The initial development of the embryonic ovary involves the migration of germ cells into the genital ridge from the yolk sac. These primordial germ cells populate sex cords that have formed in the cortical region of the embryonic gonad from the proliferation of cells from the coelomic epithelium (so-called germinal epithelium) of the genital ridge. The sex cords contribute cells, known initially as follicle cells and subsequently as granulosa cells, which immediately surround the oocyte. The mesenchyme of the genital ridge contributes cells that will become the theca. The entire structure is called a follicle, which includes oocyte, granulosa, and theca cells.

No direct connections are formed between the oocytes and the tubes destined to become the oviducts, which are derived from müllerian ducts. The final result is that oocytes are released through the surface of the ovary by rupture of tissue elements that surround the ovary; this process is called ovulation. A specialized end of the oviduct, the fimbria, develops to enable the oocyte to be removed efficiently from the surface of the ovary. In some animals, oocytes are funneled to the fimbria through the use of a bursa, which tends to encompass the ovary; oocytes are directed to a relatively small opening in the bursa.

The development of the embryonic testis is similar to that of the ovary: germ cells migrate into the genital ridge and populate sex cords that have formed from an invagination of the surface (coelomic) epithelium (Figure 35-1). Sertoli cells (male counterparts of granulosa cells) develop from the sex cords, and Leydig cells (male counterparts of thecal cells) develop from the mesenchyme of the genital ridge. One fundamental difference from ovarian development is that the invagination of the sex cords in the male continues into the medulla of the embryonic gonad, where connections are made with medullary cords from the mesonephros (primitive kidney). The duct of the mesonephros (wolffian duct) becomes the epididymis, vas deferens, and urethra, which has a direct connection to the seminiferous tubules. Thus, male germ cells pass to the exterior of the animal through a closed tubular system.

Sexual Orientation of the Genitalia and Brain Depends on the Presence or Absence of Testosterone

The development of the genital tubular system and the external genitalia (genital sexual differentiation) is under the control of the developing gonad. If the individual is female—that is, the developing gonad is an ovary—the müllerian duct develops into oviduct, uterus, cervix, and vagina, whereas the wolffian duct regresses; the absence of testosterone is important for both changes (Figure 35-2). If the individual is male, the rete testis produces müllerian-inhibiting factor, which causes regression of the müllerian ducts. The wolffian duct is maintained in the male because of the influence of androgens produced by the testis. To summarize, the müllerian ducts are permanent structures, and the wolffian ducts are temporary structures unless acted on by the presence of male hormones. The presence of an enzyme, 5α-reductase, is important for the effect of the androgens because testosterone must be converted intracellularly into dihydrotestosterone for masculinization of the tissues to occur. The use of synthetic 5α-reductase inhibitors for the treatment of benign prostatic disease in humans is contraindicated without concurrent birth control measures, because drug levels in semen deposited in the female can lead to disorders of sexual development in male fetuses.

Development of the external genitalia follows the development and direction of the gonads. If the individual’s genotype is female, folds of tissue called labia form the vulva, and a clitoris develops. If the individual is male, androgens from the testis direct formation of the penis (male counterpart of the clitoris) and the scrotum (male counterpart of the labia). Again, the absence or presence of androgens is an important factor influencing the formation of external genitalia.

The final organization of the individual with regard to gender comes with sexual differentiation of the hypothalamus. Exposure of the hypothalamus to androgens at about the time of birth causes the hypothalamus to be organized as male. A paradoxical finding is that conversion (aromatization) of androgens to estrogens is essential for maleness, mediated by enzymes in the neural tissue. In the absence of androgens, the hypothalamus is organized as female.

The fundamental concept of organization of the reproductive system with regard to genotype is that the female system is organized in the absence of testes. If the individual is to be male, there must be active intervention by the testes through the production of androgens and appropriate tissue enzymes in two circumstances: (1) within the internal genitalia for conversion to more potent androgens, and (2) within the hypothalamus for conversion to estrogens.

Gonadal activity is under the control of both the hypothalamus and the anterior pituitary gland (Figure 35-3). The hypothalamus lies near the ventral midline of the diencephalon. It is divided into halves by the third ventricle and actually forms the ventral and lateral walls of the third ventricle. The hypothalamus has clusters of neurons, collectively called nuclei, which secrete peptide hormones important for controlling pituitary activity. As described in more detail later, these peptides move to the pituitary either directly by passage through the axons of neurons or by a vascular portal system. The pituitary responds to the hypothalamic peptides to produce hormones that are important for the control of the gonads.