Ganong’s Review of Medical Physiology, 24th Edition

CHAPTER 23 Function of the Male Reproductive System


OBJECTIVES

After studying this chapter, you should be able to:



image Name the key hormones secreted by Leydig cells and Sertoli cells of the testes.

image Outline the steps involved in spermatogenesis.

image Outline the mechanisms that produce erection and ejaculation.

image Know the general structure of testosterone, and describe its biosynthesis, transport, metabolism, and actions.

image Describe the processes involved in regulation of testosterone secretion.


INTRODUCTION

The role for a functional, secreting testis in the formation of male genitalia, the action of male hormones on the brain in early development, and development of the male reproductive system through adolescence and into adulthood were discussed in the previous chapter. As observed in the female, male gonads have a dual function: the production of germ cells (gametogenesis) and the secretion of sex hormones. The androgens are the steroid sex hormones that are masculinizing in their action. The testes secrete large amounts of androgens, principally testosterone, but they also secrete small amounts of estrogens. Unlike that observed in females, male gonadotropin secretion is noncyclical, and once mature, male gonadal function slowly declines with advancing age, but the ability to produce viable gametes persists. In this chapter we will focus discussion on the structure and physiology of the mature male reproductive system.

THE MALE REPRODUCTIVE SYSTEM

STRUCTURE

The testes are made up of loops of convoluted seminiferous tubules, in the walls of which the spermatozoa are formed from the primitive germ cells (spermatogenesis). Both ends of each loop drain into a network of ducts in the head of the epididymis. From there, spermatozoa pass through the tail of the epididymis into the vas deferens. They enter through the ejaculatory ducts into the urethra in the body of the prostate at the time of ejaculation (Figure 23–1). Between the tubules in the testes are nests of cells containing lipid granules, the interstitial cells of Leydig (Figures 23–2 and 23–3), which secrete testosterone into the bloodstream. The spermatic arteries to the testes are tortuous, and blood in them runs parallel but in the opposite direction to blood in the pampiniform plexus of spermatic veins. This anatomic arrangement may permit countercurrent exchange of heat and testosterone. The principles of countercurrent exchange are considered in detail in relation to the kidney in Chapter 37.

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FIGURE 23–1 Anatomical features of the male reproductive system. Left: Male reproductive system. Right: Duct system of the testis.

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FIGURE 23–2 Section of human testis.

GAMETOGENESIS & EJACULATION

Blood–Testis Barrier

The walls of the seminiferous tubules are lined by primitive germ cells and Sertoli cells, large, complex glycogen-containing cells that stretch from the basal lamina of the tubule to the lumen (Figure 23–3). Germ cells must stay in contact with Sertoli cells to survive; this contact is maintained by cytoplasmic bridges. Tight junctions between adjacent Sertoli cells near the basal lamina form a blood–testis barrier that prevents many large molecules from passing from the interstitial tissue and the part of the tubule near the basal lamina (basal compartment) to the region near the tubular lumen (adluminal compartment) and the lumen. However, steroids penetrate this barrier with ease, and evidence suggests that some proteins also pass from the Sertoli cells to the Leydig cells, and vice versa, to function in a paracrine fashion. In addition, maturing germ cells must pass through the barrier as they move to the lumen. This appears to occur without disruption of the barrier by coordinated breakdown of the tight junctions above the germ cells and formation of new tight junctions below them.

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FIGURE 23–3 Seminiferous epithelium. Note that maturing germ cells remain connected by cytoplasmic bridges through the early spermatid stage and that these cells are closely invested by Sertoli cell cytoplasm as they move from the basal lamina to the lumen. (Reproduced with permission from Junqueira LC, Carneiro J: Basic Histology: Text & Atlas, 10th ed. McGraw-Hill, 2003.)

The fluid in the lumen of the seminiferous tubules is quite different from plasma; it contains very little protein and glucose but is rich in androgens, estrogens, K+, inositol, and glutamic and aspartic acids. Maintenance of its composition depends on the blood–testis barrier. The barrier also protects the germ cells from bloodborne noxious agents, prevents antigenic products of germ cell division and maturation from entering the circulation and generating an autoimmune response, and may help establish an osmotic gradient that facilitates movement of fluid into the tubular lumen.

Spermatogenesis

Spermatogonia, the primitive germ cells next to the basal lamina of the seminiferous tubules, mature into primary spermatocytes (Figure 23–3). This process begins during adolescence. The primary spermatocytes undergo meiotic division, reducing the number of chromosomes. In this two-stage process, they divide into secondary spermatocytes and then into spermatids, which contain the haploid number of 23 chromosomes. The spermatids mature into spermatozoa (sperm). As a single spermatogonium divides and matures, its descendants remain tied together by cytoplasmic bridges until the late spermatid stage. This arrangement helps to ensure synchrony of the differentiation of each clone of germ cells. The estimated number of spermatids formed from a single spermatogonium is 512. The formation of a mature sperm from a primitive germ cell by spermatogenesis in humans spans approximately 74 days.

Each sperm is an intricate motile cell, rich in DNA, with a head that is made up mostly of chromosomal material (Figure 23–4). Covering the head like a cap is the acrosome, a lysosome-like organelle rich in enzymes involved in sperm penetration of the ovum and other events associated with fertilization. The motile tail of the sperm is wrapped in its proximal portion by a sheath holding numerous mitochondria. The membranes of late spermatids and spermatozoa contain a special small form of angiotensin converting enzyme called germinal angiotensin converting enzyme (gACE). Germinal ACE is transcribed from the same gene as the somatic ACE (sACE); however, gACE displays tissue specific expression based on alternative transcription initiation sites and alternate splicing patterns. The full function of gACE has yet to be elucidated, although gACE-specific knockout mouse models are sterile.

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FIGURE 23–4 Human spermatozoon, profile view. Note the acrosome, an organelle that covers half the sperm head inside the plasma membrane of the sperm. (Reproduced with permission from Junqueira LC, Carneiro J: Basic Histology: Text & Atlas, 11th ed. McGraw-Hill, 2005.)

Spermatids mature into spermatozoa in deep folds of the cytoplasm of the Sertoli cells (Figure 23–3). Mature spermatozoa are released from the Sertoli cells and become free in the lumens of the tubules. The Sertoli cells secrete androgen-binding protein (ABP), inhibin, and MIS. They do not synthesize androgens, but they contain aromatase (CYP19), the enzyme responsible for conversion of androgens to estrogens, and they can produce estrogens. ABP probably functions to maintain a high, stable supply of androgen in the tubular fluid. Inhibin inhibits follicle-stimulating hormone (FSH) secretion.

FSH and androgens maintain the gametogenic function of the testis. After hypophysectomy, injection of luteinizing hormone (LH) produces a high local concentration of androgen in the testes, and this maintains spermatogenesis. The stages from spermatogonia to spermatids appear to be androgen-independent. However, the maturation from spermatids to spermatozoa depends on androgen acting on the Sertoli cells in which the developing spermatozoa are embedded. FSH acts on the Sertoli cells to facilitate the last stages of spermatid maturation. In addition, it promotes the production of ABP.

An interesting observation is that the estrogen content of the fluid in the rete testis (Figure 23–1) is high, and the walls of the rete testis contain numerous α estrogen receptors (ERα). In this region, fluid is reabsorbed and the spermatozoa are concentrated. If this does not occur, the sperm entering the epididymis are diluted in a large volume of fluid, resulting in reduced fertility.

Further Development of Spermatozoa

Spermatozoa leaving the testes are not fully mobile. They continue their maturation and acquire motility during their passage through the epididymis. Motility is obviously important in vivo, but fertilization occurs in vitro if an immotile spermatozoon from the head of the epididymis is microinjected directly into an ovum. The ability to move forward (progressive motility), which is acquired in the epididymis, involves activation of a unique set of proteins from the CatSper family, which are localized to the principal piece of the sperm tail. CatSpers form an alkaline-sensitive Ca2+ channel that becomes more active as the sperm go from the acidic vagina (pH ∼5) to the cervical mucus (pH ∼8). Sperm from knockout mice that do not express CatSper1-4 have altered motility and are infertile, emphasizing the important role of these proteins. In addition, spermatozoa express olfactory receptors, and ovaries produce odorant-like molecules. Recent evidence indicates that these molecules and their receptors interact, fostering movement of the spermatozoa toward the ovary (chemotaxis).

Ejaculation of the spermatozoon involves contractions of the vas deferens mediated in part by P2X receptors, ligand-gated cation channels that respond to ATP (see Chapter 7), and fertility is reduced in mice in which these receptors are knocked out.

Once ejaculated into the female, the spermatozoa move up the uterus to the isthmus of the uterine tubes, where they slow down and undergo capacitation. This further maturation process involves two components: increasing the motility of the spermatozoa and facilitating their preparation for the acrosome reaction. However, the role of capacitation appears to be facilitatory rather than obligatory, because fertilization is readily produced in vitro. From the isthmuses the capacitated spermatozoa move rapidly to the tubal ampullas, where fertilization takes place.

Effect of Temperature

Spermatogenesis requires a temperature considerably lower than that of the interior of the body. The testes are normally maintained at a temperature of about 32°C. They are kept cool by air circulating around the scrotum and probably by heat exchange in a countercurrent fashion between the spermatic arteries and veins. When the testes are retained in the abdomen or when, in experimental animals, they are held close to the body, degeneration of the tubular walls and sterility result. Situations that increase heat around the testes in humans (eg, hot baths (43–45°C for 30 min/d) and insulated athletic supporters) can reduce sperm counts, in some cases by 90%. However, the reductions produced in this manner are not consistent enough to make the procedures reliable forms of male contraception. In addition, evidence suggests a seasonal effect in men, with sperm counts being greater in the winter regardless of the temperature to which the scrotum is exposed.

Semen

The fluid that is ejaculated at the time of orgasm, the semen, contains sperm and the secretions of the seminal vesicles, prostate, Cowper’s glands, and, probably, the urethral glands (Table 23–1). An average volume per ejaculate is 2.5–3.5 mL after several days of abstinence from sexual activity. The volume of semen and the sperm count decrease rapidly with repeated ejaculation. Even though it takes only one sperm to fertilize the ovum, each milliliter of semen normally contains about 100 million sperm. Reduction in sperm production is associated with infertility: 50% of men with counts of 20–40 million/mL and essentially all of those with counts under 20 million/mL are sterile. The presence of many morphologically abnormal or immotile spermatozoa also correlates with infertility. The prostaglandins in semen, which come from the seminal vesicles, are at high concentrations, but their function in semen is unknown. The causes of male infertility, as well as the underlying mechanisms of sperm in fertilization, are used as clues in developing male contraception (Clinical Box 23–1).

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TABLE 23–1 Composition of human semen.


CLINICAL BOX 23–1



Male Contraception

Several methods independent of physical intervention (such as hormonal control of sperm development; targeting of proteins important in fertilization (eg, CatSpers) and the use of natural compounds that limit sperm function) have been explored as male contraceptives. However, considering the number of sperm and their ability to regenerate, methods that sufficiently reduce sperm production or limit function with an absence of side effects have been difficult to obtain. In lieu of pharmacological control, the most common male contraception continues to be bilateral ligation of the vas deferens (vasectomy), a relatively safe and convenient contraceptive procedure. Interestingly, ∼50% of the men who have been vasectomized develop antibodies against spermatozoa; in monkeys the presence of such antibodies is associated with a higher incidence of infertility after restoration of the patency of the vas. However, the anti-sperm antibodies do not appear to have any other adverse effects. Alternatives to ligation are vas occlusion methods, such as silicone plugs, that aim to block the vas deferens while leaving the tube intact, making reversal easier if desired. Not surprisingly, such methods are not as effective as traditional vasectomy.


THERAPEUTIC HIGHLIGHTS

Vasectomy reversal: Whereas it was once quite difficult to restore the patency of the vas in those wishing to restore fertility, the success rate for such operations has improved steadily. Successful reversal of vasectomy usually results in meaningful sperm counts within months, although delays of a year or more are not unusual. The ultimate success, as measured by pregnancy, is recorded in ∼50% of reversals within 2 years.



Human sperm move at a speed of about 3 mm/min through the female genital tract. Sperm reach the uterine tubes 30–60 min after copulation. Contractions of the female organs may facilitate the transport of the sperm to the uterine tubes.

Erection

Erection is initiated by dilation of the arterioles of the penis. As the erectile tissue of the penis fills with blood, the veins are compressed, blocking outflow and adding to the turgor of the organ. The integrating centers in the lumbar segments of the spinal cord are activated by impulses in afferents from the genitalia and descending tracts that mediate erection in response to erotic psychologic stimuli. The efferent parasympathetic fibers are in the pelvic splanchnic nerves (nervi erigentes). The fibers presumably release acetylcholine and the vasodilator vasoactive intestinal polypeptide (VIP) as cotransmitters (see Chapter 7).

Nonadrenergic noncholinergic fibers are also present in the nervi erigentes, and these contain large amounts of nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide (NO; see Chapter 32). NO activates soluble guanylyl cyclase, resulting in increased production of cyclic GMP (cGMP), and cGMP is a potent vasodilator. Injection of inhibitors of NO synthase prevents the erection normally produced by stimulation of the pelvic nerve in experimental animals. Thus, it seems clear that NO plays a prominent role in the production of erection. The drugs sildenafil, tadalafil, and vardenafil all inhibit the breakdown of cGMP by phosphodiesterases and have gained worldwide fame for the treatment of erectile dysfunction. The multiple phosphodiesterases (PDEs) in the body have been divided into seven isoenzyme families, and these drugs are all most active against PDE V, the type of phosphodiesterase found in the corpora cavernosa (Clinical Box 5–7). It is worth noting, however, that these drugs can also produce significant inhibition of PDE VI (and others, if taken at high doses). Phosphodiesterase VI is found in the retina, and one of the side effects of these drugs is a transient loss of the ability to discriminate between blue and green (see Chapter 9).

Normally, erection is terminated by sympathetic vasoconstrictor impulses to the penile arterioles.

Ejaculation

Ejaculation is a two-part spinal reflex that involves emission, the movement of the semen into the urethra; and ejaculation proper, the propulsion of the semen out of the urethra at the time of orgasm. The afferent pathways are mostly fibers from touch receptors in the glans penis that reach the spinal cord through the internal pudendal nerves. Emission is a sympathetic response, integrated in the upper lumbar segments of the spinal cord and effected by contraction of the smooth muscle of the vasa deferentia and seminal vesicles in response to stimuli in the hypogastric nerves. The semen is propelled out of the urethra by contraction of the bulbocavernosus muscle, a skeletal muscle. The spinal reflex centers for this part of the reflex are in the upper sacral and lowest lumbar segments of the spinal cord, and the motor pathways traverse the first to third sacral roots and the internal pudendal nerves.

PSA

The prostate produces and secretes into the semen and the bloodstream a 30 kDa serine protease generally called prostate specific antigen (PSA). The gene for PSA has two androgen response elements. PSA hydrolyzes the sperm motility inhibitor semenogelin in semen, and it has several substrates in plasma, but its precise function in the circulation is unknown. An elevated plasma PSA occurs in prostate cancer and has been widely used as a screening test for this disease. However, PSA is also elevated in benign prostatic hyperplasia and prostatitis, and the effectiveness of PSA screening as a sole tool in diagnosis of prostate cancer has been called into question.

ENDOCRINE FUNCTION OF THE TESTES

Chemistry & Biosynthesis of Testosterone

Testosterone, the principal hormone of the testes, is a C19 steroid with a hydroxyl group in the 17 position (Figure 23–5). It is synthesized from cholesterol in the Leydig cells and is also formed from androstenedione secreted by the adrenal cortex. The biosynthetic pathways in all endocrine organs that form steroid hormones are similar, the organs differing only in the enzyme systems they contain. In the Leydig cells, the 11- and 21-hydroxylases found in the adrenal cortex (see Figure 20–7) are absent, but 17(α-hydroxylase is present. Pregnenolone is therefore hydroxylated in the 17 position and then subjected to side chain cleavage to form dehydroepiandrosterone. Androstenedione is also formed via progesterone and 17-hydroxyprogesterone, but this pathway is less prominent in humans. Dehydroepiandrosterone and androstenedione are then converted to testosterone.

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FIGURE 23–5 Biosynthesis of testosterone. The formulas of the precursor steroids are shown in Figure 22–7. Although the main secretory product of the Leydig cells is testosterone, some of the precursors also enter the circulation.

The secretion of testosterone is under the control of LH, and the mechanism by which LH stimulates Leydig cells involves increased formation of cAMP via the G protein-coupled LH receptor and Gs. Cyclic AMP increases the formation of cholesterol from cholesterol esters and the conversion of cholesterol to pregnenolone via the activation of protein kinase A.

Secretion

The testosterone secretion rate is 4–9 mg/d (13.9–31.33 μmol/d) in normal adult males. Small amounts of testosterone are also secreted in females, with the major source being the ovary, but possibly from the adrenal as well.

Transport & Metabolism

Ninety-eight per cent of the testosterone in plasma is bound to protein: 65% is bound to a β-globulin called gonadal steroid-binding globulin (GBG) or sex steroid-binding globulin, and 33% to albumin (Table 23–2). GBG also binds estradiol. The plasma testosterone level (free and bound) is 300–1000 ng/dL (10.4–34.7 nmol/L) in adult men (Figure 22–8), compared with 30–70 ng/dL (1.04–2.43 nmol/L) in adult women. It declines somewhat with age in males.

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TABLE 23–2 Distribution of gonadal steroids and cortisol in plasma.

A small amount of circulating testosterone is converted to estradiol, but most of the testosterone is converted to 17-ketosteroids, principally androsterone and its isomer etiocholanolone (Figure 23–6), and excreted in the urine. About two thirds of the urinary 17-ketosteroids are of adrenal origin, and one third are of testicular origin. Although most of the 17-ketosteroids are weak androgens (they have 20% or less the potency of testosterone), it is worth emphasizing that not all 17-ketosteroids are androgens and not all androgens are 17-ketosteroids. Etiocholanolone, for example, has no androgenic activity, and testosterone itself is not a 17-ketosteroid.

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FIGURE 23–6 Two 17-ketosteroid metabolites of testosterone.

Actions

In addition to their actions during development, testosterone and other androgens exert an inhibitory feedback effect on pituitary LH secretion; develop and maintain the male secondary sex characteristics; exert an important protein-anabolic, growth-promoting effect; and, along with FSH, maintain spermatogenesis.

Secondary Sex Characteristics

The widespread changes in hair distribution, body configuration, and genital size that develop in boys at puberty—the male secondary sex characteristics—are summarized in Table 23–3. The prostate and seminal vesicles enlarge, and the seminal vesicles begin to secrete fructose. This sugar appears to function as the main nutritional supply for the spermatozoa. The psychic effects of testosterone are difficult to define in humans, but in experimental animals, androgens provoke boisterous and aggressive play. The effects of androgens and estrogens on sexual behavior are considered in detail in Chapter 15. Although body hair is increased by androgens, scalp hair is decreased (Figure 23–7). Hereditary baldness often fails to develop unless dihydrotestosterone (DHT) is present.

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FIGURE 23–7 Hairline in children and adults. The hairline of the woman is like that of the child, whereas that of the man is indented in the lateral frontal region.

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TABLE 23–3 Changes at puberty in boys (male secondary sex characteristics).

Anabolic Effects

Androgens increase the synthesis and decrease the breakdown of protein, leading to an increase in the rate of growth. It used to be argued that they cause the epiphyses to fuse to the long bones, thus eventually stopping growth, but it now appears that epiphysial closure is due to estrogens (see Chapter 21). Secondary to their anabolic effects, androgens cause moderate image, and image retention; and they also increase the size of the kidneys. Doses of exogenous testosterone that exert significant anabolic effects are also masculinizing and increase libido, which limits the usefulness of the hormone as an anabolic agent in patients with wasting diseases. Attempts to develop synthetic steroids in which the anabolic action is separated from the androgenic action have not been successful.

Mechanism of Action

Like other steroids, testosterone binds to an intracellular receptor, and the receptor/steroid complex then binds to DNA in the nucleus, facilitating transcription of various genes. In addition, testosterone is converted to DHT by 5α-reductase in some target cells (Figure 23–5 and Figure 23–8), and DHT binds to the same intracellular receptor as testosterone. DHT also circulates, with a plasma level that is about 10% of the testosterone level. Testosterone–receptor complexes are less stable than DHT–receptor complexes in target cells, and they conform less well to the DNA-binding state. Thus, DHT formation is a way of amplifying the action of testosterone in target tissues. Humans have two 5α-reductases that are encoded by different genes. Type 1 5α-reductase is present in skin throughout the body and is the dominant enzyme in the scalp. Type 2 5α-reductase is present in genital skin, the prostate, and other genital tissues.

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FIGURE 23–8 Schematic diagram of the actions of testosterone (solid arrows) and dihydrotestosterone (dashed arrows). Note that they both bind to the same receptor, but DHT binds more effectively. (Reproduced with permission from Wilson JD, Griffin JE, Russell W: Steroid 5α-reductase 2 deficiency. Endocr Rev 1993;14:577. Copyright © 1993 by The Endocrine Society.)

Testosterone–receptor complexes are responsible for the maturation of Wolffian duct structures and consequently for the formation of male internal genitalia during development, but DHT–receptor complexes are needed to form male external genitalia (Figure 23–8). DHT–receptor complexes are also primarily responsible for enlargement of the prostate and probably of the penis at the time of puberty, as well as for the facial hair, the acne, and the temporal recession of the hairline. On the other hand, the increase in muscle mass and the development of male sex drive and libido depend primarily on testosterone rather than DHT (see Clinical Box 23–2).


CLINICAL BOX 23–2



Congenital 5α-Reductase Deficiency

Congenital 5α-reductase deficiency, in which the gene for type 2 5α-reductase is mutated, is common in certain parts of the Dominican Republic. It produces an interesting form of male pseudohermaphroditism. Individuals with this syndrome are born with male internal genitalia including testes, but they have female external genitalia and are usually raised as girls. However, when they reach puberty, LH secretion and circulating testosterone levels are increased. Consequently, they develop male body contours and male libido. At this point, they usually change their gender identities and “become boys.” The clitoris enlarges (“penis-at-12 syndrome”) to the point that some of the individuals can have intercourse with women. This enlargement probably occurs because with the high LH, enough testosterone is produced to overcome the need for DHT amplification in the genitalia.


THERAPEUTIC HIGHLIGHTS

5α-Reductase-inhibiting drugs are now being used clinically to treat benign prostatic hyperplasia, and finasteride, the most extensively used drug, has its greatest effect on type 2 5α-reductase.



Testicular Production of Estrogens

Over 80% of the estradiol and 95% of the estrone in the plasma of adult men is formed by extragonadal and extraadrenal aromatization of circulating testosterone and androstenedione. The remainder comes from the testes. Some of the estradiol in testicular venous blood comes from the Leydig cells, but some is also produced by aromatization of androgens in Sertoli cells. In men, the plasma estradiol level is 20–50 pg/mL (73–184 pmol/L) and the total production rate is approximately 50 μg/d (184 nmol/d). In contrast to the situation in women, estrogen production moderately increases with advancing age in men.

CONTROL OF TESTICULAR FUNCTION

FSH is tropic for Sertoli cells, and FSH and androgens maintain the gametogenic function of the testes. FSH also stimulates the secretion of ABP and inhibin. Inhibin feeds back to inhibit FSH secretion. LH is tropic for Leydig cells and stimulates the secretion of testosterone, which in turn feeds back to inhibit LH secretion. Hypothalamic lesions in animals and hypothalamic disease in humans lead to atrophy of the testes and loss of their function.

Inhibins

Testosterone reduces plasma LH but, except in large doses, it has no effect on plasma FSH. Plasma FSH is elevated in patients who have atrophy of the seminiferous tubules but normal levels of testosterone and LH secretion. These observations led to the search for inhibin, a factor of testicular origin that inhibits FSH secretion. There are two inhibins in extracts of testes in men and in antral fluid from ovarian follicles in women. They are formed from three polypeptide subunits: a glycosylated α subunit with a molecular weight of 18,000; and two nonglycosylated β sub-units, βA and βB, each with a molecular weight of 14,000. The subunits are formed from precursor proteins (Figure 23–9). The α subunit combines with βA to form a heterodimer and with βB to form another heterodimer, with the subunits linked by disulfide bonds. Both αβA (inhibin A) and αβB (inhibin B) inhibit FSH secretion by a direct action on the pituitary, though it now appears that it is inhibin B that is the FSH-regulating inhibin in adult men and women. Inhibins are produced by Sertoli cells in males and granulosa cells in females.

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FIGURE 23–9 Inhibin precursor proteins and the various inhibins and activins that are formed from the carboxyl terminal regions of these precursors. SS, disulfide bonds.

The heterodimer βAβB and the homodimers βAβA and βBβB are also formed. They stimulate rather than inhibit FSH secretion and consequently are called activins. Their function in reproduction is unsettled. However, the inhibins and activins are members of the TGFβ superfamily of dimeric growth factors that also includes MIS. Activin receptors have been identified and belong to the serine/threonine kinase receptor family. Inhibins and activins are found not only in the gonads but also in the brain and many other tissues. In the bone marrow, activins are involved in the development of white blood cells. In embryonic life, activins are involved in the formation of mesoderm. All mice with a targeted deletion of the α-inhibin subunit gene initially exhibit normal growth but then develop gonadal stromal tumors, so the gene is a tumor suppressor gene.

In plasma, α2-macroglobulin binds activins and inhibins. In tissues, activins bind to a family of four glycoproteins called follistatins. Binding of the activins inactivates their biologic activity, but the relation of follistatins to inhibin and their physiologic function remain unsettled.

Steroid Feedback

A current “working hypothesis” of the way the functions of the testes are regulated by steroids is shown in Figure 23–10. Castration is followed by a rise in the pituitary content and secretion of FSH and LH, and hypothalamic lesions prevent this rise. Testosterone inhibits LH secretion by acting directly on the anterior pituitary and by inhibiting the secretion of GnRH from the hypothalamus. Inhibin acts directly on the anterior pituitary to inhibit FSH secretion.

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FIGURE 23–10 Postulated interrelationships between the hypothalamus, anterior pituitary, and testes. Solid arrows indicate excitatory effects; dashed arrows indicate inhibitory effects.

In response to LH, some of the testosterone secreted from the Leydig cells bathes the seminiferous epithelium and provides the high local concentration of androgen to the Sertoli cells that is necessary for normal spermatogenesis. Systemically administered testosterone does not raise the androgen level in the testes to as great a degree, and it inhibits LH secretion. Consequently, the net effect of systemically administered testosterone is generally a decrease in sperm count. Testosterone therapy has been suggested as a means of male contraception. However, the dose of testosterone needed to suppress spermatogenesis causes sodium and water retention. The possible use of inhibins as male contraceptives is now being explored.

ABNORMALITIES OF TESTICULAR FUNCTION

Cryptorchidism

The testes develop in the abdominal cavity and normally migrate to the scrotum during fetal development. Testicular descent to the inguinal region depends on MIS, and descent from the inguinal region to the scrotum depends on other factors. Descent is incomplete on one or, less commonly, both sides in 10% of newborn males, with the testes remaining in the abdominal cavity or inguinal canal. Gonadotropic hormone treatment speeds descent in some cases, or the defect can be corrected surgically. Spontaneous descent of the testes is the rule, and the proportion of boys with undescended testes (cryptorchidism) falls to 2% at age 1 year and 0.3% after puberty. However, early treatment is now recommended despite these figures because the incidence of malignant tumors is higher in undescended than in scrotal testes and because after puberty the higher temperature in the abdomen eventually causes irreversible damage to the spermatogenic epithelium.

Male Hypogonadism

The clinical picture of male hypogonadism depends on whether testicular deficiency develops before or after puberty. In adults, if it is due to testicular disease, circulating gonadotropin levels are elevated (hypergonadotropic hypogonadism); if it is secondary to disorders of the pituitary or the hypothalamus (eg, Kallmann syndrome), circulating gonadotropin levels are depressed (hypogonadotropic hypogonadism). If the endocrine function of the testes is lost in adulthood, the secondary sex characteristics regress slowly because it takes very little androgen to maintain them once they are established. The growth of the larynx during adolescence is permanent, and the voice remains deep. Men castrated in adulthood suffer some loss of libido, although the ability to copulate persists for some time. They occasionally have hot flushes and are generally more irritable, passive, and depressed than men with intact testes. When the Leydig cell deficiency dates from childhood, the clinical picture is that of eunuchoidism. Eunuchoid individuals over the age of 20 are characteristically tall, although not as tall as hyperpituitary giants, because their epiphyses remain open and some growth continues past the normal age of puberty. They have narrow shoulders and small muscles, a body configuration resembling that of the adult female. The genitalia are small and the voice high-pitched. Pubic hair and axillary hair are present because of adrenocortical androgen secretion. However, the hair is sparse, and the pubic hair has the female “triangle with the base up” distribution rather than the “triangle with the base down” pattern (male escutcheon) seen in normal males.

Androgen-Secreting Tumors

“Hyperfunction” of the testes in the absence of tumor formation is not a recognized entity. Androgen-secreting Leydig cell tumors are rare and cause detectable endocrine symptoms only in prepubertal boys, who develop precocious pseudopuberty (Table 22–2).

Hormones and Cancer

Some carcinomas of the prostate are androgen-dependent and regress temporarily after the removal of the testes or treatment with GnRH agonists in doses that are sufficient to produce down-regulation of the GnRH receptors on gonadotropes and decrease LH secretion.

CHAPTER SUMMARY

image The gonads have a dual function: the production of germ cells (gametogenesis) and the secretion of sex hormones. The testes secrete large amounts of androgens, principally testosterone, but they also secrete small amounts of estrogens.

image Spermatogonia develop into mature spermatozoa in the seminiferous tubules via a process called spermatogenesis. This is a multistep process that includes maturation of spermatogonia into primary spermatocytes, which undergo meiotic division, resulting in haploid secondary spermatocytes. Several further divisions result in spermatids. Each cell division from a spermatogonium to a spermatid is incomplete, with cells remaining connected via cytoplasmic bridges. Spermatids eventually mature into motile spermatozoa to complete spermatogenesis; this last part of maturation is called spermiogenesis.

image Testosterone is the principal hormone of the testis. It is synthesized from cholesterol in Leydig cells. The secretion of testosterone from Leydig cells is under control of luteinizing hormone at a rate of 4–9 mg/day in adult males. Most testosterone is bound to albumin or to gonadal steroid-binding globulin in the plasma. Testosterone plays an important role in the development and maintenance of male secondary sex characteristics, as well as other defined functions.

MULTIPLE-CHOICE QUESTIONS

For all questions, select the single best answer unless otherwise directed.

1. Full development and function of the seminiferous tubules require

A. somatostatin.

B. LH.

C. oxytocin.

D. FSH.

E. androgens and FSH.

2. In human males, testosterone is produced mainly by the

A. Leydig cells.

B. Sertoli cells.

C. seminiferous tubules.

D. epididymis.

E. vas deferens.

3. Nitric oxide synthase contributes to erection by:

A. raising cAMP levels that relax smooth muscles and increase blood flow.

B. blocking phosphodiesterases to increase cGMP levels that release smooth muscle and increase blood flow.

C. activating soluble guanylate cyclases to increase cGMP levels that relax smooth muscle and increase blood flow.

D. raising inctracellular Ca2+ concentrations that relax smooth muscles and increase blood flow.

4. Testosterone is produced

A. in the testes after reduction of dihydrotestosterone.

B. in Leydig cells from cholesterol and pregnenolone precusors.

C. by leutinizing hormone in Leydig cells.

D. as a precursor for several membrane lipids.

CHAPTER RESOURCES

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Primakoff P, Nyles DG: Penetration, adhesion, and fusion in mammalian sperm–egg interaction. Science 2002;296:2183.

Yen SSC, Jaffe RB, Barbieri RL: Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 4th ed. Saunders, 1999.

Yu H-S: Human Reproductive Biology, CRC Press, 1994.