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MD Consult: Books: Goldman: Cecil Medicine: Chapter 253 – THE TESTIS AND MALE SEXUAL FUNCTION

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier



Ronald S. Swerdloff   Christina Wang


The testis is a bifunctional organ serving as the site of sex steroid (i.e., testosterone) synthesis and sperm production in the male. Thus, the testis controls both sexuality and the perpetuity of the species (fertility). In addition, androgens and their metabolites (including estrogens) serve essential metabolic roles and may be important inducers and effectors of brain function in men. The discussion in this chapter focuses on male reproductive physiology and its disorders: androgen deficiency, sexual dysfunction, infertility, and androgen excess states.



The male reproductive axis consists of six main components: (1) extrahypothalamic central nervous system (CNS), (2) hypothalamus, (3) pituitary, (4) testes, (5) sex steroid–sensitive end organs, and (6) sites of androgen transport and metabolism ( Fig. 253-1 ). The components of this system function in an integrative fashion to control the concentrations of circulating gonadal steroids required for normal male sexual development and function; for androgen- and estrogen-mediated metabolic effects on critical end organs such as brain, bone, muscle, liver, skin, and bone marrow; and for immune systems. The reproductive axis is also responsible for normal germ cell maturation and sperm transport necessary for male fertility.



FIGURE 253-1  The hypothalamic-pituitary-gonadal axis in the male. DHT = dihydrotestosterone; E = estrogen; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone; NE = norepinephrine; NO = nitric oxide; T = testosterone.

Hypothalamic Pituitary Function


The hypothalamus is the principal integrative unit responsible for the normal pulsatile secretion of gonadotropin-releasing hormone (GnRH), which is delivered through the hypothalamic-hypophyseal portal blood system to the pituitary gland ( Chapter 241 ). Although GnRH has been identified in many areas of the CNS, it is most concentrated in the medial basal, arcuate, and suprachiasmatic nuclei in the hypothalamus and travels by axonomic flow to the axon terminals of the median eminence. The pulsatile release of GnRH provides the signals for the timing of the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in normal circumstances occurs approximately every 60 to 90 minutes. The secretion of GnRH is regulated in a complex fashion by neuronal input from higher cognitive and sensory centers and by circulating levels of sex steroids and peptide hormones such as prolactin and leptin. The local effectors of GnRH synthesis and release include a number of neuropeptides (galanin-like peptide, kisspeptins, neuropeptide Y, vasoactive intestinal peptide, corticotropin-releasing peptide), catecholamines, indolamines, nitric oxide and excitatory amino acids, γ-aminobutyric acid, and dopamine. Testosterone either directly or through its metabolic products (i.e., estradiol and dihydrotestosterone) has inhibitory effects on the secretion and release of GnRH as well as direct inhibitory effects on secretion and release of LH and FSH. Prolactin is a potent inhibitor of GnRH secretion, thus explaining its role in inhibiting LH and testosterone secretion in conditions of hyperprolactinemia.

LH and FSH are glycopeptides consisting of two subunits (α and β). They share the same α subunit, with specificity endowed by the β subunit. The heterodimer is required for biologic activity; the subunits can be detected in serum and may be increased in certain pathologic conditions (e.g., α subunit elevations in gonadotropin-secreting pituitary adenomas). LH and FSH are synthesized in the same pituitary cell (gonadotrophs) and secreted in a pulsatile pattern. The clearance of these two gonadotrophic hormones differs, with LH having a shorter half-life than FSH. LH and FSH are secreted in a pulsatile pattern regulated by GnRH pulse generator in the hypothalamus. Puberty is heralded by nighttime pulsatile serum patterns before obvious increases are noted in the daytime. Feedback regulation of LH and FSH secretion also occurs at the pituitary, with testosterone, dihydrotestosterone (DHT), and estrogens inhibiting the synthesis or release of both gonadotropins. Circulating testicular peptide products of the Sertoli cell (i.e., inhibin) also produce selective inhibition of FSH. LH and FSH circulate unbound to carrier proteins and act predominantly through specific cell surface receptors on the Leydig and Sertoli cells of the testes, respectively.

Testis Function


The testis is a complex organ consisting of (1) seminiferous tubules containing Sertoli cells and germ cells in various stages of maturation and (2) the interstitium, where the steroid-secreting cells (Leydig), macrophages, myoid cells, and blood vessels reside ( Fig. 253-2 ). The Leydig cells synthesize steroid hormones under the regulation of LH. The LH receptors on the cell surface of the Leydig cells lead to G protein/cyclic adenosine monophosphate–mediated events. This process involves a steroid acute regulatory (StAR) protein essential for steroidogenesis in the gonads and adrenal glands ( Fig. 253-3 ).



FIGURE 253-2  Testis. Light micrograph of the glutaraldehyde-fixed, epoxy-embedded testicular section from a normal man showing seminiferous tubules (ST) and interstitium (IT). The seminiferous tubules contain Sertoli cells and germ cells at various phases of maturation. The interstitium consists of Leydig cells (LC), blood vessels, and lymphatic space.



FIGURE 253-3  The steroid acute regulatory (StAR) protein mobilizes cholesterol from cellular stores to the mitochondria. Intratesticular steroidogenic pathways for synthesis of testosterone. Although both the Δ5 (left) and Δ4 (right) pathways exist, the Δ5 pathway predominates in the testis. DHEA = dehydroepiandrosterone; HSD = hydroxysteroid dehydrogenase.



Testosterone is the principal male hormone secreted by the testes; about 7 mg is produced per day in adult men. Testosterone synthesis occurs in the human testes through either the Δ4 or the Δ5 pathway (see Fig. 253-3 ); the Δ5 pathway is predominant. The enzymatic rate-limiting step in the process is the LH-inducible StAR protein and the conversion of cholesterol to pregnenolone by the cholesterol side-chain cleavage enzyme P450SCC.



Testosterone circulates mainly bound to two plasma proteins, sex hormone–binding globulin (SHBG; also known as testosterone-binding globulin) and albumin. In young adult men, about 54% of testosterone is bound to albumin, 44% is bound to SHBG, and 2 to 3% is unbound or free. The SHBG-testosterone fraction is tightly bound and serves a storage role. Bioavailable testosterone refers to the sum of albumin-bound and free testosterone and is measured by separating SHBG-bound testosterone from the total testosterone in the serum. Serum SHBG levels are increased in endogenous and exogenous hyperestrogenemic states, hyperthyroidism, aging, phenytoin treatment, anorexia nervosa, and prolonged stress. SHBG levels are lowered with androgen treatment, obesity, acromegaly, and hypothyroidism. In most instances, measurement of serum total testosterone will detect individuals with androgen deficiency. In conditions with abnormal SHBG levels, the total testosterone measurement (usual laboratory test requested) may be misleading. In these situations, direct measurement of free testosterone by the dialysis method, measurement of bioavailable testosterone, or calculation of the free testosterone by a formula requiring the serum testosterone and SHBG concentrations may be necessary to separate true chemical testosterone deficiency from binding protein problems. Testosterone secretion has a diurnal variation and is highest in the morning in young adult men; this rhythm is blunted or lost with aging.



Testosterone exerts its effects at different end organs either through direct action or after conversion to an active metabolite such as DHT by 5α-reductase or estradiol by the aromatase enzyme ( Fig. 253-4 ). Thus, testosterone can act as an androgenic hormone or as a precursor for DHT with effects mediated by the intracellular androgen receptor. Different tissues may also have coactivators or coinhibitors that modify the action of the androgen-receptor complex, providing tissue selectivity. Testosterone can also serve as a precursor for estradiol in some tissues, and subsequently, after conversion, estrogen binds the estrogen receptors (α or β) to induce its effects. Various end organs differ in their 5α-reductase and aromatase activity and in their requirements for conversion of testosterone to DHT for androgenic activity. Congenital and acquired defects in these two enzymes as well as in the estrogen and androgen receptors result in distinct syndromes with characteristic phenotypes ( Chapter 252 ).



FIGURE 253-4  Testosterone action is mediated directly (androgen receptor), after conversion to estradiol (estrogen receptor α or β), or after conversion to DHT (androgen receptor).  (From Kuiper GCJM, Carlquist M, Gustafsson JA: Estrogen is a male and female hormone. Sci Med 1998;5:36-45; with permission.)



The spermatogenic compartment consists of the Sertoli and germ cells and is intimately interactive with the interstitial compartment ( Fig. 253-5 ). The Sertoli cells bridge the entire space between the basement membrane and the lumen of the tubules (see Fig. 253-2 ). They are the target of androgenic and FSH stimulation of spermatogenesis and also the source of a multitude of paracrine regulators of spermatogenesis (e.g., inhibin, activin, growth factors, cytokines).



FIGURE 253-5  Stages of human spermatogenesis.  (From Hermo L, Clemont Y: How are germ cells produced and what factors control their production? In Robaine B, Pryor J, Trasler J [eds]: Handbook of Andrology. New York, American Society of Andrology, 1995, pp 13-15.)

Germ cell maturation is dependent on the proper hormonal (FSH) and paracrine (testosterone) milieu for proliferation to occur. Not all germ cells reach maturity. Spontaneous death of certain germ cells is a constant feature of germ cell homeostasis. In fact, considerable data indicate that major effects of both testosterone and FSH are to limit the amount of germ cell death (apoptosis).



After spermatogenesis is completed, mature spermatozoa are released into the excretory system and travel through the rete testes and epididymis, where they functionally mature before traversing the vas deferens. The semen gains constituents from the seminal vesicles, prostate, and bulbourethral glands before ejaculation.

Normal Sexual Function and Erectile Physiology


Normal sexual function in men requires normal sexual desire (libido) and erectile, ejaculatory, and orgasmic capacity. The process is complex, involving cognitive, sensory, hormonal, autonomic neuronal, and penile vascular integrative actions for normal function. Defects occur at multiple levels. Although considerable progress has occurred in the past few years in therapeutic options, an understanding of the normal physiology is essential for proper assessment and treatment of men with sexual dysfunction.

The brain is the integrative center of the sexual response system. It processes sensory input, stored fantasy information, purposeful thoughts, spontaneous nocturnal reflex activity, and hormonal signals (e.g., testosterone) to create the hypothalamic neuronal message that traverses the spinal cord to the thoracic 9-12 sympathetic and sacral parasympathetic outflow tracts. The nonadrenergic, noncholinergic autonomic plexus nerves initiate vasodilation of the cavernosal arterial and corpora cavernosal sinusoids of the penis through release of local vasodilators such as nitric oxide and vasoactive intestinal peptide from the vascular endothelium and the smooth muscle cells of the sinusoids ( Fig. 253-6 ). A family of enzymes (nitric oxide synthetases) regulates nitric oxide synthesis, which produces smooth muscle dilation through activation of cyclic guanosine monophosphate (cGMP) and modification of calcium flux. The cGMP levels are rapidly reversible through inactivation by phosphodiesterase. The neurogenic mechanisms leading to vasodilation of the cavernosal arterioles and sinusoids lead to a rapid increase in penile blood flow and expansion of the vascular channels; this, in turn, inhibits venous return through compression of the venous channels against the tunica albuginea and limits drainage of the obliquely penetrating veins. After orgasm, detumescence occurs owing to less vasodilatory (nitric oxide) and greater vasoconstrictive (α2-adrenergic, endothelins) signals.



FIGURE 253-6  The interaction among cholinergic, adrenergic, and nonadrenergic, noncholinergic (NANC) neuronal pathways and their contribution to penile smooth muscle contraction (patterned arrows) and dilation (open arrows). NO = nitric oxide; VIP = vasoactive intestinal polypeptide.  (From Lue TF: Physiology of penile erection and pathophysiology of erectile dysfunction and priapism. In Walsh P, Retick A, Vaughn E, Wein A [eds]: Campbell’s Urology, 7th ed. Philadelphia, WB Saunders, 1998, p 1164.)

Testosterone seems to have its primary effect on erectile function by enhancing libido with secondary effects on penile nitric oxide synthase activity. Sexual desire and fantasy are highly sensitive to testosterone, thus explaining the preservation of erectile capacity in many men with partial androgen deficiency. In contrast, erectile dysfunction is common in older men despite normal serum testosterone levels; this effect appears to be the result of impaired penile vasodilatory capacity. This is often reversible through local (intracavernosal or transurethral) administration of potent vasodilators (prostaglandins, papaverine, and phentolamine) or by oral administration of penile-selective phosphodiesterase-5 inhibitors (i.e., sildenafil, vardenafil, and tadalafil). Combined androgen deficiency with decreased libido and decreased penile responsiveness due to impaired nitric oxide synthase activity may be common in elderly men. With the availability of effective penile vasodilatory medications to ensure erectile capacity, complaints of diminished libido may be effectively treated with androgen supplementation.

Physiology in Development and Aging


Reproductive Axis during Fetal Development, Childhood, and Puberty




Normal male sexual differentiation is complex and includes the establishment of genetic and phenotypic sex ( Chapter 252 ).



Adrenarche occurs at about 7 or 8 years of age when the zona reticularis of the adrenal gland undergoes maturation, leading to increased secretion of androgen precursors, such as androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S). Although the physiologic events initiating adrenarche are incompletely understood, the process is probably under the control of adrenocorticotropic hormone and independent of the control of LH and FSH. Adrenarche usually heralds subsequent activity in the hypothalamic-pituitary-gonadal axis. Androstenedione and DHEA are technically androgenic prehormones and do not bind to the androgen receptor. In part, the prepubertal growth spurt and the early development of pubic and axillary hair are mediated by conversion of these precursors to testosterone and DHT at the peripheral tissue sites.

Puberty occurs when a hypothalamic clock is activated, resulting in increased GnRH and gonadotropin secretion. In the interval before the onset of puberty, LH and FSH are secreted in low amounts and are subject to feedback control by the small amounts of circulating testosterone from the testes. Initiation of puberty is determined by increase in the pulsatile pattern of hypothalamic GnRH secretion. This is marked by nocturnal bursts of LH secretion when puberty begins. As puberty progresses, feedback sensitivity of the hypothalamus and pituitary to circulating steroids lessens, and increasing concentrations of both gonadotropins and gonadal steroids ensue. The increasing concentrations of intratesticular testosterone and circulating FSH stimulate the Sertoli cell to produce factors leading to the maturation of spermatogenesis and inhibition of germ cell apoptosis. The phenotypic equivalents of the hormonal changes in puberty have been well documented. Pediatricians and endocrinologists routinely perform staging of the genital and pubic hair development ( Table 253-1 ). The majority of the extratesticular end-organ events of puberty are secondary to the increased circulating levels of testosterone and its metabolic products (DHT and estradiol). The penis and scrotum grow and become pigmented. As spermatogenesis advances, the testes increase in size from 1 to 2 mL at the outset of puberty to 15 to 35 mL in adulthood. There is a progressive increase in facial, axillary, chest, abdominal, thigh, and pubic hair; frontal scalp hair regresses, and the voice deepens ( Fig. 253-7 ). Genital and sexual hair development as well as temporal scalp hair regression requires conversion of testosterone to DHT for its full effects.

Pubic Hair Genital
Stage 1 Absence of pubic hair Childlike penis, testes, and scrotum (testes 2 mL)
Stage 2 Sparse, lightly pigmented hair mainly at the base of the penis Scrotum enlarged with early rugation and pigmentation; testes begin to enlarge (3–5 mL)
Stage 3 Hair becomes coarse, darker, and more curled and more extensive Penis has grown in length and diameter; testes now 8–10 mL; scrotum more rugated
Stage 4 Hair adult in quality, but distribution does not include medial aspect of thighs Penis further enlarged with development of the glans; scrotum and testes (10–13 mL) further enlarged
Stage 5 Hair is adult and extends to thighs Penis and scrotum fully adult; testes 15 mL and greater

Modified from Marshall WA, Tanner JM: Variation in pattern of pubertal changes in boys. Arch Dis Child 1970;45:13–23.



FIGURE 253-7  Diagram of the timing of the various components of puberty. The range of ages in which each parameter begins and is completed is shown for each bar. These data are from European children obtained 30 years ago. There may be a slight trend for earlier onset of puberty during the past 30 years.  (From Marshall WA, Tanner JM: Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13-23.)



Delayed puberty in boys is usually defined as a temporary (physiologic) form of hypothalamic hypogonadotropic hypogonadism in which sexual development has not begun by the age of 13.5 years. These children usually have a height age (the age that is representative for 50% of normal children at the patient’s height) that is delayed with respect to their chronologic age and is concordant with their bone age. Once it is initiated, puberty should be completed within 4.5 years. Although delayed sexual maturation is an inevitable component of prepubertal onset of hypogonadism or androgen resistance, the majority of boys with delayed development have a constitutional delayed physiologic clock and eventually attain full sexual adulthood. There is often a family history of a parent or sibling being a “late bloomer.” The physiologic stimuli responsible for the initiation of puberty are not fully understood, but increases in leptin precede the maturation of the GnRH pulse generator, possibly as a signal of the availability of metabolic fuel. The GPR54 gene encodes a kisspeptin-responsive G protein–coupled receptor whose absence results in hypogonadotropic hypogonadism due to impaired secretion of GnRH. The kisspeptin-GPR system has been proposed as a stimulus for pubertal awakening of the reproductive axis. Careful documentation of changing physical findings and measurement of serum LH, FSH, and testosterone concentrations may provide valuable clues of the beginning of puberty. An increase in testicular size to more than 3 mL usually heralds other signs of pubertal onset. Inquiring and testing for hyposmia or anosmia and other midline defects may indicate a common variant of congenital hypogonadotropic hypogonadism (Kallmann’s syndrome). A family history of delay in puberty may encourage patience and observation. The decision of how early to treat depends on the perceived degree of psychological stress associated with the maturational delay. The major concern about treatment is early fusion of the epiphyses, which compromises optimal height. With proper dosing and monitoring of bone age, this is unusual because bone age is usually retarded in delayed puberty. In adolescent boys with delayed puberty and low levels of gonadotropins, periodic withdrawal of treatment is used to determine whether spontaneous puberty has occurred. Many adult men diagnosed with and treated for hypogonadotropic hypogonadism at the age of 15 to 19 years have proved to have normal reproductive function when they discontinue testosterone therapy many years later.

Precocious puberty in boys is defined as the onset of pubertal (genital and secondary sexual) development before 9 years of age (2.5 SD above the mean age of progression to stage 2). Sexual precocity can be subcategorized to true (complete and incomplete) isosexual precocious puberty and pseudoprecocious puberty. The distinction is that true precocious puberty is associated with increases in GnRH-stimulated LH and FSH secretion (hypothalamic-pituitary origin), whereas pseudoprecocious puberty is independent of GnRH stimulation of LH and FSH secretion. True precocious puberty is often associated with CNS disease (two thirds of boys and less than 10% of girls), including hypothalamic tumors, cysts, inflammatory conditions, and seizure disorders. The diagnosis is based on the finding of sexual precocity, inappropriately elevated serum LH levels, and associated elevations of serum testosterone. CNS visualizations by magnetic resonance imaging can localize most lesions. Pseudoprecocious puberty is characterized by increased testosterone with suppressed β-LH levels. Causes of precocious puberty include human chorionic gonadotropin secretory tumors (i.e., testicular, hepatic, hypothalamic, and pineal tumors), congenital virilizing adrenal hyperplasia, testicular testosterone-secreting neoplasms, and constitutively active LH receptor mutations, resulting in uncontrolled testosterone secretion (testotoxicosis). Treatment of true precocious puberty is removal of the CNS lesion if possible and treatment with GnRH analogues. Treatment of pseudoprecocious puberty depends on the cause but includes glucocorticoids for congenital virilizing adrenal hyperplasia and ketoconazole (suppresses steroidogenesis) with or without antiandrogens (e.g., spironolactone and flutamide).

Male Senescence: Decreased Testosterone and Other Anabolic Hormones




Blood concentrations of testosterone, other anabolic hormones (e.g., growth hormone), and prehormones (e.g., DHEA and DHEA-S) are significantly lower in older men than in young adult men ( Table 253-2 ). Unlike in women, aging in men is associated not with an abrupt cessation of gonadal hormone secretion but rather with a gradual decline in serum testosterone concentration, beginning in young adulthood and progressing throughout life. Multiple cross-sectional and longitudinal studies have shown a progressive decrease in both total and bioavailable or free serum testosterone levels with aging ( Fig. 253-8 ). The rate of decline in total testosterone levels documented in longitudinal studies ranged from 0.1 to 0.38 nM per year. The percentage decline in serum testosterone has also been estimated between 0.8 and 1.6% per year. The reasons for these discrepancies in the absolute and relative decline with age are unclear but may include the inclusion and exclusion criteria in some studies and the comorbid state of obesity or illness in some populations. Many men with low serum testosterone are not symptomatic of typical hypogonadism seen in younger androgen-deficient men. Serum SHBG levels also rise with age in men, resulting in a higher percentage of circulating testosterone tightly bound and less bioavailable. Recent data indicate that between 40 and 80% of men older than 70 years have blood levels of bioavailable or free testosterone below the normal range for young adults ( Fig. 253-9 ).

↑LH,[*] ↑FSH No change in ACTH ↓GHRH message and receptor
↓T (↓Leydig cells) ↓DHEA and DHEA-S ↓GH secretory pulses
↓Free T ↓DHEA and DHEA-S ↓Circulating GH
↑SHBG Response to ACTH ↓Serum IGF-I
* Decreased LH pulse amplitude and decreased responsiveness to GnRH. ACTH = adrenocorticotropic hormone; CRH = corticotropin-releasing hormone; DHEA = dehydroepiandrosterone; DHEA-S = DHEA sulfate; FSH = follicle-stimulating hormone; GH = growth hormone; GHRH = growth hormone–releasing hormone; GnRH = gonadotropin-releasing hormone; IGF-I = insulin-like growth factor I; LH = luteinizing hormone; SHBG = sex hormone–binding globulin; T = testosterone.



FIGURE 253-8  Relationship between plasma testosterone (A) and free testosterone (B) levels and age in normal males.  (From Baker HWG, Berger HG, DeKretser DM, et al: Changes in the pituitary-testicular system with age. Clin Endocrinol 1996; 5:349-372.)



FIGURE 253-9  Hypogonadism in aging men. Bar height indicates the percentage of men in each 10-year interval, from the third to the ninth decades, with at least one testosterone value in the hypogonadal range. The criteria used for these determinations are total testosterone less than 11.3 nmol/L (325 ng/dL) and testosterone and SHBG (free T index) less than 0.153 nmol/nmol. The numbers above each pair of bars indicate the number of men studied in the corresponding decade. The fraction of men who are hypogonadal increases progressively after the age of 50 years by either criterion. More men are hypogonadal by free T index than by total testosterone after 50 years, and there seems to be a progressively greater difference, with increasing age, between the two criteria.

The effects of low testosterone levels in aging men are similar to those observed in younger hypogonadal men. These include decreases in muscle mass, muscle strength, bone mass, libido, and erectile function and impaired mood and sense of well-being. Older men have increased body fat, particularly visceral fat. The effect of reduced androgen levels on cognition and memory is unknown. The benefits of testosterone treatment of symptomatic older men with low serum testosterone levels remain controversial because randomized, controlled large-scale international trials have not been performed. In recent years, a number of studies have demonstrated the beneficial effects of testosterone replacement in elderly men with relatively low serum testosterone levels. Testosterone replacement therapy (up to 3 years) decreases fat mass, increases lean body mass, improves strength, and increases bone mineral density in some studies. Data on fracture rates with androgen replacement therapy for older men with low serum biologically active testosterone levels are not yet available. Because erectile dysfunction in the older man is multifactorial, with impaired vasodilatory function in the penis predominating in many cases (see section on sexual dysfunction), testosterone replacement therapy in older men may enhance libido but often does not improve erectile dysfunction. Improved sense of well-being and increased energy levels have been reported but are not consistently observed after treatment with testosterone. More data are clearly needed to prove efficacy as well as to properly evaluate risks of treatment with testosterone. At present, testosterone treatment is not recommended for men known to have or suspected of having prostate cancer, severe and uncorrected sleep apnea, and high red blood cell mass.

Digital rectal examination should be performed, prostate-specific antigen level determined, and symptoms of severe urinary tract obstruction evaluated to ensure that there are no findings suggestive of severe benign prostatic hypertrophy or prostate cancer (nodules, irregularities).



In recent years, a marked decline in the circulating levels of adrenal androgens, especially DHEA and DHEA-S, has been recognized in elderly men and women ( Fig. 253-10 ) ( Chapter 252 ). Serum levels of DHEA and DHEA-S peak at about the third decade of life and then decline at about 2% per year, resulting in levels 10 to 20% of baseline by 80 years of age. This decline in DHEA and DHEA-S is not accompanied by a decrease in adrenocorticotropic hormone. DHEA is a precursor to true androgens such as testosterone and DHT but does not bind to the androgen receptor itself. It is unclear whether DHEA binds to a unique nuclear receptor to initiate its action. Studies have reported that DHEA administered to aging experimental animals and humans may improve the sense of well-being, reduce anxiety and depression, enhance memory, prevent development of cancer, decrease body fat, decrease risk of cardiovascular disease, and provide other beneficial effects on immune function. Most studies in humans used oral doses of 1 to 5 mg/kg/day. An oral dose of 50 mg/day will increase testosterone and DHT to or above the normal physiologic range for women but not for men. Much higher doses of DHEA can increase testosterone to male ranges but at the expense of very high serum DHEA concentrations. Studies showed that oral administration of 50 mg of DHEA to older men raised serum DHEA and DHEA-S concentrations to the levels found in young men but had no beneficial effects on quality of life, sexual function, mood, body composition, or exercise capacity. In the United States, DHEA is available without prescription as a health supplement and is widely used, creating a situation in which large-scale multicenter, prospective, placebo-controlled trials are difficult to perform. There is no documented benefit to the administration of DHEA to older men who may have low serum DHEA levels.



FIGURE 253-10  Declining serum DHEA concentration with aging. Serum DHEA-S levels (not shown) parallel the decrease in DHEA.  (Modified from Labrie F, et al: Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 1997;82:2396-2402. © The Endocrine Society.)



Hypothalamic growth hormone–releasing hormone messenger RNA, pituitary growth hormone–releasing hormone receptor concentrations, pituitary secretion of growth hormone, and serum insulin-like growth factor I levels decrease with aging (see Table 253-2 ). Part of the decline may be related to falling testosterone levels because testosterone is known to enhance growth hormone secretion. Growth hormone is an anabolic and lipolytic hormone, and many of its actions on peripheral tissues are mediated by insulin-like growth factor I. Growth hormone deficiency in adults results in changes in body composition and mood (decreased muscle mass, increased body fat, decreased strength, and a decline in sense of well-being), which are similar to the changes observed with aging. Studies show that although growth hormone induced changes in body composition compared with placebo, the individual’s muscle strength, exercise endurance, mood, and cognitive function remained unchanged. The side effects of growth hormone treatment are dose related but include edema of lower extremities, diffuse arthralgias, hand stiffness, and tiredness.





Hypogonadism refers to low circulating levels of testosterone. Most androgen-deficient men are infertile. Primary hypogonadism indicates that the abnormality originates in the testis; secondary hypogonadism indicates a defect at the hypothalamus or pituitary, resulting in decreased gonadotropins (LH, FSH, or both) and secondary impairment of testicular function. Combined primary and secondary hypogonadism occurs in aging and in a number of systemic diseases, such as alcoholism, liver disease, diabetes mellitus, human immunodeficiency virus (HIV) infection, and sickle cell disease. Obesity leads to low total and free testosterone levels. Greater decreases are seen in the total testosterone level as obesity not only decreases testosterone secretion but also lowers SHBG levels. Decreased androgen action, with normal or elevated testosterone levels, mimicking androgen deficiency may occur in patients with androgen receptor defects (androgen resistance), postreceptor signaling abnormalities, and inability to convert testosterone to the active metabolite DHT (5α-reductase abnormalities).



Many of the causes of primary and secondary hypogonadism are listed in Tables 253-3 and 253-4 [3] [4] (see also Chapter 252 ).

Congenital disorders
Chromosome disorders
Klinefelter’s and related syndromes (e.g., XXY, XXY/XY, XYY, XX males)
Testosterone biosynthetic enzyme defects
Myotonic dystrophy
Developmental disorders
Prenatal diethylstilbestrol syndrome
Acquired defects
Mumps and other viruses
Granulomatous (e.g., tuberculosis, leprosy)
Human immunodeficiency virus infection
Infiltrative diseases (e.g., hemochromatosis, amyloidosis)
Surgical, traumatic injuries, and torsion of testis
Toxins (e.g., alcohol, fungicides, insecticides, heavy metals, cottonseed oil, DDT, and other environmental estrogens)
Cytotoxic agents
Inhibitors of testosterone synthesis and antiandrogens (e.g., ketoconazole, cimetidine, flutamide, cyproterone, spironolactone)
Ethanol, opioids, and other recreational drugs
Autoimmune testicular failure
Associated with other organ-specific disorders (e.g., Addison’s disease, Hashimoto’s thyroiditis, insulin-dependent diabetes)
Systemic diseases (e.g., cirrhosis, chronic renal failure, sickle cell disease, acquired immunodeficiency syndrome, amyloidosis)
Androgen resistance syndromes
5α-Reductase deficiency
* Aging produces a mixed pattern of testicular and hypothalamic-pituitary dysfunction.


Isolated deficiency of gonadotropin-releasing hormone

With anosmia (Kallmann’s syndrome)
With other abnormalities (Prader-Willi syndrome, Laurence-Moon-Biedl syndrome, basal encephalocele)
Partial deficiency of gonadotropin-releasing hormone (fertile eunuch syndrome)
Multiple hypothalamic and pituitary hormone deficiency
Pituitary hypoplasia or aplasia
Trauma, postsurgery, postirradiation
Pituitary adenomas (prolactinomas, other functional and nonfunctional tumors)
Craniopharyngiomas, germinomas, gliomas, leukemia, lymphomas
Pituitary infarction, carotid aneurysm
Infiltrative and infectious diseases of hypothalamus and pituitary (sarcoidosis, tuberculosis, coccidioidomycosis, histoplasmosis, syphilis, abscess, histiocytosis X, hemochromatosis)
Autoimmune hypophysitis
Malnutrition and systemic disease
Anorexia nervosa, starvation, renal failure, liver failure
Exogenous hormones and drugs
Antiandrogens, estrogens and antiestrogens, progestogens, glucocorticoids, cimetidine, spironolactone, digoxin, drug-induced hyperprolactinemia (metoclopramide, tranquilizers, antihypertensives)
* Aging produces a mixed pattern of central and testicular dysfunction.

Clinical Manifestations




The medical history should focus on testicular descent, pubertal development, shaving frequency, changes in body hair, and present and past systemic illnesses. A complete sexual history includes changes in libido, erectile and ejaculatory functions, and frequency of masturbation, coital activity, and fertility (including that of present and previous partners). Information should be obtained on previous orchitis, sinopulmonary complaints, sexually transmitted diseases, HIV status, genitourinary infections, and previous surgical procedures that might affect the reproductive tract (e.g., vasectomy, hernia repair, prostatectomy, varicocele ligation). Social history should include tobacco and alcohol intake. Medication and drug history should include any agent that could affect hormonal, spermatogenic, and erectile function. These include recreational drugs; anabolic steroids; psychiatric, antihypertensive, antiandrogenic, cytotoxic, alternative medicine therapies; environmental toxins; and exposure to heat (including saunas and Jacuzzis) and irradiation.

Physical Examination


The general physical examination is supplemented by height and span measurements; assessment of muscle mass and adiposity; characterization of facial, pubic, and body hair distribution; presence of acne and facial wrinkling; breast examination for gynecomastia; examination of the scrotal contents; measurement of penile length and urethral integrity; digital rectal prostate examination; and visual field assessment. The scrotal examination should include assessment of midline fusion (e.g., bifid scrotum, hypospadias); measurement of testicular size (a ruler will suffice, but Prader or Takihara orchidometers are preferred) and consistency; presence of intratesticular masses; abnormalities of the epididymis; bilateral presence of vas deferens; and presence of varicoceles, hydroceles, or hernias. Normal testicular size ranges from 3.6 to 5.5 cm in length, 2.1 to 3.2 cm in width, and 15 to 35 mL in volume in white and black men. Asian men have slightly smaller mean testicular size. A decrease in testicular volume usually implies decreased spermatogenic cells because the seminiferous tubules account for more than 80% of testicular volume.

Laboratory Studies


Because a strong diurnal rhythm in testosterone secretion results in the highest serum levels in the morning hours and the lowest levels in the evening, the measurement of testosterone, LH, and FSH is routinely determined from morning blood samples. The value of free testosterone measurements when symptoms suggest hypogonadism but serum total testosterone concentrations are borderline was discussed in an earlier section of this chapter. Some of the variability in the normal ranges for testosterone as determined by immunometric assays may disappear when measurements of testosterone based on gas-liquid chromatography–tandem mass spectroscopy become more readily available. Elevated LH and FSH levels distinguish primary from secondary hypogonadism (both have low serum testosterone levels), but many older men with low serum testosterone levels have normal LH concentrations. Serum prolactin levels should be measured in all cases of hypogonadotropic hypogonadism, pituitary mass lesions, and galactorrhea. DHT is measured in cases of abnormal differentiation of the genitalia and when DHT deficiency is suspected. Serum estradiol should be measured in cases of gynecomastia. Assessment of other testosterone precursors and products may be required in special circumstances, including suspected congenital enzyme defects. The semen analysis is the “cornerstone” of the laboratory examination for infertility.

   Hypogonadism and Androgen Resistance


   Primary Testicular Hypogonadism




Primary hypogonadism refers to a condition of androgen deficiency with or without infertility in which the pathologic process lies at the testis level. A list of common causes is given in Table 253-3 .



Congenital Disorders


See Chapter 252 .

Acquired Defects




After puberty, mumps is associated with clinical orchitis in 25% of cases, and 60% of those affected become infertile. During acute orchitis, the testes are inflamed, painful, and swollen. After the acute inflammatory phase, the testes gradually decrease in size, although swelling can persist for months. The testes may return to normal size and function or undergo atrophy. Spermatogenic changes occur more often and earlier than Leydig cell dysfunction. Thus, patients with postorchitic infertility may have normal testosterone and LH levels with increased serum FSH levels. With time, elevations in LH and lowered serum testosterone levels may appear. Leprosy may also cause orchitis, and gonadal insufficiency. HIV infection is often associated with hypogonadism, which can be either hypogonadotropic or hypergonadotropic ( Chapter 416 ). Hemochromatosis and amyloidosis are examples of infiltrative diseases of the testis that can result in hypogonadism.



The exposed position of the testes in the scrotum makes them particularly susceptible to injury. Surgical injury during scrotal surgery for hernias, varicocele, and vasectomy can result in permanent testicular damage.



Irradiation to the testes from accidental exposure in the treatment of an associated malignant disease will produce testicular damage.



Chemotherapy, in particular with alkylating agents such as busulfan, for malignant disorders frequently leads to irreversible germ cell damage. Toxins may also directly damage the testes. Many agents, such as fungicides and insecticides (e.g., DBCP, metabolites of DDT), heavy metals (lead, cadmium), and cottonseed oil (gossypol), produce damage to the germ cells. Leydig cells are relatively less susceptible to most chemotherapeutic drugs than are Sertoli and germ cells. Serum testosterone levels are usually normal despite infertility in the exposed men.

Some medications may interfere with testosterone biosynthesis (e.g., ketoconazole, spironolactone) or action (cyproterone, flutamide). Ethanol, independent of its effect in causing liver disease, will inhibit testosterone biosynthesis. Marijuana, heroin, methadone, medroxyprogesterone acetate, other progestins, and estrogens lower testosterone, but mainly by decreasing the pituitary secretion of LH. Medical treatment with androgens such as testosterone, DHT, and synthetic anabolic steroids or their illicit use (e.g., in athletes, body builders) will lower serum LH and FSH levels and lower sperm counts in the absence of clinical signs and symptoms of androgen deficiency. Serum testosterone levels will be normal to elevated after testosterone treatment but will be low after use of DHT and synthetic anabolic agents.

Autoimmune Testicular Failure


Antibodies against the microsomal fraction of the Leydig cells may occur either as an isolated disorder or as part of a multiglandular disorder involving, to variable degrees, the thyroid, pituitary, adrenals, pancreas, and other organs.

Testicular Defects Associated with Systemic Diseases


Abnormalities of the hypothalamic-pituitary-testicular axis occur in a number of systemic diseases. These include liver failure, renal failure, severe malnutrition, sickle cell anemia, advanced malignant disease, severe obesity, diabetes, cystic fibrosis, and amyloidosis. About half of men undergoing chronic hemodialysis for renal failure experience decreased libido, infertility, and impotence. The effects of cirrhosis of the liver on testicular function are complex and may be either independent or associated with direct toxic effects of continued use of alcohol. Gynecomastia, testicular atrophy, and impotence are concomitant signs of cirrhosis. Decreased spermatogenesis with peritubular fibrosis occurs in at least 50% of patients. In contrast to the decrease in serum testosterone levels, estradiol levels are usually elevated. This results in an increased ratio of serum estradiol to testosterone with an increased proclivity for gynecomastia. Patients with sickle cell anemia often have impaired testicular function. Boys with sickle cell anemia may have impaired sexual maturation, and men are often infertile. The defect in sickle cell anemia seems to be ischemic in origin, probably with accelerated apoptosis; it may occur either at the testicular or at the hypothalamic-pituitary level. Diabetes and obesity are two major factors in hypogonadism. Emerging data show that diabetes is associated with low blood testosterone levels and that the decrease in serum testosterone correlates with the degree of hyperglycemia.

   Secondary Gonadal Insufficiency (Hypogonadotropic Hypogonadism)




Hypogonadotropic hypogonadism represents a deficiency in the secretion of gonadotropins (LH and FSH) due to an intrinsic or functional abnormality in the hypothalamus or pituitary glands (see earlier and Chapter 252 ). Such disorders result in the secondary Leydig cell dysfunction (see Table 253-4 ). The clinical manifestations depend on the age of the patient at the onset of the disorder.

Acquired Hypogonadotropic Disorders and Functional Disorders




Anorexia nervosa and weight loss are examples of functional defects resulting in low serum testosterone levels. Anorexia nervosa, predominantly a disorder of adolescent girls, is characterized by excessive weight loss as a result of dietary restriction or bulimia. On occasion, anorexia nervosa is seen in men, but in such an instance, it usually implies a variant of a more severe psychiatric disorder. Men and women present with manifestations of hypogonadotropic hypogonadism. Starvation from other than a psychological basis may also reduce gonadotropic secretion, although women seem more susceptible to this disorder. Although strenuous exercise commonly produces reproductive dysfunction in female athletes (e.g., long-distance runners and dancers), it has minimal effects on testicular function in men.



Severe stress and systemic illness also lower gonadotropin and testosterone levels. Organic hypothalamic-pituitary disorders include neoplastic, granulomatous, infiltrative, and post-traumatic lesions in the region of the hypothalamus and pituitary.



Prolactinomas present differently in men and women ( Chapter 242 ). Unlike in women, in whom small tumors can be detected early because of symptoms of amenorrhea and galactorrhea, in men the tumors are usually large (>1 cm in diameter [macroadenomas]) by the time they are detected. It is unclear whether the large size of the adenoma at the time of presentation in men is due to the late diagnosis, caused by failure of patients and physicians to appreciate early signs, or the more rapid growth of these tumors in men. Male patients with prolactin-secreting macroadenomas usually present with hypogonadism, erectile dysfunction, and visual manifestations from suprasellar extension. Hypogonadism in microprolactinomas is usually the result of prolactin suppression of GnRH secretion. In macroadenomas, the suppression of gonadotropins and hypogonadotropic hypogonadism may be due to the GnRH suppressive effects described earlier or a mass effect damaging the non-neoplastic gonadotrophs.

Large non–prolactin-secreting pituitary tumors (growth hormone, adrenocorticotropic hormone, glycopeptide, and null cell) may also produce gonadotropin insufficiency from damage to the adjacent normal pituitary gland ( Chapter 242 ), resulting in decreased serum LH and testosterone levels.

   Androgen Resistance (Androgen-Sensitive End-Organ Deficiency)


Certain conditions have clinical phenotypes mimicking testosterone deficiency in the absence of lowered testosterone levels. These are either drug induced (antiandrogens) or congenital defects in the androgen receptor, postreceptor defects, or 5α-reductase deficiency ( Chapter 252 ).



The diagnosis is based on clinical symptoms and signs and a reduced serum testosterone level. The most available and commonly used blood measurement of testosterone is serum total testosterone. The normal range of a young adult male population varies for different laboratories but should be in the general range of 300 to 1000 ng/dL (10 to 38 nmol/L). Accurate measurements of testosterone in the female or severely hypogonadal range are best done by tandem mass spectroscopy. Total testosterone measurements may be misleading indicators of Leydig cell status in conditions in which SHBG levels are abnormal (see earlier section). In these circumstances, a measurement of free testosterone (by dialysis method), bioavailable testosterone (free and albumin bound), or calculated free testosterone (by total testosterone and SHBG measurements) is useful to characterize circulating bioactive testosterone levels.

The following rules apply to most young and middle-aged men thought to have hypogonadism. If a morning serum total testosterone level is repeatedly below 250 ng/dL (8.5 nmol/L), the patient is most probably hypogonadal, and testosterone replacement is indicated. If the serum testosterone level is between 250 and 300 ng/dL with normal serum LH levels, the patient may not be hypogonadal, and androgen replacement may not improve the symptoms (e.g., sexual dysfunction). Thus, when serum total testosterone is borderline and LH is not increased, measurement of one of the bioactive testosterone levels is indicated. The guidelines for men older than 60 years are less certain; because SHBG levels are increased in this age group, total testosterone levels may overestimate the biologically active forms of circulating testosterone. In men older than 60 years with signs or symptoms of androgen deficiency, a serum total testosterone level above 400 ng/dL argues strongly against hypogonadism; a serum level below 200 ng/dL is almost always a clinically significant level, and total testosterone concentrations between 200 and 400 ng/dL deserve further testing with one of the tests of bioactive testosterone.






The main medical indication for androgen replacement therapy is male hypogonadism ( Table 253-5 ).

Androgen deficiency (hypogonadism)
Microphallus (neonatal)
Delayed puberty in boys
Elderly men with low total or bioavailable or free testosterone levels
Angioneurotic edema
Other possible uses or under investigation

Hormonal male contraception
Wasting disease associated with cancer, human immunodeficiency virus infection, chronic infection
Postmenopausal women

Contraindications to Testosterone Therapy


Absolute contraindications to androgen replacement therapy include carcinoma of the prostate and the male breast. These cancers are androgen dependent for growth and proliferation. Androgens should be used with caution in older men with enlarged prostates and urinary symptoms, elevated hematocrit, and sleep-related breathing disorders.

Androgen Preparations


Testosterone esters such as testosterone enanthate (or cypionate) are widely used preparations in the United States and throughout the world ( Table 253-6 ). The recommended dose is 150 to 200 mg administered intramuscularly once every 2 to 3 weeks.

Modified 17α-alkylated androgens (methyltestosterone and many anabolic steroids), which are available in oral preparations, are not recommended as androgen replacement. These agents may lead to abnormalities in liver function and marked decreases in high-density lipoprotein cholesterol and increases in total cholesterol levels compared with the testosterone esters. Orally active testosterone undecenoate is not available in the United States but is used in Canada, Europe, and other places in the world. This ester is absorbed into the lymphatics and has variable bioavailability; it must be taken with fatty food or liquid at least twice daily for optimal blood testosterone levels. Transbuccal delivery of testosterone by mucoadhesive tablets (30 mg applied twice daily) gives physiologic-range testosterone levels through absorption directly into the systemic circulation, thus avoiding first-pass effects on the liver.

Testosterone Implants


Implants are pellets of crystalline testosterone. The serum testosterone levels are maintained in the physiologic range for 4 to 6 months. Implants are not popular in the United States but are widely used in Australia and the United Kingdom.

Transdermal testosterone delivery through skin patches and hydroalcoholic gels is available and widely used throughout the world. The nonscrotal patches deliver 5 mg of testosterone per day, which is the physiologic production rate. Some patches use alcohol-based absorption enhancement systems that decrease the patch size. These patches deliver levels of testosterone within the normal range but have a high incidence of skin irritability (redness, swelling, and blisters). Other patches are large and less likely to cause skin irritation but have a tendency to fall off with activity. Hydroalcoholic testosterone gels have been developed for transdermal application. They have become the most widely used testosterone formulations in the United States. The usual dosage is 5 to 10 g of 1% testosterone gel applied daily. Transfer from user to others through direct contact is possible. They give reasonably constant serum concentrations and cause little skin irritation.

Benefits versus Risks of Androgen Therapy


Table 253-7 shows the benefits and potential side effects of androgen treatment. In hypogonadal men, androgen replacement leads to the development and maintenance of secondary sexual characteristics. Testosterone has important anabolic effects on muscle and bone and improves libido and sexual dysfunction. It has less effect on erectile dysfunction (see later section on sexual dysfunction).


Route Preparation Dose and Frequency of Administration
Oral[*] Testosterone undecenoate (not available in United States; available in Canada, Mexico, Europe, Asia) 40–80 mg orally two or three times per day
Injectable Transbuccal testosterone, mucoadhesive tablets (Striant) 30 mg two times daily
Testosterone enanthate and cypionate 100 mg intramuscularly per week or 150–200 mg intramuscularly per 2–3 weeks
Implants Testosterone implants 200-mg pellets, four inserted once every 4 to 6 months
Transdermal Scrotal patch One patch delivering 4 or 6 mg of testosterone per day
Nonscrotal patch, Androderm Two patches delivering 2.5 mg of testosterone each per day or one patch delivering 5 mg of testosterone per day
Testoderm TTS One patch delivering 5 mg of testosterone per day
Transdermal hydroalcoholic gels AndroGel or Testogel; Testim 5–10 g containing 5-10 mg of testosterone is applied once daily
* Oral modified 17α-alkylated androgens such as methyltestosterone, fluoxymesterone, oxymetholone, stanozolol, and oxandrolone are not recommended for use in treatment of androgen deficiency states because of potential hepatotoxicity and adverse effects on serum lipids.


Benefits Risks
Development or maintenance of secondary sex characteristics
Improves libido and sexual function
Increases muscle mass and strength
Increases bone mineral density
Decreases body and visceral fat
Improves mood
Effect on cognition (?)
Effect on quality of life (?)
Fluid retention
Acne, oily skin
Increases hematocrit
Decreases high-density lipoprotein cholesterol (oral 17-alkylated agents produce the greatest effect)
Sleep apnea
Prostate diseases

Benign prostate hyperplasia (?)
Carcinoma of prostate (aggravate existing cancer)
Aggressive behavior (?)





Infertility is defined as the failure of a couple to achieve a pregnancy after at least 1 year of frequent unprotected intercourse. If a pregnancy has not occurred after 3 years, infertility most likely will persist without medical treatment.

Incidence and Prevalence


Studies in the United States and Europe showed a 1-year prevalence of infertility in 15% of couples. The prevalence in developing countries is likely to be higher because of the higher prevalence of genital tract infection. As shown in multicenter studies, 30 to 35% of subfertility can be attributed to predominantly female factors, 25 to 30% to male factors, and 25 to 30% to problems in both partners; in the remaining cases, no cause can be identified.



Hypothalamic-pituitary disorders are infrequent causes of male infertility and are discussed in the section on hypogonadism and androgen deficiency. Primarily, testicular disorders are the most frequent identifiable cause of infertility (see Table 253-3 ).



The approach to the diagnosis of an infertile couple includes management of the male and the female partner (Figs. 253-11 and 253-12 [11] [12]).



FIGURE 253-11  Algorithmic approach to the diagnosis and treatment of male infertility. ART = assisted reproductive technology; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; ICSI = intracytoplasmic sperm injection; LH = serum luteinizing hormone; T = serum testosterone.



FIGURE 253-12  Algorithmic approach to the diagnosis and treatment of male infertility in patients with normal serum hormone concentrations. ART = assisted reproductive technology; FSH = follicle-stimulating hormone; ICSI = intracytoplasmic sperm injection; LH = serum luteinizing hormone; T = serum testosterone.

Examination of the ejaculate is the cornerstone for the investigation of an infertile man ( Table 253-8 ). Semen samples are collected when possible at the physician’s office or at home, preferably after 2 to 7 days of abstinence from sexual intercourse.

Semen Analyses Hormone Analyses (in patients with abnormal semen analyses)
Volume, pH
Microscopy: agglutination, debris
Sperm: concentration, motility, morphology, vitality
Immature germ cells
Sperm autoantibodies (sperm and semen biochemistry, sperm function tests)
Serum luteinizing hormone and follicle-stimulating hormone
Serum testosterone
If luteinizing hormone and testosterone levels are low, serum prolactin

The generally accepted reference values for a semen analysis are given in Table 253-9 . A normal sperm concentration is greater than 20 million/mL; however, men with lower sperm counts can be fertile. More than 50% of the spermatozoa should be motile, and more than 25% should demonstrate a rapidly progressive motility pattern.

Parameter Reference Range
Semen volume >2 mL
Concentration >20 million/mL
Total count >40 million/ejaculate
Motility >50% motile
>25% rapid progressively motile
Morphology >15% normal[*]
Vitality (live) >75%
Leukocytes <1 million/mL

From World Health Organization Laboratory Manual for Examination of Human Semen and Sperm–Cervical Mucus Interaction, 4th ed. Cambridge, Cambridge University Press, 1999.

* This value is based on the strict criteria for assessment of sperm morphology in studies using in vitro fertilization as an end point. This value will be adjusted to a lower level based on recent studies in fertile men.

Numerous studies have demonstrated that considerable overlap is observed in the semen quality of fertile and subfertile men. No definite threshold is defined below which a man would be infertile except when azoospermia is present.

In patients with abnormal semen analyses, measurements of serum FSH, LH, and testosterone are indicated (see Fig. 253-10 ). Elevated FSH levels usually indicate severe germinal epithelium damage and may be associated with a guarded prognosis. A decreased serum inhibin β level also reflects poor Sertoli cell function and may be a marker of spermatogenic dysfunction. Elevated serum LH and FSH concentrations together with a low serum testosterone level indicate pantesticular failure. Low serum FSH, LH, and testosterone concentrations suggest hypothalamic pituitary dysfunction; serum prolactin should be measured, and additional appropriate investigations (as discussed in the section on secondary hypogonadism) may be required. The low sperm concentration and suppressed LH level with increased, normal, or low serum testosterone level (without clinical manifestations of androgen deficiency) may suggest exogenous androgen therapy. The hormonal pattern in androgen insensitivity (an uncommon cause of male infertility) is elevated LH, normal FSH, and high-normal to increased serum testosterone levels. Normal hormonal parameters in azoospermic (no sperm in the ejaculate) men with normal-sized testes may suggest congenital or acquired obstruction in the epididymis or vas deferens. Studies have shown that up to 20% of men with azoospermia or severe oligospermia (<1 to 3 million germ cells per milliliter of ejaculate) have microdeletions in the long arm of the Y chromosome (often in the AZF regions).






An algorithmic approach to the treatment of male infertility is illustrated in Figures 253-11 and 253-12 [11] [12]. The principles of management of male factor infertility can be summarized as follows. (1) Men with mild to moderate oligozoospermia with or without decreased sperm motility and some impairment of motility are subfertile rather than infertile. Spontaneous pregnancies occur in this group. (2) Reliable medical treatment is limited to the 1 to 2% of infertile men with gonadotropin insufficiency. (3) Assisted reproductive technologies including in vitro fertilization and intracytoplasmic sperm injection have dramatically improved the pregnancy rates in partners of men with severe oligozoospermia, poor morphologic characteristics, and poor to absent motility. (4) Azoospermia (absence of sperm in the ejaculate) may occur in men with obstruction of the ejaculatory system. In these patients, in vitro fertilization and intracytoplasmic sperm injection after either percutaneous epididymal sperm extraction or microsurgical epididymal sperm extraction give comparable and highly successful results. (5) Azoospermia due to impaired spermatogenesis may not be a sterile state because sperm may be present within the testes. These sperm can be extracted by testicular sperm extraction, and intracytoplasmic sperm injection can be performed with good success.



Sexual dysfunction can be divided into four main categories: (1) loss of desire (libido), (2) erectile dysfunction, (3) ejaculatory insufficiency, and (4) anorgasmic states.

   Decreased Libido


Loss of libido refers to reduction in sexual interest, initiative, and frequency and intensity of responses to internal or external erotic stimuli. Causal factors include psychogenic factors, CNS disease, androgen deficiency and resistance, and side effects from medications (e.g., antihypertensives, psychotropics, alcohol, narcotics, dopamine blockers, antiandrogens). Treatment is directed toward the causal mechanism.

   Ejaculatory Failure and Impaired Orgasm


Ejaculatory insufficiency refers to absent or reduced seminal emission or impaired ejaculatory contraction. It is usually associated with neurologic conditions and medication therapy. Anorgasmic state is a distressing but relatively uncommon condition in men when the normal process of erection and ejaculation occurs in the absence of the subjective sensation of pleasure initiated at the time of emission and ejaculation. Premature ejaculation is the most common form of male sexual dysfunction. Estimates of prevalence vary, but 25 to 30% seems a reasonable estimate. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, defines the diagnostic criteria for premature ejaculation as follows: persistent or recurrent ejaculation with minimal sexual stimulation that (1) occurs before, upon, or shortly after penetration and before the person wishes, (2) is associated with marked distress or interpersonal difficulty, and (3) is not a direct effect of substance abuse such as opiate withdrawal.

   Erectile Dysfunction




Erectile dysfunction can be defined as the inability of a man to obtain rigidity sufficient to permit coitus of adequate duration to satisfy himself and his partner.



Current estimates suggest that 10 to 15% of all American men suffer from erectile dysfunction, with the incidence progressively increased as men become older. Data from the Massachusetts Aging Study report that 52% of men 40 to 70 years of age experience some degree of erectile dysfunction.



The causes of erectile dysfunction are many but can be generally categorized in the following areas: psychological, endocrine, systemic illness, neurologic, iatrogenic, drug related, and aging.






Medical Therapy 

Oral Medications 

Oral and selective inhibitors of cGMP phosphodiesterase-5 (the primary phosphodiesterase in the penile cavernosal tissue) are effective drugs for at least 50% of the men with this disorder. Inhibition of phosphodiesterase-5 causes persistence of normally (sexually) stimulated GMP in the corpora cavernosa, resulting in protracted cavernosal tumescence and rigidity. Patients with diabetes mellitus, spinal cord injuries, prostatic surgery, and pelvic irradiation also benefit but with a somewhat lower response rate. The usual starting dose of sildenafil is 50 mg, increasing in 25-mg increments up to 100 mg when it is required. The most serious side effect is cardiovascular collapse, particularly in patients taking long-acting nitrate or nitroglycerin preparations. Because of its mechanism of action, sildenafil is used on demand; it is administered 20 to 60 minutes before intercourse. Two additional phosphodiesterase-5 inhibitors (vardenafil and tadalafil) are widely used for treatment of erectile dysfunction and appear to be equally effective. Vardenafil has a relatively longer duration of action (4 to 6 hours); tadalafil has a much longer action (17.5 hours). Hypogonadal men with erectile dysfunction and low libido may benefit from combined treatment of testosterone and phosphodiesterase-5 inhibitors. Apomorphine is a selective dopamine receptor agonist that stimulates the CNS, generating an arousal response that includes a penile erection. Apomorphine has not been approved by the Food and Drug Administration and appears inferior to phosphodiesterase-5 inhibitors. Yohimbine is an indolalquinolonic alkaloid with central-acting effects, including α2-adrenergic blockade and cholinergic and dopaminergic stimulation. Despite its widespread use, placebo-controlled studies have shown variable degrees of success, and yohimbine seems most useful in conditions in which there is a mechanism of organic disease. Trazodone, an antidepressant, possesses both serotonin and α2-adrenergic antagonistic properties. It appears to be moderately effective in approximately one third of patients; the main side effect is sedation.

The intraurethral prostaglandin E1 suppository alprostadil is believed to work locally on the corpora cavernosa as a vasodilatory agent. The suppository is apparently successful in improving erectile function in one third to two thirds of cases.

Intracavernosal Injections of Vasodilating Drugs


Until the recent availability of oral phosphodiesterase-5 inhibitors, intracavernosal injection with prostaglandin E1 and other vasodilators (papaverine, phentolamine) was the mainstay of pharmacologic therapy for erectile dysfunction. The medications are injected with a 27- to 30-gauge needle and may be useful in men who are refractory to oral agents.

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