New chapter 35
The Male Reproductive System
The male reproductive system has three principal functions:
- The differentiation and maintenance of the primary and secondary sex characteristics under the influence of the hormone testosterone, made in the testes.
- Spermatogenesis—the creation of the male gametes inside the testes.
- The penile delivery of sperm from the testes into the female’s vagina in the act of procreation. This includes penile erection and ejaculation.
The male reproductive system comprises not only the male genitals, but also the cranial structures that help regulate the performance of the male reproductive system—namely, the hypothalamus and pituitary. At the hypothalamic and pituitary level, however, male and female anatomy and histology are more or less the same. For more details on the hypothalamic and pituitary structures involved in human reproduction, see Chapter 36. In the section that follows, we will focus on the anatomy and histology of the testes, the penis, and the ductal connections between the testes and penis.
The male gonads, or testes, are suspended from the perineum in an external contractile sac called the scrotum(Figure 37.1A). Each testis is about 4 cm long, and the testes are perfused by the spermatic arteries. The spermatic arteries are closely apposed with the spermatic venous plexus, and this close contact allows countercurrent heat exchange between artery and vein, cooling the blood that flows to the testes. Countercurrent heat exchange helps keep the testicular temperature cool enough for optimal spermatogenesis (1°C to 2°C cooler than body temperature). The external location of the testes in the scrotum serves as a second important cooling mechanism. Because the testes develop within the abdomen, they descend into the scrotum during fetal life, reaching the deep inguinal rings around week 28 of gestation and inhabiting the scrotum by birth. In some instances (3% of the time in full-term male infants), the testes do not descend—a condition called cryptorchidism. Cryptorchidism must be corrected if the male is to have properly functioning, fertile gonads.
The testes are composed of coiled seminiferous tubules embedded in connective tissue (see Figure 37.1B). The connective tissue, which makes up about 20% of the testicular mass, contains Leydig cells, which make testosterone. The seminiferous tubules, constituting 80% of the testicular mass, generate the sperm. The tubules contain two main cell types: spermatogonia and Sertoli cells. Spermatogonia are the germ cells that undergo meiosis to give rise to spermatids, the immediate precursors to spermatozoa. The copious cytoplasm of the Sertoli cells completely envelops and protects the spermatids, sealing them off from any contact with the tubules’ outer basement membrane or blood supply. This Sertoli sheath hence forms a blood-testis barrier to protect the male gametes from any harmful bloodborne agents, and to prevent the immune system from attacking the unique sperm-specific proteins as though they were foreign antigens. By virtue of their position between the blood and the spermatids, the Sertoli cells also transport nutrients, oxygen, and hormones, such as testosterone, to the spermatids.
Figure 37.1 Anatomy of the male reproductive system. A.Overview. B. A closer look at the testis. C. The ducts of the reproductive system shown in isolation. The ducts arising from both testes are depicted, converging on the posterior urethra inside the prostate gland.
The spermatogonia sit outside the blood-testis barrier near the basement membrane. Here, they continuously conduct mitosis. The products of mitosis are pushed toward the tubule lumen and undergo meiosis and differentiation into sperm cells. The Sertoli barrier is fluid and accommodates the passage of cells developing into spermatids. The testes make around 120 million sperm a day. As they differentiate, the sperm migrate into the tubule lumen for transport distally to the rete testis, a plexus of ducts that collects sperm from each of roughly 900 seminiferous tubules. The rete testis empties into the epididymis, a single coiled tubule running from the top of the testis down its posterior aspect. In the epididymis, sperm are stored and undergo maturation before continuing their voyage outside the testis.
The Ducts and Penis
Each epididymis leads to a long, straight tube called the vas deferens (see Figure 37.1C). The vas deferens from the epididymis of each testis rises in the scrotum, ranges laterally through the inguinal canals, runs along the pelvic wall toward the posterior, and descends along the posterior aspect of the bladder. Here the two vas deferens tubes widen into ampullae, which are attached to glands called the seminal vesicles. (There are two seminal vesicles, one for each vas deferens.) The seminal vesicles secrete more than half the volume of the semen. The two ampullae each send an ejaculatory duct through the prostate gland, and the ejaculatory ducts join the urethra inside the tissue of the prostate gland. From this point onward, the male urethra serves as part of both the reproductive and urinary tracts, unlike female anatomy, in which the reproductive and urinary tracts are completely separate. Male physiology ensures that micturition and ejaculation do not occur simultaneously.
The urethra next passes through the muscle tissue of the urogenital diaphragm, a consciously controllable sphincter. Sitting just under the urogenital diaphragm are the bulbourethral glands (also called Cowper’s glands), which lubricate the urethra with mucus. Finally, the urethra enters the penis. The cylindrical penis houses the urethra in erectile tissue, which helps effect the transition between the excretory and reproductive functions of the urethra (Figure 37.2). This erectile tissue contains cavernous sinuses that fill with blood under circumstances of increased penile blood flow, leading to erection of the penis. When erect, the penis may be inserted into the vagina so that sperm may be delivered to the fallopian tubes.
Figure 37.2 Cross-section of the penis.
The erectile tissue is present in three cylinders inside the penis, each called a corpus cavernosum and together called the corpora cavernosa. Two of the corpora lie dorsally and are sheathed by the ischiocavernosus muscles. One lies ventrally and is sheathed by the bulbospongiosus muscle. The ventral corpus cavernosum is also called the corpus spongiosum, and it is special in that it contains the urethra and forms the glans penis, the spongy head of the penis. The corpora are each supplied by a cavernous artery that gives out helicine arteries. The penis averages 8.8 cm (3.5 in) in length when flaccid and 12.9 cm (5.1 in) when erect, indicating no correlation between flaccid and erect size.
Just as the female reproductive system is coordinated by the hypothalamus and pituitary, the activities of the male reproductive system are coordinated by the HPG axis, in this case the hypothalamic-pituitary-testicular (HPT) axis (Figure 37.3). (The gonadal HPT axis is not to be confused with the hypothalamic-pituitary-thyroid axis, also labeled HPT.) The male axis shares with the female the exact same hypothalamic hormone, gonadotropin- releasing hormone (GnRH), and the same pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). (The gonadotropins are named for their female reproductive functions, but they act in the male nonetheless.) The same array of gonadal steroid hormones that is produced by the ovary is also synthesized by the male reproductive system, but in different proportions. Because of differential expression of enzymes in the steroid synthesis pathway, the female gonad makes predominantly progesterone and estrogen, while the male gonad predominantly makes the androgen steroid hormone testosterone. Testosterone inhibits the secretion of GnRH, LH, and FSH in a classic negative-feedback loop.
Figure 37.3 Hypothalamic-pituitary-testicular axis. Plus signs represent stimulation; minus signs represent inhibition.
The HPT Axis
GnRH is the initial driver of testicular function. It is secreted in a pulsatile fashion (one pulse every 1 to 3 hours) and distributes to the pituitary gonadotrophs through the hypothalamic-pituitary portal circula- tion. There, the releasing hormone stimulates the LH- and FSH-secreting cells. Each GnRH pulse directly prompts an LH pulse from the gonadotrophs. More frequent or larger-amplitude GnRH pulses result in more frequent or larger-amplitude LH pulses. GnRH also increases FSH release, but the correlation between GnRH and FSH release is not as exact.
LH acts on the Leydig cells. The LH signal is transduced by a seven- transmembrane receptor linked through a G protein to adenylyl cyclase, which produces cAMP. LH-dependent elevations in cAMP promote testosterone synthesis from cholesterol and promote the growth of Leydig cells. Testosterone synthesis is increased by the activation and increased expression of key proteins involved in steroidogenesis, such as the steroidogenic acute regulatory protein (StAR). StAR shuttles cholesterol into steroid-manufacturing cells. The Leydig cells of the testis are unique in their ability to make testosterone in large amounts (Figure 37.4). While the zona reticulata cells of the adrenal gland also make androgens, the adrenal pathway stops at androstenedione, the immediate precursor to testosterone. (Some peripheral tissues can make testosterone from androstenedione in small amounts.)
FSH, meanwhile, binds to receptors on the Sertoli cells, activating the production of proteins involved in spermatogenesis. FSH also stimulates glucose metabolism, thereby providing energy to the sperm precursors. (Spermatogenesis will be discussed in more detail below.) Finally, FSH upregulates the expression of the androgen receptor in Sertoli cells, thereby potentiating the influence of testosterone upon spermatogenesis.
Like all steroids, testosterone binds an intracellular receptor, which binds DNA transcription factors and influences gene expression. The distribution of testosterone receptors in the body tissues determines the targets of testosterone action. In addition, target tissues express an enzyme that converts testosterone to its more active form, dihydrotestosterone (DHT). This enzyme is 5ï¡-reductase. DHT binds more avidly to the androgen receptor than does testosterone itself. Testosterone from the Leydig cells passes through the Sertoli cells and into the seminiferous tubules, where, alongside FSH, it promotes spermatogenesis. The Sertoli cells make androgen-binding protein (ABP), which helps them to retain testosterone. Testosterone also acts systemically, promoting growth and sustaining gene expression in many peripheral tissues. Testosterone is transported in the blood by sex hormone-binding protein (SHBP), also called sex hormone-binding globulin, a liver-produced carrier protein that is structurally similar to ABP. It is thought that testosterone and SHBP itself may act at cell membrane receptors, in addition to testosterone’s genomic effects. This is parallel to the genomic and nongenomic modes of signal transduction employed by thyroid hormone.
Finally, testosterone inhibits GnRH and gonadotropin secretion. Thus, testosterone limits its own production and action. Inhibin from the Sertoli cells also inhibits the pituitary and hypothalamus. Inhibin is a TGF-ï¢ glycoprotein hormone. Investigations suggest that additional feedback mechanisms link Sertoli cell behavior with Leydig cell behavior. Table 37.1 summarizes the actions of testosterone.
Table 37.1 Testosterone Actions
Causes and sustains expression of the male sex characteristics:
Embryologic development of male genitals and ducts
Growth of penis, testes, and prostate at puberty
Growth of hair, larynx
Promotion of positive nitrogen balance in muscles, bones, and skin (promotion of increased protein anabolism, requiring retention of more nitrogen-containing amino acids)
Increased libido and aggression
Inhibits HPT axis (negative feedback)
The Expression of Male Sex Characteristics
The male reproductive system begins to function during embryonic life. As soon as the testes form and are capable of secreting testosterone, the androgen begins to act on the body tissues. At this stage, the hormone differentiates the fetus into a male with the appropriate primary sex characteristics—the male genitals. At puberty, testosterone causes sustained expression of the secondary sex characteristics, which are gender-based phenotypes other than the genitals, such as hair growth, muscle development, and a low voice.
Fetal Life and Infancy (Primary Sex Characteristics) While the testes do act in utero, they cannot act before they have formed, and they do not form right away. In fact, before 6 weeks of gestation, the gonads of genotypically male or female embryos have not begun to differentiate into either ovaries or testes. The so-called “indifferent gonad” has an inner medullary (male) and an outer cortical (female) layer. In addition, the anatomic precursors of both males (the Wolffian ducts) and females (the Müllerian ducts) are present. Only at 6 to 8 weeks of gestation is male sexual development initiated by the SRY gene, a gene on the short arm of the Y chromosome. SRY encodes a zinc finger DNA-binding protein called testis determining factor (TDF). Under the influence of TDF, the medullae of the indifferent gonads develop while the cortices regress. The previously indifferent gonads differentiate into testes: embryonic germ cells form spermatogonia, coelomic epithelial cells form Sertoli cells (6 to 7 weeks of gestation), and mesenchymal stromal cells form Leydig cells (8 to 9 weeks of gestation).
Now the testes can begin to act. The Sertoli cells secrete a Müllerian-inhibiting factor (MIF), which causes regression of the Müllerian ducts. Human chorionic gonadotropin (hCG)—which is structurally related to LH—stimulates the Leydig cells to proliferate and secrete testosterone. The testosterone is reduced to DHT in target tissues by 5ï¡-reductase. As long as target tissues contain the androgen receptor and 5ï¡-reductase, DHT induces those tissues to form the primary male sex characteristics, the male reproductive organs. Under the influence of DHT, the Wolffian ducts differentiate into the epididymis, vas deferens, and seminal vesicles. The genital tubercle transforms into the glans penis, the urethral folds grow into the penile shaft, and the urogenital sinus becomes the prostate gland. Finally, DHT causes the genital swellings to fuse, forming the scrotum.
At its peak, the fetal testosterone level reaches 400 ng/dL, but by birth it falls below 50 ng/dL. There is a brief spike in the male infant’s testosterone level between 4 and 8 weeks after birth, but its function is not well understood. Otherwise, the testosterone level remains low throughout childhood, until puberty.
Puberty and Beyond (Secondary Sex Characteristics) Puberty is the process by which males and females achieve reproductive capacity, and it begins in both sexes with an increase in hypothalamic GnRH secretion. It is possible that this increase is in response to decreasing hypothalamic sensitivity to testosterone’s negative-feedback effects. As the child approaches adolescence, the hypothalamus gradually escapes inhibition and GnRH secretion rises. LH and FSH secretion in turn rise, and testosterone secretion from the testes increases. Gradual maturation of hypothalamic neurons probably plays a role in this pubertal change in GnRH secretion.
Increased testicular production of testosterone and other androgens at puberty has a host of effects. The earliest one is enlargement of the penis and testes. From the beginning to the end of puberty, the testicular volume more than quadruples. Spermatogenesis commences (with testosterone effects perhaps being most important on the spermatids), and the prostate gland is stimulated to grow. Growth occurs in many tissues outside the reproductive system as well.
Androgens are anabolic steroids; they promote the storage of energy in complex molecules. While androgens promote protein synthesis, an anabolic hormone like insulin has a greater effect on the formation of complex carbohydrates and fats. Increased protein synthesis is associated with the growth of skeletal muscle, bones, skin, and hair (pubic, axillary, facial, chest, arms, and legs) and the growth of the larynx (which deepens the voice and causes the thyroid cartilage, or Adam’s apple, to protrude). Men on average have around 50% more muscle mass than women; they have stronger, denser bone matrices and thicker skin. Muscle does not contain 5ï¡-reductase, so it appears that testosterone, not DHT, promotes muscular protein anabolism. However, testosterone or DHT may promote muscular anabolism via extramuscular effects, such as the stimulation of growth hormone and insulin-like growth factor (IGF-1) production.
Collectively, the development of the secondary sex characteristics is called virilization (after the Latin vir for man). It appears that while testosterone promotes all of these effects—genital growth and spermatogenesis, hair growth, behavioral changes, and anabolism in peripheral tissues—certain androgen precursors, metabolic byproducts, and pharmaceutical androgen analogs preferentially serve peripheral anabolism. Many of these metabolites and drugs are abused by bodybuilders and athletes. (See Clinical Application Box The Use and Abuse of Anabolic Steroids.)
Testosterone, combined with a genetic predisposition, also influences hair growth on the head. Male-pattern baldness typically begins with a decrease in hair growth on the top of the head and progresses to a complete lack of hair growth extending from the top of the head down. Both factors, the androgens and the genes, are necessary for baldness to occur; a man without the genetic predisposition will not become bald regardless of his testosterone level. A woman with the genetic predisposition will usually not become bald unless she suffers from excess androgen production. Similarly, a castrated male with low testosterone levels will not become bald even if he has a genetic predisposition.
Once testosterone levels rise during puberty, they reach a plateau and remain elevated until a man reaches his seventies, when they begin to decline. This event, called the male climacteric, may create some symptoms resembling those of female menopause. However, hormone replacement therapy (HRT) is not commonly used to treat these symptoms. One reason is that men in this age group are at increased risk for prostate cancer. Because testosterone has proliferative effects on the prostate, HRT might further increase the risk of prostate cancer. While testosterone does promote spermatogenesis,this testicular function is remarkably well preserved in men even after the climacteric.
The Haploid Life Cycle in the Male
As mentioned above, spermatogenesis begins with puberty and continues into the eighth decade of life. Spermatogenesis has three phases: spermatocytogenesis, during which the primordial spermatogonia divide by mitosis and differentiate into spermatocytes; meiosis, resulting in four haploid gametes called spermatids, each with a quarter of the cytoplasm of the original spermatogonium (see Chapter 36); and spermiogenesis, during which the spermatids are nourished and physically reshaped by the surrounding Sertoli cells. The product of spermiogenesis is spermatozoa, or sperm (Figure 37.5). After spermiogenesis, the epididymis and reproductive tract glands help prepare the sperm for fertilization.
Spermatocytogenesis and Meiosis The evolving group of cells spanning from spermatogonia to spermatozoa is sometimes called the spermatogenic series. Not all spermatogonia enter into the spermatogenic series. If they did, they would be consumed—as happens to the oogonia in the ovary, eventually leading to menopause. Instead, the testis csontinually replenishes its own supply of spermatogonia. As they undergo mitosis, some of the new ones are committed to the spermatogenic series, while some remain undifferentiated. The undifferen- tiated stem cells are called type A spermatogonia, and the differentiated spermatogonia committed to becoming spermatocytes are called type B spermatogonia.
Once this allocation of mitotic products into one group or another occurs, spermatocytogenesis continues as follows. Type A spermatogonia remain on the outside of the blood-testis barrier, while type B spermatogonia cross it, becoming enveloped by the cytoplasmic processes of the Sertoli cells. These type B spermatogonia differentiate further and enlarge to become primary spermatocytes. The primary spermatocytes then enter meiosis, a process that takes around 3.5 weeks to complete, almost all of which is spent in prophase (when the newly replicated chromosomes condense). Each primary spermatocyte divides into two secondary spermatocytes, which in turn divide again into a total of four haploid spermatids. Each spermatid contains either an X chromosome or a Y chromosome. The male’s gamete thus decides the sex of his offspring.
Spermiogenesis Spermiogenesis begins once the spermatids are created and delivered into the embrace of the amoeboid Sertoli cells (Figure 37.6). The spermatid elongates and reorganizes its nuclear and cytoplasmic contents into a spermatozoon with a distinct head and tail. The head consists of a condensed nucleus surrounded by a thin layer of cytoplasm. The rest of the retained cytoplasm and cell membrane is shifted toward the opposite end of the sperm, the tail. A large amount of the spermatid’s cytoplasm is shed into the surrounding Sertoli cell during spermiogenesis. As the transformed sperm is extruded into the seminiferous tubule lumen, the discarded cytoplasm remains embedded in the cytoplasm of the Sertoli cell, where it is ultimately phagocytized.
Figure 37.6 Spermiogenesis
The structure of sperm cells enables them to swim up the female reproductive tract and fertilize oocytes. The tail of a sperm contains a flagellum for motility. Originating from one of the centrioles of the sperm cells, the flagellum consists of a central skeleton of microtubules called the axoneme. The axoneme is arranged in the ancient 9 + 2 pattern characteristic of eukaryotic cilia and flagella across all kingdoms and phyla of life: 9 pairs of microtubules surrounding 2 central tubules, linked via a complex array of protein bridges. The sperm cell’s mitochondria aggregate along the proximal end of the flagellum and supply energy for movement to the flagellum. The flagellum enables the sperm to swim.
The anterior two thirds of the head of the sperm cell is surrounded by a thick capsule known as the acrosome, formed from the Golgi apparatus. The Golgi apparatus contains numerous hydrolytic and proteolytic enzymes, similar to those found in lysosomes, and ultimately facilitates the sperm’s penetration of the egg for fertilization. There is also evidence to suggest a role for the acrosomal enzymes in penetrating the mucus of the female cervix.
Epididymal Sperm Maturation and Storage After spermiogenesis is complete, the sperm pass out of the testis (through the rete testis) and into the epididymis, where growth and differentiation continue. After the first 24 hours in the epididymis, the sperm acquire the potential for motility. However, the epithelial cells of the epididymis secrete inhibitory proteins that suppress this potential. Thus, the 120 million sperm produced each day in the seminiferous tubules are stored in the epididymis, as well as in the vas deferens and ampulla. The sperm can remain in these excretory genital ducts in a deeply suppressed and inactive state for over a month without losing their potential fertility.
The epididymis also secretes a special nutrient fluid that is ultimately ejaculated with the sperm and is thought to mature the sperm. This fluid contains hormones, enzymes (such as glycosyltransferases and glycosidases), and nutrients that are essential to achieving fertilization. The precise function of many of these factors is not known, but enzymes like gamma-glutamyl transpeptidase are thought to serve as antioxidants defending against mutations in the sperm.
Potentiation in the Ejaculate The accessory genital glands—the seminal vesicles, prostate gland, and bulbourethral glands—also contribute to potentiation. During ejaculation, their secretions dilute the epididymal inhibitory proteins, allowing the sperm’s motile potential to be realized. In addition, the glands make individual contributions to sperm preparation and support. The seminal vesicles secrete semen, a mucoid yellowish material containing nutrients and sperm-activating substances such as fructose, citrate, inositol, prostaglandins, and fibrinogen. Carbohydrates such as fructose provide a source of energy for the sperm mitochondria as they power the sperm’s flagellar movements. The prostaglandins are believed to aid the sperm by affecting the female genital tract—making the cervical mucus more receptive to the sperm, and dampening the peristaltic contractions of the uterus and fallopian tubes to prevent them from expelling the sperm.
The prostate gland secretes a thin, milky, and alkaline fluid during ejaculation that mixes with the contents of the vas deferens. The prostatic secretion contains calcium, zinc, and phosphate ions, citrate, acid phosphatase, and various clotting enzymes. The clotting enzymes react with the fibrinogen of the seminal fluid, forming a weak coagulum that glues the semen inside the vagina and facilitates the passage of sperm through the cervix in larger numbers. The alkalinity imparted to semen by the prostate counteracts vaginal acidity, which is a natural defense against microbial pathogens and which can kill sperm or impair sperm motility. By titrating the acidity, the prostate ensures that the sperm can elude this antimicrobial defense.
Capacitation in the Female Reproductive Tract Ejaculated sperm is not immediately capable of fertilizing the female oocyte. In the first few hours after ejaculation, the spermatozoa must undergo capacitation inside the female reproductive tract. This is the final step in preparation for fertilization. First, the fluids of the female reproductive tract wash away more of the inhibitory factors of the male genital fluid. The flagella of the sperm hence act more readily, producing the whiplash motion that is needed for the sperm to swim to the oocyte in the fallopian tube. Second, the cell membrane of the head of the sperm is modified in preparation for the ultimate acrosomal reaction and penetration of the oocyte. Capacitation is an incompletely understood phenomenon.
Fertilization Once capacitated, the spermatozoa travel to the oocyte. There is an enormous rate of attrition among the hundreds of millions of ejaculated sperm, and at most a few hundred reach the oocyte. However, the female reproductive tract is simultaneously increasing receptivity to the male gametes (see Chapter 36).
When the few hundred sperm reach the egg, they begin to try to penetrate the granulosa cells surrounding the secondary oocyte. The sperm’s acrosome contains hyaluronidase and proteolytic enzymes, which open this path. As the anterior membrane of the acrosome reaches the zona pellucida (the glycoprotein coat surrounding the oocyte), it rapidly dissolves and releases the acrosomal enzymes. Within minutes, these enzymes open a pathway through the zona pellucida for the sperm cytoplasm to merge with the oocyte cytoplasm. From beginning to end, the process of fertilization takes about half an hour.
Figure 37.7 Sexual response and changes in the penis.
Penile Erection and Ejaculation
The practice of internal fertilization, in which the male deposits gametes directly into the reproductive tract of the female, is at least 300 million years old. Early cartilaginous fishes probably were its innovators. These elasmobranchs retained their concepti internally until the eggs could be waterproofed and thus protected from the osmotic stress of seawater. Eventually, almost all the higher vertebrates would practice internal fertilization for the sake of defending the next generation.
For this reason, the male vertebrate possesses a special apparatus for penetrating the body of the female and delivering semen to an internal location. There are two physiologic events crucial to this internal delivery of semen: penile erection, which makes it possible for the penis to penetrate the vagina, bringing the urethral opening, or meatus, into close contact with the female cervix; and ejaculation, in which the semen is secreted into the male reproductive ductal system, mixed with sperm, and then mechanically squirted out of the penis. Both of these events are initiated and controlled by the nervous system in connection with the subjective state of sexual arousal.
Sexual Response in the Male William H. Masters and Virginia E. Johnson in 1966 described four phases of sexual response in males and females: excitement, plateau, orgasm, and resolution (Figure 37.7). Desire or libido precedes excitement, and testosterone is known to increase libido. Excitement that leads to erection derives from a combination of psychological factors and genital stimulation. Erotic feelings can initiate an erection without physical stimulation, and physical stimulation can initiate erection in the absence of psychological stimuli. The pudendal nerve transmits sensory information from the penis to the spinal cord and brain.
Erection As excitement builds in the central nervous system, efferent parasympathetic fibers in the pelvic nervedischarge more and more impulses through the pelvic plexus to the smooth muscle of the penile cavernous artery, which runs down the center of each of the corpora cavernosa. These parasympathetic impulses lead to the secretion of nitric oxide (directly from the parasympathetic nerve terminals and also from the endothelial cells in the arterial vasculature). The nitric oxide (NO) diffuses into the smooth muscle in the wall of the cavernous artery and relaxes it. (New data suggest that testosterone is also involved in the regulation of NO secretion.) NO-mediated arterial dilation leads to up to a 60-fold increase in penile blood flow. The penis swells with blood. When the spongy tissues are stretched to their full extent, intracavernous pressure then begins to rise. The penis becomes rigid and elevates. The increasing pressure eventually compresses the cavernous veins and reduces venous outflow, building the pressure even higher.
Ejaculation As sexual excitement continues to build, bulbourethral and urethral secretions lubricate the urethra. These secretions are small in volume compared with the ejaculate, but they do contain sperm and can by themselves lead to fertilization. As genital stimulation excites the pudendal nerve more and more, a subjective sensation of orgasm ensues, followed immediately by the ejaculatory spinal cord reflex. (While the ejaculatory reflex is involuntary, it can be suppressed and delayed by input from the cerebral cortex; it is possible that at orgasm, the central nervous system releases the spinal reflex from its inhibition.) Once the reflex is initiated, sympathetic nerves stimulate the closure of the bladder neck and contraction of the ampulla of the vas deferens, the seminal vesicles, and the prostate. The contractions cause the seminal vesicles and prostate to secrete their semen into the ejaculatory duct just as the sperm are propelled from the ampulla into the ejaculatory duct. The semen briefly pools in the posterior urethra. This first stage of ejaculation is called emission.
Emission is directly followed by the rhythmic contraction of muscles surrounding the urethra: the bulbospongiosus muscle that surrounds the corpus spongiosum, the urethral smooth muscle, and other pelvic floor muscles. These contractions expel the semen from the posterior urethra and out the penile meatus in spurts.
Resolution The total ejaculate contains about 400 million sperm in about 3 to 4 mL of secretions. The normal sperm concentration ranges anywhere from 35 million to 200 million sperm per milliliter of fluid. If the sperm have been delivered into an ovulatory female reproductive tract, they now begin their journey toward the egg. Meanwhile, the resolution phase occurs a few minutes after ejaculation with detumescence (drainage of blood from the penis) and a refractory period of varying lengths, in which erection and ejaculation cannot be repeated. The cavernous arteries constrict, preventing arterial inflow, and venous outflow lowers the intracavernous pressure. As the pressure falls, the veins decompress and venous outflow increases further. This shift from net inflow to net outflow rapidly returns the penis to its flaccid state. Elastic tissues in the corpora cavernosa also assist in this shrinkage.
Common problems associated with the male reproductive tract include prostatitis, erectile dysfunction, infertility, and benign and malignant growth of the prostate.
Prostatitis is inflammation of the prostate, usually due to the ascent of a urinary tract infection.
Some 10 to 20 million men suffer from erectile dysfunction (ED), also known as impotence. Any cause of vascular insufficiency, including athero- sclerosis, diabetes mellitus, and antihypertensive medication can lead to ED, as can psychological factors. (See Clinical Application Box Treating Erectile Dysfunction.)
An estimated 10% to 15% of couples cannot conceive after 1 year of trying; they are considered to have infertility. In 20% of infertile couples, the cause is never discovered. In the remaining 80%, around half of the cases of infertility are due to a problem in the male reproductive system.
Prostate cancer is by far the most common cancer in men and the second most frequent cause of male cancer deaths. Benign prostatic hyperplasia affects nearly all men as they age.
Some of the causes of male infertility have been discussed previously. Cryptorchidism results in sterility, as the spermatogonia cannot survive at the increased temperatures of the body cavity. Other abnormalities of the testes and genital tract may also impair fertility, including varicoceles, trauma, and scarring. A careful history may reveal environmental exposures (chemical, radiation [e.g., due to cancer treatment], heat [due to tight underwear, fever, etc.]); sexually transmitted infections; mumps orchitis (which can destroy the seminiferous tubular epithelium); trauma; or previous surgery around the urogenital tract. (See Clinical Application Box What Is a Varicocele?)
The workup includes a semen analysis, which assesses ejaculate volume, sperm count, sperm morphology and motility, semen pH, and white blood cell count. Sperm counts of less than 20 million sperm per milliliter render a male infertile. Abnormal morphology of the sperm, including multiple heads or tails and abnormally shaped heads or tails, will impair fertility. Abnormal functioning of the sperm heads (acrosomes) or tails (flagella), despite seemingly normal morphology, can also impair fertility.
A postcoital test may also be performed to evaluate the interaction between the sperm in the semen and the female cervical mucus. The inability of the sperm to penetrate the cervical mucosa may suggest an abnormality of the fluid contents of the semen or an abnormality of the acrosomal head of the sperm itself.
Analysis of serum FSH and testosterone levels may also be helpful in diagnosing testicular disease. If the testes are damaged and failing to make testosterone, the testosterone level will be low and the FSH level will be high, resulting from hypothalamic disinhibition. Thyroid function tests are also indicated (most importantly a TSH level), since abnormal thyroid function interferes with spermatogenesis.
Clinical Correlate: Testosterone Replacement Therapy: Men with low libido or energy may be suffering from low levels of testosterone, which gradually decrease with age. Suplementation of testosterone has clinically significant effects such as bossting mood, libido, energy, and___
Benign Prostatic Hyperplasia and Prostate Cancer
The development and growth of the prostate gland are stimulated by testosterone. This mitogenic (proliferative) effect on the prostate continues throughout life, often resulting in the development of benign prostatic hyperplasia (BPH). As many as 20% of men are affected by BPH before the age of 40, and the number increases with age: about 70% of men at age 60 and 90% of men in their seventies show evidence of some BPH. The main symptoms of BPH result from the enlarged prostate impinging on or obstructing the urethra, and include urinary frequency, urgency, nocturia (waking at night to urinate), urinary retention, and even urinary obstruction. As its name implies, BPH is otherwise benign and is not considered to be a premalignant lesion.
Prostate cancer is a slow-growing cancer. Its incidence increases with age, and it often has an insidious onset; that is, it may grow for a long time asymptomatically before coming to the attention of the patient or his doctor. Therefore, the cancer is frequently metastatic by the time of presentation. Because prostate cancer is so common and because it has an insidious onset, the medical community encourages screening by digital rectal exam (DRE) or the prostate-specific antigen (PSA) test for men above a certain age. (There is no consensus, however, on whether such screening would reduce mortality rates.) Questionable results from a rectal exam are usually followed with transrectal ultrasound and/or an ultrasound-guided transrectal biopsy. Testo- sterone is a growth stimulant for prostate cancer, just as it is for BPH. Certain therapies, especially those used in cases of known metastases, therefore aim at inhibiting testosterone production or preventing testosterone from stimulating the prostatic tissue, thereby slowing the growth and spread of the cancer. Men with both BPH and prostate cancer are candidates for transurethral prostate resection (TURP).
Heart Disease Male gender is a risk factor for atherosclerosis. In 1999 in the United States, 49% more men than women died of heart disease. Many of the phenotypic differences between men and women may account for this statistic. One particular explanation may be that testosterone increases the plasma level of low-density lipoproteins (LDL, or “bad” cholesterol) and decreases the level of high-density lipoproteins (HDL, or “good” cholesterol). High LDL levels and low HDL levels are both cardiac risk factors.
- There are three principal functions of the male reproductive system: the expression of male sex characteristics, spermatogenesis (the creation of sperm), and the delivery of sperm into the female for procreation.
- Male reproduction is coordinated by the hypothalamic-pituitary-testicular (HPT) axis, which is characterized by classic negative feedback. The hypothalamus secretes GnRH, which releases FSH and LH from the pituitary.
- FSH acts on the Sertoli cells in the seminiferous tubules of the testis and stimulates spermato- genesis.
- LH acts on the Leydig cells in the testicular parenchyma and stimulates secretion of the androgen steroid, testosterone. Testosterone inhibits GnRH and FSH/LH release.
- Testosterone is converted to its active form, dihydrotestosterone (DHT), at its sites of action.
- Testosterone causes development of the male genital system in utero and at puberty. It causes growth of the genitals; hair growth; the start of spermatogenesis; deepening of the voice; protein anabolism in muscle, bone, and skin; and increased libido and aggression.
- Spermatogenesis takes place in the seminiferous tubules of the testis and has three phases: spermatocytogenesis (mitosis and differentiation of some spermatogonia into spermatocytes), meiosis (resulting in four haploid spermatids), and spermiogenesis (the production of spermatozoa from spermatids). Testosterone and FSH promote this process.
- Newly created sperm pass from each of 900 seminiferous tubules into the epididymis of each testis. Here, sperm acquire potential motility, are bathed in inhibitory proteins, and are stored. Stored, suppressed sperm fill the vas deferens, the tube connecting the epididymis to the urethra, where they await ejaculation (expulsion from the penis) in the fluid called semen.
- Ejaculation is preceded by sexual excitement and penile erection.
- Excitement develops via psychological stimuli and tactile stimulation of the genitals. The pudendal nerve transmits afferent sensory information from the genitals to the brain.
- During excitement, the pelvic nerve transmits efferent parasympathetic impulses to the smooth muscle of the cavernous arteries in the erectile tissues of the penis, cylindrical bodies called the corpora cavernosa. These impulses dilate the penile arteries through a nitric oxide-mediated mechanism. Blood flow increases into the two dorsal corpora cavernosa and into the special ventral one, which houses the urethra; it is called the corpus spongiosum.
- When the three corpora cavernosa fill with blood, they eventually increase intracavernous pressure and reduce venous outflow, further increasing penile pressure. The penis becomes fully erect (that is, rigid and elevated).
- Increasing tactile stimulation of the pudendal nerve builds excitement until orgasm is reached, accompanied by release of the ejaculatory spinal cord reflex. The efferent limb of the reflex sends out impulses along sympathetic nerves that close the bladder neck and contract the seminal vesicles, prostate, and ampulla of the vas deferens. Contractions of urethral and pelvic muscles expel semen through the ejaculatory ducts and into the posterior urethra, an event called emission.
- If sperm are deposited into the vagina, they are capacitated, or rendered more motile and ready to fertilize, by the female reproductive tract. The acrosome, the head of the sperm cell, releases enzymes that digest a path into the oocyte, and fertilization occurs.
- Common problems associated with the male reproductive tract include prostatitis, erectile dysfunction, infertility, and benign and malignant growth of the prostate gland. Male gender is itself a cardiac risk factor.
Andersson KE, Wagner G. Physiology of penile erection. Physiol Rev. 1995;75(1):191–236.
Barry MJ, Roehrborn CG. Benign prostatic hyperplasia. Br Med J. 2001;323(7320):1042–1046.
Hiort O. Androgens and puberty. Best Pract Res Clin Endocrinol Metab. 2002;16(1):31–41.
Kandeel FR, Koussa VKT, Swerdloff RS. Male sexual function and its disorders: physiology, pathophysiology, clinical investigation, and treatment. Endocrinol Rev. 2001;22(3):342–388.
Kuhn CM. Anabolic steroids. Recent Prog Horm Res. 2002; 57:411–434.
Directions: Each of the numbered items or incomplete statements in this section is followed by answers or by completions of the statement. Select the ONE lettered answer or completion that is BEST in each case.
- The hypogastric nerve supplies sympathetic tone to the bladder and genitals. Its most important role in male reproductive function is probably that of stimulating:
- Testosterone production.
- Urethral lubrication.
- Capacitation of sperm.
- A 35-year-old man who is an avid bodybuilder complains of having developed what look like female breasts. A history reveals several years of drug abuse with a form of testosterone. Physical exam reveals acne, gynecomastia, and small testes. The mechanism behind his gynecomastia is:
- Negative feedback on the hypothalamus.
- Suppression of gonadal function.
- Positive nitrogen balance.
- Increased testosterone metabolism.
- Increased testosterone action.
- A 31-year-old man undergoes semen analysis after 1 year of trying unsuccessfully to impregnate his wife. If some of his sperm have abnormal flagella, this most likely reflects an error during which phase of sperm development?
- Epididymal maturation
- Mixing with seminal and prostatic fluid in the posterior urethra
ANSWERS TO REVIEW QUESTIONS
- The answer is H. Ejaculation is mediated by sympathetic impulses from the spinal cord. Remember “point and shoot”: “p” for parasympathetic mediation of erection and “s” for sympathetic mediation of ejaculation. The pudendal nerve carries afferent information to the central nervous system, and the pelvic nerve carries efferent parasympathetic impulses.
- The answer is D. The drug has increased the testosterone level, thereby increasing the peripheral metabolism of testosterone to estrogen, which has proliferative effects on the breast tissue of males and females. While increased testosterone action at the androgen receptor, hypothalamic inhibition, and gonadal suppression all occur in this context, they do not cause gynecomastia.
- The answer is D. Spermatids acquire their tails and become spermatozoa at the spermiogenesis phase of spermatogenesis. Thus, it is here that abnormalities in tail morphology are likely to arise. Abnormalities at other stages of sperm development are more likely to lower the sperm count or reduce sperm motility or penetrative ability.