Medical Physiology A Cellular and Molecular Approach, Updated 2nd Ed.

THE MALE REPRODUCTIVE SYSTEM

Ervin E. Jones

The male reproductive system (Fig. 54-1A) consists of two essential elements: the gonads and the complex array of glands and conduits that constitute the sex accessories. The gonads in males are the testes, and they are responsible for the production of gametes, the haploid cells (spermatozoa) necessary for sexual reproduction. The gonads also synthesize and secrete the hormones that are necessary for functional conditioning of the sex organs, control of gonadotropin secretion, and modulation of sexual behavior.

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Figure 54-1 The anatomy of the male internal genitalia and accessory sex organs. A, The two major elements of the male sexual anatomy are the gonads (i.e., testes) and the sex accessories (i.e., epididymis, vas deferens, seminal vesicles, ejaculatory duct, prostate, bulbourethral or Cowper’s glands, urethra, and penis). The urethra can be subdivided into the prostatic urethra, the bulbous urethra, and the penile urethra. B, The vas deferens expands into an ampulla before coursing across the rear of the urinary bladder and merging with the outflow from the seminal vesicle. The merger forms the ejaculatory duct. The left and right ejaculatory ducts penetrate the prostate gland and open into the prostatic urethra. C, The spermatozoa form in the seminiferous tubules and then flow into the rete testis and from there into the efferent ductules, the epididymis, and the vas deferens. D, The seminiferous tubule is an epithelium formed by the Sertoli cells, with interspersed germ cells. The most immature germ cells (the spermatogonia) are near the periphery of the tubule, whereas the mature germ cells (the spermatozoa) are near the lumen of the tubule. The Leydig cells are interstitial cells that lie between the tubules.

The testis (Fig. 54-1B, C) is largely composed of seminiferous tubules and the interstitial cells of Leydig, located in the spaces between the tubules. The seminiferous tubules are lined by seminiferous epithelium, which rests on the inner surface of a basement membrane (Fig. 54-1D). The basement membrane is supported by a thin lamina propria externa.

The sex accessories in the male include the paired epididymides, the vas deferens, the seminal vesicles, and the ejaculatory ducts. Also included among the sex accessories are the prostate, the bulbourethral glands (Cowper’s glands), the urethra, and the penis. The primary role of the male sex accessory glands and ducts is to store and transport spermatozoa to the exterior at the proper time, thus enabling spermatozoa to come in contact with and fertilize female gametes.

PUBERTY

Puberty occurs in five defined stages

During the final month of fetal life, the testes descend (see the box titled Androgen Dependence of Testicular Descent in Chapter 53) into an integumentary pouch called the scrotum. The inguinal canals through which the testes descend are sealed off shortly after birth. Because the internal temperature of the testicle must be closely regulated for optimum function, localization of the testes within the scrotum appears to be a necessary adaptation for testicular function. Aberrant retention of the testes in the abdominal cavity (cryptorchidism) causes marked damage to the seminiferous tubules and diminished testicular function.

Puberty is the transition between the juvenile and adult states, during which time the individual develops secondary sexual characteristics, experiences the adolescent growth spurt, and achieves the ability to procreate. The range of onset of normal male puberty extends from 9 to 14 years. Boys complete pubertal development within 2 to 4½ years. In a normal boy, the first sign of puberty (stage 2) is enlargement of the testes to greater than 2.5 cm. Testicular enlargement is mainly a result of growth of the seminiferous tubules, but enlargement of the Leydig cells contributes as well. Androgens from the testes are the driving force behind secondary sexual development, although adrenal androgens play a role in normal puberty. The Tanner method of describing the stages of pubertal development is widely accepted. Genital development and growth of pubic hair are best described separately, as indicated by the two columns in Table 54-1. Thus, it is possible for an adolescent boy to be at genital stage 3, pubic hair stage 2.

Table 54-1 Stages in Male Puberty

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Testicular size is generally determined by using a ruler or calipers. It is expected that a length greater than 2.5 cm is compatible with the onset of normal pubertal development. The testicular volume index is defined as the sum of the length times width product for the left and right testes. An orchidometer allows direct comparison of the patient’s testes with an oval of measured volume. A popular method uses the Prader orchidometer, a set of solid or hollow ovals encompassing the range from infancy to adulthood (1 to 25 mL). The volumes of the testes are then recorded; a volume of 3 mL closely correlates with the onset of pubertal development.

Spermarchy, or the first appearance of spermatozoa in early morning urine, occurs at a mean age of ~13.4 years and corresponds to genital stages 3 to 4 and pubic hair stages 2 to 4. The pubertal spurt, a marked increase in growth rate (total body size), occurs late in puberty in boys, at genital stages 3 to 4. The acceleration of growth appears to be partly a result of increased secretion of growth hormone at puberty and partially a result of testosterone production. Boys experience, on average, 28 cm of growth during the pubertal spurt. The 10-cm mean difference in adult stature between men and women is the result of a greater pubertal growth spurt in boys and to greater height at the onset of peak height velocity in boys versus girls. Before puberty, boys and girls have the same mean body mass, skeletal mass, and body fat. However, men have 150% of the average woman’s lean and skeletal body mass, and women have 200% of the body fat of men. Men have twice the number of muscle cells that women have and 1.5 times the muscle mass.

Androgens determine male secondary sexual characteristics

The male sex steroids, which are known as androgens, affect nearly every tissue in the body, including the brain. The development of both the external and the internal genitalia depends on male sex hormones (see Chapter 53). Androgens stimulate adult maturation of the external genitalia and accessory sexual organs, including the penis, the scrotum, the prostate, and the seminal vesicles. Androgens also determine the male secondary sexual characteristics, which include deepening of the voice, as well as evolving male patterns of hair growth. The effects on the voice are a result of androgen-dependent effects on the size of the larynx, as well as the length and thickness of the vocal cords. In boys, the length of the vocal cords increases by ~50% during puberty, whereas girls have little increase in vocal cord length. The surfaces of the human body that bear secondary sexual hair include the face (particularly the upper lip, chin, and the sideburn areas), the axilla, and the pubic region. Temporal hair recession and male-pattern balding are also androgen-dependent phenomena.

Muscle development and growth are androgen-dependent processes

Androgens have anabolic effects, including stimulation of linear body growth, nitrogen retention, and muscular development in adolescent boys and in men. The biological effects of testosterone and its metabolites have been classified according to their tissue sites of action. Effects that relate to growth of the male reproductive tract or development of secondary sexual characteristics are referred to as androgenic, whereas the growth-promoting effects on somatic tissue are called anabolic. These androgenic and anabolic effects are two independent biological actions of the same class of steroids. Experimental evidence, however, indicates that these responses are organ specific and that the molecular mechanisms that initiate androgenic responses are the same as those that stimulate anabolic activity.

HYPOTHALAMIC-PITUITARY-GONADAL AXIS AND CONTROL OF MALE SEXUAL FUNCTION

The male hypothalamic-pituitary-gonadal axis (Fig. 54-2) controls two primary functions: (1) production of male gametes (spermatogenesis) in the seminiferous tubules and (2) androgen biosynthesis in the Leydig cells in the testes. The hypothalamus produces gonadotropin-releasing hormone (GnRH), which stimulates the gonadotrophs in the anterior pituitary to secrete the two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). As discussed in Chapter 55, the names of these hormones reflect their function in the female reproductive system. LH and FSH control, respectively, the Leydig and Sertoli cells of the testes.

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Figure 54-2 The hypothalamic-pituitary-testicular axis. Small-bodied neurons in the arcuate nucleus and preoptic area of the hypothalamus secrete GnRH, a decapeptide that reaches the gonadotrophs in the anterior pituitary through the long portal veins. Stimulation by GnRH causes the gonadotrophs to synthesize and release FSH and LH. The LH binds to receptors on the Leydig cells, thus stimulating the transcription of several proteins involved in the biosynthesis of testosterone. FSH binds to receptors on the basolateral membrane of the Sertoli cells, thereby stimulating gene transcription and protein synthesis. These proteins include ABP, aromatase, growth factors, and inhibin. Negative feedback on the hypothalamic-pituitary-testicular axis occurs by two routes. First, testosterone inhibits the pulsatile release of GnRH by the hypothalamic neurons and the release of LH by the gonadotrophs in the anterior pituitary. Second, inhibin inhibits the release of FSH by the gonadotrophs in the anterior pituitary.

The hypothalamus secretes GnRH, which acts on gonadotrophs in the anterior pituitary

GnRH, which is synthesized by small-bodied peptidergic neurons in the hypothalamus, stimulates the synthesis, storage, and secretion of gonadotropins by gonadotroph cells in the anterior pituitary. The hypothalamic-pituitary-portal system (see Chapter 47) describes the route by which GnRH and other releasing hormones emanating from the hypothalamus reach the anterior pituitary gland. The neurons that synthesize, store, and release GnRH are dispersed throughout the hypothalamus but are principally located in the arcuate nucleus and preoptic area. Studies involving both rats and primates showed that sites other than the hypothalamus (e.g., the limbic system) of GnRH production can also participate in the control of sex behavior. Neuronal systems originating from other areas of the brain impinge on the hypothalamic GnRH-releasing neurons and thus form a functional neuronal network.

GnRH is a decapeptide hormone synthesized by aforementioned hypothalamic neurons in the secretory pathway (see Chapter 2). Like many other peptide hormones, GnRH is synthesized as a prohormone—69 amino acids long in this case—from which the mature GnRH is generated by enzymatic cleavage. The synthesis of GnRH is discussed in more detail in Chapter 55. The neurons release GnRH into the extracellular space, to be carried to the anterior pituitary through the long portal vessels.

GnRH stimulates the release of both FSH and LH from the gonadotroph cells of the anterior pituitary. FSH and LH are the primary gonadotropins; in males, they stimulate testicular function. The cell surface of the pituitary gonadotrophs is the site of high-affinity membrane receptors for GnRH. These receptors are coupled to the G protein Gαq, which activates phospholipase C (PLC; see Chapter 3). PLC acts on membrane phosphoinositides to liberate inositol 1, 4, 5-triphosphate (IP3), which triggers Ca2+ release from internal stores, and diacylglycerol (DAG), which stimulates protein kinase C. The results are the synthesis and release of both LH and FSH from the gonadotrophs. Because secretion of GnRH into the portal system is pulsatile, secretion of both LH and FSH by the gonadotrophs is also episodic. The frequency of pulsatile LH discharge in men is ~8 to 14 pulses over a 24-hour period. FSH pulses are not as prominent as LH pulses, both because of their lower amplitude and because of the longer half-life of FSH in the circulation.

Although pulsatile GnRH discharge elicits a corresponding pulsatile release of LH and FSH, continuous administration of GnRH—or intermittent administration of high doses of GnRH analogues—suppresses the release of gonadotropins. As described in the box titled Therapeutic Uses of GnRH in Chapter 55, the mechanism is inhibition of the replenishment of GnRH receptors so that insufficient receptors are available for GnRH function. A clinical application of this principle is in prostatic cancer, in which the administration of GnRH analogues lowers LH and FSH levels and thereby reduces testosterone production (i.e., chemical castration).

Products of the testes, particularly sex steroids and inhibin (see later), exert negative feedback control on hypothalamic and anterior pituitary function. Neural elements in the arcuate nucleus respond to sex steroids. Sex steroids alter the frequency and amplitude of the LH secretory pulses in both men and women. Androgens also exert powerful influences on higher brain function, as evidenced by alterations in sex behavior.

Under the control of GnRH, gonadotrophs in the anterior pituitary secrete LH and FSH

LH and FSH, which are secreted by the gonadotrophs of the anterior pituitary, are the primary regulators of testicular function. LH and FSH are members of the same family of hormones as human chorionic gonadotropin (hCG; see Chapter 56) and thyroid-stimulating hormone (TSH; see Chapter 49). All these glycoprotein hormones are composed of two polypeptide chains designated α and β. Both subunits, α and β, are required for full biological activity. The α subunits of LH and FSH, as well as the α subunits of hCG and TSH, are identical. In humans, the common α subunit has 92 amino acids and a molecular weight of ~20 kDa. The β subunits differ among these four hormones and thus confer specific functional and immunologic characteristics to the intact molecules.

Each of the unique β subunits of FSH and LH is 115 amino acids in length. The β subunits of LH and hCG are identical, except the β subunit of hCG has an additional 24 amino acids and additional glycosylation sites at the C terminus. hCG is secreted by the placenta, and some reports have described that small amounts of this substance are made in the testes, pituitary gland, and other nonplacental tissue. The biological activities of LH and hCG are very similar. Indeed, in most clinical uses (e.g., in an attempt to initiate spermatogenesis in oligospermic men), hCG is substituted for LH because hCG is much more readily available. (See Note: Plasma Lifetime of LH, hCG, and FSH)

The specific gonadotropin and the relative proportions of each gonadotropin released from the anterior pituitary depend on the developmental age, as well as the existing hormonal milieu. The pituitary gland of the male fetus contains functional gonadotrophs by the end of the first trimester of gestation. Thereafter, gonadotropin secretion rises rapidly and then plateaus. Gonadotropin secretion begins to decline in utero during late fetal life and increases again during the early postnatal period.

Male primates release LH in response to GnRH administration at 1 to 3 months of age, a finding indicative of functional competence of the anterior pituitary gland. Also during this time, a short-lived postnatal surge of LH and testosterone secretion occurs in males. Although the cause of this short-lived surge of gonadotropins remains to be understood, it is clearly independent of sex steroids. The sensitivity of the gonadotrophs to stimulation subsequently diminishes, and the system remains quiescent until just before puberty.

Release of FSH is greater than that of LH during the prepubertal period, a pattern that is reversed after puberty. GnRH preferentially triggers LH release in men. This preferential release of LH may reflect maturation of the testes, which secrete inhibin, a specific inhibitor of FSH secretion at the level of the anterior pituitary gland. Increased sensitivity of the pituitary to increasing gonadal steroid production may also be responsible for the diminished secretion of FSH.

Luteinizing hormone stimulates the Leydig (interstitial) cells of the testis to produce testosterone

LH derives its name from effects observed in the female, that is, from the ability to stimulate luteal function. The comparable substance in the male was originally referred to as interstitial cell–stimulating hormone (ICSH). Subsequently, investigators realized that LH and ICSH are the same substance, and the common name became LH.

Testosterone production decreases in males after hypophysectomy. This observation led to our current understanding that LH secreted by the anterior pituitary gland is essential for testosterone production by the testis. The interstitial cells of the testis, the Leydig cells, are the primary source of testosterone production in the male. Leydig cells synthesize androgens from cholesterol by using a series of enzymes that are part of the steroid biosynthetic pathways (see later).

LH binds to specific high-affinity cell surface receptors on the plasma membrane of Leydig cells (Fig. 54-3). Binding of LH to this G protein–coupled receptor on the Leydig cell stimulates membrane-bound adenylyl cyclase (see Chapter 3), which catalyzes the formation of cAMP and thus activates protein kinase A (PKA). Activated PKA modulates gene transcription (see Chapter 4) and increases the synthesis of enzymes and other proteins necessary for the biosynthesis of testosterone. Two of these other proteins are the sterol-carrier protein (SCP-2) and the steroidogenic acute regulatory protein or (StAR or STARD1). SCP is a 13.5-kDa protein that appears to transport cholesterol from the plasma membrane or organellar membranes to other organellar membranes, including the outer mitochondrial membrane.

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Figure 54-3 Physiology of the Leydig and Sertoli cells. The Leydig cell (left) has receptors for LH. The binding of LH increases testosterone synthesis. The Sertoli cell (right) has receptors for FSH. (Useful mnemonics: “L” for LH and Leydig, “S” for FSH and Sertoli.) FSH promotes the synthesis of ABP, aromatase, growth factors, and inhibin. Crosstalk occurs between the Leydig cells and the Sertoli cells. The Leydig cells make testosterone, which acts on the Sertoli cells. Conversely, the Sertoli cells convert some of this testosterone to estradiol (because of the presence of aromatase), which can act on the Leydig cells. The Sertoli cells also generate growth factors that act on the Leydig cells.

StAR belongs to a large family of proteins that contain a ~210-residue START domain and are involved in lipid trafficking and metabolism. The 37-kDa pro-StAR protein—the precursor to StAR—may participate in ferrying cholesterol from the endoplasmic reticulum (ER) to the outer mitochondrial membrane. The 30-kDa mature StAR protein resides in the mitochondrial intermembrane space (see Fig. 58-10) and extracts cholesterol from the mitochondrial outer membrane, ferries it across the space to the mitochondrial inner membrane, and then deposits the cholesterol in the mitochondrial inner membrane where the cytochrome P-450 side-chain–cleavage (SCC) (P-450scc) enzyme is located. As discussed later, the P-450scc–mediated conversion of cholesterol to pregnenolone is the rate-limiting step in steroidogenesis—including testosterone synthesis. Thus, the net effect of LH on Leydig cells is to stimulate testosterone synthesis.

Follicle-stimulating hormone stimulates the sertoli cells to synthesize certain products needed by both the Leydig cells and the developing spermatogonia

The Sertoli cells seem to be the primary testicular site of FSH action (Fig. 54-3), as clearly shown by experiments involving suppression of LH secretion. FSH also regulates Leydig cell physiology through effects on the Sertoli cells. The early biochemical events after FSH binding are similar to those described for LH on the Leydig cell. Thus, binding of FSH to a G protein–coupled receptor initiates a series of reactions involving stimulation of adenylyl cyclase, increase in [cAMP]i, stimulation of PKA, transcription of specific genes, and increased protein synthesis. Several proteins are synthesized in response to FSH. Some are important for steroid action:

1. FSH leads to the synthesis of androgen-binding protein (ABP), which is secreted into the luminal space of the seminiferous tubule, near the developing sperm cells. ABP helps to keep local testosterone levels high (see Chapter 53).

2. FSH causes the synthesis of a P-450 aromatase (P-450arom; see Chapter 55). Inside the Sertoli cells, this enzyme converts testosterone, which diffuses from the Leydig cells to the Sertoli cells, into estradiol.

3. FSH leads to the production of certain growth factors and other products by the Sertoli cells that support sperm cells and spermatogenesis. These substances significantly increase the number of spermatogonia, spermatocytes, and spermatids in the testis. Therefore, it appears that the stimulatory effect of FSH on spermatogenesis is not a direct action of FSH on the spermatogonia; instead, stimulation of spermatogenesis occurs through the action of FSH on the Sertoli cells. FSH may also increase the fertility potential of sperm; it appears that this effect of FSH results from stimulation of motility, rather than from an increase in the absolute number of sperm.

4. FSH causes the Sertoli cells to synthesize inhibins. The inhibins are members of the so-called transforming growth factor β (TGF-β) gene family, which also includes the activins and antimüllerian hormone (see Chapter 53). Inhibins are glycoprotein heterodimers consisting of one α and one β subunit that are covalently linked. The granulosa cells in the ovary and the Sertoli cells in the testis are the primary sources of inhibin in humans, other primates, and the lower vertebrates. I discuss the biology of inhibins and activins in more detail in Chapter 55. Inhibins are secreted into the seminiferous tubule fluid and into the interstitial fluid of the testicle. Inhibins have both paracrine and endocrine actions. Locally, the inhibins are some of the growth factors secreted by the Sertoli cells that are thought to act on the Leydig cells. More importantly, inhibins in the male play an important feedback role in the hypothalamic-pituitary-testicular axis (see later).

The Leydig cells and the Sertoli cells engage in crosstalk. For example, the Leydig cells make testosterone, which acts on the Sertoli cells. In the rat, β endorphin produced by the fetal Leydig cells binds to opiate receptors in the Sertoli cells and inhibits their multiplication. Synthesis of β endorphins could represent a local feedback mechanism by which the Leydig cells modulate the Sertoli cell numbers. Conversely, the Sertoli cells also have an effect on the Leydig cells. For example, the Sertoli cells convert testosterone—manufactured by the Leydig cells—to estradiol, which then acts on the Leydig cells. In addition, FSH acting on the Sertoli cells produces growth factors that may increase the number of LH receptors on the Leydig cells during development and may thus result in an increase in steroidogenesis (i.e., an increase in testosterone production).

What, then, is required for optimal spermatogenesis to occur? It appears that two testicular cell types (the Leydig cells and the Sertoli cells) are required, as well as two gonadotropins (LH and FSH) and one androgen (testosterone). First, LH and the Leydig cells are required to produce testosterone. Thus, LH, or rather its substitute hCG, is used therapeutically to initiate spermatogenesis in azoospermic or oligospermic men. Second, FSH and the Sertoli cells are important for the nursing of developing sperm cells and for the production of inhibin and growth factors, which affect the Leydig cells. Thus, FSH plays a primary role in regulating development of the appropriate number of the Leydig cells such that adequate testosterone levels are available for spermatogenesis. During early puberty in boys, both FSH and LH levels increase while, simultaneously, the Leydig cells proliferate and plasma levels of testosterone increase (Fig. 54-4). (See Note: Effects of FSH on Leydig and Sertoli Cells during Puberty)

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Figure 54-4 Plasma testosterone versus age in male humans. (Data from Griffin JE, et al: In Bondy PK, Rosenberg LE: Metabolic Control and Disease. Philadelphia: WB Saunders, 1980; and Winter JS, Hughes IA, Reyes FI, Faiman C: J Clin Endocrinol Metab 1976; 42:679-686.)

The hypothalamic-pituitary-testicular axis is under reciprocal inhibition by testicular hormones and inhibin

The hypothalamic-pituitary-testicular axis not only generates testosterone and inhibin but also receives negative feedback from these substances (Fig. 54-2). Normal circulating levels of both testosterone and estradiol exert inhibitory effects on LH secretion in males. Testosterone inhibits the pulsatile release of LH, presumably by inhibiting the pulsatile release of GnRH by the hypothalamus. Testosterone also appears to have negative feedback action on LH secretion at the level of the pituitary gonadotrophs.

A testicular hormone also feeds back on FSH secretion. Evidence for negative feedback by a testicular substance on FSH secretion is that plasma FSH concentrations increase in proportion to the loss of germinal elements in the testis. The FSH-inhibiting substance—inhibin—is a nonsteroid present in both the testis and cultures of Sertoli cells. Thus, FSH specifically stimulates the Sertoli cells to produce inhibin, and inhibin “inhibits” FSH secretion. The preponderance of evidence indicates that inhibin diminishes FSH secretion by acting at the level of the anterior pituitary gland (not at the level of the hypothalamus).

TESTOSTERONE

The Leydig cells of the testis synthesize and secrete testosterone

Cholesterol is the obligate precursor for androgens, as well as for other steroids produced by the testis. The Leydig cell can synthesize cholesterol de novo from acetyl coenzyme A or can take it up as low-density lipoproteins from the extracellular fluid by receptor-mediated endocytosis (see Chapter 1). The two sources appear to be equally important in humans.

The Leydig cell uses a series of five enzymes to convert cholesterol to testosterone. Three of these enzymes are P-450 enzymes (see Table 50-2). As summarized in Figure 54-5, because 3β-hydroxysteroid dehydrogenase (3β-HSD) can oxidize the A ring of four intermediates, testosterone synthesis from cholesterol can take four pathways. The following is the “preferred” pathway:

1. The pathway for testosterone synthesis begins in the mitochondria, where P-450scc (also called 20, 22-desmolase) removes the long side chain (carbons 22 to 27) from the carbon at position 20 of the cholesterol molecule (27 carbon atoms). The rate-limiting step in the biosynthesis of testosterone, as for other steroid hormones, is the conversion of cholesterol to pregnenolone. LH stimulates this reaction and is the primary regulator of the overall rate of testosterone synthesis by the Leydig cell. LH appears to promote pregnenolone synthesis in two ways. First, it increases the affinity of the enzyme for cholesterol. Second, LH has long-term action in which it increases steroidogenesis in the testis by stimulating synthesis of the SCC enzyme.

2. The product of the SCC-catalyzed reaction is pregnenolone (21 carbon atoms). In the smooth ER (SER), 17α-hydroxylase (P-450c17) then adds a hydroxyl group at position 17 to form 17α-hydroxypregnenolone.

3. In the SER, the 17, 20-desmolase (a different activity of the same P-450c17 whose 17α-hydroxylase activity catalyzes the previous step) removes the side chain from carbon 17 of 17α-hydroxypregnenolone. That side chain begins with carbon 20. The result is a 19-carbon steroid called dehydroepiandrosterone (DHEA).

4. In the SER of the Leydig cell, a 17β-hydroxysteroid dehydrogenase (17β-HSD, which is not a P-450 enzyme) converts the ketone at position 17 to a hydroxyl group to form androstenediol.

5. Finally, 3β-HSD (not a P-450 enzyme) oxidizes the hydroxyl group at position 3 of the A ring to a ketone to form testosterone.

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Figure 54-5 Biosynthesis of testosterone. This scheme summarizes the synthesis of the androgens from cholesterol. The individual enzymes are shown in the horizontal and vertical boxes; they are located in either the SER or the mitochondria. The SCC enzyme that produces pregnenolone is also known as 20, 22 desmolase. The chemical groups modified by each enzyme are highlighted in the reaction product. Four possible pathways from pregnenolone to testosterone are recognized; the preferred pathway in the human testis appears to be the one along the left edge of the figure to androstenediol, followed by oxidation of the A ring to testosterone. Some of these pathways are shared in the biosynthesis of the glucocorticoids and mineralocorticoids (see Fig. 50-2) as well as estrogens (see Fig. 55-9).

In addition, the testis can also use 5α-reductase, which is located in the SER, to convert testosterone to dihydrotestosterone (DHT). However, extratesticular tissue is responsible for most of the production of DHT. The conversion of testosterone to DHT is especially important in certain testosterone target cells (see Chapter 53).

The Leydig cells of the testes make ~95% of the circulating testosterone. Although testosterone is the major secretory product, the testis also secretes pregnenolone, progesterone, 17-hydroxyprogesterone, androstenedione, androsterone, and DHT. Androstenedione is of major importance because it serves as a precursor for extraglandular estrogen formation.

Other organs—such as adipose tissue, skin, and the adrenal cortex—also produce testosterone and other androgens

In men between the ages of 25 and 70 years, the rate of testosterone production remains relatively constant (Table 54-2). Figure 54-4 summarizes the changes in plasma testosterone levels as a function of age in male humans. (See Note: Testosterone Secretion and Production Rates)

Table 54-2 Androgen Production and Turnover

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Several tissues besides the testes—including adipose tissue, brain, muscle, skin, and adrenal cortex—produce testosterone and several other androgens. These substances may be synthesized de novo or produced by peripheral conversion of precursors. Moreover, the peripheral organs and tissues may convert sex steroids to less active forms (Fig. 54-5). Notable sites of extragonadal conversion include the skin and adipose tissue. Androstenedione is converted to testosterone in peripheral tissues. In this case, androstenedione is the precursor for the hormone testosterone. Testosterone can be converted to estradiol or DHT or go “backward” by reversible interconversion to androstenedione. Thus, a potent hormone such as testosterone may also serve as a precursor for a weaker hormone (androstenedione), a hormone with different activities (estradiol), or a more potent hormone having similar activities (DHT). This last example may be illustrated by the effects of DHT on hair follicles, sebaceous glands, and the sex accessories.

The adrenal gland (see Chapter 50) is another source of androgen production in both males and females. Normal human adrenal glands synthesize and secrete the androgens DHEA, conjugated DHEA sulfate, and androstenedione. Essentially, all the DHEA in male plasma is of adrenal origin. However, less than 1% of the total testosterone in plasma is derived from DHEA. As summarized in Table 54-2, the plasma concentration of androstenedione in males is only ~25% that of testosterone. About 20% of androstenedione is generated by peripheral metabolism of other steroids. Although the adrenal gland contributes significantly to the total androgen milieu in males, it does not appear to have significant effects on stimulation and growth of the male accessory organs.

Testosterone acts on target organs by binding to a nuclear receptor

Most testosterone in the circulation is bound to specific binding proteins. About 45% of plasma testosterone is bound to sex hormone–binding globulin (SHBG)—also called testosterone-binding globulin (TeBG), whereas ~55% is bound to serum albumin and corticosteroid-binding globulin (CBG) (see Chapter 50). A small fraction (~2%) of the total circulating testosterone circulates free, or unbound, in plasma. The free form of testosterone enters the cell by passive diffusion and subsequently exerts biological actions or undergoes metabolism by other organs such as the prostate, liver, and intestines (see the next section). The quantity of testosterone entering a cell is determined by the plasma concentration and by the intracellular milieu of enzymes and binding proteins.

Once it diffuses into the cell, testosterone either binds to a high-affinity androgen receptor in the nucleus or is converted to DHT, which also binds to the androgen receptor. The androgen receptor functions as a homodimer (AR/AR) and is a member of the family of nuclear receptors (see Table 4-2) that includes receptors for glucocorticoids, mineralocorticoids, progestins, estrogens, vitamin D, thyroid hormone, and retinoic acid. The gene coding for the androgen receptor is located on the X chromosome. The androgen receptor is a protein with a molecular weight of ~110 kDa. The androgen-AR complex is a transcription factor that binds to hormone response elements on DNA located 5′ from the genes that the androgens control. Interaction between the androgen-AR complex and nuclear chromatin causes marked increases in transcription, ultimately leading to the synthesis of specific proteins. As a result of these synthetic processes, specific cell functions ensue, including growth and development. The presence of the androgen receptor in a cell or tissue determines whether that tissue can respond to androgens.

Whether the active compound in any tissue is DHT or testosterone depends on the presence or absence in that tissue of the microsomal enzyme 5α-reductase, which converts testosterone to DHT. The biological activity of DHT is 30 to 50 times higher than that of testosterone. Some tissues, including the brain, aromatize testosterone to estradiol, and thus the action of this metabolite occurs through the estrogen receptor.

Testosterone and the Aging Man

For a long time, the abrupt hormonal alterations that signal the dramatic changes of female menopause were believed to have no correlate in men. We now know that men do experience a gradual decline in their serum testosterone levels (Fig. 54-4) and that this decline is closely correlated with many of the changes that accompany aging: decreases in bone formation, muscle mass, growth of facial hair, appetite, and libido. The blood hematocrit also decreases. Testosterone replacement can reverse many of these changes by restoring muscle and bone mass and correcting the anemia.

Although the levels of both total and free testosterone decline with age, levels of LH are frequently not elevated. This finding is believed to indicate that some degree of hypothalamic-pituitary dysfunction accompanies aging.

Some of the effects of androgens may be nongenomic. For example, androgens may stimulate hepatic microsomal protein synthesis by a mechanism independent of binding to the androgen receptor. Other evidence indicates that the action of androgens on the prostate gland may occur through the adenylyl cyclase/PKA system (see Chapter 4) and could result in gene activation under some circumstances.

Metabolism of testosterone occurs primarily in the liver and prostate

Only small amounts of testosterone enter the urine without metabolism; this urinary testosterone represents less than 2% of the daily testosterone production. The large remaining balance of testosterone and other androgens is converted in the liver to 17-ketosteroids and in the prostate to DHT. The degradation products of testosterone are primarily excreted in the urine as water-soluble conjugates of either sulfuric acid or glucuronic acid. These conjugated testosterone metabolites are also excreted in the feces.

BIOLOGY OF SPERMATOGENESIS AND SEMEN

Spermatogenesis includes the mitotic divisions of spermatogonia, the meiotic divisions of spermatocytes to haploid spermatids, and maturation to spermatozoa (See Note: Definitions)

Mature spermatozoa are derived from germ cells through a series of complex transformations. When seminiferous tubules are viewed in cross section (Fig. 54-1D), the least mature cells are located adjacent to the basement membrane, whereas the most differentiated germ cells are located nearest the lumen.

As discussed in Chapter 53, the primordial germ cells migrate into the gonad during embryogenesis; these cells become immature germ cells, or spermatogonia (Fig. 54-6). Beginning at puberty and continuing thereafter throughout life, these spermatogonia, which lie next to the basement membrane of the stratified epithelium lining the seminiferous tubules, divide mitotically (Fig. 54-7). The spermatogonia have the normal diploid complement of 46 chromosomes (2N): 22 pairs of autosomal chromosomes plus 1 X and 1 Y chromosome.

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Figure 54-6 Spermatogenesis. Early during embryogenesis, the primordial germ cells migrate to the gonad, where they become spermatogonia. Beginning at puberty, the spermatogonia undergo many rounds of mitotic division. Some of these spermatogonia (2N DNA) enter the first meiotic division, at which time they are referred to as primary spermatocytes. During prophase, each primary spermatocyte has a full complement of duplicated chromosomes (4N DNA). Each primary spermatocyte divides into two secondary spermatocytes, each with a haploid number of duplicated chromosomes (2N DNA). The secondary spermatocyte enters the second meiotic division, producing two spermatids, each of which has a haploid number of unduplicated chromosomes (1N DNA). Further maturation of the spermatids yields the spermatozoa (mature sperm). One primary spermatocyte yields four spermatozoa.

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Figure 54-7 Interaction of the Sertoli cells and sperm. This figure is an idealized high-magnification view of a portion of the wall of a seminiferous tubule (see Fig. 54-1C). A single Sertoli cell spans from the basal lamina to the lumen of the seminiferous tubule. The adjacent Sertoli cells are connected by tight junctions and surround developing germ cells. From the basal lamina to the lumen of the tubule, gradual maturation of the germ cells occurs.

Some of the spermatogonia enter into their first meiotic division and become primary spermatocytes. At the prophase of this first meiotic division, the chromosomes undergo crossing over (see Fig. 53-1). At this stage, each cell has a duplicated set of 46 chromosomes (4N): 22 pairs of duplicated autosomal chromosomes, a duplicated X chromosome, and a duplicated Y chromosome. After completing this first meiotic division, the daughter cells become secondary spermatocytes, which have a haploid number of duplicated chromosomes (2N): 22 duplicated autosomal chromosomes and either a duplicated X or a duplicated Y chromosome. These secondary spermatocytes enter their second meiotic division almost immediately. This division results in smaller cells called spermatids, which have a haploid number of unduplicated chromosomes (1N). Spermatids form the inner layer of the epithelium and are found in rather discrete aggregates inasmuch as the cells derived from a single spermatogonium tend to remain together—with cytoplasm linked in a syncytium—and differentiate synchronously. Spermatids transform into spermatozoa in a process called spermiogenesis, which involves cytoplasmic reduction and differentiation of the tail pieces. Thus, as maturation progresses, developing male gametes decrease in volume. Conversely, maturation leads to an increase in cell number, with each primary spermatocyte producing four spermatozoa, two with an X chromosome and two with a Y chromosome. (See Note: Definitions)

As additional generations of spermatogonia mature, the advanced cells are displaced toward the lumen of the tubule. Groups of spermatogonia at comparable stages of development undergo mitosis simultaneously. Transformation of spermatogonia into functional spermatozoa requires ~74 days. Each stage of spermatogenesis has a specific duration. In humans, the life span of the germ cells is 16 to 18 days for spermatogonia, 23 days for primary spermatocytes, 1 day for secondary spermatocytes, and ~23 days for spermatids. The rate of spermatogenesis is constant and cannot be accelerated by hormones such as gonadotropins or androgens. Germ cells must move forward in their differentiation; if the environment is unfavorable and makes it impossible for them to pursue their differentiation at the normal rate, they degenerate and are eliminated.

The most reliable expression of the sperm production rate is the daily number of sperm cells produced per gram of testicular parenchyma. In 20-year-old men, the production rate is ~6.5 million sperm per gram per day. The rate falls progressively with age and averages ~3.8 million sperm per gram per day in men 50 to 90 years old. This decrease is probably related to the high rate of degeneration of germ cells during meiotic prophase. Among fertile men, those aged 51 to 90 years exhibit a significant decrease in the percentage of morphologically normal and motile spermatozoa.

In summary, three processes occur concurrently in the seminiferous epithelium: (1) an increase in the number of cells by mitosis, (2) a reduction in the number of chromosomes by meiosis, and (3) the production of mature sperm from spermatids by spermiogenesis. Thus, spermatogenesis is a regular, ordered, sequential process resulting in the production of mature male gametes.

It is instructive to consider how spermatogenesis in the male differs from oogenesis in the female. In fact, the two processes differ in each of the three steps just noted: (1) in the female, the mitotic proliferation of germ cells takes place entirely before birth, whereas in the male, spermatogonia proliferate only after puberty and then throughout life; (2) the meiotic divisions of a primary oocyte in the female produce only one mature ovum, whereas in the male, the meiotic divisions of a primary spermatocyte produce four mature spermatozoa; and (3) in the female, the second meiotic division is completed only on fertilization (see Chapter 56) and thus no further development of the cell takes place after the completion of meiosis, whereas in the male, the products of meiosis (the spermatids) undergo substantial further differentiation to produce mature spermatozoa. (See Note: Meiosis in Males versus Females)

The Sertoli cells support spermatogenesis

The Sertoli cells are generally regarded as support or nurse cells for the spermatids (Fig. 54-7). The Sertoli cells are large, polyhedral cells extending from the basement membrane toward the lumen of the seminiferous tubule. Spermatids are located adjacent to the lumen of the seminiferous tubules during the early stages of spermiogenesis and are surrounded by processes of Sertoli cell cytoplasm. Tight junctions connect the adjacent Sertoli cells, to forming a blood-testis barrier—analogous to the blood-brain barrier (see Chapter 11)—that presumably provides a protective environment for developing germ cells. In addition, gap junctions between the Sertoli cells and developing spermatozoa may represent a mechanism for transferring material between these two types of cells. Release of the spermatozoa from the Sertoli cell has been called spermiation. Spermatids progressively move toward the lumen of the tubule and eventually lose all contact with the Sertoli cell after spermiation.

Sperm maturation occurs in the epididymis

The seminiferous tubules open into a network of tubules, the rete testes, which serve as a reservoir for sperm. The rete testes are connected to the epididymis through the efferent ductules (see Chapter 53), which are located near the superior pole of the testicle. The epididymis is a highly convoluted single long duct, 4 to 5 m in total length, on the posterior aspect of the testis. The epididymis can be divided anatomically into three regions: the head (the segment closest to the testis), the body, and the tail.

The Sertoli Cell–Only Syndrome

Investigators have described a group of normally virilized men whose testes are small bilaterally and whose ejaculates contain no sperm cells (azoospermia). The seminiferous tubules of these men are lined by the Sertoli cells, but the tubules show a complete absence of germ cells. The Sertoli cell–only syndrome (or germinal cell aplasia) accounts for 10% to 30% of male infertility secondary to azoospermia and can either be caused by a single-gene defect or be acquired (e.g., as a result of orchitis, alcoholism, toxic agents). The Leydig cell function is usually preserved. Plasma testosterone and LH levels are usually normal, whereas FSH levels are often, but not always, elevated. It is not entirely clear why FSH levels are elevated in these men. This elevation may result from the absence of germ cells or from suboptimal secretion of inhibin by the Sertoli cells, inasmuch as inhibin is a powerful inhibitor of FSH secretion at the level of the anterior pituitary gland. Segments of Sertoli cell–only tubules may be observed in conditions such as orchitis or exposure to other agents that are toxic to the gonads. However, these individuals generally have functional spermatogenesis in the other seminiferous tubules.

Spermatozoa are essentially immotile on completion of spermiogenesis. Thus, transfer of spermatozoa from the seminiferous tubule to the rete testes is passive. Secretions flow from the testes through the epididymis, with assistance by ciliary action of the luminal epithelium and contractility of the smooth muscle elements of the efferent duct wall. Thus, sperm transport through this ductal system is also primarily passive. As noted earlier, ~74 days is required to produce spermatozoa, ~50 days of which is spent in the seminiferous tubule. After leaving the testes, sperm take 12 to 26 days to travel through the epididymis and appear in the ejaculate. The epididymal transit time for men between the ages of 20 and 80 years does not differ significantly.

Sperm are stored in the epididymis, where they undergo a process of maturation before they are capable of progressive motility and fertilization (Table 54-3). Spermatozoa released at ejaculation are fully motile and capable of fertilization, whereas spermatozoa obtained directly from the testis are functionally immature insofar as they cannot penetrate an ovum. However, these immature spermatozoa can fertilize if they are injected into an ovum. During maturation in the epididymis, spermatozoa undergo changes in motility, metabolism, and morphology. Spermatozoa derived from the head (caput) of the epididymis (Fig. 54-1C) are often unable to fertilize ova, whereas larger proportions of spermatozoa captured from the body (corpus) are fertile. Spermatozoa obtained from the tail (cauda) of the epididymis, or from the vas deferens, are almost always capable of fertilization. (See Note: Sperm Maturation)

Table 54-3 Sperm Maturation in the Epididymis

Progressive increase in forward motility

Increased ability to fertilize

Maturation of acrosome

Molecular reorganization of the plasma membrane: Lipids (stabilization of plasma membrane) Proteins (shedding as well as acquisition of new proteins)

Ability to bind to zona pellucida

Acquisition of receptors for proteins of the zona pellucida

Increased disulfide bonds between cysteine residues in sperm nucleoproteins

Topographic regionalization of glycosidic residues

Accumulation of mannosylated residues on the periacrosomal plasma membrane

Decreased cytoplasm and cell volume

The epididymis empties into the vas deferens, which is responsible for the movement of sperm along the tract. The vas deferens contains well-developed muscle layers that facilitate sperm movement. The vas deferens passes through the inguinal canal, traverses the ureter, and continues medially to the posterior and inferior aspect of the urinary bladder, where it is joined by the duct arising from the seminal vesicle; together, they form the ejaculatory duct. The ejaculatory duct enters the prostatic portion of the urethra after passing through the prostate. Sperm are stored in the epididymis as well as in the proximal end of the vas deferens. All these accessory structures depend on androgens secreted by the testis for full functional development.

The accessory male sex glands—the seminal vesicles, prostate, and bulbourethral glands—produce the seminal plasma

Only 10% of the volume of semen (i.e., seminal fluid) is sperm cells. The normal concentration of sperm cells is greater than 20 million/mL, and the typical ejaculate volume is greater than 2 mL. The typical ejaculate content varies between 150 and 600 million spermatozoa.

Aside from the sperm cells, the remainder of the semen (i.e., 90%) is seminal plasma, the extracellular fluid of semen (Table 54-4). Very little seminal plasma accompanies the spermatozoa as they move through the testes and epididymis. The seminal plasma originates primarily from the accessory glands (the seminal vesicles, prostate gland, and the bulbourethral glands). The seminal vesicles contribute ~70% of the volume of semen. Aside from the sperm, the remaining ~20% represents epididymal fluids, as well as secretions of the prostate gland and bulbourethral glands. However, the composition of the fluid exiting the urethral meatus during ejaculation is not uniform. The first fluid to exit is a mixture of prostatic secretions and spermatozoa with epididymal fluid. Subsequent emissions are composed of mainly secretions derived from the seminal vesicle. The first portion of the ejaculate contains the highest density of sperm; it also usually contains a higher percentage of motile sperm cells.

Table 54-4 Normal Values for Semen

Parameter

Value

Volume

2-6 mL

Viscosity

Liquefaction in 1 hr

pH

7-8

Count

≥20 million/mL

Motility

≥50%

Morphology

60% normal

The seminal plasma is isotonic. The pH in the lumen of the epididymis is relatively acidic (6.5 to 6.8) as the result of H+ secretion by clear cells that are analogous to intercalated cells in the nephron. Addition of the relatively alkaline secretions of the seminal vesicles raises the final pH of seminal plasma to between 7.3 and 7.7. The quiescence of epididymal sperm is not well correlated with pH. Spermatozoa generally tolerate alkalinity better than acidity. A pH near neutrality or slightly higher is optimal for the motility and survival of sperm cells in humans and in other species as well.

Seminal plasma contains a plethora of sugars and ions. Fructose and citric acid are contributed to the seminal plasma by the accessory glands, and their concentrations vary with the volume of semen ejaculated. The fructose is produced in the seminal vesicles. In a man with oligospermia (i.e., a low daily sperm output) and a low ejaculate volume (recall that more than half of the ejaculate comes from the seminal vesicles), the absence of fructose suggests obstruction or atresia of the seminal vesicles. Ascorbic acid and traces of B vitamins are also found in human seminal plasma. The prostate gland releases a factor—which contains sugars, sulfate, and a vitamin E derivative—that acts to prevent the clumping of sperm heads. In addition, human semen also contains high concentrations of choline and spermine, although their roles remain to be clarified.

Seminal plasma is also rich in Ca2+, Na+, Mg2+, K+, Cl, and phosphate. Concentrations of Zn2+ and Ca2+ are higher in semen than in any other fluid and most other tissues. Calcium ions stimulate the motility of immature epididymal spermatozoa, but they inhibit the motility of spermatozoa in ejaculates obtained from humans. It appears that the diminished response of sperm to Ca2+ and the acquisition of progressive motility are functions of epididymal maturation.

Semen also contains low-molecular-weight polypeptides and proteins. The free amino acids probably arise from the breakdown of protein after the semen is ejaculated. The amino acids may protect spermatozoa by binding heavy metals, which may be toxic, or by preventing the agglutination of proteins.

Human semen coagulates immediately after ejaculation. Coagulation is followed by liquefaction, which is apparently caused by proteolytic enzymes, which are contained in prostatic secretions. Prostatic secretion is rich in acid phosphatase. The natural substrate for acid phosphatase is phosphorylcholine, which is contributed by the seminal vesicles. Hyaluronidase is also present in human semen, although its functional role remains to be clarified. Hyaluronidase is not a product of the accessory glands; rather, it is contained within the sperm cell cytoplasm and is rapidly released into the seminal plasma. Hyaluronidase may perform a role in facilitating penetration of the oocyte by the sperm cell because of the ability of hyaluronidase to depolymerize hyaluronic acid.

Congenital and Acquired Ductal Obstruction

Genital duct obstruction may be congenital and may result from ductal absence or structural abnormality, or it may be acquired as a result of stricture, infection, or vasectomy. Genital duct obstruction is found in ~7% of infertile men. An uncommon cause of male infertility is congenital absence of the vas deferens, which accounts for as many as 50% of cases of congenital ductal obstruction. These patients generally have azoospermic ejaculates with low volume. Congenital absence of the vas deferens is common in male patients with cystic fibrosis (CF) and is sometimes the only manifestation of CF.

Epididymal abnormalities range from the presence of an incomplete epididymis to the presence of only small portions of the epididymis; in addition, the seminal vesicles are often absent. Spermatogenesis is thought to be normal inasmuch as testicular biopsy specimens demonstrate germ cells in several stages of development. Obstruction of the epididymis may also occur as a result of gonococcal or tuberculous epididymitis. Smallpox and filariasis are common causes of ductal obstruction in areas where these diseases are endemic. Inspissated secretions may occlude the epididymis in men with Young syndrome or CF.

Elective vasectomy, a simple surgical procedure in which a small segment of the vas deferens is removed to ensure male infertility, is currently the leading cause of ductal obstruction.

Azoospermia in men with normal testes is the hallmark of genital duct obstruction. However, when specimens of testicles from men who have had vasectomies are examined microscopically, interstitial fibrosis has been found in as many as 20% of cases. This group exhibits low fertility after elective reversal of vasectomy. When the seminiferous tubules are examined, increased thickness of the tubule wall, an increase in cross-sectional tubular area, and decreased numbers of the Sertoli cells are usually noted. Testosterone and gonadotropin levels are normal in most patients with ductal obstruction.

MALE SEX ACT

Sex steroids influence the central nervous system, even in utero, and play important roles in determining and regulating complex patterns of sexual behavior. However, reproductive behavior is extraordinarily complex and is influenced by numerous factors other than sex steroids, such as one’s genetic constitution, social contacts, and the age at which hormones exert their effects. In this section, I describe the neurophysiology of the male sex act.

The sympathetic and parasympathetic divisions of the autonomic nervous system control the male genital system

The testes, epididymis, male accessory glands, and erectile tissue of the penis receive dual innervation from the sympathetic and parasympathetic branches of the autonomic nervous system (ANS). The penis also receives both somatic efferent (i.e., motor) and afferent (i.e., sensory) innervation through the pudendal nerve (S2 through S4).

Sympathetic Division of the ANS As described in Chapter 15, the preganglionic sympathetic neurons originate in the thoracolumbar segments of the spinal cord (T1 through T12, L1 through L3; see Fig. 14-4). For the lower portion of the sympathetic chain (T5 and lower), the preganglionic fibers may pass through the paravertebral sympathetic trunk and then pass through splanchnic nerves to a series of prevertebral plexuses and ganglia (see later). Once within one of these plexuses or ganglia, the preganglionic fiber may either (1) synapse with the postganglionic fiber or (2) pass on to a more caudal plexus or ganglion without synapsing.

The sympathetic efferent (motor) nerve fibers that are supplied to the male sex organs emanate from five primary prevertebral nerve plexuses (Fig. 54-8): the celiac, superior mesenteric, inferior mesenteric, superior hypogastric, and inferior hypogastric or pelvic plexuses. The celiac plexus is of interest in a discussion of male sex organs only because preganglionic sympathetic fibers pass through this plexus on their way to more caudal plexuses. The superior mesenteric plexus lies on the ventral aspect of the aorta. Preganglionic fibers from the celiac plexus pass through the superior mesenteric plexus on their way to more caudal plexuses.

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Figure 54-8 Innervation of the male genital system. A, The sympathetic innervation of the male genital system involves a series of prevertebral nerve plexuses and ganglia. B, Three motor pathways as well as a sensory pathway are involved in erection: (1) parasympathetic innervation: preganglionic parasympathetic fibers arise from the sacral spinal cord and from the pelvic nerve, and they synapse in the pelvic plexus; the postganglionic parasympathetic fibers follow the cavernous nerve to the penile corpora and vasculature; (2) sympathetic innervation: preganglionic sympathetic fibers exit the thoracolumbar cord and synapse in one of several prevertebral ganglia; postganglionic fibers reach the genitalia through the hypogastric nerve, the pelvic plexus, and the cavernous nerves; and (3) somatic innervation: somatic (i.e., not autonomic) motor fibers originate in the sacral spinal cord and form the motor branch of the pudendal nerve; the fibers innervate the striated penile muscles. In addition to these three motor pathways, there is also an afferent pathway from the penis. The dorsal nerve of the penis is the main terminus of the sensory pudendal nerve and is the sole identifiable root for tactile sensory information from the penis.

Most of the preganglionic sympathetic fibers pass from the superior mesenteric plexus to the inferior mesenteric plexus, although some of the nerves pass directly to the hypogastric plexus. The superior hypogastric plexus is a network of nerves located distal to the bifurcation of the aorta. The inferior hypogastric or pelvic plexus receives sympathetic supply from the hypogastric nerve.

In addition to these five plexuses, two other small ganglia are of interest. The spermatic ganglion is located near the origin of the testicular artery from the aorta. The spermatic ganglion receives fibers directly from the lumbar sympathetic nerves and from branches of several other ganglia. The hypogastric (or pelvic) ganglion is located at the junction of the hypogastric and pelvic nerve trunks.

Parasympathetic Division of the ANS The preganglionic parasympathetic neurons relating to the male reproductive system originate in the sacral segments of the spinal cord (S2 through S4; see Fig. 14-4). These fibers pass through the pelvic nerve to the pelvic plexus, where they synapse with the postganglionic parasympathetic neurons.

Visceral Afferents Sensory fibers are present in all the nerve tracts described (see Fig. 14-2). These fibers travel (1) with the pelvic nerves to the dorsal root of the spinal cord, (2) with the sacral nerves to the sympathetic trunk and then rising in the sympathetic trunk to the spinal cord, or (3) with the hypogastric nerve and ascending to more rostral prevertebral plexuses and then to the spinal cord. The principal functions of motor innervation to the male accessory glands include control of smooth muscle contraction, vascular tone, and epithelial secretory activity.

Erection is primarily under parasympathetic control

The two corpora cavernosa and the corpus spongiosum are usually coordinated in their erection (i.e., tumescence) and detumescence. However, they may act independently inasmuch as their vascular and neuroeffector systems are relatively independent. During erection, relaxation of the smooth muscles of the corpora allows increased inflow of blood to fill the corporal interstices and results in an increase in volume and rigidity. Vascular actions of the smooth muscles of the corpora and the perineal striated muscles are coordinated. For example, contraction of the striated muscles overlying the vascular reservoirs of the penile bulb increases the pressure of the blood in the corpora and promotes increased rigidity. The three major efferent (i.e., motor) pathways for the regulation of penile erection are parasympathetic (pelvic nerve), sympathetic (hypogastric nerve), and somatic (pudendal nerve). (See Note: Nonvascular Contributions to Erection)

Parasympathetic Innervation The first and most important pathway for erection is the parasympathetic division of the ANS. These fibers derive from the lumbar and sacral portions of the spinal cord and travel through the pelvic nerve, the pelvic plexus, and the cavernous nerve to the penile corpora and vasculature (Fig. 54-8). This pathway is almost entirely parasympathetic, but apparently it also carries some sympathetic fibers (see later). The parasympathetic activity results in vasodilatation of the penile blood vessels, thus increasing blood flow to the cavernous tissue and engorging the organ with blood. In erectile tissue, parasympathetic postganglionic terminals release acetylcholine (ACh) and nitric oxide (NO), similar to the system discussed in Chapter 14 (see Fig. 14-11). First, ACh may bind to M3muscarinic receptors on endothelial cells. Through Gαq, these receptors would then lead to stimulation of PLC, increased [Ca2+]i, activation of NO synthase, and local release of NO (see Chapter 3). Second, the nerve terminals may also directly release NO. Regardless of the source of NO, this gas diffuses to the vascular smooth muscle cell, where it stimulates guanylyl cyclase to generate cGMP, which, in turn, causes vasodilation (see Chapter 23). See the box titled Erectile Dysfunction.

Sympathetic Innervation The second pathway, which is thought to be entirely sympathetic, exits the thoracolumbar spinal cord. The preganglionic fibers then course through the least splanchnic nerve, the sympathetic chain, and the inferior mesenteric ganglion. The postganglionic fibers reach the genitalia through the hypogastric nerve, the pelvic plexus, and the cavernous nerves (see earlier). Tonic sympathetic activity contributes to penile flaccidity. During erection, a decrease in this sympathetic tone allows relaxation of the corpora and thus contributes to tumescence.

Somatic Innervation The third pathway is the motor branch of the pudendal nerve. It has primarily somatic (i.e., not autonomic) fibers, originates in the sacral spinal cord, and innervates the striated penile muscles. Contraction of the striated ischiocavernosus muscle during the final phase of erection increases pressure inside the corpora cavernosa to values that are even higher than systemic arterial pressure. Contraction of the striated bulbospongiosus muscle increases engorgement of the corpus spongiosum, and thus the glans penis, by pumping blood up from the penile bulb underlying this muscle. Humans are apparently less dependent on their striated penile muscle for achieving and maintaining erection. However, these muscles are active during ejaculation and contribute to the force of seminal expulsion. Postganglionic neurons release other so-called nonadrenergic, noncholinergic neurotransmitters (see Chapter 23)—including NO—that also contribute to the erectile process.

Afferent Innervation The penis also has an afferent pathway. The dorsal nerve of the penis is the main terminus of the sensory pudendal nerve and is the sole identifiable root for tactile sensory information from the penis.

Emission is primarily under sympathetic control

The term seminal emission refers to movement of the ejaculate into the prostatic or proximal part of the urethra. Under some conditions, seminal fluid escapes episodically or continuously from the penile urethra; this action is also referred to as emission. Emission is the result of peristaltic contractions of the ampullary portion of the vas deferens, the seminal vesicles, and the prostatic smooth muscles. These actions are accompanied by constriction of the internal sphincter of the bladder, which is under sympathetic control (see Chapter 33), thus preventing retrograde ejaculation of sperm into the urinary bladder (see the box on Ejaculatory Dysfunction: Retrograde Ejaculation).

The rhythmic contractions involved in emission result from contraction of smooth muscle. In contrast to other visceral organ systems, the smooth muscle cells of the male ducts and accessory glands fail to establish close contact with one another and show limited electrotonic coupling. In the male accessory glands, individual smooth muscle cells are directly innervated and have only limited spontaneous activity (i.e., multiunit smooth muscle; see Chapter 9). This combination allows a fast, powerful, and coordinated response to neural stimulation.

Motor Activity of the Duct System A gradation between two forms of smooth muscle activity occurs along the male duct system. The efferent ducts and proximal regions of the epididymis are sparsely innervated, but they display spontaneous contractions that can be increased through adrenergic agents acting on α-adrenergic receptors. In contrast, the distal end of the epididymis and the vas deferens are normally quiescent until neural stimulation is received during the ejaculatory process. Contraction of the smooth muscle of the distal epididymis, vas deferens, and accessory sex glands occurs in response to stimulation of the sympathetic fibers in the hypogastric nerve and release of norepinephrine. Indeed, an intravenous injection of epinephrine or norepinephrine can induce seminal emission, whereas selective chemical sympathectomy or an adrenergic antagonist can inhibit seminal emission. The role of parasympathetic innervation to the musculature of these ducts and accessory glands in the male is not entirely clear. Parasympathetic fibers may be preferentially involved in basal muscular activity during erection (i.e., before ejaculation) and during urination.

Erectile Dysfunction

Sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) are reasonably well tolerated oral medications used to treat erectile dysfunction. Men with erectile dysfunction experience significant improvement in rigidity and duration of erections after treatment with these medications.

As indicated in the text, the smooth muscle tone of the human corpus cavernosum is regulated by the synthesis and release of NO, which raises [cGMP]i in vascular smooth muscle cells, thereby relaxing the smooth muscle and leading to vasodilatation and erection. Breakdown of cGMP by cGMP-specific phosphodiesterase type 5 limits the degree of vasodilation and, in the case of the penis, limits erection. Sildenafil, vardenafil, and tadalafil are highly selective, high-affinity inhibitors of cGMP-specific phosphodiesterase type 5 and thereby raise [cGMP]i in smooth muscle and improve erection in men with erectile dysfunction.

The new medications are attractive because they have established efficacy that benefit most men with insufficient erection. These medications stimulate erection only during sexual arousal and thus have a rather natural effect. They can be taken as little as 1 hour before planned sexual activity.

One of the side effects of sildenafil is “blue vision,” a consequence of the effect of inhibiting cGMP-specific phosphodiesterase in the retina. In individuals taking other vasodilators, sildenafil can lead to sudden death. In women, sildenafil may improve sexual function by increasing blood flow to the accessory secretory glands (see Chapter 55).

Secretory Activity of the Accessory Glands The effect of autonomic innervation on the secretory activity of the epithelia of the male accessory glands has been studied extensively. Electrical stimulation of the pelvic nerves (parasympathetic) induces copious secretions. The secretory rate depends on the frequency of stimulation and can be blocked with atropine, a competitive inhibitor of muscarinic ACh receptors. Cholinergic drugs induce the formation of copious amounts of secretions when these drugs are administered systemically. Secretions from the bulbourethral glands also contribute to the ejaculate. The bulbourethral glands do not store secretions but produce them during coitus. The secretory activity of the bulbourethral glands also appears to be under cholinergic control inasmuch as administration of atropine causes marked inhibition of secretion from these glands.

Ejaculatory Dysfunction: Retrograde Ejaculation

As noted in the text, emission is normally accompanied by constriction of the internal urethral sphincter. Retrograde ejaculation occurs when this sphincter fails to constrict. As a result, the semen enters the urinary bladder rather than passing down the urethra. Retrograde ejaculation should be suspected in patients who report absent or small-volume ejaculation after orgasm. The presence of more than 15 sperm per high-power field in urine specimens obtained after ejaculation confirms the presence of retrograde ejaculation.

Lack of emission or retrograde ejaculation may result from any process that interferes with innervation of the vas deferens and bladder neck. Several medical illnesses, such as diabetes mellitus (which can cause peripheral neuropathy) and multiple sclerosis, or the use of pharmaceutical agents that interfere with sympathetic tone can lead to retrograde ejaculation. Retrograde ejaculation may also occur as a result of nerve damage associated with certain surgical procedures, including bladder neck surgery, transurethral resection of the prostate, colorectal surgery, and retroperitoneal lymph node dissection. Retrograde ejaculation from causes other than surgery involving the bladder neck may be treated with pharmacological therapy. Sympathomimetic drugs such as phentolamine (an α-adrenergic agonist), ephedrine (which enhances norepinephrine release), and imipramine (which inhibits norepinephrine re-uptake by presynaptic terminals) may promote normal (i.e., anterograde) ejaculation by increasing the tone of the vas deferens (propelling the seminal fluid) and the internal sphincter (preventing retrograde movement).

Control of the motor activity of the ducts and of the secretory activity of the accessory glands is complex and involves both the sympathetic and the parasympathetic divisions of the ANS. The central nervous system initiates and coordinates all these activities.

Ejaculation is under control of a spinal reflex

As discussed, seminal emission transports semen to the proximal (posterior) part of the urethra. Ejaculation is the forceful expulsion of this semen from the urethra. Ejaculation is normally a reflex reaction triggered by the entry of semen from the prostatic urethra into the bulbous urethra. Thus, emission sets the stage for ejaculation. The ejaculatory process is a spinal cord reflex, although it is also under considerable cerebral control. The afferent (i.e., sensory) impulses reach the sacral spinal cord (S2 through S4) and trigger efferent activity in the somatic motor neurons that travel through the pudendal nerve. The resulting rhythmic contractions of the striated muscles of the perineal area—including the muscles of the pelvic floor, as well as the ischiocavernosus and bulbospongiosus muscles—forcefully propel the semen through the urethra through the external meatus. In addition, spasmodic contractions of the muscles of the hips and the anal sphincter generally accompany ejaculation.

Neuronal Lesions Affecting Erection and Ejaculation

Erectile dysfunction is often associated with disorders of the central and peripheral nervous systems. Spinal cord disease and peripheral neuropathies are of particular interest, and spinal cord injuries have been studied in some detail. Erectile capacity is usually preserved in men with lesions of the premotor neurons (neurons that project from the brain to the spinal cord; Table 54-5). In these men, reflexogenic erections occur in 90% to 100% of cases, whereas psychogenic erections do not occur because the pathways from the brain are blocked. Ejaculation is more significantly impaired in upper than in lower motor neuron lesions, presumably because of loss of the psychogenic component.

Table 54-5 Effects of Neural Lesions on Erection and Ejaculation

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A clinically important feature of the spinal segmentation of nerve roots for generating erection (i.e., thoracolumbar and lumbosacral) is that spinal or peripheral nerve damage may affect only one of the effector systems. Because the lumbosacral system also carries most of the penile afferents, erection in response to penile stimulation (reflexogenic) is most affected by damage to the lower spinal cord or the nerves that project there. Evidence from men with spinal injuries in the T10 through T12 region has implicated the sympathetic thoracolumbar pathway in mediating erections resulting from sexual stimuli received through the cranial nerves or generated within the brain as memories, fantasies, or dreams. In men with lower motor neuron lesions, reflexogenic erections are absent. However, psychogenic erections still occur in most men with incomplete lesions and in about one fourth of men with complete lesions. It remains uncertain whether this sympathetic pathway is normally the principal route for psychogenic erections or whether it just assumes the role when lumbosacral parasympathetic pathways are damaged.

Orgasm is a term best restricted to the culmination of sexual excitation, as generally applied to both men and women. Orgasm is the cognitive correlation of ejaculation in the male human. Although orgasm, the pleasurable sensation that accompanies ejaculation, is not well understood, clearly, it is as much a central phenomenon as it is a peripheral one.

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