Medical Physiology, 3rd Edition

Differentiation of the Gonads

The primary sex organs of an individual are the gonads: testes in males and ovaries in females. During embryonic development, the gonads originate as bilateral swellings in the intermediate mesoderm (coelomic epithelium and the underlying urogenital mesenchyme) adjacent to the developing kidneys. Early on (approximately fifth week in humans; Fig. 53-4A), these gonadal ridges are identical in the two sexes and are referred to as the indifferent gonads (see Fig. 53-4B). They are composed of an outer cortex and an inner medulla (see Fig. 53-4C) and capable of becoming either testis (see Fig. 53-4D) or ovary (see Fig. 53-4E). The products of genes on the sex chromosomes determine whether each indifferent gonad differentiates into a testis or an ovary. Thus, genotypic sex determines gonadal sex.

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FIGURE 53-4 Early gonad and germ cell migration. A, The PGCs originate in the endodermal endothelium of the yolk sac. B, The PGCs migrate along the mesentery of the hindgut and reach the region of the urogenital ridge called the gonadal ridge. C, The indifferent gonad consists of an outer cortex and an inner medulla. D, The testis develops from the medulla of the indifferent gonad; the cortex regresses. E, The ovary develops from the cortex of the indifferent gonad; the medulla regresses.

Primordial germ cells migrate from the yolk sac to the primordial gonad

Germ cells—cells that give rise to gametes—play a key role in sexual differentiation by affecting gonad development. The primordial germ cells (PGCs) do not originate in the gonad; instead, they migrate to the gonad from the yolk sac along the mesentery of the hindgut at about the fifth week of embryo development (see Fig. 53-4A, B). The PGCs of humans are first found in the endodermal epithelium of the yolk sac in the vicinity of the allantoic stalk, and from there the germ cells migrate into the adjoining mesenchyme. During their journey they divide by mitosis. They eventually take up their position embedded in the gonadal ridges. Gonadal development fails to progress normally in the absence of germ cells. Thus, any event that interferes with germ cell migration may cause abnormal gonadal differentiation.

The gonad forms from a portion of the coelomic epithelium, the underlying mesenchyme, and the PGCs that migrate from the yolk sac. At 5 weeks' development, a thickened area of coelomic epithelium develops on the medial aspect of the urogenital ridge as a result of proliferation of both the coelomic epithelium and cells of the underlying mesenchyme. This prominence, which forms on the medial aspect of the mesonephros, is known as the gonadal ridge (see Fig. 53-4B, C).

Migration of the PGCs to the gonadal ridge establishes the anlagen for the primordial gonad. The primordial gonad at this early stage of development consists of both a peripheral cortex and a central medulla (see Fig. 53-4C) and has the capacity to develop into either an ovary or a testis. The cortex and medulla have different fates in males and females. The genotypic sex of the embryo directs the sexual development of the gonads. In an embryo with a 46,XY karyotype, the medullary portion of the gonad develops to become a testis and the cortex regresses. Conversely, 46,XX germ cells stimulate development of the cortex of the early gonad to become an ovary and the medulla regresses.

The primitive testis develops from the medulla of the primordial gonad

In male embryos, PGCs migrate from the cortex of the gonad, in which they were originally embedded, into the primitive sex cords of the medulla. There the PGCs induce maturation of primitive sex cord structures, which become hollowed out (see Fig. 53-4D) and develop into the seminiferous tubules, including the Sertoli cells. The PGCs also give rise to spermatogonia (see p. 1100), the first cells in the pathway to mature sperm. Remnants of the primitive sex cords also form the rete testis, a system of thin, interconnected tubules that develop in the dorsal part of the gonad; they drain the seminiferous tubules into the efferent ductules, which develop from the adjoining tubules of the mesonephros (see pp. 1079–1080). These tubular structures establish a pathway from the male gonad to the mesonephric duct, which evolves into the outlet for sperm. At the same time, the cortex regresses to form a thin epithelial layer covering the coelomic surface of the testis, and mesenchymal cells take up residence among the sex cords and eventually become the Leydig cells of the testis. At around the 10th week of development, the Leydig cells respond to fetal pituitary and placental hormones (mainly human chorionic gonadotropin; see p. 1111) by producing testosterone, which influences the differentiation of the external genitalia.

The main cell types within the seminiferous tubules are Sertoli cells and spermatogonia, which continue to divide by mitosis (albeit slowly) until puberty. At puberty the rate of spermatogonia division increases and a subgroup of spermatogonia begin meiosis and enter the process of spermatogenesis to produce mature sperm. A stem-cell population of spermatogonia is maintained by mitosis throughout the life of the male.

The primitive ovary develops from the cortex of the primordial gonad

In female embryos, the medulla of the gonad regresses, the primary sex cords are resorbed, and the interior of the gonad is filled with a loose mesenchyme that is highly permeated by blood vessels. However, the cortex greatly increases in thickness, due to the investment of mitotically dividing PGCs, which remain embedded within it and give rise to oogonia (see Fig. 53-4E). By the eighth week the developing ovaries contain around 600,000 oogonia and that number increases to 6 to 7 million by week 20. A large number of oogonia die and become resorbed; the remainder become surrounded by a single layer of granulosa cells to form primordial follicles and enter meiosis to become primary oocytes (see pp. 1120–1121). Unlike spermatogonia, the entire investment of oogonia (surviving PGCs) in the developing ovary is irreversibly committed to meiosis by the 20th week of development. At this stage, the oocytes are arrested at prophase I of meiosis and remain in that state until the follicle is selected for maturation or death later in life. At birth, each ovary holds around 1 million primordial follicles, each containing one primary oocyte arrested at prophase I. Because all the oogonia are depleted at midgestation (they either die or become oocytes), the number of primordial follicles formed at that time is all that will be available for reproduction for the rest of the female's life. This process is distinct from spermatogenesis, which occurs continually after puberty due to the replenishment of spermatogonia by mitosis.