Hypoactive Sexual Desire Disorder and Erectile Dysfunction.

Libido, the desire or drive for sexual activity, is generated by external visual, auditory, and tactile stimuli as well as internal psychic stimuli acting on cortical and subcortical brain regions such as the limbic system (amygdala, hippocampus, anterior thalamic nuclei, and prefrontal cortex) and the temporal lobe. Stimuli from these areas are relayed to the medial preoptic area, which serves to integrate central inputs and sends impulses to the paraventricular nuclei; these, in turn, send projections to the thoracolumbar and sacral spinal cord centers that regulate penile erection. This neural pathway explains why brain disorders that cause hypoactive sexual desire disorder are usually accompanied by varying degrees of erectile dysfunction (see later discussion).¹⁴² In particular, there is a loss of the spontaneous evening and morning erections that are associated with brain activation of sexual neural pathways during rapid eye movement (REM) sleep and dreaming. Clinically, libido may be influenced by previous or recent sexual activity and by experiences, psychosocial background, overall state of general health, androgen sufficiency, and brain function.

The neurotransmitter systems that regulate the physiology of normal libido are not known precisely. However, there is evidence that central dopamine neurotransmission may be important in mediating CNS regulation of sexual desire and erections. In humans, treatment with dopamine receptor agonists (e.g., bromocriptine, pergolide) may stimulate spontaneous erections, and in 20% to 30% of men with Parkinson disease, levodopa therapy is associated with stimulation of libido and spontaneous erections. The use of pharmacologic agents with dopamine receptor antagonist activity is frequently associated with reduced libido and erectile dysfunction. However, these agents also affect a number of other neurotransmitter systems. Dopamine antagonism (e.g., by neuroleptic or antipsychotic agents) results in elevated prolactin levels that suppress endogenous gonadotropin and testosterone secretion and may contribute to reduced libido and erectile dysfunction.

Hypoactive sexual desire disorder is defined as persistent or recurrent deficiency or absence of desire for sexual activity resulting in marked personal distress or interpersonal difficulty or both.^142,146,147 It is estimated to affect more than 15% of men. The causes of hypoactive sexual desire disorder are primarily disorders that affect normal brain function and are usually associated with erectile dysfunction, in particular loss of spontaneous evening or morning erections (Table 19-2). Erectile dysfunction is defined as the inability to achieve or maintain penile erection that is adequate for completion of satisfactory sexual intercourse or activity.¹⁴⁸ Erectile dysfunction is a common condition that increases with aging. It is estimated to affect fewer than 10% of men younger than 40 years of age but approximately 50% of men between 40 and 70 years of age, with 35% of men in the latter age group having moderate or complete erectile dysfunction.

Ejaculatory Disorders and Orgasmic Dysfunction.

After the plateau phase of erection is achieved, sympathetic nervous system stimulation from the thoracolumbar (T10-L2) spinal erection center travels via the hypogastric nerve and pelvic plexus, enters the penis via the cavernosal nerve, and causes α-adrenergic receptor–mediated contraction of the cauda epididymis, vas deferens, accessory sex glands (the bulbourethral or Cowper glands and the urethral glands or glands of Littre), prostate, seminal vesicles, and ejaculatory ducts that moves sperm and semen into the posterior urethra (emission). It also stimulates closure of the internal urethral sphincter to prevent retrograde ejaculation of sperm into the bladder.¹⁴² After emission, con­tinued sensory stimulation of the penis with sexual intercourse or masturbation stimulates reflex rhythmic contractions of the ischiocavernosus and bulbocavernosus muscles, resulting in expulsion of semen from the urethra (ejaculation).¹⁴²

Like erection, ejaculation is under considerable control by higher brain centers, with both voluntary and involuntary regulation.¹⁴² Premature ejaculation is ejaculation that occurs before or shortly after vaginal penetration during sexual intercourse and is followed by a rapid loss of erection.¹⁵⁷ The cause of premature ejaculation is usually a psychological disturbance such as performance anxiety; it is rarely the result of an organic cause. There is evidence that serotoninergic neurotransmission inhibits sexual function and ejaculation. Selective serotonin reuptake inhibitors retard ejaculation, an effect that is used therapeutically to treat premature ejaculation.^157,158 Other men with psychological disorders such as excessive anxiety may have retarded ejaculation (inability to ejaculate), either in isolation or in combination with impaired libido and erections. The ejaculate is composed of spermatozoa (10%) and seminal fluid (90%), the latter derived mostly from the seminal vesicles (65%) and the prostate gland (30%). Because secretions from these accessory sex glands are androgen dependent, severe androgen deficiency may result in absent or reduced ejaculation. Absent or reduced ejaculation may also be caused by urethral abnormalities. Autonomic neuropathy, such as that caused by diabetes mellitus, sympatholytic drugs, thoracolumbar sympathectomy, extensive retroperitoneal or pelvic surgery, or bladder neck surgery, may be associated with absent or reduced ejaculation by causing retrograde ejaculation into the bladder.

Orgasm, the pleasurable sensation associated with ejaculation, usually occurs simultaneously with ejaculation and is mediated by CNS activation via ascending pathways from the spinal cord erection centers to regions of the temporal lobe and limbic system.¹⁴² Because of impaired libido and erectile dysfunction, men with androgen deficiency may also fail to achieve an orgasm. Isolated absence of orgasm in the presence of normal libido, erections, and ejaculation is relatively rare and is almost always caused by a psychological disorder.

Disorders of Detumescence.

After ejaculation, the thoracolumbar sympathetic outflow acts via α-adrenergic receptor stimulation to cause contraction of trabecular smooth muscle, which results in collapse of lacunar spaces, vasoconstriction of arterioles of the corpora cavernosa (reducing blood flow into the penis), and decompression of subtunical venules, leading to an increase in venous outflow and a flaccid penis (detumescence).¹⁴² Premature detumescence may contribute to erectile dysfunction, such as that caused by penile venous incompetence. Intracorporal injection of an α-adrenergic receptor antagonist, phentolamine, together with papaverine and PGE₁, causes sustained lacunar smooth muscle relaxation, arteriole vasodilatation, and penile tumescence and is used to treat erectile dysfunction caused by premature detumescence.

Priapism is failure of detumescence with persistence of erection lasting for longer than 4 hours that is unrelated to sexual stimulation and is usually painful.^142,159 An erection that persists for more than 4 hours is an emergency and may be complicated by ischemia, thrombosis, and vascular damage that contribute further to erectile dysfunction; if ischemia is severe, it can cause gangrene and eventual loss of the penis. Priapism may be idiopathic, or it may be caused by medications (e.g., intracavernosal injection therapy for erectile dysfunction, phenothiazines, trazodone, cocaine), by hematologic disorders such as sickle cell disease or chronic myelogenous leukemia, by neurologic disorders such as spinal cord injury, or by infiltrative diseases such as amyloidosis. The initial treatment is administration of the α-adrenergic receptor agonist, pseudoephedrine; if this is unsuccessful, aspiration of blood from the corpora cavernosa is performed with local anesthesia.

Causes of Gynecomastia.

Physiologic gynecomastia occurs normally in neonatal and pubertal boys. Transient gynecomastia (neonatal gynecomastia) occurs in 60% to 90% of neonatal boys as a result of exposure in utero to high concentrations of maternal estrogens; it resolves within several weeks after delivery (Table 19-3).^160-162 At the time of puberty, breast enlargement greater than 0.5 cm in diameter, which is often tender, initially occurs in 60% to 70% of boys by 14 years of age and then regresses within 1 to 2 years. This pubertal gynecomastia is thought to be caused by a transient rise in serum concentrations of estrogen relative to testosterone during puberty.

Pathologic gynecomastia may result from excessive estrogen levels or action or from androgen deficiency or resistance/insensitivity in isolation. In some conditions, both estrogen excess and androgen deficiency contribute to proliferation of glandular breast tissue.^160-162 For example, in most conditions that cause gynecomastia as a result of excessive estrogen exposure, high circulating estrogen concentrations inhibit endogenous gonadotropin and testosterone secretion and cause secondary hypogonadism, which also contributes to the growth of breast tissue. Also, some disorders of the testes that cause androgen deficiency (i.e., primary hypogonadism), such as Klinefelter syndrome, result in high circulating LH levels that stimulate aromatase activity in Leydig cells, leading to higher levels of estradiol relative to testosterone and contributing to the pathogenesis of gynecomastia.

Estrogen excess disorders that cause gynecomastia include exposure to exogenous estrogens (e.g., diethylstilbestrol treatment of prostate cancer, contact with an estrogen-containing cream or cosmetic, accidental occupational exposure to estrogens, ingestion of estrogen-containing nutritional supplements or excessive amounts of phytoestrogens) and exposure to ER agonists such as marijuana smoke (unidentified phenolic components but not active cannabinoids¹⁶⁴) or digitoxin. Ingestion of normal dietary amounts of phytoestrogens (e.g., soybean isoflavones) does not usually cause gynecomastia.¹⁶⁵ Uncommonly, administration of testosterone or other aromatizable androgens, usually to prepubertal boys or men with long-standing, severe androgen deficiency, induces or worsens gynecomastia by initially causing relatively higher estradiol than testosterone levels.

Increased peripheral aromatase activity with increased conversion of androgens to estrogens in excessive amounts of adipose tissue is thought to cause mild to moderate gynecomastia in men with obesity.^160-162 Also, increased aromatization of androgens to estrogens with increasing amounts of adipose tissue (including that within the breast) probably contributes substantially to the increased prevalence of gynecomastia with aging, which occurs in up to 65% of men 50 to 80 years of age.^160-162 Familial gynecomastia, an autosomal dominant or X-linked genetic disorder caused by constitutive activation of the CYP19A1 (aromatase) gene that results in increased peripheral conversion of androgen to estrogen, is a very rare cause of gynecomastia that manifests as prepubertal gynecomastia persisting into adulthood.

Estrogen-secreting tumors of the adrenal gland or testis are uncommon causes of gynecomastia. Feminizing adrenal tumors are usually malignant and large, manifesting with a palpable abdominal mass. In contrast, estrogen-secreting Leydig or Sertoli tumors are usually small and benign. Feminizing Sertoli tumors (in particular, the large cell calcifying variety) may occur in isolation or in association with autosomal dominant disorders such as Peutz-Jeghers syndrome (multiple intestinal polyps and mucocutaneous pigmented macules) or the Carney complex (cardiac or cutaneous myxomas, pigmented skin lesions, and endocrinopathy, including functioning endocrine tumors of the adrenal and testis). hCG-secreting tumors (e.g., germ cell, lung, gastric, renal cell, or hepatic carcinomas in adults; hepatoblastomas in boys) or hCG treatment of gonadotropin deficiency increases aromatase activity in Leydig cells and stimulates excessive secretion of estradiol relative to testosterone, causing relative rapid onset of symptomatic gynecomastia.

Disorders and drugs that cause androgen deficiency, such as conditions that cause either primary or secondary hypogonadism (including medications such as cytotoxic agents) or androgen resistance, are major causes of gynecomastia.^160-162 Although prolactin acts on the breast to facilitate milk production in developed glandular tissue, the major mechanism by which hyperprolactinemia causes gynecomastia is inhibition of endogenous gonadotropin and testosterone production (inducing androgen deficiency), which acts indirectly to stimulate breast development by reducing the inhibitory influence of androgens on the breast. Hyperprolactinemia is a main reason that a number of CNS-active medications, such as antipsychotics, antidepressants, and sedatives, are associated with gynecomastia. Drugs that interfere with androgen action, such as spironolactone (in contrast to eplerenone, a selective aldosterone receptor antagonist that does not cause gynecomastia), AR antagonists (e.g., flutamide, bicalutamide, nilutamide), marijuana, and histamine 2 (H₂) receptor antagonists, may cause gynecomastia.

Androgen deficiency contributes to the pathogenesis of gynecomastia in systemic disorders such as major organ failure—and, in particular, in hepatic cirrhosis and CKD, which are commonly associated with combined primary and secondary hypogonadism—and in endocrine disorders such as acromegaly and Cushing syndrome, which may be associated with secondary hypogonadism.^160-162 In hepatic cirrhosis, there is reduced catabolism of Δ⁴-androstenedione, resulting in increased peripheral conversion of Δ⁴-androstenedione to estrone and increased circulating estrogen levels. Also, in both hepatic cirrhosis and hyperthyroidism, increased serum concentrations of SHBG, which binds testosterone with greater affinity than estradiol, result in relatively higher free estradiol compared with free testosterone levels and thereby contribute to stimulation of breast tissue and development of gynecomastia. LH levels are often elevated in men with hyperthyroidism, which stimulates relatively more estradiol than testosterone secretion by Leydig cells of the testes. Excessive GH with acromegaly or GH treatment and excessive cortisol with Cushing syndrome directly stimulate breast tissue growth in addition to causing secondary hypogonadism, both of which contribute to the pathogenesis of gynecomastia.

Gynecomastia often accompanies nutritional disorders, in particular during nutritional repletion after a period of starvation and weight loss (refeeding gynecomastia) and analogously during recovery from chronic illness.^160-162 In both starvation and severe chronic illness that is commonly associated with anorexia and weight loss, central GnRH production and concomitant gonadotropin and testosterone secretion are markedly suppressed. With refeeding or restitution of appetite and weight gain, there is activation of the hypothalamic-pituitary-testicular axis and restoration of gonadal function, similar to what occurs during puberty but occurring more rapidly (a “second puberty”), resulting in transiently higher levels of estrogen relative to androgen levels and inducing gynecomastia. Refeeding gynecomastia was described initially in World War II prisoners who developed painful gynecomastia after liberation and nutritional repletion. Analogously, refeeding-like gynecomastia may occur in stage 5 CKD with the initiation of hemodialysis, in type 1 diabetes mellitus (T1DM) with insulin therapy, in tuberculosis with antituberculosis medications, and in human immunodeficiency virus (HIV) infection or AIDS with highly active antiretroviral treatment (HAART). As mentioned, these chronic systemic disorders also cause androgen deficiency that may contribute to the pathogenesis of gynecomastia. HAART also may cause lipohypertrophy and fat accumulation in the breast (pseudogynecomastia), and efavirenz has estrogenic activity.

The mechanisms of gynecomastia associated with a number of drugs are not entirely clear, and these cases are usually classified as idiopathic. Such drugs include HAART, calcium channel blockers (e.g., nifedipine, verapamil), amiodarone, antidepressants (selective serotonin reuptake inhibitors, tricyclic antidepressants), alcohol, amphetamines, penicillamine, sulindac, phenytoin, omeprazole (much less commonly than H₂-receptor antagonists), and theophylline.^{160-162,166,167}

In a number of cases of adult-onset gynecomastia, the cause remains idiopathic. Most of these cases are probably caused by increased aromatization of androgens to estrogens associated with increased peripheral adiposity, enhanced breast production of estrogens, enhanced sensitivity to estrogens, or some combination of these factors. Rarely, boys may develop severe pubertal gynecomastia (female size breast development, Tanner stage III through V) that persists to adulthood (persistent pubertal macromastia). This disorder is not associated with specific hormonal or receptor abnormalities and remains idiopathic.

Evaluation.

Most gynecomastia is asymptomatic and of mild degree but can be appreciated on a properly performed, careful physical examination (as described earlier). Mild, asymptomatic gynecomastia found incidentally on examination and in isolation does not warrant evaluation. However, breast enlargement that is recent and rapid in onset, large (>5 cm in obese men, >2 cm in lean men), symptomatic (i.e., associated with breast pain, tenderness, or galactorrhea), asymmetric, or suspicious for malignancy (eccentrically located, rock-hard, fixed to overlying or underlying tissues, or associated with bloody nipple discharge or lymphadenopathy) should trigger further evaluation.

A careful history, including medication history, and physical examination usually identify potential predisposing conditions or medications causing gynecomastia that in older men may be mulifactorial.^160-162 Clinical evaluation should focus on evidence of androgen deficiency; assessment of prescription and over-the-counter medications, substance abuse, herbal or nutritional supplement intake, cosmetic use, and usual dietary intake; symptoms and signs of systemic illness (e.g., hepatic or renal disease), malignancy, or endocrine disorders (e.g., thyroid, GH, cortisol excess); and history of recent recovery from malnutrition, severe weight loss, or chronic illness. At a minimum, the initial laboratory evaluation comprises serum testosterone, LH, FSH, TSH, and renal and liver function tests. Evaluation also usually includes measurements of estradiol, prolactin, and β-hCG, although elevations of these hormones usually affect testosterone and gonadotropin concentrations. Breast enlargement suspicious for malignancy should be evaluated by mammography and biopsy.

Treatment.

Pubertal gynecomastia usually regresses spontaneously without treatment in 1 to 2 years and by age 17 in about 90% of cases. In adults, spontaneous regression of symptoms (breast pain and tenderness, nipple sensitivity) associated with inflammatory glandular proliferation usually occurs within 6 months, after which progressive stromal fibrosis causes more or less permanent palpable breast tissue and only partial regression of gynecomastia by 1 year.

Initial treatment of gynecomastia is directed at cor­rection of the underlying cause of breast enlargement or discontinuation or replacement of a potentially offending medication.¹⁶⁸ Testosterone replacement therapy in androgen-deficient men may result in partial regression of gynecomastia, especially if breast enlargement is of recent onset. Prophylactic low-dose breast irradiation (10 to 15 Gy over 1 to 3 days) may be used before androgen deprivation therapy in men with prostate cancer to prevent the development of gynecomastia; this is more common in surgical orchidectomy and in AR antagonist monotherapy rather than combined therapy with a GnRH agonist or antagonist. ER antagonists (tamoxifen, 10 to 20 mg daily, or raloxifene, 60 mg daily) are effective in treating pubertal and adult gynecomastia and preventing gynecomastia induced by androgen deprivation therapy. For unclear reasons, aromatase inhibitors (e.g., anastrazole) are not effective. Although tamoxifen is not approved for treatment of gynecomastia, it has been shown to be effective in the treatment of idiopathic gynecomastia, resulting in partial regression in approximately 80% and complete regression in about 60% of cases. A gel formulation of DHT, a nonaromatizable androgen, is used to treat gynecomastia in some countries outside the United States.

Gynecomastia of recent onset, during the initial phase of ductal proliferation, periductal inflammation and edema, and subareolar fat accumulation, is usually responsive to medical therapy (e.g., androgen replacement in hypogonadal men, ER antagonist therapy). With long-standing gynecomastia (>1 year), there is progressive stromal fibrosis of the breast that is not responsive to medical treatment. In these cases, surgical reduction mammoplasty (i.e., removal of breast tissue [subcutaneous mastectomy] with or without periareolar adipose tissue [liposuction]) is necessary, especially if breast enlargement is severe, painful, socially embarrassing, or disfiguring.

Causes of Male Infertility.

In about 80% to 90% of infertile men, infertility is caused by primary or secondary hypogonadism, manifested mostly by an isolated impairment of sperm production or function, much less commonly by androgen deficiency and impaired spermatogenesis, and rarely by androgen resistance (Table 19-4).^170,171 The evaluation and specific causes of hypogonadism are discussed in detail in subsequent sections. Most men with isolated impairment in sperm production have a primary disorder of the testes that is idiopathic in 60% to 70% of cases (if one includes both idiopathic oligozoospermia or azoospermia and varicocele, given that relationship of varicocele to the pathogenesis of infertility is unclear). If isolated impairment of spermatogenesis is severe in men with primary hypogonadism, serum FSH levels may be selectively elevated as a result of reduced negative feedback by inhibin B from Sertoli cells of the testis. In men with less severely impaired spermatogenesis, serum gonadotropin levels are normal, but this is still classified with disorders of primary hypogonadism because gonadotropin treatment has not been demonstrated to improve fertility.

Disorders of spermatogenesis caused by primary hypogonadism may be associated with chromosomal or genetic disorders. There is an 8- to 10-fold increase in the prevalence of chromosomal abnormalities among infertile men with impaired spermatogenesis—specifically, sex chromosomal aneuploidy (e.g., Klinefelter syndrome) or Robertsonian translocations of two nonhomologous chromosomes, most commonly involving chromosomes 13 and 14 or chromosomes 14 and 21.¹⁷² The long arm of the Y chromosome (Yq), specifically the azoospermia factor (AZF) region (Yq11), contains a number of genes that encode for proteins that have important roles in spermatogenesis. This region contains highly homologous palindromic DNA repeat sequences that are susceptible to rearrangement and deletions. Small deletions in the AZF region (Y chromosome microdeletions) are the most common genetic cause of impaired sperm production and male infertility; they are found in 5% to 10% of men with azoospermia or severe oligozoospermia (sperm concentration <5 million/mL).¹⁷² Y chromosome microdeletions have been identified in three regions: in the AZFa region, microdeletions are uncommon but are usually associated with azoospermia and Sertoli cell–only histology; in the AZFb region, they are usually associated with severe oligozoospermia and germ cell arrest at the pachytene primary spermatocyte stage; and in the AZFc region, where the majority of Y chromosome microdeletions reside, they are usually associated with germ cell arrest at the spermatid stage or hypospermatogenesis with some mature spermatids present. Occasionally, microdeletions in the AZFb and AZFc regions are associated with azoospermia and Sertoli cell–only histology. Genes encoding a number of candidate proteins for male infertility include DDX3Y (DEAD box Y, an ATP-dependent RNA helicase), RBMY (RNA-binding motif Y-linked, an RNA-binding protein), and DAZ (deleted in azoospermia, another RNA-binding protein) in the AZFa, AZFb, and AZFc regions, respectively.^172,173

Approximately 15% to 20% of male infertility is caused by disorders of sperm transport from the testes to the urethra, most commonly by genital tract obstruction. Congenital bilateral absence of the vas deferens (CBAVD) is present in 1% to 2% of men with infertility.^172,174,175 Seventy-five percent of men with CBAVD are heterozygous for the cystic fibrosis transmembrane conductance regulator gene (CFTR), which encodes for an epithelial chloride channel, or carry compound heterozygous mutations of CTFR. They do not have obvious clinical manifestations of cystic fibrosis, although some manifest abnormalities on sweat chloride testing and sinopulmonary infections. Conversely, almost all men with cystic fibrosis have CBAVD. CBAVD is also commonly associated with absence of the seminal vesicles, ejaculatory ducts, and epididymides due to fetal atrophy of these wolffian duct derivatives; in 10% of cases, there is also renal agenesis or hypoplasia.

Other causes of genital tract obstruction include other congenital defects of the epididymides and vas deferens (e.g., epididymal cysts associated with prenatal diethylstilbestrol exposure); vasectomy (surgical ligation of the vas deferens); postinfectious fibrosis (e.g., associated with gonorrhea, Chlamydia infection, other sexually transmitted diseases; tuberculosis; leprosy); and Young syndrome, a rare, congenital primary ciliary dyskinesia syndrome characterized by bronchiectasis, recurrent sinopulmonary infections, and obstructive azoospermia caused by thickened, inspissated mucous secretions obstructing the epididymides.

Although a causal link to infertility has not been clearly established, other genital tract abnormalities may contribute to impaired sperm transport and the pathogenesis of infertility in some men. Accessory gland dysfunction, such as reduced seminal vesicle and prostate secretions associated with disorders that cause severe androgen deficiency or resistance, may contribute to reduced fertility, although the main effects of these disorders are to impair spermatogenesis and cause sexual dysfunction. Infection or inflammation of the epididymides, seminal vesicles, or prostate gland may affect fertility directly by impairing sperm maturation or function or secondarily by causing scarring of the genital tract or induction of antisperm antibodies in semen (resulting in sperm agglutination and impaired sperm function).^176,177 Sympathetic nervous system dysfunction (e.g., associated with autonomic neuropathy, sympatholytic drugs, sympathectomy, retroperitoneal or abdominopelvic surgery, spinal cord injury or disease, vasovasostomy) may contribute to impaired sperm transport and male infertility.

Ejaculatory dysfunction may cause or contribute to male infertility by preventing normal or efficient deposition of sperm into the vagina and female genital tract. Premature or retarded ejaculation may contribute to infertility if ejaculation occurs during arousal or foreplay before vaginal penetration or after withdrawal from the vagina. Retrograde ejaculation of semen into the bladder rather than the urethra occurs with neuromuscular failure of normal bladder sphincter contraction during ejaculation. Retrograde ejaculation may be associated with prostatectomy or bladder neck surgery (e.g., transurethral resection of the prostate [TURP]), autonomic neuropathy (e.g., complicating diabetes mellitus), or sympathetic nervous system dysfunction, and in particular with sympatholytic drugs (e.g., α-adrenergic receptor antagonists such as prazosin or terazosin), retroperitoneal or abdominopelvic surgery (e.g., retroperitoneal lymph node dissection), and spinal cord injury or disease. Reduced ejaculation caused by androgen deficiency or resistance, sympathetic nervous system dysfunction, or urethral abnormalities may contribute to reduced sperm delivery to the female genital tract.

Erectile dysfunction may contribute to male infertility by causing unsuccessful completion of intercourse. Coital disorders are uncommon causes of male infertility, but they are potentially correctable with proper education. Infrequent sexual intercourse, excessive intercourse with other partners or masturbation, intercourse during menses rather than just before or around the time of ovulation, and premature withdrawal of the penis during intercourse may contribute to reduced fertility.

Evaluation.

Because a coexisting female factor contributes to infertility in 30% of cases, it is important for the female partner to undergo evaluation for ovulation (menstrual periods, androgenization) and for cervical disorders (postcoital testing) and uterine and tubal disorders (hysterosalpingogram, pelvic ultrasound). In men, the history and physical examination are usually able to identify the potential cause of male infertility.^170-172

In addition to an assessment of general health and medical comorbid conditions, the initial clinical evaluation should focus on the following:

The initial laboratory evaluation of male infertility should begin with at least two or three seminal fluid analyses performed over a period of a few months (see later discussion) to assess semen volume, sperm count and concentration, and sperm motility and morphologic appearance, with the aim of identifying men who have impaired sperm production or function, the major cause of male infertility. The presence of leukocytes in semen (>10⁶/mL, termed leukospermia or pyospermia) may suggest a genitourinary inflammation or infection, but routine cultures are not usually helpful in guiding treatment. Agglutination of spermatozoa in semen (i.e., sticking of motile sperm to each other) suggests the presence of antisperm antibodies, which can be measured in semen and and may indicate an immunologic cause of male infertility.

Seminal fluid fructose is derived mostly from the seminal vesicles (60%) and to a lesser extent from the prostate gland (30%). Absent or low seminal fluid fructose and low semen volume suggest either congenital absence of the vas deferens and seminal vesicles or obstruction of the ejaculatory ducts. Dilated seminal vesicles may be detected on transrectal ultrasonography to confirm the presence of ejaculatory duct obstruction. In men who have little or no ejaculate, a postejaculatory urine specimen should be collected and examined for the presence of sperm, indicating retrograde ejaculation.

If there are clinical manifestations of androgen deficiency, serum testosterone levels should be measured on at least two occasions to confirm androgen deficiency, and measurements of LH and FSH should be performed to determine whether the patient has primary or secondary hypogonadism (see later discussion). Identification of infertile men with secondary hypogonadism potentially has important therapeutic implications. In men with impaired sperm production due to gonadotropin deficiency, spermatogenesis may be stimulated and fertility restored with the use of gonadotropin or GnRH therapy. Secondary hypogonadism is one of few treatable causes of male infertility. Elevated levels of testosterone, LH, and FSH suggest androgen resistance.

Measurements of FSH levels specifically as a marker of Sertoli cell and seminiferous tubule function are useful in identifying men with severe defects in spermatogenesis and impairment of seminiferous tubule and Sertoli cell function; such patients often demonstrate selective elevation in serum FSH concentrations with normal or high-normal LH levels due to loss of negative feedback inhibition of pituitary FSH secretion by inhibin B.¹⁷⁸ However, men with less severe seminiferous tubule dysfunction and impairment of spermatogenesis and those with azoospermia due to genital tract obstruction (obstructive azoospermia) have normal serum FSH levels.

Genetic disorders make up a small but significant proportion of the causes of male infertility. Because ART, and specifically ICSI, which involves direct injection of spermatozoa into the cytoplasm of an ovum (discussed later), is commonly used to treat male infertility, the potential exists for transmission of genetic defects to offspring. Therefore, genetic testing and counseling should be undertaken for men who are considering ICSI, particularly for those with severe oligozoospermia or azoospermia.^170-172

Men in whom bilateral congenital absence of the vas or genital tract obstruction is suspected (i.e., those with low semen volume, low fructose level, and nonpalpable vas deferens in the scrotum) and those who have unexplained obstructive azoospermia should undergo genetic testing for CFTR mutations and genetic counseling before ICSI. In men with severe oligozoospermia (sperm concentration <5 million/mL) or azoospermia, testing for Y chromosome microdeletions in the AZF region should be performed routinely. There is a high prevalence of sex chromosome and autosomal chromosome defects, often in the absence of other phenotypic abnormalities, in men with moderately impaired spermatogenesis and infertility. Therefore, karyotyping is recommended before ICSI for infertile men with impaired sperm production, and in particular for those with a sperm concentration of less than 10 million/mL.

In azoospermic men with normal semen volume, a normal fructose level, and a normal FSH level in whom it is unclear whether azoospermia is caused by germ cell failure, genital tract obstruction, or both, surgical exploration of the scrotum and testis biopsy are needed. Biopsy is also used to harvest sperm for ICSI, even in men with known severe impairment in spermatogenesis, such as those with Klinefelter syndrome.^{170,171,179,180}

Specialized tests of in vitro sperm function, such as detailed examination of sperm motility using computer-assisted semen analysis (CASA), cervical mucus penetration tests, acrosome reaction, and human zona pellucida binding tests, may be useful in some men who are considering intrauterine insemination or in vitro fertilization. However, these tests should be performed only in highly specialized laboratories that have demonstrated excellent quality control. Even in such laboratories, there is a high rate of clinical false-positive and false-negative results, limiting the clinical utility of these tests.

Treatment.

In men with infertility caused by primary hypogonadism (whether due to androgen deficiency and impairment of sperm production or to isolated impairment of sperm production or function), defects in sperm production are not treatable, although spontaneous recovery of spermatogenesis may occur at variable times after discontinuation of cytotoxic drugs or ionizing radiation. Because intratesticular testosterone concentrations are normally approximately 100-fold higher than serum levels, exogenous testosterone treatment of men with androgen deficiency cannot deliver sufficient amounts of testosterone to support sperm production in the testis.

In men with secondary hypogonadism, on the other hand, sperm production can be stimulated with gonadotropin or GnRH treatment, or spermatogenesis may recover sufficiently to restore fertility after discontinuation of drugs that suppress gonadotropins, such as androgenic anabolic steroids, progestins, glucocorticoids, and drugs causing hyperprolactinemia.

Most men with a varicocele and infertility have abnormal seminal fluid. However, varicocele repair has not been demonstrated to be effective in restoring fertility to these men. Therefore, unless a varicocele is very large or symptomatic, surgical repair is not recommended.^12,181 Although the efficacy of treatment is unclear, infertile men with leukospermia or sperm agglutination are usually treated empirically with a 14-day course of antibiotics, such as doxycycline, trimethoprim-sulfamethoxazole, or a fluoroquinolone. Although high-dose prednisone (40 to 60 mg for several months) has been shown to be effective in treating infertile men with antisperm antibodies, the risks of high-dose glucocorticoid treatment are substantial, and this therapy cannot be recommended given the safer alternative of ICSI.

Although ICSI is costly, it is used increasingly to treat male infertility, and it dramatically improves the prognosis for men with impaired sperm production regardless of the cause.^179,180 Spermatozoa that are ejaculated or obtained by testicular biopsy (testicular sperm extraction [TESE]) or from the epididymis (microsurgical epididymal sperm aspiration [MESA]) are used for ICSI and other ARTs. With ICSI, fertilization rates of about 60% and pregnancy rates of approximately 20% are achieved, irrespective of the cause of male infertility or source of spermatozoa. ICSI after TESE using microsurgical testis biopsy or fine-needle aspiration to retrieve sperm has been successful in restoring fertility to men with primary hypogonadism who had severe impairments in spermatogenesis and azoospermia that were previously thought to be untreatable (e.g., Klinefelter syndrome, prolonged azoospermia after chemotherapy).¹⁸² Because of the potential for chromosomal abnormalities and transmission of Y chromosome microdeletions and CFTR mutations that cause infertility in male offspring, genetic testing and counseling should be conducted if ICSI is being considered (see earlier discussion).¹⁷²

Obstruction of the epididymides or the ejaculatory ducts can be corrected surgically, such as with end-to-end anastomosis of the epididymides or transurethral resection of the ejaculatory ducts. More commonly, MESA is used to obtain spermatozoa that can be incubated with ova in vitro (in vitro fertilization [IVF]) or directly injected into an ovum (ICSI), and this method is more successful in restoring fertility than surgical options. In contrast, microsurgical reanastomosis of the vas (vasovasostomy) to reverse vasectomy is less costly and more successful in restoring fertility than MESA followed by IVF or ICSI. Return of sperm in the ejaculate occurs in approximately 90% of men who undergo vasectomy reversal, but restoration of fertility occurs in only about 50%, probably because of stenosis or blockage of the previous vasovasostomy, epididymal blockage, or the development of antisperm antibodies in response to the vasectomy.¹⁸³

In men with retrograde ejaculation, collection of spermatozoa in alkalinized postejaculation urine, followed by extensive washing and intrauterine insemination (IUI) or ICSI, has been used successfully to treat infertility. With proper education, coital disorders that contribute to infertility may be corrected. Also, the timing of intercourse may be optimized to occur a few days before and after ovulation (the period of highest probability for conception) based on basal body temperature measurements or, more accurately, on commercially available rapid urinary LH kits to estimate the timing of ovulation in the female partner.

If the treatment options described previously are not available or affordable to infertile couples who desire children, artificial insemination with donor sperm or adoption may be considered.

Variability in Testosterone Levels.

Because serum testosterone levels exhibit both biologic and assay variability, a single measurement is not a reliable indicator of an individual's average concentration. Serum testosterone levels exhibit both ultradian and circadian variation, providing physiologic sources of biologic variability. Ultradian fluctuations in serum testosterone levels, characterized by peaks of incremental amplitude that average approximately 240 ng/dL (40% fractional amplitude) with a 95-minute duration,⁴⁵ have been reported in a small number of young men; more chaotic peaks with lower amplitude have been reported in older men.¹⁹¹ As described previously, the circadian variation in serum testosterone peaks at about 8 AM and has a maximum excursion averaging 140 ng/dL.⁶⁴ The circadian variation in testosterone is blunted but still present in older men, with a maximum excursion averaging 60 ng/dL. In young men, serum testosterone levels are 20% to 25% lower at 4 PM than at 8 AM (i.e., over the course of usual clinic hours).¹⁹² This difference decreases with age: in 70-year-old men, testosterone levels are 10% lower at 4 PM than at 8 AM. Most importantly, many young and old men who have testosterone concentrations that are below normal in the afternoon have consistently normal levels in the morning. Testosterone levels are also suppressed with glucose infusion or food intake,^193,194 and thus measurements should preferably be done in the fasting state. Given these findings and the fact that normal ranges of testosterone concentration are usually based on morning blood samples, testosterone measurements to confirm the diagnosis of hypogonadism should preferably be performed in the morning in the fasting state.

There is also substantial day-to-day variation in serum testosterone concentrations, underscoring the need to repeat the measurement to confirm low levels, particularly if the first result was only moderately below normal. Among men with serum testosterone levels of less than 300 ng/dL on an initial test, 30% to 35% were found to have a normal level on repeat testing.¹⁹⁵ Among community-dwelling middle-aged to older men who had an initial serum testosterone concentration of less than 250 ng/dL, 20% were found to have an average testosterone level higher than 300 ng/dL (i.e., within the normal range) when six samples were drawn over the subsequent 6 months.¹⁹⁶ However, none of the subjects who had an initial average serum testosterone concentration of less than 250 ng/dL on two separate samples obtained 1 to 3 days apart had an average level higher than 300 ng/dL in six samples drawn over the next 6 months. These findings support the need to measure testosterone on at least two occasions to confirm the diagnosis of androgen deficiency.

Total Testosterone Assays.

Total testosterone assays are performed in most local laboratories and are readily available to clinicians. Therefore, total testosterone is recommended as the initial measurement for the assessment of androgen deficiency. In local clinical laboratories, total testosterone is usually measured by automated platform-based direct immunoassays on unextracted serum or plasma. However, there is substantial variability in results from different assays, mostly because the accreditation of laboratories has been based on the reproducibility of results in comparison to other laboratories using the same method or kit, rather than on the accuracy of results. For example, when identical quality control samples were assayed by different methods or kits, the reported measured values ranged from 160 to 508 ng/dL. Moreover, the lower limit of the normal range in some assays was as low as 132 to 210 ng/dL (clearly in the hypogonadal range for most conventional assays).¹⁹⁷ In contrast, the lower limit of the normal range based on conventional radioimmunoassays after extraction is approximately 280 to 300 ng/dL.

Most commercial reference laboratories now measure testosterone by liquid chromatography tandem mass spectrometry methods after solid phase extraction that have the potential to be more accurate than immunoassays. To address the problems in the quality control of testosterone assays, the U.S. Centers for Disease Control and Prevention (CDC) has initiated a program to standardize and harmonize testosterone assays using accuracy-based quality control standards to which most commercial reference laboratories participate.¹⁹⁸ Recently, the College of American Pathologists also instituted an accuracy-based quality control program that unfortunately is not mandatory for certification.

The prevalence of low testosterone concentrations is high in a number of clinical conditions, namely, presence of a pituitary or sellar mass; irradiation; disease; use of certain medications, such as opiates or high-dose glucocorticoids; HIV disease with weight loss; late-stage CKD, especially with hemodialysis; moderate to severe chronic lung disease; infertility; BMD levels that reveal osteoporosis or low-trauma fracture; and type 2 diabetes mellitus (T2DM). If clinical manifestations consistent with androgen deficiency are present in men with these conditions, testosterone measurements should be performed.¹¹³

Total Testosterone Affected by Alterations in Sex Hormone–Binding Globulin.

Because a substantial proportion (30% to 40%) of circulating testosterone is bound tightly to SHBG, alterations in SHBG concentration may affect total testosterone levels without altering free or bioavailable testosterone. Conditions that suppress SHBG levels (even within the broad normal range) lower total testosterone (sometimes to below the normal range) without affecting circulating free or bioavailable testosterone levels (Table 19-5).¹¹³ Common conditions that lower SHBG concentrations include moderate obesity, often associated with T2DM; protein-losing states, such as nephrotic syndrome; administration of glucocorticoids, progestins, or androgens; hypothyroidism; acromegaly; and familial SHBG deficiency. SHBG concentrations are increased with increasing age; hepatic cirrhosis and inflammation (hepatitis of any cause); estrogens; hyperthyroidism; anticonvulsants; and HIV disease.

If conditions that affect SHBG concentration are present in a patient or if total testosterone concentrations are close to the lower limit of the normal range, serum free or bioavailable testosterone measurements should be obtained to confirm androgen deficiency. Unfortunately, accurate and reliable assays for free or bioavailable testosterone are not performed routinely in most local clinical laboratories. Although direct free testosterone assays using automated platform-based analogue immunoassay methods are available, these assays are inaccurate and are affected by alterations in SHBG, so they offer no advantage over total testosterone measurements and are not recommended.^199-201

The gold standard method for measurement of free testosterone levels is equilibrium dialysis or centrifugal ultrafiltration. Free testosterone concentrations may be calculated accurately from measurements of total testosterone, SHBG, and albumin using affinity constants for binding of testosterone to its binding proteins and published formulas. Calculated free testosterone values are comparable to those measured by equilibrium dialysis.²⁰⁰ However, calculated values depend on the specific testosterone and SHBG assays employed and the formula used to estimate free testosterone.²⁰² There are a number of formulae used for calculation of free testosterone that all demonstrate some bias relative to the equilibrium dialysis method, largely as a result of assuming a single or two identical, noninteracting binding sites on SHBG.¹¹⁰ However, they all provide reasonable approximations of free testosterone in the normal to low range of values that are less prone to misinterpretation and overdiagnosis of hypogonadism than total testosterone measurements when alterations in SHBG levels are present.

Bioavailable testosterone is measured by ammonium sulfate precipitation of SHBG-bound testosterone and measurement of free and albumin-bound testosterone in the supernatant. Bioavailable testosterone levels may also be calculated from measurements of total testosterone, SHBG, and albumin. These accurate and reliable measurements of free and bioavailable testosterone are available in commercial laboratories and should be used to confirm androgen deficiency in men who have conditions that affect SHBG and in those with total testosterone levels near the lower limit of the normal range. In a recent report, 60% of over 3700 men in a single health care system who had low total testosterone levels were found to have normal calculated free testosterone concentrations using the laboratory reference range that was utilized by practitioners to make clinical decisions. These findings highlight the potential clinical importance of using free testosterone to confirm a biochemical diagnosis of hypogonadism.²⁰³

Transient Suppression of Testosterone.

In evaluating men for a diagnosis of male hypogonadism, it is important to recognize that serum testosterone levels may be suppressed transiently during acute (particularly critical) and subacute illness and recovery; with the short-term use of certain medications, such as opioids, high-dose glucocorticoids, and CNS-active medications or recreational drugs that suppress gonadotropin and testosterone production; and during transient malnutrition, such as that associated with illness, eating disorders, or excessive or prolonged strenuous exercise (resulting in low energy intake relative to energy expenditure). In such situations, measurement of serum testosterone should be delayed until the patient is completely recovered from the illness, the offending drugs are discontinued, the malnutrition is corrected, or the excessive exercise is stopped.¹¹³

Isolated Impairment of Sperm Production or Function.

Most men with isolated impairment of sperm production have low sperm counts or abnormalities in sperm motility or morphologic appearance (or both) but no clinical manifestations of androgen deficiency and normal levels of testosterone and gonadotropins. Most men with isolated impairment of sperm production or function are classified as having primary hypogonadism with an isolated defect in the seminiferous tubule compartment of the testes (Table 19-7); in such cases, there is no response to gonadotropin treatment, as there is in secondary hypogonadism. Men with severe seminiferous tubule failure and azoospermia or severe oligozoospermia may demonstrate a selective elevation in FSH levels as a result in reduced negative feedback from inhibin B with normal LH levels (Fig. 19-23).⁹ Occasionally, isolated impairment in sperm production is caused by gonadotropin deficiency (i.e., secondary hypogonadism) (Table 19-8); this may occur in men who are taking high doses of testosterone and in those who have androgen-secreting tumors, congenital adrenal hyperplasia, or, rarely, isolated FSH deficiency.

Men with nonfunctioning or gonadotropin-secreting pituitary tumors often have secondary hypogonadism with clinical manifestations of androgen deficiency and low testosterone levels.⁵³ Many of these men secrete excessive amounts of intact FSH and biologically inactive free α-, FSHβ-, and LHβ-subunits but rarely intact LH. Therefore, a gonadotropin-secreting pituitary tumor should be suspected in a man who has clinical manifestations of androgen deficiency, low testosterone, and elevated FSH but normal or low LH (or, rarely, elevated LH but normal or low FSH), which is an atypical gonadotropin pattern for men with androgen deficiency.

Rarely, disorders of androgen action or androgen resistance manifest in adults (Table 19-9). These men usually present with clinical manifestations similar to those of men with mild androgen deficiency, usually with an almost normal male phenotype and frequently with varying degrees of hypospadias, cryptorchidism, scrotal abnormalities, or impairment in sperm production. Usually, both serum testosterone and gonadotropin levels are elevated (Fig. 19-24).⁹