respectively. In each sex, the other duct system typically disappears by the 3rd fetal month, leaving behind vestiges that are usually unimportant clinically.
In the normal male embryo, the secretion of a peptide called Müllerian-inhibiting substance (MIS; also known as anti-Mullerian hormone or AMH) occurs under the direction of sex-determining region of the Y chromosome (SRY). MIS is secreted by cells that will become Sertoli cells in the adult testis. MIS causes the Müllerian duct to degenerate. Testosterone is produced by those testicular cells des- tined to become Leydig cells in the adult. Testosterone directs development of the Wolffian duct system to form the epididymis, vas deferens and seminal vesicles. In contrast to the adult, testosterone production by the embryonic testes is controlled not by the hypothalamic-pituitary system, but by the placental hormone human chorionic gonadotropin (hCG).
The absence of MIS in the female embryo permits the Müllerian system to persist. Upon reaching the urogenital sinus, the Müllerian ducts induce the formation of a vaginal plate. Contact of the Müllerian ducts with the vaginal plate also initiates the fusion of the ducts to form the body of the uterus. The Müllerian ducts will form the fallopian tubes, uterus and the upper portion of the vagina. Failure of the Müllerian ducts to develop or fuse completely can cause uterine and cervical anomalies. In the absence of testosterone, the Wolffian system regresses. A vestige of the Wolffian duct, known as Gartner’s duct, persists in its length from the ovary to the hymen. Clinically apparent cysts may form anywhere along Gartner’s duct.
Most of the prostate gland develops from the same primordial area of the urogenital sinus that forms the vaginal plate in the female, making the prostate a homolog of the upper vagina. Mesenchyme in this tissue differentiates into the peripheral zone of the prostate, under the influence of dihydrotestosterone (DHT). In the presence of a functional fetal testis, DHT is produced locally from testosterone by the enzyme 5α-reductase. The more central tissue in this area, which may be of Wolffian derivation, forms the central and transition zones of the prostate. Cancers of the prostate are most likely to arise from the peripheral zone (Chapter 41).
Like the primordial gonads, the anlagen of the external genitalia are bipotential. In the 8th embryonic (10th menstrual) week, a urogenital slit, a genital tubercle, two lateral genital folds and two labioscrotal swellings become apparent as precursors to the external genitalia (Fig. 6.2).
While differentiation of the internal Wolffian duct system is testosterone dependent, the primordial external genital structures require the presence of DHT to differentiate into recognizably male structures. The source of the DHT is testicular testosterone, converted locally to DHT in the primordial external genitalia. In the presence of DHT, the lobes of the prostate gland grow out from the seminal colliculus where the urethra is developing from the bladder. The genital folds fuse to form the penis around the elongating urethra. The labioscrotal swellings enlarge and fuse to form the scrotum.
Descent of the testes from the abdomen into the scrotum is an androgen-dependent event during which the testes are pulled down- ward by a fibrous cord anchored to the developing scrotum – the gubernaculum. During development, a peritoneal fold around the Wolffian and Müllerian ducts (destined to eventually become the tunica vaginalis) connects to the genital swelling, and the gubernaculum forms as a ridge under the peritoneum. The gubernaculum connecting the testis to the genital swelling does not grow as rapidly as the remainder of the embryo and hence each testis is progressively pulled down toward the developing scrotum. The testes sit just above the inguinal ring until the last 3 months of pregnancy, at which time they complete their descent through the inguinal canal into the scrotum. After full descent of the testes, the inguinal canal narrows, thereby preventing abdominal contents from herniating into the scrotum. Unlike differentiation of the external and internal genitalia that relies on placental hCG stimulation of testicular androgen production, testicular descent requires fetal gonadotropins. Disruptions in the fetal hypothalamic–pituitary–testicular axis result in failure of the testes to descend properly (cryptorchidism).
In the female, the folds of the urogenital slit remain open. The posterior aspect of the urogenital sinus forms the lower two-thirds of the vagina and the anterior aspect forms the urethra. The lateral genital folds form the labia minora and the labioscrotal swellings form the labia majora. The clitoris forms above the urethra. The gubernaculum that forms between the edge of the Müllerian duct and the ovary becomes secondarily attached to the cornua of the uterus as it differentiates. The gubernaculum in the female becomes the ovarian and round ligaments. Female phenotypic differentiation occurs in the absence of androgen and is not dependent on an ovary.
Exposure to specific androgens beginning in the 5th embryonic (7th menstrual) week of pregnancy is critical to the development of a recognizable newborn male phenotype. Fetuses exposed to endogenous or exogenous DHT at this time will undergo male differentiation, regardless of the genetic or gonadal sex. Lack of androgen activity will result in a female phenotype.