Sexual Differentiation

Primordial components of both male and female reproductive tracts are present in early embryos of both sexes, and their development is either stimulated or suppressed by humoral factors arising in the testes. The indifferent gonads present in the early embryo differentiate into testes under the influence of the product of the sex determining gene SRY (for sex-determining region of the Y chromosome). By about the seventh week of embryonic life, the medulla of the primitive gonad becomes distinguishable as a testis with the appearance of cords of cells that give rise to seminiferous tubules. Leydig cells appear about 10 days later and undergo rapid proliferation for the next 6 to 8 weeks in response to chorionic gonadotropin, which is produced by the placenta in large amounts at this time, and perhaps also to LH secreted by the fetal pituitary gland. Fetal Leydig cells secrete sufficient testosterone to raise blood concentrations to the same levels as those seen in adult men. Testosterone accumulation is enhanced by an additional effect of the SRY gene product, which blocks expression of aromatase and thus prevents conversion of testosterone to estrogens.

Development of Internal Reproductive Ducts and Their Derivatives

Regardless of its genetic sex, the embryo has the potential to develop phenotypically either as male or female. The pattern for female development is expressed unless overridden by secretions of the fetal testis. The early embryo develops two sets of ducts that are the precursors of either male or female internal genitalia (Fig. 9). Seminal vesicles, epididymes, and vasa deferentia arise from primitive mesonephric, or wolffian, ducts. Internal genitalia of the female, including the uterus, fallopian tubes, and upper vagina, develop from paramesonephric, or Miillerian, ducts. When stimulated by testosterone, the wolffian ducts differentiate into male reproductive structures, but in the absence of androgen they regress and disappear. In contrast, Miillerian ducts develop into female reproductive structures unless actively suppressed. Testosterone does not stimulate mullerian regression. Under the influence of the SRY gene product and specific transcription factors, Sertoli cells in newly differentiated seminiferous tubules secrete a glycoprotein called vagina ovary

gonad mesonephros mullerian duct wolffian duct urogenital sinus fallopian tubes uterus gonad mesonephros mullerian duct wolffian duct ovary fallopian tubes uterus urogenital sinus vagina vas deferens seminal vesicle prostate epididymis testes vas deferens seminal vesicle prostate female male

FIGURE 9 Development of the male and female internal genitalia. (From Jaffe RB, In: Yen SC, Jaffe RB, Eds., Reproductive endocrinology, 2nd ed., Philadelphia: W.B. Saunders, 1986, p. 283. With permission.)

anti-mullerian hormone (AMH), which causes apoptosis of tubular epithelial cells and reabsorption of the Mullerian ducts. In experiments in which only one testis was removed from embryonic rabbits, the Mullerian duct regressed only on the side with the remaining gonad, indicating that anti-mullerian hormone must act locally as a paracrine factor. The wolffian duct regressed on the opposite side, suggesting that testosterone, too, must act locally to sustain the adjacent wolffian duct, as the amounts that reached the contralateral duct through the circulation were inadequate to prevent its regression (Fig. 10).

Sertoli cell production of AMH is not limited to the embryonic period but continues into adulthood. AMH is present in adult blood serum and in seminal plasma, where it binds to sperm and may increase their motility. Plasma concentrations of AMH are highest in the pre-pubertal period and fall as testosterone concentrations rise. Its secretion is stimulated by FSH and strongly inhibited by testosterone. In the testis, AMH inhibits Leydig cell differentiation and expression of steroidogenic enzymes, particularly P450c17. AMH is also expressed in the adult ovary and is found in the plasma of women as well as men. No extragonadal role for AMH in adults has yet been established.

AMH is a member of the transforming growth factor P (TGF-P) family of growth factors. As for other members of the TGF-P family, AMH signals by way of membrane receptors that have intrinsic enzymatic activity that catalyzes phosphorylation of proteins on serine and threonine residues. The AMH receptor consists of two non-identical subunits, each of which has a single membrane-spanning region and an intracellular kinase domain. Binding of AMH to its specific primary receptor causes it to complex with and phosphorylate a secondary signal-transducing subunit that may also be a component of receptors for other agonists of the TGF-P family. The activated receptor complex associates with and phosphorylates cytosolic proteins called Smads, which enter the nucleus and activate transcription of specific genes (Fig. 11).

Development of the External Genitalia

The urogenital sinus and genital tubercle are the primitive structures that give rise to the external genitalia in both sexes. Masculinization of these structures to form the penis, scrotum, and prostate gland depends on secretion of testosterone by the fetal testis. Unless stimulated by androgen, these structures develop into female external genitalia. When there is insufficient

indifferent stage

male differentiation female differentiation indifferent stage male differentiation female differentiation male or female bilateral early castrate male unilateral early castrate male or female bilateral early castrate male unilateral early castrate

FIGURE 10 Normal development of the male and female reproductive tracts. Tissues destined to form the male tract are shown in blue; tissues that develop into the female tract are shown in gray. Bilateral castration of either male or female embryos results in development of the female pattern. Early unilateral castration of male embryos results in development of the normal male duct system on the side with the remaining gonad, but female development on the contralateral side. This pattern develops because both testosterone and anti-miillerian hormone act as paracrine factors. (Modified from Jost A, In: Jones HW, Scott WW, Eds., Hermaphroditism, genital anomalies and related endocrine disorders, 2nd ed., Baltimore, MD: Williams & Wilkins, 1971, p. 16.)

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