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.

An inner smooth muscle circular layer, of increasing thickness from head to tail, and an outer longitudinal layer, visible from the body on, surround the epithelium and basal lamina. The muscle layer displays peristaltic movements to facilitate sperm transport along the epididymal duct (Box 21-B).

The vas deferens (ductus deferens) is a 45-cm-long muscular tube with the following features: (1) the lining epithelium is pseudostratified columnar with stereocilia similar to that of the epididymis, and is supported by a connective tissue lamina propria with elastic fibers; (2) the muscular wall consists of inner and outer layers of longitudinally oriented muscle separated by a middle circular layer; and (3) the external layer consists of loose connective tissue and adipose cells.

In addition to the vas deferens, the spermatic cord contains the following components (Figure 21-6): (1) the cremaster muscle, (2) arteries (spermatic artery, cremasteric artery, and artery to the vas deferens), (3) veins of the pampiniform plexus, and (4) nerves (genital branch of the genitofemoral nerve, cremasteric nerve, and sympathetic branches of the testicular plexus). All these structures are surrounded by loose connective tissue.

Figure 21-6 Spermatic cord

An ampulla, the dilated portion of the vas deferens, leads directly into the prostate gland. The distal end receives the ducts of the seminal vesicle, forming the ejaculatory ducts, which pass through the prostate gland to empty secretion into the prostatic urethra at the seminal colliculus

SEMINAL VESICLES

The seminal vesicles are androgen-dependent organs. Each seminal vesicle is an outpocketing of the wall of ampulla of each vas deferens. It consists of three components (Figure 21-7): (1) an external connective tissue capsule; (2) a middle smooth muscle layer (inner circular and outer longitudinal layers), and (3) an internal highly folded mucosa lined by a simple cuboidal-to-pseudostratified columnar epithelium.

Figure 21-7 Seminal vesicle

The epithelial cells display a large Golgi apparatus with vesicles containing secretory granules. Seminal vesicles secrete an alkaline viscous fluid rich in seminal coagulating proteins, fructose, and prostaglandins. The fluid contributes about 70% to 85% of the human ejaculate.

Fructose is the major source of energy of the ejaculated sperm. Seminal vesicles do not store sperm. They contract during ejaculation. The excretory duct of each seminal vesicle penetrates the prostate after joining the vas deferens to form the ejaculatory duct (Figure 21-8).

Figure 21-8 Ejaculatory ducts

PROSTATE GLAND

The prostate is the largest accessory genital gland surrounded by a capsule. It consists of 30 to 50 branched tubuloalveolar glands that empty their contents into the prostate urethra via long excretory ducts.

The prostate glands are arranged in three zones (Figure 21-9): (1) a central zone with periurethral mucosal glands, (2) a transition zone with periurethral submucosal glands, and (3) a peripheral zone consisting of branched (compound) glands. About 70% to 80% of prostate cancer originates in the peripheral zone.

Figure 21-9 Prostate gland

The prostate glands are lined by simple or pseudostratified columnar epithelium (Figure 21-10). The lumen contains concretions (corpora amylacea) rich in glycoproteins and, sometimes, a site of calcium deposition. Cells contain abundant rough endoplasmic reticulum and Golgi apparatus.

Figure 21-10 Prostate tubuloalveolar glands

The prostate produces a zinc-rich alkaline fluid that neutralizes the acidic vaginal content, provides nutrients and transports sperm, and liquefies semen.

Protein products include prostate-specific acid phosphatase, prostate-specific antigen (PSA, a valuable marker for early detection of prostate cancer), amylase, and fibrinolysin.

Clinical significance: Benign prostate hyperplasia and prostate cancer

Benign prostate hyperplasia (or BPH) is a noncancerous enlargement of the prostate gland that can restrict the flow of urine through the prostatic urethra.

The periurethral mucosal (central zone) and submucosal (transition zone) prostate glands and the stroma undergo nodular hyperplasia (see Figure 21-9) in older men.

Nodular hyperplasia produces:

1. Difficulty in urination and urinary obstruction caused by compression of the prostatic urethra by the nodular growth.

2. Retention of urine in the bladder or inability to empty the urinary bladder completely. The possibility of infection leads to inflammation of the urinary bladder (cystitis) and renal infection (pyelonephritis). Acute and persistent urinary retention requires emergency catheterization.

BPH is caused by DHT, a metabolite of testosterone (Figure 21-11). The enzyme 5α-reductase, present mainly in prostate stromal cells, converts testosterone to DHT.

Figure 21-11 Stromal-prostate epithelial cell interaction

DHT binds to cytosol and nuclear androgen receptors to induce the expression of growth factors mitogenic to prostate epithelial and stromal cells. Inhibitors of 5α-reductase reduce the production of DHT, decrease the periurethral nodular hyperplasia, and alleviate urinary obstruction.

Carcinoma of the prostate originates from the main prostate glands of the peripheral zone, farthest from the urethra. Urinary symptoms are not present at the early stage and tumor growth is often detected by digital palpation of the prostate, by elevated serum levels of PSA, or by back pain caused by vertebral metastasis. Transperineal or transrectal biopsy, if required, confirm a clinical diagnosis.

As in BPH, androgens also play a role in the development of prostate carcinoma. Tumor growth can be controlled by reducing androgen production (for example, using luteinizing hormone–releasing hormone [LH-RH] agonists and antiandrogens) or, in hormone-resistant prostate cancer, by orchidectomy (surgical removal of the testes, the major source of androgens) and chemotherapy.

Surgery (radical prostatectomy by retropubic or perineal surgery) and radiotherapy (external beam radiation therapy or radioactive seed implants in the prostate) are suitable when the tumor is localized as determined by computer imaging techniques.

MALE AND FEMALE URETHRA

The urethra in the male is 20 cm long and has three segments:

Figure 21-12 Female and male urethra

The epithelium of the prostate urethra is transitional (urothelium). It changes to a pseudostratified-to-stratified columnar epithelium in the membranous and penile urethra. The muscle layer in the membranous urethra consists of a smooth muscle sphincter (involuntary) and a striated muscle sphincter (voluntary). It controls the passage of urine or semen.

The urethra in the female is 4 cm long and is lined by transitional epithelium changing to pseudostratified columnar and stratified squamous nonkeratinized epithelium near the urethral meatus. The mucosa contains mucus-secreting glands (see Figure 21-12). An inner layer of smooth muscle is surrounded by a circular layer of striated muscle that closes the urethra when contracted.

BULBOURETHRAL GLANDS

The bulbourethral glands consist of several lobules containing tubuloalveolar secretory units and a main excretory duct lined by a stratified columnar epithelium. The lining epithelium of the secretory units is columnar and secretes a mucus product. The secretion, containing abundant galactose and a moderate amount of sialic acid, is discharged into the penile urethra. This secretion has a lubrication function and precedes the emission of semen along the penile urethra.

PENIS

The penis consists of three cylindrical columnar masses of erectile tissue (see Figure 21-12): the right and left corpora cavernosa, and the ventral corpus spongiosum, transversed by the penile urethra. The three columns converge to form the shaft of the penis. The distal tip of the corpus spongiosum is the glans penis.

The corpora cavernosa and corpus spongiosum contain irregular and communicating blood spaces, or sinusoids, supplied by an artery and drained by venous channels. During erection, arterial blood fills the sinusoids, which enlarge and compress the draining venous channels (Figure 21-13).

Figure 21-13 Mechanism of penile erection

Two chemicals control erection: nitric oxide and phosphodiesterase (see Figure 21-13).

Clinical significance: Erectile dysfunction

Factors that affect the cerebral cortex–hypothalamus–spinal cord–autonomic nerve pathway and vascular diseases can cause erectile dysfunction. Traumatic head and spinal cord injuries, stroke, Parkinson’s disease, and systemic diseases, such as diabetes and multiple sclerosis, reduce nerve function and lead to erectile dysfunction. In addition, anxiety disorders can be a primary cause of erectile dysfunction.

Sildenafil (Viagra) was originally tested as a treatment for heart failure. During clinical trials, it was noticed that a significant number of patients were getting erections after taking the drug. This observation initiated an independent clinical study to evaluate the effect of sildenafil in the treatment of erectile dysfunction.

In the penis, sildenafil blocks a specific phosphodiesterase found in smooth muscle cells, and, by this mechanism, inhibits the degradation of cGMP. High levels of cGMP induce Ca²⁺ to enter storage areas in the cell and induce the perisinusoidal smooth muscle cells to relax.

Sildenafil can cause dose-dependent side effects such as facial flushing, gastrointestinal distress, headaches, and a blue tinge to vision.

Concept mapping

Sperm Transport and Maturation

Sperm Transport and Maturation

Essential concepts

• Primordial germinal cells (PGCs), the precursors of the female and male gametes, have an extra-embryonic origin. They appear first in the wall of the yolk sac in the 4-week fetus.

Between 4 and 6 weeks, PGCs migrate to the gonadal ridges by translocation from the yolk sac to the hindgut, migration from the hindgut to the gonadal ridges across the mesentery, and colonization in the gonadal ridges. The migration step involves the participation of the c-kit receptor, a tyrosine kinase, and stem cell factor, the c-kit ligand. A lack of c-kit receptor or its ligand causes the gonadal ridges and gonads to be deficient in PGCs.

In the gonadal ridges, XX chromosome-containing PGCs occupy the cortex, and XY chromosome-containing PGCs localize in the medulla, the central portion of the gonadal ridges. After 7 weeks, the indifferent gonad contains a cortex, which develops into an ovary, and a medulla, which develops into a testis.

The development of the testis is controlled by testis-determining factor, a product of a gene on the sex-determining region of the Y chromosome (SRY).

The initial components of the fetal testis are the testicular cords. A testicular cord contains Sertoli cells and prespermatogonia (also called gonocytes) derived from PGCs. Leydig cells are present between the testicular cords. Fetal Sertoli cells secrete anti-müllerian hormone (AMH), which induces regression by apoptosis of the müllerian duct (paramesonephric duct). Leydig cells, stimulated by human chorionic gonadotropin, secrete testosterone. Testosterone is converted to dihydrotestosterone (DHT) by 5α-reductase. Testosterone stimulates the cephalic end of the wolffian duct (mesonephric duct) to develop the epididymis, vas deferens, and seminal vesicle. DHT stimulates the development of the prostate gland and urethra from the urogenital sinus. Testosterone and DHT bind to androgen receptor, a cytosol-nuclear protein encoded by a gene on the X chromosome.

Klinefelter’s syndrome (47,XXY) is observed in males with an extra X chromosome. Individials are phenotypically males, have atrophic testes, and the blood levels of testosterone are low but the levels of estradiol are high. Excess of estradiol causes gynecomastia.

Androgen insensitivity syndrome (AIS, also called testicular feminization) is determined by a complete or partial defect in the expression of androgen receptor. A lack of development of the wolffian duct and regression of the müllerian duct are observed. Testes remain in the abdomen, and external genitalia develop as female. Blood levels of androgens and estradiol are high.

5α-Reductase deficiency determines a decrease in the conversion of testosterone to DHT. Individuals have normal internal genitalia but female external genitalia.

• Sperm maturation pathway. After leaving the seminiferous tubule, immature sperm follow this sequential pathway:

1. Tubuli recti (straight tubules): Narrow tubular structures lined by a simple cuboidal epithelium. Tight junctions occupy an apical position, in contrast to the basally located inter–Sertoli cell tight junctions.

2. Rete testis: A network of anastomosing channels lined by simple cuboidal epithelium. The wall consists of myoid cells and fibroblasts.

3. Ductuli efferentes (efferent ductules): They connect the rete testis to the initial region of the epididymal duct. The epithelial lining consists of principal cells with microvilli (instead of stereocilia) and ciliated cells, involved in the transport of nonmotile sperm toward the epididymis. Clusters of these two cell types, differing in height, give the epithelium a characteristic scalloped outline.

4. Epididymis: A highly coiled duct (4 to 6 cm long) with three typical anatomic regions: Head or caput, body or corpus, and tail or cauda. The lining epithelium is pseudostratified columnar with stereocilia. The wall contains smooth muscle cells. The two major epithelial cell types are the columnar principal cells with apical stereocilia, and basal cells, associated with the basal lamina. Intraepithelial lymphocytes are frequently seen. The height of the principal cells decreases towards the tail region. Consequently, the lumen becomes progressively wider. The thickness of the muscle wall increases toward the epididymal tail region.

5. Vas deferens (ductus deferens): A muscular tube with a length of 45 cm. It can be seen in the spermatic cord. The vas deferens is lined by pseudostratified columnar epithelium with stereocilia. The smooth muscle cell layer consists of a middle circular layer surrounded by inner and outer longitudinal layers. Additional components of the spermatic cord include the cremaster muscle, arteries (spermatic, cremasteric, and vas deferens arteries), veins of the pampiniform plexus (important for spermatic artery–pampiniform plexus heat transfer to maintain testicular temperature 2°C to 3°C below body temperature for normal spermatogenesis), and nerves. The vas deferens ends in a dilated ampulla receiving the duct of the seminal vesicle to form the ejaculatory duct passing through the prostate gland.

• Accessory genital glands. The accessory glands of the male reproductive system are the seminal vesicles, the prostate gland, and the bulbourethral glands of Cowper.

Each seminal vesicle consists of three components: (1) an external connective tissue capsule, (2) a middle smooth muscle layer, and (3) an internal highly folded mucosa lined by a simple cuboidal-to-pseudostratified columnar epithelium supported by a lamina propria. Under the influence of androgens, the seminal vesicle epithelium contributes 70% to 85% of an alkaline fluid to the human ejaculate. The fluid contains seminal coagulating proteins, fructose, and prostaglandins.

The prostate gland is a branched (compound) tubuloalveolar gland. The prostate glands are distributed in three zones: (1) central zone with periurethral mucosal glands, (2) transition zone with periurethral submucosal glands, and (3) peripheral zone with branched tubuloalveolar glands, called main glands. Glands are lined by simple or pseudostratified columnar epithelium. The lumen contains corpora amylacea, rich in glycoproteins. The alkaline fluid produced by the prostate gland contains acid phosphatase and prostate-specific antigen (PSA). The alkaline nature of the semen neutralizes the acidic vaginal environment produced by vaginal lactic acid.

A combined enlargement of the periurethral mucosal and submucosal glands and surrounding stroma accounts for benign prostate hyperplasia (BPH). BPH is determined by growth factors with mitogenic action produced by both stromal and glandular epithelial cells stimulated by dihydrotestosterone (DHT). Testosterone is converted to DHT by the enzyme 5a-reductase. Blocking agents of 5a-reductase activity and antiandrogens are used in the nonsurgical treatment of BPH. Cancer of the prostate is the result of the malignant transformation of the prostate glands of the peripheral zone. Blood levels of PSA are elevated in patients with prostate cancer.

Bulbourethral glands secrete a lubricating mucus product into the penile urethra.

• Male and female urethra. The male urethra has a length of 20 cm and consists of three segments: (1) the prostatic urethra, whose lumen receives fluid transported by the ejaculatory ducts and products from the prostatic glands, (2) the membranous urethra, and (3) the penile urethra, which receives a lubricating fluid from the bulbourethral glands. The epithelium of the prostatic urethra is transitional (urothelium) with regional variations. Smooth muscle and striated muscle sphincters are present in the membranous urethra. The female urethra is shorter (4 cm long) and is lined by transitional epithelium, also with regional variations. The mucosa contains mucus-secreting glands. Inner smooth and outer striated muscle cell layers are observed.

• Penis. The penis consists of three cylindrical structures of erectile tissue: a pair of corpora cavernosa and a single corpus spongiosum. The three cylindrical structures converge to form the shaft of the penis. The tip of the corpus spongiosum is the glans penis. The erectile tissue contains vascular spaces, called sinusoids, supplied by arterial blood and drained by venous channels. During erection, arterial blood fills the sinusoids, which compress the adjacent venous channels preventing draining.

Nitric oxide, produced by branches of the dorsal nerve, spreads across gap junctions between smooth muscle cells surrounding the sinusoids. Within smooth muscle cells, nitric oxide activates guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). cGMP relaxes the smooth muscle by sequestering calcium into intracellular storage sites, and arterial blood accumulates in the distended sinusoids and the penis becomes erect. The enzyme phosphodiesterase degrades cGMP, thus terminating erection. Sildenafil, a phosphodiesterase inhibitor, is used to prevent rapid cGMP degradation in cases of erectile dysfunction.