Male reproductive physiology

INTRODUCTION — The mature male testis has two primary functions: sex steroid hormone production and spermatogenesis. This topic review will cover the normal anatomy, physiology, and regulation of the mature hypothalamic-pituitary-testicular axis and testicular production of sex steroid hormones and sperm. It will also cover the function of the male hypothalamic-pituitary-testicular axis during the fetal, neonatal, pubertal, and adult phases of life.

The roles of testosterone and 5-alpha-dihydrotestosterone (DHT) in male sexual differentiation are discussed separately. (See "Typical sex development".)

THE HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS — This axis is controlled by a classic feedback loop. The major endocrine stimulators of human testes are luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are made by the pituitary and secreted into the systemic circulation. LH stimulates testicular synthesis of testosterone and its two major active metabolites, estradiol and 5-alpha-dihydrotestosterone (DHT). LH is secreted in a pulsatile pattern with peaks approximately every 90 to 120 minutes [1]; FSH has a subtler pattern of pulsatility. LH and FSH secretion are stimulated by the pulsatile release of gonadotropin-releasing hormone (GnRH) from neurons in the hypothalamus; GnRH reaches the gonadotroph cells of the anterior pituitary via a portal vascular system. (See "Hypothalamic-pituitary axis".)

The hypothalamic GnRH pulse generator — The medial basal region of the hypothalamus (particularly the arcuate nucleus) contains neurons that secrete gonadotropin-releasing hormone (GnRH) from axon terminals in the median eminence into the hypothalamic-pituitary portal system. These neurons constitute the GnRH pulse generator and act as the metronome of the axis. Because serum concentrations of GnRH in the portal system are normally low, peripheral circulating GnRH concentrations are very low and not measurable in humans. Several hormones, neuropeptides, neurotransmitters, and cytokines modulate GnRH secretion.

Kisspeptin and its hypothalamic receptor, KISS1R (formerly called GPR54), play a major role in stimulating GnRH secretion, and it is likely that a synchronized interaction between the secretion of kisspeptin and the co-expressed neuropeptides, neurokinin B and dynorphin (from KNDy neurons of the arcuate nucleus), regulate the pulsatility of GnRH secretion [1,2]. A number of neurotransmitters and hormones regulate GnRH secretion, including gamma-aminobutyric acid (GABA), glutamate, and leptin (stimulatory) and sex steroid hormones, corticosteroids, and opioids (inhibitory). (See "Physiology of gonadotropin-releasing hormone".)

Pituitary gonadotropes — GnRH binds to cell-surface G protein-coupled receptors on the pituitary gonadotropes to stimulate the release of LH and FSH. The pituitary gonadotropes produce and secrete LH and FSH when stimulated by pulsatile peaks of GnRH. Continuous stimulation of gonadotropes with GnRH results in downregulation of pituitary GnRH receptors and inhibition of LH and FSH secretion; administration of long-acting GnRH agonists, which mimic continuous GnRH receptor stimulation, suppresses circulating LH and FSH concentrations in normal males [2]. LH and FSH are glycoprotein hormones similar to human chorionic gonadotropin (hCG) and thyroid-stimulating hormone (TSH). Glycoprotein hormones (LH, FSH, hCG, and TSH) share a common alpha subunit that is noncovalently linked to unique beta subunits that are essential for binding to their specific receptors. FSH and LH undergo varying amounts of glycosylation and sialylation after synthesis, resulting in considerable heterogeneity circulating LH and FSH isoforms. The half-life of gonadotropins is directly related to the amount of glycosylation and sialylation. The serum half-life of hCG is significantly longer than the serum half-life of FSH, which, in turn, is significantly longer than that of LH [3,4].

Gonadotropin actions in the testes — LH (and human chorionic gonadotropin [hCG]) bind to LH/CG receptors on the Leydig cell membrane to stimulate adenyl cyclase and the formation and release of cyclic adenosine monophosphate (cAMP). cAMP activates the testicular protein kinase A that stimulates Leydig cell testosterone production. Adult males produce 5 to 7 mg of testosterone daily [5]. This average daily production forms the basis of the typical dosages for testosterone therapy for male hypogonadism. (See "Testosterone treatment of male hypogonadism".).

FSH binds to receptors on the basal aspect of the Sertoli cell membrane (see 'Structure of the testes' below) to stimulate cAMP generation and activate protein kinase A and other signal transduction proteins such as mitogen-activated protein kinase (MAPK) [6]. Activated protein kinase A activates a number of Sertoli cell proteins, including cAMP response element-binding protein (CREB), which in turn regulate gene expression and production of proteins that support spermatogenesis.

Testicular negative feedback control of gonadotropin secretion — In males, LH secretion is regulated by negative feedback. Testosterone can be converted to estradiol by aromatase in the brain and the pituitary, but androgens (eg, testosterone and DHT) and estradiol inhibit gonadotropin secretion independently in healthy males [7,8]. In healthy males, estradiol suppresses LH by inhibiting GnRH secretion from the hypothalamus, whereas testosterone (and DHT) directly suppress pituitary secretion of LH [7]. LH concentrations are elevated in males with aromatase deficiency and estrogen resistance and males treated with aromatase inhibitors [9,10]. However, aromatization of testosterone is not required for negative feedback control of LH, because DHT (an androgen that cannot be aromatized) inhibits LH secretion at high doses [11,12].

Testosterone acts on the hypothalamus to slow the hypothalamic pulse generator and decrease LH pulse frequency [13], probably by a mechanism involving kisspeptin and endogenous opioids [14-16]. Testosterone also appears to inhibit LH release directly at the level of the pituitary [17]. Some of these effects are likely mediated by the local pituitary aromatization of testosterone to estradiol. In adult males, estradiol inhibits LH secretion both by decreasing GnRH pulse frequency at the level of the hypothalamus and by reducing the amplitude of LH pulses by impairing pituitary responsiveness to GnRH [9].

Feedback control of FSH secretion involves a testicular peptide (inhibin B) and sex steroid hormones. The two primary inhibitors of FSH secretion are inhibin B, a Sertoli cell product, and estradiol. Inhibin B appears to be the most important inhibitor of FSH secretion because FSH concentrations rise in males with normal serum testosterone concentrations (and preserved Leydig cell function) but with low concentrations of circulating inhibin B due to damage to the seminiferous tubules, including the Sertoli cells [18-20]. Estradiol appears to be more important than testosterone in the regulation of FSH secretion in males [8].

Regulation of the hypothalamic-pituitary-testicular axis during stress and disease — The hypothalamic-pituitary-testicular axis is exquisitely sensitive to stressors. Acute and chronic illnesses lower serum gonadotropin and testosterone concentrations through a variety of potential mechanisms including increased release of corticotropin-releasing hormone (CRH), cytokines, and endogenous dopamine and opioids [21]. Fasting and caloric restriction reduces serum leptin (which is required for normal GnRH pulse generation) and testosterone concentrations in healthy, normal-weight males [22,23]. In addition, exogenous opioids, corticosteroids, and medications or disorders that cause hyperprolactinemia may result in suppression of the axis [24].

STRUCTURE OF THE TESTES — The testes contain two anatomical compartments:

●The interstitial compartment is composed of Leydig cells that produce and secrete testosterone, peritubular myoid cells, fibroblasts, neurovascular cells, and macrophages.

●The seminiferous tubule compartment (80 to 90 percent of testicular volume) consists of Sertoli cells that produce inhibin B and germ cells in various stages of spermatogenesis.

A basal lamina of extracellular matrix forms the outer rim of the seminiferous tubules and separates the seminiferous tubule compartment from the nests of Leydig cells and other cells in the interstitial compartment. The basal lamina provides the scaffolding of the tubules and a structural layer between the tubular and interstitial compartments. On cross-section, the tubular compartment appears like a bundle of straws viewed end-on, and the interstitial compartment is tucked between the tubules.

Within the seminiferous tubules, the basal lamina is lined with undifferentiated germ cells (called spermatogonia) and Sertoli cells that envelop the differentiating germ cells (spermatocytes, spermatids, and spermatozoa). The Sertoli cells have tight junctions between them, and the ring created by the Sertoli cells and these tight junctions form the blood-testis barrier between the undifferentiated germ cells and the differentiating germ cells. Thus, the Sertoli cells straddle the basal (ie, next to the basal lamina) and luminal sides of the blood testis-barrier. The Sertoli cells and undifferentiated spermatogonia are directly affected by hormones and other circulating factors, as well as paracrine factors from the interstitium. By contrast, the differentiating spermatocytes, spermatids, and spermatozoa are insulated from these circulating factors by the blood-testis barrier and require factors produced by Sertoli cells that are secreted on the luminal side to support progressive differentiation [25].

During spermatogenesis, the spermatogonia pass through the tight junctions between Sertoli cells and begin differentiating sequentially to spermatocytes, then spermatids, and finally spermatozoa as they migrate toward the lumen of the tubules. The Sertoli cells have extensions to the luminal surface of the tubules, and these extensions surround and nourish the germ cells that are differentiating into mature spermatozoa that are eventually released (tail first) into the tubular lumen. The seminiferous tubules empty into a network of ducts called the rete testes, through which the sperm move to the epididymides and then to the vas deferens for eventual ejaculation.

FUNCTION OF THE INTERSTITIAL COMPARTMENT — The primary function of the interstitial compartment is Leydig cell synthesis of testosterone and its principal active metabolites, estradiol and 5-alpha-dihydrotestosterone (DHT), from cholesterol (figure 1). Leydig cells can synthesize these steroid hormones from cholesterol that is synthesized and stored in Leydig cells, or from circulating cholesterol (via uptake of low-density lipoproteins).

Testosterone synthesis — Testosterone synthesis is regulated by luteinizing hormone (LH); LH is required for normal adult testosterone production. There are several proteins involved in testosterone synthesis that are stimulated by LH (figure 1):

●Steroidogenic acute regulatory (StAR) protein – Regulates the first rate-limiting step of steroid hormone production, the transfer of cholesterol from the outer to the inner membrane of mitochondria in steroid-producing cells such as the Leydig cell.

●Cholesterol side-chain cleavage enzyme (CYP11A1) – Catalyzes the conversion of cholesterol to pregnenolone in the mitochondria and represents the first enzymatic rate-limiting step of specific biosynthesis of testosterone.

●17-alpha-hydroxylase (CYP17) – Catalyzes pregnenolone to 17-OH-pregnenolone and 17-OH pregnenolone to DHEA in the first steps that occur in the endoplasmic reticulum.

The initial step in Leydig cell synthesis of testosterone (conversion of cholesterol to pregnenolone) occurs in the mitochondria. The conversion of cholesterol to pregnenolone is the rate-limiting reaction in steroid biosynthesis, but the rate of delivery of cholesterol to the inner mitochondrial membrane by the StAR protein is the most important rate-limiting step in steroid hormone production [26].

Pregnenolone is translocated to the endoplasmic reticulum where it is converted to 17-hydroxypregnenolone and then to dehydroepiandrosterone (DHEA) by a single enzyme (CYP17) that possesses both 17-alpha-hydroxylase and 17,20-lyase activities. However, mutations in different parts of the CYP17 gene can influence the two processes selectively [27]. Approximately 5 to 7 mg of testosterone is secreted daily in a dyssynchronous pulsatile fashion under the control of LH [4]. In normal young adult males, sleep-induced increases in testosterone cause testosterone concentrations to peak in the early morning [28].

Testosterone metabolism — In the testes, a small percentage of testosterone is aromatized (by aromatase) to estradiol or reduced (by 5-alpha reductase) to DHT (figure 1).

Approximately 20 percent of circulating estradiol is synthesized in the testes, and the remainder is produced in adipose, brain, skin, and bone tissue by aromatization of testosterone [29]. Adipose tissue is the most significant site of estradiol formation in healthy males. LH stimulates aromatase, and increased serum LH (or hCG) concentrations stimulate secretion of estradiol by the testes. Circulating and locally produced estradiol plays an important role in males in body fat, sexual function, regulating bone growth, optimizing bone density, mediating closure of epiphyseal growth plates during puberty, and prevention of vasomotor symptoms (hot flashes) in hypogonadal males [29-32].

Estradiol deficiency (eg, congenital or acquired from aromatase inhibitors) results in decreased bone density, delayed epiphyseal closure, increased body fat, and decreased sexual function. Estradiol acts in concert with testosterone to inhibit gonadotropin secretion and to promote bone maturation in the adolescent male [33]. Estradiol excess in males can be either relative or absolute and is usually manifested by breast enlargement (gynecomastia). (See "Epidemiology, pathophysiology, and causes of gynecomastia".)

The majority of circulating DHT in healthy males originates from extratesticular synthesis in the skin and liver, but prostatic synthesis does not appear to contribute significantly. The ratio of plasma testosterone to DHT is approximately 10 to 15:1 [34]. DHT is an androgen that is significantly more potent than testosterone, largely due to more avid binding to the androgen receptor. Circulating and locally produced DHT mediates the effects of androgen action on prostate formation and external genital differentiation in the male fetus and has important effects on prostatic growth and male-pattern balding in the adult male (figure 1) (see "Typical sex development" and "Male pattern hair loss (androgenetic alopecia in males): Pathogenesis, clinical features, and diagnosis"). There are two separate 5-alpha-reductase isoenzymes [35]. 5-alpha-reductase type 1 is expressed in liver and nongenital skin. 5-alpha-reductase type 2 is expressed in the male urogenital tract, genital skin, and liver, and it is defective in subjects with 5-alpha-reductase 2 deficiency. (See "Steroid 5-alpha-reductase 2 deficiency".)

Transport of gonadal steroids — Gonadal steroids are transported in the plasma largely bound to protein. In healthy males, approximately 0.5 to 3 percent of plasma testosterone is free or unbound, and the rest is bound to sex hormone-binding globulin (SHBG), albumin, corticosteroid-binding globulin, and orosomucoid [36]. According to the free hormone hypothesis, the 30 to 44 percent of circulating testosterone that is bound avidly by SHBG is not available to tissues and therefore not "active." Although albumin has approximately 1000-fold lower affinity for testosterone binding than does SHBG, it binds half or more of circulating testosterone because of its high concentration. Albumin binds testosterone weakly, and therefore, testosterone may dissociate rapidly into some tissues. Bioavailable testosterone in plasma is the sum of free plus albumin-bound hormone. The free testosterone hypothesis remains unproven, but the limited available data tend to support it [36]. Although some experts recommend the measurement of bioavailable testosterone, there are very little clinical data to support its use [36].

Serum SHBG concentration is decreased by obesity, androgen administration, and untreated hypothyroidism and increased by advanced age, estrogen, and untreated hyperthyroidism. Therefore, serum SHBG concentrations are higher in females, prepubertal males, and hypogonadal males than those measured in healthy males. Alterations in the SHBG concentration do not affect androgen physiology in healthy males, because the hypothalamic-pituitary system responds to acute changes in concentrations of free testosterone by altering testosterone synthesis and reestablishing a normal serum free testosterone concentration.

Androgen action — As described above, the physiological actions of testosterone are the result of the combined effects of testosterone plus its active metabolites, estradiol and DHT. The major functions of androgens in males include the following (see "Pathogenesis and clinical features of disorders of androgen action", section on 'Pathogenesis'):

●Normal development of the fetal male phenotype during embryogenesis (see "Typical sex development")

●Regulation of gonadotropin secretion by the hypothalamic-pituitary system

●Stimulation of sexual maturation at puberty and maintenance during adulthood

●Normal sexual function, including normal libido, erectile function, and sexual satisfaction

●Increasing muscle mass and bone mass at puberty and maintenance during adulthood

●Closure of long-bone epiphyses resulting in cessation of growth at puberty

●Maintenance of lower fat mass (compared with females and hypogonadal males)

●Initiation and maintenance of spermatogenesis [37]

●Increasing and maintenance of erythropoiesis and hematocrit

Classical pathway — Inside target cells, testosterone and DHT bind to the same high-affinity androgen receptor (AR) protein. Binding of the hormone to the receptor causes a conformational change that causes dissociation of the receptor from heat shock proteins. The hormone-receptor complex translocates to the nucleus, then forms a homodimer with a second hormone-AR molecule. This active transcriptional regulatory complex, together with tissue-specific coregulator proteins, binds with high affinity to androgen response elements (AREs) in DNA sequences of genes resulting in up- or downregulation of transcription of genes and subsequent protein synthesis under androgen control [38].

The AR is a member of the steroid-thyroid-retinoid superfamily of hormone receptors that act as transcription regulatory factors and have conserved C-terminal regions for hormone and DNA binding. The N-terminal domain contains a glutamine repeat region that averages approximately 20 glutamine repeats, but this region is highly polymorphic in length. A significant expansion of the glutamine repeats is associated with Kennedy syndrome (X-linked spinal and bulbar muscular atrophy), which is associated with partial androgen resistance, and in general, there is an inverse relationship between the number of glutamine repeats and AR function. (See "Pathogenesis and clinical features of disorders of androgen action".)

Nonclassical pathways — The term "nonclassical" androgen action refers to mechanisms that do not involve binding of the AR-transcription regulatory complex to AREs in DNA and changes in transcription hours to days later. Nonclassical actions are also sometimes referred to as "nongenomic" actions or "rapid" actions because they take place within seconds and may involve cell-surface receptor binding. The term "nongenomic" is inaccurate because some nonclassical androgen action pathways involve second messengers that eventually lead to genomic effects [39-41].

The nonclassical action pathway can be mediated by several mechanisms [41]:

●The classical intracellular AR via activation of a coregulator such as steroid receptor co-activator (Src) kinase not requiring gene transcription

●Direct binding to specific binding sites of target molecules in the absence of the AR

●Distinct, nonclassical cell-surface transmembrane ARs or seven transmembrane receptors that transmit signals via G-proteins

●Changes in membrane permeability

Nonclassical androgen actions have been demonstrated in reproductive, cardiovascular, immune, and musculoskeletal systems [39]. In Sertoli cells, for example, nonclassical androgen signaling pathways are responsible for the stimulation of calcium influx and activation of the mitogen-activated protein kinase (MAPK) pathway [39]. Nonclassical actions of testosterone in Sertoli cells likely work in tandem with the classical actions to activate MAPK and promote spermatogenesis [42].

FUNCTION OF THE TUBULAR COMPARTMENT

Spermatogenesis — The principal function of the tubular compartment is spermatogenesis. Spermatogenesis begins after puberty, and it consists of three distinct phases:

●During the first (mitotic or proliferative) phase, undifferentiated stem cells (dark spermatogonia) undergo mitosis to replenish the stem cell pool, but a small number of spermatogonia differentiate into pale spermatogonia that are "committed" to further differentiation to B spermatogonia that progress to complete spermatogenesis. The B spermatogonia are sensitive to the effects of radiation exposure.

●During the second (meiotic) phase, each B spermatogonium loses contact with basement membrane of seminiferous tubule, passes through the blood-testis barrier, and becomes two primary spermatocytes. Each primary spermatocyte undergoes two sequential meiotic divisions to become two secondary spermatocytes and four spermatids, respectively.

●In the final phase (spermiogenesis), spermatids differentiate to mature spermatozoa. Approximately 100 million mature sperm are produced each day.

Transformation of the spermatid into a mature sperm requires reorganization of the nucleus and cytoplasm, development of a flagellum, and release of mature spermatozoa into the lumen of the tubule [43]. The nucleus relocates to the head of the spermatid and is covered by an acrosomal cap that contains proteolytic enzymes necessary for penetration of the ovum at the time of fertilization. The sperm tail (flagellum) forms on the luminal side of the spermatid so that the sperm "backs" into and is released into the seminiferous tubule lumen.

Sperm motility is due to the sliding action of microtubules that form the axoneme cytoskeleton of the tail. The microtubules are attached to each other by arms that contain the protein dynein. Hydrolysis of ATP generated in adjacent mitochondria provides energy for motility. Altered sperm motility may occur due to structural defects, such as lack of the dynein arms, or functional defects, such as deficiency of the dynein ATPase.

Sperm formation takes approximately 74 days from differentiation of pale spermatogonia to B spermatogonia, the mitotic and meiotic phases (which result in spermatocytes and then spermatids), and spermiogenesis (which results in spermatozoa). However, one study reported that the time for newly formed sperm to appear in the ejaculate averaged 64 days with substantial individual variation (ranging from 42 to 76 days) [44]. The transport of sperm through the epididymis to the ejaculatory ducts requires another 12 to 21 days. Thus, there is a delay of up to three months before an effect on the early phase of spermatogenesis (spermatogonial differentiation) is reflected by an effect on ejaculated sperm concentrations. Some maturation of sperm (enhancement of motility) occurs during passage through the epididymis, but the final step in fertilizing capacity (or capacitation) of sperm occurs after ejaculation into the female urogenital tract.

Normal spermatogenesis requires the 1 to 2 degrees lower temperature of the scrotum compared with that in the abdomen. However, a slight or transient increase in scrotal temperature (eg, wearing tight-fitting underwear or short periods of immersion in hot water) does not appear to impair fertility in most males [45].

Hormonal control — The main hormones that control spermatogenesis are follicle-stimulating hormone (FSH) (directly) and luteinizing hormone (LH) (indirectly by raising intratesticular testosterone concentrations many times higher than normal serum concentrations). The production of testosterone in Leydig cells under the control of LH results in an intratesticular testosterone concentration 60 to 100 times greater than that in the peripheral circulation [46]. Testosterone acts as a LH-induced paracrine factor to stimulate spermatogenesis.

Both hormones are required to initiate spermatogenesis after onset of puberty. FSH receptors are present in Sertoli cells and spermatogonia, and androgen receptor (AR) is present in Sertoli cells, Leydig cells, and peritubular myoid cells. Both LH and FSH play roles in normal spermatogenesis [6,47,48]. For example, spermatogenesis does not occur spontaneously in males with hypogonadotropic hypogonadism of prepubertal onset. Spermatogenesis can be initiated in these males with gonadotropin therapy. (See "Induction of fertility in males with secondary hypogonadism".)

Intratesticular paracrine factors and regulation of spermatogenesis — The primary function of the Sertoli cell barrier of tight junctions between the spermatogonia and primary spermatocyte is to maintain proper conditions for germ cell development in the tubules . Some molecules, such as glucose and testosterone, penetrate the tubule readily, whereas large molecules and peptides are almost completely excluded. It is likely that there are unidentified paracrine factors other than testosterone that regulate human spermatogenesis. However, investigators have not yet definitively identified other human paracrine factors that play an important role in spermatogenesis.

TESTICULAR FUNCTION DURING DIFFERENT PHASES OF LIFE — Testicular function has four distinct phases of male sexual life: fetal, neonatal, pubertal, and adult. In the fetal phase, testosterone production by the testes begins during the seventh week of gestation, and serum total testosterone concentrations increase to 300 to 400 ng/dL (10.4 to 13.9 nmol/L) and remain at those concentrations through the second trimester, then fall to very low concentrations at birth. At birth, males and females have similar serum testosterone concentrations.

During the neonatal phase, serum testosterone again rises in males and remain just below the adult normal range for three to six months before falling to low concentrations by one year of age. The neonatal surge in testosterone secretion results from a rise in serum LH concentrations (termed "mini-puberty"). The serum testosterone concentration remains very low until puberty, when serum gonadotropin and testosterone concentrations rise, and serum testosterone reaches normal adult concentrations by approximately age 17 years (265 to 900 ng/dL [9.2 to 31.2 nmol/L]) [49].

The serum concentrations of free and total testosterone remain constant until the fifth decade when they begin to decline at a rate of approximately 0.5 to 1 percent per year. Because sex hormone-binding globulin (SHBG) concentrations tend to increase with aging, free testosterone concentrations tend to decline faster than total testosterone concentrations [50,51]. (See "Approach to older males with low testosterone".)

The physiological and pathological importance of the fetal and pubertal phases of increased testosterone production are clear. Male phenotypic sex differentiation takes place during the fetal phase, and higher testosterone concentrations are necessary for a normal male neonatal phenotype (see "Typical sex development"). The pubertal rise in serum gonadotropins and testosterone is necessary for completion of the normal adult male phenotype and sexual maturation (including spermatogenesis). (See "Normal puberty".)

The physiological importance of the neonatal rise in gonadotropins and testosterone is less clear, but it is thought to enhance penile growth and Sertoli cell number. The neonatal mini-puberty seems to be important for normal penile size and normal postpubertal spermatogenesis. On the other hand, the physiological importance of the decline in testosterone and sperm production that occurs in older adult males is unknown.

SUMMARY

●Testicular anatomical units – The testes contain two anatomical units: the interstitial compartment that produces sex steroid hormones and the tubular compartment that makes sperm. (See 'Structure of the testes' above.)

●Hypothalamic-pituitary-testicular axis – The testes are regulated by the hypothalamus and pituitary. Luteinizing hormone (LH) stimulates the testicular Leydig cells to produce and secrete testosterone, and follicle-stimulating hormone (FSH) combined with high testicular concentrations of testosterone stimulate the seminiferous tubules to produce sperm. (See 'The hypothalamic-pituitary-testicular axis' above.)

Both high intratesticular testosterone concentrations and FSH are required for qualitatively and quantitatively normal spermatogenesis. (See 'Spermatogenesis' above.)

●Testosterone production – Adult males produce 5 to 7 mg of testosterone daily. This average daily production forms the basis of the typical dosages for testosterone therapy for male hypogonadism. (See 'Testosterone synthesis' above.)

●Testosterone metabolism – Testosterone is aromatized to estradiol that is important for normal bone strength, closure of long-bone epiphyses, body fat, and sexual function in adult males. Of the 50 mcg of estradiol formed daily in healthy adult males, approximately 20 percent is made in the testes, and the remainder is synthesized in extraglandular tissues, primarily in adipose tissue (figure 1).

Testosterone can also be converted to 5-alpha-dihydrotestosterone (DHT) that is important in normal male genital tract development (See 'Testosterone synthesis' above.).  

●Congenital abnormalities – Congenital abnormalities of DHT production or male fetal exposure to a 5-alpha reductase inhibitor results in abnormalities such as hypospadias and/or micropenis and small prostate, but otherwise normal male phenotype. (See "Pathogenesis and clinical features of disorders of androgen action".)

●Transport of gonadal steroids – Gonadal steroids are transported in the plasma bound to albumin and sex hormone-binding globulin (SHBG). In healthy males, 0.5 to 3 percent of plasma testosterone is free or unbound, 30 to 44 percent is bound to SHBG, and the remainder is bound to other proteins (principally albumin).

●Actions of testosterone – The physiological actions of testosterone are the result of the combined effects of testosterone itself and its active metabolites, estradiol and DHT.

The major functions of testosterone in males include (see 'Androgen action' above):

•Normal development of the fetal male phenotype during embryogenesis (see "Typical sex development")

•Regulation of gonadotropin secretion by the hypothalamic-pituitary system

•Stimulation of sexual maturation at puberty and maintenance during adulthood

•Normal sexual function, including normal libido, erectile function, and sexual satisfaction

•Increasing muscle mass and bone mass at puberty and maintenance during adulthood

•Closure of long-bone epiphyses resulting in cessation of growth at puberty

•Maintenance of lower fat mass (compared with females and hypogonadal males)

•Prevention of hot flashes in males with hypogonadism

•Initiation and maintenance of spermatogenesis

•Increasing and maintenance of erythropoiesis and hematocrit

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges James Griffin, MD, and Jean Wilson, MD, who contributed to an earlier version of this topic review.