DEVELOPMENT OF THE GONADS

We start Chapter 21 by reviewing the major developmental steps of the gonads and excurrent (efferent) ducts. This review will lead us to an understanding of the histology, function, and clinical significance of the pathway followed by male and female gametes in the pursuit of fertilization.

An important aspect to keep in mind is that the cell precursors of both gametes have an extra-embryonic origin. Primordial germinal cells (PGCs) appear first in the endoderm of the yolk sac wall in the 4-week fetus (Figure 21-1).

Figure 21-1 Migration of primordial germinal cells from the yolk sac to the gonadal ridges

Between 4 and 6 weeks, about 10 to 100 primordial germ cells migrate by ameboid movements from the yolk sac to the gut tube and from there to the right and left sides of the dorsal body wall through the mesentery.

The migration and proliferation of primordial germinal cells are dependent on the interaction of the c-kit receptor, a tyrosine kinase, with its corresponding cell membrane ligand, stem cell factor (or c-kit ligand). Both the c-kit receptor and stem cell factor are produced by primordial germinal cells along their migration route.

A lack of the c-kit receptor or stem cell factor results in gonads deficient in primordial germ cells. Hematopoiesis and the development of melanocytes and mast cells depend on the c-kit receptor and its ligand.

About 2500 to 5000 primordial germinal cells lodge in the mesenchyme and induce cells of the mesonephros and lining coelomic epithelium to proliferate, forming a pair of gonadal ridges. Coelomic epithelial cords grow into the mesenchyme of the gonadal ridge to form an outer cortex and inner medulla of the indifferent gonad.

Role of the anti-müllerian hormone and testosterone in the development of male and female internal genitalia

The fetal testis is formed by testicular cords connected to the rete testis by tubuli recti. The cords are formed by Sertoli cells, derived from the coelomic epithelium, and prespermatogonia (also called gonocytes), derived from primordial germinal cells. Leydig cells, derived from the mesonephric mesenchyme, are present between the testicular cords.

Fetal Sertoli cells secrete anti-müllerian hormone (AMH), which prevents müllerian ducts (also called paramesonephric ducts) from developing into the uterovaginal primordium (Figure 21-2). In the absence of AMH, the müllerian ducts persist and become the female internal genitalia.

Figure 21-2 Transformation of the indifferent gonad into the testis

By 8 weeks of gestation, fetal Leydig cells produce testosterone, which is regulated by placental human chorionic gonadotropin (hCG), because the fetal hypophysis is not secreting luteinizing hormone (LH).

The cephalic end of the wolffian ducts (also called mesonephric ducts) forms the epididymis, vas deferens, and ejaculatory duct. A diverticulum of the vas deferens forms the seminal vesicles.

The prostate gland and urethra develop from the urogenital sinus. The prostate gland has a dual origin: the glandular epithelium forms from outgrowths of the prostatic urethral endoderm; the stroma and smooth muscle derive from the surrounding mesoderm.

In the absence of androgen, the wolffian duct regresses and the prostate fails to develop. If high levels of androgen are present in the female fetus, both müllerian and wolffian ducts can persist (see Box 21-A).

Box 21-A Development of internal genitalia

• When Sertoli cell-derived AMH is not present, the müllerian ducts become the fallopian tubes (oviducts), uterus, cervix, and upper one third of the vagina.

• When Leydig cell-derived testosterone is present, the wolffian ducts become the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts.

• When 5-α reductase is present, testosterone is converted into dihydrotestosterone (DHT). DHT induces the genital tubercle, genital fold, genital swelling, and urogenital sinus to become the penis, scrotum, and prostate.

• When DHT is not present, the genital tubercle, genital fold, genital swelling, and urogenital sinus become the labia majora, labia minora, clitoris, and lower two thirds of the vagina.

SPERM MATURATION PATHWAY

After transport to the rete testis through a connecting tubulus rectus (Figure 21-3), sperm enter the ductuli efferentes. Ductuli efferentes link the rete testis to the initial segment of the epididymal duct, an irregularly coiled duct extending to the ductus, or vas deferens.

Figure 21-3 Sperm transport from testis to rete testis via straight tubules

Tubuli recti (straight tubules) are located in the mediastinum of the testis. They are lined by a simple cuboidal epithelium with structural features similar to those of Sertoli cells except that occluding junctions are now at the apical domain, instead of at the basal domain. Spermatogenic cells are not present.

The rete testis consists of irregularly anastomosing channels within the mediastinum of the testis (Figure 21-4). These channels are lined by a simple cuboidal epithelium. The wall, formed by fibroblasts and myoid cells, is surrounded by large lymphatic channels and blood vessels associated with large clusters of Leydig cells.

Figure 21-4 Sperm transport and fluid reabsorption in the efferent ductule and proximal epididymis

About 12 to 20 ductuli efferentes (efferent ductules) link the rete testis to the epididymis after piercing the testicular tunica albuginea. Each ductule is lined by a columnar epithelium with principal cells with microvilli—with a role in the reabsorption of fluid from the lumen—and ciliated cells, which contribute to the transport of nonmotile sperm toward the epididymis. The epithelium has a characteristic scalloped outline that enables identification of the ductuli efferentes (see Figure 21-4). A thin inner circular layer of smooth muscle cells underlies the epithelium and its basal lamina.

The epididymis is a highly coiled tubule (4 to 6 cm long) where spermatozoa mature (acquire a forward motility pattern essential to their fertilizing ability).

The epididymal duct is subdivided into three major segments: (1) the head or caput; (2) the body or corpus; and (3) the tail or cauda (see Figure 21-4).

The epithelium is pseudostratified columnar with long and branched stereocilia. The epithelium consists of two major cell types (Figure 21-5):

Figure 21-5 Epididymis

Other cell types are the apical cells, rich in mitochondria and predominant in the head of the epididymis, and the clear cells, predominant in the tail of the epididymis. Intraepithelial lymphocytes are distributed throughout the epididymis. They may be an important component of the epididymal immunologic barrier.

The height of the epithelium varies with respect to the segment of the epididymal duct. The epithelium is taller in the head region and shorter in the tail region. In an opposite fashion, the lumen of the epididymal duct is narrow in the head region and wider in the tail region.