Chapter 8. Male Reproductive System

• Describe the physiologic functions of the principal components of the male reproductive system.
• Describe the endocrine regulation of testicular function by gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, testosterone, and inhibin.
• Identify the cell of origin for testosterone, its biosynthesis, mechanism of transport within the blood, metabolism, and clearance. List other physiologically produced androgens.
• List the target organs or cell types, the cellular mechanisms of action, and the physiologic effects of testosterone.
• Describe spermatogenesis and the role of different cell types in this process.
• Understand the neural, vascular, and endocrine factors involved in the erection and ejaculation response.
• Compare and contrast the actions of testosterone, dihydrotestosterone, estradiol, and müllerian inhibitory factor in the process of sexual differentiation.
• Identify the causes and consequences of androgen oversecretion and undersecretion in prepubertal and postpubescent adult males.

In utero sexual differentiation, maturation, spermatogenesis, and ultimately reproduction are all functions of the male reproductive system that are under endocrine regulation. The 2 principal functions of the testicles, the adult male sex organs, are the production of sperm and the synthesis of testosterone. These processes ensure fertility and maintain male sexual characteristics, or virility. Testicular function is under central nervous system control in a classic neuroendocrine feedback loop with the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) as the key hormonal signals. These gonadotropins, as discussed in Chapter 2, are under the influence of hypothalamic gonadotropin-releasing hormone (GnRH) stimulation. Additional paracrine, neural, and endocrine factors contribute to the complex regulation of the hypothalamic-pituitary-gonadal axis. This chapter discusses the basic principles of endocrine regulation of the male reproductive system.

Sertoli cells form tight junctions creating a “blood-testis” barrier that functionally divide the seminiferous tubules into 2 compartments or environments for the development of spermatozoa. The basal compartment below the tight junctions has contact with the circulation and is the space in which spermatogonia develop to primary spermatocytes. The tight junctions open at specific times and allow progression of spermatocytes to the adluminal compartment, where meiosis is completed. The principal functions of Sertoli cells are as follows:

• Provide support for germ cells, forming an environment in which they develop and mature.
• Provide the signals that initiate spermatogenesis and sustain spermatid development.
• Regulate pituitary gland function and, in turn, control of spermatogenesis.

Together, the Sertoli and Leydig cells are the 2 principal cell types responsible for testicular function.

The tubuli seminiferi are united to form larger ducts called tubuli recti. These larger tubules form a close anastomosing network of tubes called the rete testis, terminating in the ductuli efferentes (see Figure 8–1). This tubular network carries the seminal fluid containing sperm from the testis to the epididymis; from here, spermatozoa enter the vas deferens and then the ejaculatory ducts. The ejaculatory ducts move semen (sperm containing fluid) into the urethra. The tubular network or excretory system and the accessory organs contribute to the final composition of sperm-containing semen through absorptive and secretory processes (summarized in Table 8–1). Sperm constitutes approximately 10% of the volume of the ejaculated semen, which is composed of testicular and epididymal fluid together with the secretory products of male accessory glands. Most of the volume of the ejaculate is formed by the seminal vesicles with the remainder consisting of epididymal fluids and secretions from the prostrate gland and bulbourethral glands.

The penis is composed of 2 functional compartments: the paired corpora cavernosa and the corpus spongiosum. The corpora cavernosa form the greater part of the substance of the penis and consist of bundles of smooth muscle fibers intertwined in a collagenous extracellular matrix. Interspersed within this parenchyma is a complex network of endothelial cell–lined sinuses, or lacunae, arteries, and nerve terminals. The penis is innervated by somatic and autonomic (both sympathetic and parasympathetic) nerve fibers. The somatic innervation supplies the penis with sensory fibers and supplies the perineal skeletal muscles with motor fibers. Autonomic nerves mediate vascular dilation leading to penile erection, stimulate prostatic secretions, and control smooth muscle contraction of the vas deferens during ejaculation.

The arterial blood supply to the male reproductive organs is predominantly derived from the superficial and deep external pudendal branches of the femoral artery, the superficial perineal branch of the internal pudendal artery, and the cremasteric branch from the inferior epigastric artery. Venous drainage follows the course of the corresponding arteries. Lymphatics drain into the inguinal lymph glands.

The gonadotropins produce their physiologic responses by binding to cell membrane Gαs protein–coupled receptors located in the Leydig and Sertoli cells, leading to activation of adenylate cyclase and increased formation of cyclic 3′,5′-adenosine monophosphate (cAMP) (Figure 8–2; see Figure 1–5). The increase in intracellular cAMP results in the activation of protein kinase A and subsequent kinase-mediated protein phosphorylation, which mediates the cellular effects of the gonadotropins. This process is similar to that used for adrenocorticotropic hormone–mediated stimulation of adrenal steroid hormone production (discussed below).

LH is the principal regulator of testosterone production by the Leydig cells. FSH plays an important role in the development of the immature testis, particularly by controlling Sertoli cell proliferation and seminiferous tube growth. Because the tubules account for approximately 80% of the volume of the testis, FSH is of major importance in determining testicular size, normally 4.1–5.2 cm in length and 2.5–3.3 cm in width in the adult male. FSH is important in the initiation of spermatogenesis during puberty. It is necessary for the production of androgen-binding protein by Sertoli cells and for the development of the blood-testis barrier.

Control of Gonadotropin Synthesis and Release

Pulsatile release of GnRH is determined by a pulse generator. The neuronal structures and chemical interactions that result in pulsatile GnRH release have not been fully elucidated. However, several central and peripheral signals modulate the activity of GnRH-releasing neurons. Some of these signals are stimulatory to GnRH release, such as norepinephrine and neuropeptide Y; others are inhibitory, such as β-endorphin and interleukin 1; others are both stimulatory and inhibitory, such as the estrogen 17β-estradiol. GnRH binds to a G protein–coupled receptor (Gq and G11) in the anterior pituitary gonadotrophs, activating phospholipase C and leading to the stimulation of inositol trisphosphate, diacylglycerol and protein kinase C. Activation of inositol trisphosphate leads to an increase in intracellular Ca2+ concentrations. GnRH also indirectly stimulates cAMP, contributing to control of LH and FSH release. The ratio between LH and FSH production is determined by the frequency of GnRH pulses. Synthesis of FSH β-subunit is highest in response to low-frequency pulses of GnRH and is suppressed at higher-frequency pulses of GnRH. Higher frequency and amplitude of GnRH stimulation increase LH β-subunit synthesis.

LH stimulates testosterone production by the Leydig cell. Testosterone released into the circulation inhibits LH release in a negative feedback loop. At the level of the hypothalamus, testosterone inhibits GnRH release, and at the anterior pituitary, it decreases the gonadotropin-specific β-subunit synthesized (see Figure 8–2). Testosterone reduces LH levels and the LH pulse amplitude. It is important to mention that most of the inhibitory effect of testosterone on LH release is mediated by 17β-estradiol, a locally produced metabolite of testosterone aromatization (Figure 8–3). The negative feedback inhibition of FSH release occurs at the level of the pituitary and is mediated mainly by inhibin B, a Sertoli cell–derived peptide (discussed later).

Inhibin-Activin

In addition to the traditional feedback inhibition of gonadotropin hormone release described above (see Figure 8–2), locally produced factors (inhibin and activin) are also involved in regulation of gonadotropin release. Inhibins are peptide hormones that belong to the transforming growth factor beta (TGF-β) superfamily of growth factors. Inhibin B is produced by Sertoli cells in response to FSH stimulation (discussed later), and it produces feedback inhibition of FSH β-subunit production (and thus, FSH release). An additional factor involved in the regulation of FSH release is activin. Activin is expressed in several tissues including the pituitary. Its role is to antagonize inhibin B action, resulting in stimulation of FSH release. Thus, in addition to the negative feedback inhibition produced by gonadal androgens, the interaction between inhibin and activin contributes to the regulation of gonadotropin release.

The 2 principal physiologic functions of the testes—the production of hormones involved in sexual differentiation, maturation, and virilization and spermatogenesis—are closely related to each other. This chapter first discusses hormone production in the testes and then describes the process of spermatogenesis.

Gonadal Hormone Synthesis

Testosterone

Testosterone, produced by the Leydig cells, is the principal and most important testicular and circulating androgen. LH stimulates testosterone biosynthesis by increasing mobilization and transport of cholesterol into the steroidogenic pathway, an action that takes place within minutes; as well as by stimulating gene expression and activity of the steroidogenic enzymes (steroidogenic acute regulatory protein and P450scc), a slower process that requires several hours (Figure 8–4). As discussed in Chapter 6, steroidogenic acute regulatory protein (also found in the adrenal cortex cells) has a key role in the transfer of cholesterol from the outer to the inner mitochondrial membrane, the first step in steroid hormone biosynthesis, for the conversion of cholesterol to pregnenolone. Pregnenolone diffuses out of the mitochondria to the smooth endoplasmic reticulum, where it is further metabolized by the action of 3β-hydroxysteroid dehydrogenase to progesterone. Progesterone in turn is converted by a 2-step process to androstenedione by the action of 17α-hydroxylase. The conversion of androstenedione to testosterone is catalyzed by 17β-hydroxysteroid dehydrogenase. Note that up until this last enzymatic reaction, the enzymatic steps involved in testosterone synthesis are similar to those involved in androstenedione synthesis by the adrenal glands (see Figure 6–3). It is the activity of 17β-hydroxysteroid dehydrogenase and the enzymatic conversion of androstenedione to testosterone that are specific to the gonads.

Inhibin

Inhibin is produced and released from the Sertoli cells in response to FSH stimulation and exerts both paracrine and endocrine responses. Inhibin belongs to the family of glycoprotein hormones and growth factors including TGF-β, müllerian-inhibiting substance (MIS), and activin. Inhibins are heterodimer glycoproteins consisting of an α- and a β-subunit (βA or βB). Of the 2 forms of inhibin (α-βA and α-βB), inhibin B is the physiologically important form in males. Its main function is to suppress the secretion of FSH from the pituitary in a classic negative feedback endocrine mechanism through binding to a membrane-spanning serine/threonine kinase receptor. Inhibin B secretion appears to be dependent on Sertoli cell proliferation, maintenance, and spermatogenesis, all of these functions regulated by FSH. Inhibin B levels correlate with total sperm count and testicular volume and can be used as an index of spermatogenesis.

Activins, members of the same family of peptides as the inhibins, are homodimers or heterodimers of the β-subunit of the inhibins. They are synthesized in many adult tissues and cell types, and their receptors have been identified in those same tissues, a pattern more consistent with autocrine or paracrine mechanisms of action. At the pituitary, locally produced activin opposes inhibin’s actions and favors the synthesis of β-FSH (see Figure 8–2).

Estradiol

Testosterone conversion to 17β-estradiol is mediated by the enzyme aromatase, expressed in Leydig cells as well as in extragonadal tissues, particularly adipose tissue and placenta (see Figure 8–4). The contribution of 17β-estradiol produced by the Leydig cells to the total circulating estrogens in males is approximately 20%.

Gonadal Hormone Metabolism

Testosterone Metabolism

Most of the testosterone released into the circulation is bound to plasma proteins, primarily sex hormone-binding globulin (SHBG) and albumin (44% and 54%, respectively); both proteins made in the liver. In the testes, testosterone is bound to androgen-binding protein (ABP), a protein synthesized by Sertoli cells and released into the lumen of the seminiferous tubules. ABP has great similarity to SHBG. SHBG is expressed in several tissues, including brain, placenta, and testes and appears to function as part of a newly identified steroid-signaling system that is independent of the cytosolic androgen receptor. Unlike the effects mediated through binding to the intracellular steroid receptor produced by testosterone, SHBG interacts with a membrane form of the receptor and triggers cAMP signaling pathways. The physiologic relevance of the effects mediated through this pathway has not been elucidated.

Testosterone to Estradiol Conversion

The majority of estradiol in males is produced in adipose tissue through the aromatization of testosterone and, to a smaller extent, of adrenal-derived androstenedione. Aromatase expression is directly related to the degree of adiposity; it is dependent on cytokine stimulation and requires the presence of glucocorticoids. Although some of the 17β-estradiol produced in peripheral tissues is released into the circulation, not all estrogens produced from testosterone are involved in mediating endocrine responses. Some are involved in intracrine regulation of physiologic responses through estrogen receptor stimulation (see Figure 8–3). An example is the negative feedback regulation of GnRH in the hypothalamus and of gonadotropins in the anterior pituitary by testosterone. Another important example is the effect of testosterone on bones, where epiphysial closure is mediated through osteoblast and chondroblast aromatase conversion of testosterone to estradiol. In addition, the production of estrogens in the brain plays an important role in the masculinization of the brain during development and the maintenance of sexual behavior in the adult.

In the liver, testosterone is converted to androstenedione, which is then reduced and conjugated (glucuronidation) to form 17-ketosteroids (see Figure 8–4). A similar degradation pathway is used in the metabolism of dehydroepiandrosterone (DHEA) and androstenedione. After 17β-estradiol is produced by the testes or by the peripheral metabolism of testosterone, it is initially converted to estrone, which is converted into either catecholestrogens or 16α-hydroxyestrone. Catecholestrogens are degraded by catechol-O-methyltransferase (involved in catecholamine degradation; discussed in Chapter 6), while 16α-hydroxyestrone is converted to estriol before being conjugated in the liver and excreted by the kidney. Thus, the excretion of testosterone and its metabolites in the urine is approximately 50% in the form of 17-ketosteroids and 50% in the form of polar metabolites such as -diols, -triols, and conjugated forms.

Testosterone to 5a-Dihydrotestosterone Conversion

The conversion of testosterone to DHT in peripheral tissues, particularly in the skin, produces the most potent natural androgen (see Figure 8–4). Two isoenzymes (type 1 and type 2) of 5α-reductase are involved in the conversion of testosterone to DHT. The type 2 isoenzyme generates 3 times as much DHT as the type 1 isoenzyme and plays a critical role during sexual differentiation. During puberty, the contribution of the type 2 isoenzyme decreases and the type 1 reductase plays a more important role in adult males. A small amount of DHT can enter the circulation (approximately 10% of the total testosterone in blood) and can therefore exert effects at target cells that do not express 5α-reductase activity (see Figure 8–3). DHT is inactivated to the weak androgen 3α-androstenediol by the action of 3α-hydroxysteroid dehydrogenase. The enzymatic conversion of testosterone to DHT is irreversible. Because DHT is involved in some pathologic processes, the enzymatic conversion of testosterone to DHT has been used effectively as a target for pharmacologic interventions. Androgens stimulate the growth of prostate cancer and are also involved in benign prostatic hypertrophy. Finasteride, a 5α-reductase inhibitor, is currently used for the treatment of benign prostatic hyperplasia and prostate cancer.

Androgen Receptor-Mediated Physiologic Effects

The physiologic effects that are mediated by testosterone and DHT are related. DHT is the most potent activator of the androgen receptor, and the DHT-activated androgen receptor has a longer half-life, prolonging androgen action and amplifying the androgen signal. However, distinct physiologic responses can be attributed to each hormone (Table 8–2), in part determined by the localized conversion of testosterone to DHT. Testosterone controls sexual differentiation (development of the wolffian ducts), libido (the biologic need for sexual activity and sexual function), pubertal growth of the larynx, anabolic effects in muscle, and stimulation of spermatogenesis. In contrast, DHT plays a major role in embryonic and pubertal external virilization (eg, development of male external genitalia, urethra, and prostate, and growth of facial and body hair) and contributes to male-pattern balding in individuals with a genetic predisposition for baldness (Figures 8–5 and 8–6). Most of the effects of DHT are intracrine; they are mediated at target cells expressing 5α-reductase. However, as already mentioned a small amount enters the circulation (10% of testosterone levels) and may have some endocrine effects on cells that do not express 5α-reductase.

In addition to the regulation of LH release from the anterior pituitary, testosterone affects sexual development, maturation, and function, and contributes to the maintenance of fertility and secondary sexual characteristics in the adult male (see Figures 8–5 and 8–6). In addition, testosterone exerts overall anabolic effects in muscle and bone.

Sexual Development and Differentiation

Sexual differentiation in humans is genetically and hormonally controlled. Genes on the Y chromosome signal primordial cells in the embryonic gonad ridge to differentiate into Sertoli cells and stimulate newly migrated germ cells to differentiate as spermatogonia, developing into a testis (see Figure 8–5). The cells of the embryonic testis secrete hormones that lead to the development of male secondary sexual characteristics. The Sertoli cells secrete müllerian inhibitory factor or substance (MIF or MIS), causing regression of the müllerian ducts. The Leydig cells secrete testosterone, causing differentiation and growth of the wolffian duct structures. DHT causes growth of the prostate and penis and fusion of the labioscrotal folds (see Figure 8–6).

The processes and factors involved in fetal development and sexual differentiation involve genetic, embryologic, histologic, and anatomic details not covered in this monograph. This section aims to summarize the key events in sexual differentiation as they pertain to endocrine regulation and function and to highlight the role of androgens in the determination of male sexual development.

Sex Determination

• Determination of the genetic sex of the embryo when an X- or a Y-bearing sperm fertilizes the oocyte
• Determination of the fate of the bipotential or nondifferentiated gonad and thus of gonadal sex
• Differentiation of male or female internal and external genitalia, or determination of phenotypic sex.

The determination of genetic sex is mediated through the chromosomal set, which in the normal male is 46,XY. The subsequent sexual differentiation is determined by genetic factors. Several sex-specific genes have been found to regulate gonadal differentiation and subsequent male or female reproductive tract development. One of the first genes involved in sexual differentiation is a gene on the Y chromosome called SRY (sex-regulating region of the Y). The product of the SRY gene is a protein that stimulates the neutral gonadal tissues to differentiate into testes, thereby determining gonadal sex. SRY is necessary and sufficient to initiate the male development cascade. If the SRY gene is mutant or missing on the Y chromosome, the embryo develops into a female.

Sexual Differentiation

The process of differentiation of the human male gonads begins in the sixth week of gestation (see Figure 8–5). The first morphologically identifiable event is the development of precursor Sertoli cells, which aggregate to form the seminiferous cords, which are then infiltrated by primordial germ cells. By the end of the ninth week, the mesenchyme that separates the seminiferous cords gives rise to the interstitial cells, which differentiate as steroid-secreting Leydig cells. It is thought that the placenta-derived hormone, human chorionic gonadotropin (hCG), might be responsible for the initial development of Leydig cells because the onset of testosterone production precedes LH secretion. Hence, gonadotropic control of fetal testicular steroidogenesis is mediated initially by placenta-derived hCG and later by LH. The resulting increase in fetal testosterone production stimulates Leydig cell proliferation, increases the expression of steroidogenic enzymes (particularly 3β-hydroxysteroid dehydrogenase and 17α-hydroxylase), and increases the expression of the androgen receptor in the target tissues.

Following müllerian duct regression and androgen-dependent virilization of the urogenital system, the testes migrate from their site of origin next to the kidney into the scrotum. This is the final critical event in male sexual differentiation. The 2-step process of transabdominal migration followed by descent into the extraabdominal scrotal sac finalizes sexual differentiation in the male and is completed during the late gestational period. The descent of the testis results from the regression of the cranial suspensory ligament, which connects them to the abdominal wall through the gubernaculum. Regression of the cranial suspensory ligament, transabdominal migration, and the final descent of the testis into the scrotum are mediated by testosterone and insulin-like growth factor 3. This hormone, also known as Leydig insulin-like hormone or relaxin-like factor, is a member of the insulin and insulin-like growth factor peptide hormone family. In humans, failure of complete testicular descent into the scrotum (cryptorchidism) is one of the most common congenital abnormalities, involving approximately 3% of male births. Cryptorchidism is important because spermatogenesis requires lower temperatures (as in the scrotum) than those found intraabdominally. If untreated, cryptorchidism can lead to infertility, and it has been associated with an increased risk of testicular tumors.

Sexual Maturation and Function

Puberty

Puberty is the physiologic transition between childhood and adulthood and involves the development of secondary sexual characteristics and the pubertal growth spurt. The process takes place over a period of approximately 4 years. Puberty is triggered by increased pulsatile secretion of GnRH by the hypothalamus, leading to increases in serum gonadotropins and, thus, to increases in gonadal secretion of sex steroids. The hypothalamic-pituitary-gonadal system is active during the neonatal period but enters a dormant state in the juvenile, prepubertal period. During the initial phase of puberty, plasma levels of LH increase primarily during sleep. These sleep-associated surges are later present throughout the day and mediate or result in an increase in circulating testosterone levels.

Puberty is preceded by adrenarche, a period characterized by increased adrenal production of DHEA and androstenedione at around 6–8 years of age that is not associated with increased production of adrenocorticotropic hormone or cortisol. The peak concentrations of DHEA and androstenedione are reached during late puberty and early adulthood. During this stage, there is some conversion of adrenal-derived androgens to testosterone, resulting in a small increase in circulating testosterone levels. The signal that triggers upregulation of the synthesis of DHEA and androstenedione is not known.

The increase in pulsatile release of GnRH is essential for the onset of puberty. However, the mechanism controlling the pubertal increase in GnRH release is still unclear. Leptin, a hormone secreted from adipose tissue (see Chapter 10), has been shown to have a permissive role in the timing of the activation of the GnRH pulse generator. The increase in the amplitude of GnRH pulses triggers a cascade of events including increases in the amplitude of FSH and LH pulses, followed by marked increases in gonadal sex hormone production. Accompanying the increase in gonadal steroid production during puberty is an increase in the amplitude of growth hormone secretory bursts. Together, growth hormone and gonadal steroids are responsible for producing normal pubertal growth. During the adolescent growth spurt, growth velocity increases from the prepubertal rate of 4–6 cm per year to as much as 10–15 cm per year. The physiologic changes associated with puberty are summarized as follows:

• Leydig cell maturation and initiation of spermatogenesis
• Testis enlargement; reddening and wrinkling of scrotal skin
• Pubic hair growth from the base of the penis
• Penis enlargement
• Prostate, seminal vesicle, and epididymis growth
• Facial (mustache and beard) and extremities hair growth, regression of scalp line
• Larynx enlargement, thickening of the vocal cords and deepening of the voice
• Enhanced linear growth
• Increased muscle mass and hematocrit
• Increased libido and sexual potency

Maturity and Senescence

Sexual maturity is achieved at approximately age 16–18 years. During this stage, sperm production is optimal, plasma gonadotropins are normal, and most sexual anatomic changes have been completed. Beginning at age 40, there is a gradual decline in circulating testosterone levels, followed at age 50 by a reduction in sperm production. Testosterone levels in healthy, aging men decline on the order of 100 ng/dL per decade, accompanied by increases in SHBG resulting in an overall decrease in free and bioavailable testosterone levels. In addition, aging is associated with decreased testosterone to estradiol ratio, decreased LH pulse frequency, loss of the diurnal rhythm of testosterone secretion, and diminished accumulation of 5α-reduced steroids in reproductive tissues. These hormonal changes are well established by the age of 50 years. This period of androgen deficiency is called andropause and is characterized by diminished sexual desire and erectile capacity; fatigue and depression; decreased intellectual activity, lean body mass, body hair, and bone mineral density; and increased visceral fat and obesity. These age-related physiologic changes are caused by decreased testosterone, DHEA androstenedione, and growth hormone production.

Fertility and Secondary Sexual Characteristics

Spermatogenesis

Spermatogenesis is the process of continuous germ cell differentiation to produce spermatozoa (Figure 8–7). Spermatogenesis is initiated at the time of puberty, is compartmentalized within the blood-testis barrier, and is mainly under FSH regulation. Spermatogenesis involves 4 basic processes:

Proliferation of Spermatogonia (Stem Cells) Giving Rise to Spermatocytes (Diploid Cells)

Spermatogonia line the seminiferous tubule near the basement membrane. They originate at puberty by proliferation of the gonocytes and are derived from primordial germ cells. One or 2 divisions of spermatogonia occur to maintain their population in a stem cell pool (see Figure 8–7). Of the cells resulting from these mitotic divisions, some spermatogonia stay in the “resting” pool, whereas the remaining spermatogonia proliferate several times and undergo 1–5 stages of division and differentiation. After the last division, the resulting cells are termed primary spermatocytes. The “resting” or stem cell spermatogonia remain dormant for a time and then join a new proliferation cycle of spermatogonia. These cycles of spermatogonial divisions occur before the previous generation of cells has completed spermatogenesis, so that multiple stages of the process are occurring simultaneously in the seminiferous tubules. This overlap ensures a residual population of spermatogonia that maintain the ability of the testis to continuously produce sperm.

Meiosis of Spermatocytes to Yield Spermatids (Haploid Cells; 23 Chromosomes)

The primary spermatocytes undergo 2 divisions; the first meiotic division produces 2 secondary spermatocytes. Division of the secondary spermatocytes completes meiosis and produces the spermatids.

Spermiogenesis, or Maturation and Development of Spermatids into Spermatozoa (Sperm)

This phase is characterized by nuclear and cytoplasmic changes that provide spermatozoa with key elements for their function. The main events during this phase involve spermatid condensation of nuclear material, formation of the acrosome, repositioning of the spermatid to allow formation and elongation of tail structures, mitochondrial spiral formation, and removal of extraneous cytoplasm, resulting in spermatozoa. Each of the features acquired during this step plays an important role in sperm function, as summarized in Table 8–3.

Spermiation

This is the final process of release of mature sperm from the Sertoli cells into the tubule lumen.

Throughout spermatogenesis, the germ cells move from the basal to the adluminal region of the seminiferous tubule into the compartment protected by the blood-testis barrier. The mitotic phase occurs in the basal compartment, whereas the meiotic and postmeiotic phases occur in the luminal compartment. The overall results of spermatogenesis are the following: cell proliferation and maintenance of a reserve germ cell population, reduction in chromosome number and genetic variation through meiosis, and production of spermatozoa.

Regulation of Spermatogenesis

Spermatogenesis is dependent on gonadotropin stimulation and testosterone production. FSH stimulates proliferation and secretory activity of the Sertoli cells, whereas LH stimulates the production of testosterone. Testosterone in turn stimulates spermatogenesis through receptor-mediated events in the Sertoli cells. The LH-induced rise in intratesticular testosterone plays an essential role in the initiation and maintenance of spermatogenesis by the Sertoli cells. Testosterone produced by the Leydig cells are transported to the developing germ cells bound to ABP produced by the Sertoli cell in response to FSH stimulation and released into the adluminal compartment. The synthesis of ABP requires that the Sertoli cell be under androgen influence, underscoring the importance of testosterone in Sertoli cell function and the reliance on paracrine mechanisms of hormone action.

Anabolic and Metabolic Effects of Androgens

In bone, the main physiologic effect of testosterone is to reduce bone resorption by increasing osteoblast lifespan and proliferation. Testosterone enhances bone formation, increases periosteal apposition of bone, increases protein synthesis, and decreases protein breakdown, having an overall anabolic effect in bone and skeletal muscle. Much of testosterone’s action on bone results from its aromatization to 17β-estradiol and the estrogen receptor. Testosterone-derived estrogen is a critical sex hormone in the pubertal growth spurt, skeletal maturation, accrual of peak bone mass, and maintenance of bone mass in the adult. It stimulates chondrogenesis in the epiphysial growth plate, increasing pubertal linear growth. At puberty, estrogen promotes skeletal maturation and the gradual, progressive closure of the epiphysial growth plate and the termination of chondrogenesis. In the adult, estrogen is important in maintaining the constancy of bone mass through its effects on remodeling and bone turnover.

Testosterone inhibits lipid uptake and lipoprotein lipase activity in adipocytes, stimulates lipolysis by increasing the number of lipolytic β-adrenergic receptors, and inhibits differentiation of adipocyte precursor cells. Androgens stimulate resting metabolic rate and lipid oxidation and enhances glucose disposal by increasing the expression of glucose transporters on the plasma membrane of adipocytes.

The physiologic process of human reproduction involves the fertilization of a mature ovum through the deposition of sperm-containing semen in the vagina of the female. This event involves penile erection and ejaculation of the sperm-containing semen at the time of copulation. Penile erection results from smooth muscle relaxation mediated by a spinal reflex involving central nervous processing and integration of tactile, olfactory, auditory, and mental stimuli. Corporeal vasodilatation and corporeal smooth muscle relaxation allow increased blood flow into the corpus cavernosum. The concordant contraction of the perineal skeletal muscles leads to a temporary increase in corpus cavernosum blood pressure above mean systolic arterial pressure, helping to increase penile firmness.

Corporeal vasodilatation is mediated by the parasympathetic nervous system. Parasympathetic fibers directly innervating the corporeal smooth muscle and sinusoidal endothelial cells release acetylcholine, stimulating the production of constitutive endothelial nitric oxide. Nitric oxide produced locally in the smooth muscle cell, or reaching it by diffusion from the adjacent endothelial cells, is the major mediator of smooth muscle relaxation through activation of guanylate cyclase and increased production of cyclic guanosine monophosphate (cGMP). The inactivation of cGMP phosphodiesterase, the enzyme that degrades cGMP with the drug sildenafil, preserves smooth muscle relaxation, and prolongs the erection period. This is used commercially to treat erectile dysfunction.

The ejaculation phase of the sexual response consists of 2 sequential processes: emission and ejaculation. Emission is the deposition of seminal fluid into the posterior urethra and is mediated by simultaneous contractions of the ampulla of the vas deferens, the seminal vesicles, and the smooth muscles of the prostate. The second process is ejaculation, which results in expulsion of the seminal fluid from the posterior urethra through the penile meatus. This process is controlled by sympathetic innervation of the genital organs and occurs as a result of a spinal cord reflex arc. Detumescence of the penis following ejaculation and maintenance of the flaccid penis in the absence of sexual arousal, are produced by sympathetic corporeal vasoconstriction and corporeal smooth muscle contraction by noradrenergic, neuropeptide Y, and endothelin-1 fibers.

Hypergonadism

Excess androgen activity in childhood leads to precocious puberty, defined as the appearance of male secondary sex characteristics before age 9 years (see Table 8–2). Hypothalamic tumors, activating mutations of the LH receptor, congenital adrenal hyperplasia, and androgen-producing tumors are all causes of premature virilization. Two types of precocious puberty can be identified: gonadotropin dependent and independent.

Hypogonadism

Decreased testosterone production, or hypogonadism, can be caused by disorders at the hypothalamic/pituitary level (hypogonadotropic or secondary hypogonadism) or by testicular dysfunction (hypergonadotropic or primary hypogonadism). Hypogonadotropic hypogonadism can be caused by abnormalities in hypothalamic GnRH secretion or action, associated with impaired gonadotropin secretion by the anterior pituitary. This condition may result from genetic defects including Kallmann syndrome; adrenal hypoplasia; mutations of the GnRH receptor, LH, or FSH β-subunits; pituitary tumors (including prolactinoma); trauma; or surgery.

Abnormal testicular function in the presence of elevated gonadotropin levels (hypergonadotropic or primary hypogonadism) is caused by testicular damage or impaired testicular development, which can be either congenital or acquired following chemotherapy or radiation. Causes include cryptorchidism, gonadal dysgenesis, varicocele, enzyme defects in testosterone biosynthesis, or LH receptor defects. Klinefelter syndrome is the most common sex chromosome disorder, in which affected males carry an additional X chromosome. This genetic abnormality results in male hypogonadism, androgen deficiency, and impaired spermatogenesis. Klinefelter syndrome is the most common genetic cause of human male infertility. Hyperprolactinemia from any cause results in both reproductive and sexual dysfunction because of prolactin inhibition of GnRH release, resulting in hypogonadotropic hypogonadism.

Clinical Presentation

Excess testosterone in the prepubescent male is associated with the appearance of all the changes of puberty at a very early age. These changes include enlargement of the penis and testicles; appearance of pubic, underarm, and facial hair; spontaneous erections; production of sperm; development of acne; and deepening of the voice.

Androgen deficiency leads to severe symptoms, which differ according to the time of onset. Androgen deficiency during early childhood results in short stature, lack of deepening of the voice, female distribution of secondary hair, anemia, underdeveloped muscles, and genitalia with delayed or absent onset of spermatogenesis and sexual function. Androgen deficiency in the adult after normal virilization has been completed leads to a decrease in bone mineral density (bone mass), decreased bone marrow activity resulting in anemia, alterations in body composition associated with muscle weakness and atrophy, changes in mood and cognitive function, and regression of sexual function and spermatogenesis. In the adult male, androgen deficiency decreases nocturnal erections and libido.

Evaluation of Hypogonadism

Sparse facial, axillary, and pubic hair and small penis and testicles characterize the clinical presentation of the prepubescent male patient with hypogonadism. Low plasma levels of testosterone should be interpreted in conjunction with LH levels to distinguish between hypo- and hypergonadotropic forms of hypogonadism. Similar to the functional tests described for other endocrine organs, a challenge test with intravenously injected GnRH to determine the gonadotropin and testosterone response 25 and 40 minutes later is used to assess the gonadotropin reserve capacity of the pituitary. When the response is absent, a prolonged period (7 days) of GnRH can be used to further stimulate the anterior pituitary gonadotrophs. In adults, fertility assessment by semen evaluation is also indicated. Semen analysis is interpreted according to normal values shown in Table 8–4.

• Leydig cells synthesize testosterone. Sertoli cells support spermatogenesis and form the blood-testis barrier.
• The main functions of the testes are testosterone production and spermatogenesis.
• Testicular function is under LH and FSH regulation. LH and FSH production and release are under hypothalamic GnRH stimulation and feedback inhibition by gonadal hormones.
• The main hormones produced by the testis are testosterone, estradiol, and inhibin.
• Testosterone can be metabolized to DHT, a more potent androgen, or to 17β-estradiol, an estrogen.
• Androgens exert their physiologic effects through modulation of gene transcription.
• Three essential testis-derived hormones regulate male sexual development: androgens, AMH, and insulin-like growth factor 3.