Medical Physiology, 3rd Edition

Development of the Accessory Sex Organs

The embryonic gonad determines the development of the internal genitalia and the external sexual phenotype

Higher vertebrates, including humans, have evolved elaborate systems of glands and ducts—collectively referred to as the accessory sex organs—for storing and transporting gametes. Together the gonads and accessory sex organs constitute the primary sex characteristics. The accessory sex organs can be divided into the external and internal components. In males the external organs are the penis and scrotum. Although they are outside the abdominal cavity, the testicles, contained in the scrotum, are usually considered internal organs. Other internal organs are the epididymis, vas deferens, seminal vesicles, ejaculatory ducts, prostate, and bulbourethral glands. In females the external organs include the vulva, labia, and clitoris; the internal organs are the vagina, uterus, and fallopian tubes.

Secondary sex characteristics are external specializations that are not essential for the production and movement of gametes; instead, they are primarily concerned with sex behavior and with the birth and nutrition of offspring. Examples include pubic hair and breasts. Not only do the sex steroids produced by the gonads affect the accessory sex organs, they also modulate the physiological state of the secondary sex characteristics toward “maleness” in the case of the testes and “femaleness” in the case of the ovaries.

Embryos of both sexes have a double set of embryonic genital ducts

The internal genital ducts and accessory sex organs are derived from embryonic duct systems—the wolffian ducts (or mesonephric ducts) and the müllerian ducts (or paramesonephric ducts)—and the urogenital sinus (Fig. 53-5A). The genital ducts are an essential part of the genital organs and form the pathway by which the sex cells—ova and spermatozoa—move to the location of fertilization.

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FIGURE 53-5 Transformation of the genital ducts. A, At the time that the gonad is still indifferent, it is closely associated with the mesonephros as well as the excretory duct (mesonephric or wolffian duct) that leads from the mesonephros to the urogenital sinus. Parallel to the wolffian ducts are the paramesonephric or müllerian ducts, which merge caudally to form the uterovaginal primordium. B, In males, the mesonephros develops into the epididymis. The wolffian duct develops into the vas deferens, seminal vesicles, and ejaculatory duct. The müllerian ducts degenerate. C, In females, the mesonephros as well as the wolffian (mesonephric) ducts degenerate. The paramesonephric or müllerian ducts develop into the fallopian tubes, the uterus, the cervix, and the upper one third of the vagina.

It is worth recalling that during mammalian embryogenesis, three sets of kidneys develop, two of which are transient. The pronephric kidney, which develops first, is so rudimentary that it never functions. However, the duct that connects the pronephric kidney to the urogenital sinus—the pronephric duct—eventually serves the same purpose for the second kidney, the mesonephric kidney or mesonephros, as it develops embryologically. Unlike the pronephric kidney, the mesonephros functions transiently as a kidney. It has glomeruli and renal tubules; these tubules empty into the wolffian duct (see Fig. 53-5A), which in turn carry fluid to the urogenital sinus. As discussed below, the mesonephros and its wolffian ducts will—depending on the sex of the developing embryo—either degenerate or develop into other reproductive structures. In addition to the wolffian ducts, a second pair of genital ducts, the müllerian ducts, will develop as invaginations of the coelomic epithelium on the lateral aspects of the mesonephros. The müllerian ducts run caudally and parallel to the wolffian ducts. In the caudal region, they cross ventral to the wolffian ducts and fuse to form a cylindrical structure, the uterovaginal canal. The third or metanephric kidney becomes the permanent mammalian kidney. Its excretory duct is the ureter. Early in development (<7 weeks) embryos of both sexes have wolffian and müllerian ducts (see Fig. 53-4C and Fig. 53-5A). However, later in gestation (by the 10th week) only one of the duct systems survives in each sex: wolffian ducts in males and müllerian ducts in females.

In males, the wolffian ducts become the epididymis, vas deferens, seminal vesicles, and ejaculatory duct

During development, the mesonephros ceases to be an excretory organ in both sexes and disappears entirely in females. As the mesonephros degenerates in males, caudal mesonephric tubules develop into many parallel efferent ductules that connect the upstream rete testis to the head of the epididymis, which serves as a reservoir for sperm.

In male embryos, the müllerian ducts regress and the wolffian ducts develop into the channels through which the spermatozoa pass from the testis to the urethra (see Fig. 53-5B). The most proximal portion of the wolffian duct becomes the head, the body, and the tail of the epididymis. The tail of the epididymis connects to the vas deferens, which also arises from the wolffian duct. A lateral outgrowth from the distal end of the mesonephric duct forms the seminal vesicle. The portion of the mesonephric duct between the seminal vesicle and the point where the mesonephric duct joins the urethra becomes the ejaculatory duct. At about the level where the ejaculatory duct joins with the urethra, multiple outgrowths of the urethra grow into the underlying mesenchyme and form the prostate gland. The mesenchyme of the prostate gives rise to the stroma of the prostate, whereas the prostatic glands develop from endodermal cells of the prostatic urethra.

In females, the müllerian ducts become the fallopian tubes, the uterus, and the upper third of the vagina

In female embryos, the mesonephros and the wolffian ducts degenerate. The müllerian ducts persist and establish three functional regions (see Fig. 53-5C). The cranial portions of the müllerian ducts remain separate and give rise to the fallopian tubes. The upper end of the duct develops a fringe, which will become the fimbriae, by adding a series of minor pits or müllerian tunnels. The midportions of the left and right müllerian ducts fuse and give rise to the fundus and corpus of the uterus. The most distal portions of the fused bilateral müllerian ducts form the uterovaginal primordium that gives rise to the cervix and the upper third of the vagina. The lower two thirds of the vagina and external female genitalia are derived from the urogenital sinus.

In males, development of the wolffian ducts requires testosterone

As already noted, the developing embryo has two precursor duct systems (Fig. 53-6A). In a normal male embryo (see Fig. 53-6B), the wolffian ducts develop whereas the müllerian ducts regress. In a normal female embryo (see Fig. 53-6C), the müllerian ducts develop whereas the wolffian ducts regress. It appears that maturation of one of these systems and degeneration of the other depend on local factors produced by the developing gonad.

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FIGURE 53-6 Jost experiments. A, Very early in development, both the wolffian (mesonephric) and the müllerian (paramesonephric) ducts are present in parallel. B, In the normal male, the wolffian duct develops into the vas deferens, the seminal vesicles, and the ejaculatory duct. The müllerian ducts degenerate. C, In the normal female, the müllerian ducts develop into the fallopian tubes, the uterus, the cervix, and the upper one third of the vagina. The wolffian ducts degenerate. D, Bilateral removal of the testes deprives the embryo of both antimüllerian hormone (AMH) and testosterone. Absence of AMH causes the müllerian ducts to follow the female pattern of development. In the absence of testosterone, the wolffian ducts degenerate. Thus, the genetically male fetus develops female internal and external genitalia. E, After bilateral removal of the ovaries, müllerian development continues along normal female lines. Thus, the ovary is not required for female duct development. F, Unilateral removal of a testis results in female duct development on the same (ipsilateral) side as the castration. Duct development follows the male pattern on the side with the remaining testis. Virilization of the external genitalia proceeds normally. G, In the absence of both testes, administering testosterone preserves development of the wolffian ducts. However, because of the absence of AMH, there is no müllerian regression. H, In the presence of both ovaries, administration of testosterone promotes development of the wolffian ducts. Because there are no testes—and thus no AMH—the müllerian ducts develop normally.

A classic series of experiments performed by Alfred Jost in 1953 revealed that male sexual differentiation requires factors produced by fetal testicular tissue. The experimental approach was to castrate rabbit fetuses at various stages of development and allow the pregnancies to continue. Castrating a male fetus before maturation of the wolffian ducts causes the wolffian ducts to regress and the müllerian ducts to persist (i.e., fail to regress), which induces the development of female internal and external genitalia (see Fig. 53-6D). However, castrating female fetuses at a comparable stage in development has no appreciable effect, and müllerian development continues along normal female lines (see Fig. 53-6E). Thus, although normal male development requires the testes, development of the fallopian tubes and uterus does not require the ovaries.

Unilateral removal of the testis resulted in female duct development on the same (ipsilateral) side as the castration, but virilization of the external genitalia proceeded normally (see Fig. 53-6F). Removing both testes—and administering testosterone—resulted in essentially normal development of the wolffian ducts, but no müllerian regression was seen (see Fig. 53-6G). Thus, although testosterone can support wolffian development, it is unable to cause müllerian regression. It became clear that a testicular product other than testosterone is necessary for regression of the müllerian ducts. Thus, one would predict that treating a normal female with testosterone would lead to preservation of the wolffian ducts, as well as the müllerian ducts. This pattern of dual ducts is indeed observed (see Fig. 53-6H).

In males, antimüllerian hormone causes regression of the müllerian ducts

After Jost, other investigators performed experiments indicating that the Sertoli cells of the testis produce a nonsteroid macromolecule—antimüllerian hormone (AMH) or müllerian-inhibiting substance (MIS)—that causes müllerian degeneration in the male fetus. AMH, a growth-inhibitory glycoprotein, is a member of the transforming growth factor-β (TGF-β) superfamily of glycoproteins involved in the regulation of growth and differentiation (see p. 68). Besides TGF-β, this gene superfamily includes the inhibins and activins, which also play key regulatory roles in the reproductive system (see pp. 1095 and 1113–1115). The proteins produced by this gene family are all synthesized as dimeric precursors and undergo post-translational processing for activation. AMH is glycosylated and is secreted as a 140-kDa dimer consisting of two identical disulfide-linked subunits. The antimitogenic activity and müllerian duct bioactivity of AMH reside primarily in its C-terminal domain.

The human AMH gene is located on chromosome 19, and AMH is one of the earliest sexually dimorphic genes expressed during development. The transcription factor SRY, which represents the TDF, may be involved in initiating the transcription of AMH. The sequential timing of SRY and AMH expression is consistent with activation of AMH by SRY, a series of events that may control sexual dimorphism.

Although the exact mechanism of AMH action has not been completely clarified, it is thought to involve receptor-mediated dephosphorylation. AMH appears to act directly on mesenchymal cells of the müllerian duct and indirectly, through the mesenchyme, on müllerian duct epithelial cells. AMH binding has been localized to the mesenchymal cells surrounding the müllerian duct and to the developing oocytes in preantral follicles.

During embryogenesis in males, AMH—which is secreted by the Sertoli cells in the testis—causes involution of the müllerian ducts, whereas testosterone—which is secreted by the Leydig cells of the testis—stimulates differentiation of the wolffian ducts. In females, the müllerian ducts differentiate spontaneously in the absence of AMH, and the wolffian ducts involute spontaneously in the absence of testosterone.