Harrisons Manual of Medicine, 18th Ed.

CHAPTER 185. Disorders of the Male Reproductive System

The testes produce sperm and testosterone. Inadequate production of sperm can occur in isolation or in the presence of androgen deficiency, which impairs spermatogenesis secondarily.

ANDROGEN DEFICIENCY

Etiology

Androgen deficiency can be due to either testicular failure (primary hypogonadism) or hypothalamic-pituitary defects (secondary hypogonadism).

Primary hypogonadism is diagnosed when testosterone levels are low and gonadotropin levels [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)] are high. Klinefelter’s syndrome is the most common cause (~1 in 1000 male births) and is due to the presence of one or more extra X chromosomes, usually a 47,XXY karyotype. Other genetic causes of testicular development, androgen biosynthesis, or androgen action are uncommon. Acquired primary testicular failure usually results from viral orchitis but may be due to trauma, testicular torsion, cryptorchidism, radiation damage, or systemic diseases such as amyloidosis, Hodgkin’s disease, sickle cell disease, or granulomatous diseases. Testicular failure can occur as a part of polyglandular autoimmune failure syndrome. Malnutrition, AIDS, renal failure, liver cirrhosis, myotonic dystrophy, paraplegia, and toxins such as alcohol, marijuana, heroin, methadone, lead, and antineoplastic and chemotherapeutic agents also can cause testicular failure. Testosterone synthesis may be blocked by ketoconazole, and testosterone action may be blocked at the androgen receptor level by spironolactone or cimetidine.

Secondary hypogonadism is diagnosed when levels of both testosterone and gonadotropins are low (hypogonadotropic hypogonadism). Kallmann syndrome is due to maldevelopment of neurons producing gonadotropin-releasing hormone (GnRH) and is characterized by GnRH deficiency, low levels of LH and FSH, and anosmia. Several other types of GnRH deficiency or gonadotropin deficiency present without anosmia. Acquired causes of isolated hypogonadotropic hypogonadism include critical illness, excessive stress, obesity, Cushing’s syndrome, opioid and marijuana use, hemochromatosis, and hyperprolactinemia (due to pituitary adenomas or drugs such as phenothiazines). Destruction of the pituitary gland by tumors, infection, trauma, or metastatic disease causes hypogonadism in conjunction with deficiency of other pituitary hormones (see Chap. 179). Normal aging is associated with a progressive decline of testosterone production, which is due to downregulation of the entire hypothalamo-pituitary-testicular axis.

Clinical Features

The history should focus on developmental stages such as puberty and growth spurts, as well as androgen-dependent events such as early morning erections, frequency and intensity of sexual thoughts, and frequency of masturbation or intercourse. The physical examination should focus on secondary sex characteristics such as hair growth in the face, axilla, chest, and pubic regions; gynecomastia; testicular volume; prostate; and height and body proportions. Eunuchoidal proportions are defined as an arm span >2 cm greater than height and suggest that androgen deficiency occurred prior to epiphyseal fusion. Normal testicular size ranges from 3.5–5.5 cm in length, which corresponds to a volume of 12–25 mL. The presence of varicocele should be sought by palpation of the testicular veins with the pt standing. Pts with Klinefelter’s syndrome have small (1–2 mL), firm testes.

A morning total testosterone level <10.4 nmol/L (<300 ng/dL), in association with symptoms, suggests testosterone deficiency. A level of >12.1 nmol/L (>350 ng/dL) makes the diagnosis of androgen deficiency unlikely. In men with testosterone levels between 6.9 and 12.1 nmol/L (200 and 350 ng/dL), the total testosterone level should be repeated and a free testosterone level should be measured by a reliable method. In older men and in pts with other clinical states that are associated with alterations in sex hormone–binding globulin levels, a direct measurement of free testosterone by equilibrium dialysis can be useful in unmasking testosterone deficiency. When androgen deficiency has been confirmed by low testosterone concentrations, LH should be measured to classify the pt as having primary (high LH) or secondary (low or inappropriately normal LH) hypogonadism. In men with primary hypogonadism of unknown cause, a karyotype should be performed to exclude Klinefelter’s syndrome. Measurement of a prolactin level and MRI of the hypothalamic-pituitary region should be considered in men with secondary hypogonadism. Gynecomastia in the absence of androgen deficiency should be further evaluated (Fig. 185-1).

Image

FIGURE 185-1 Evaluation of gynecomastia. T, testosterone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; hCGβ, human chorionic gonadotropin β; E2, 17β;-estradiol.

TREATMENT Androgen Deficiency

Treatment of hypogonadal men with androgens restores normal male secondary sexual characteristics (beard, body hair, external genitalia), male sexual drive, and masculine somatic development (hemoglobin, muscle mass), but not fertility. Administration of gradually increasing doses of testosterone is recommended for disorders in which hypogonadism occurred prior to puberty. Testosterone levels in the normal range may be achieved through daily application of transdermal testosterone patches (5–10 mg/d) or gel (50–100 mg/d), parenteral administration of a long-acting testosterone ester (e.g., 100–200 mg testosterone enanthate at 1- to 3-week intervals) or buccal testosterone tablets (30 mg/d). Hematocrit should be monitored initially during testosterone therapy and the dose lowered if Hct is >54%. Prostate cancer, severe symptoms of lower urinary tract obstruction, baseline hematocrit >50%, severe sleep apnea, and class IV congestive heart failure are contraindications for androgen replacement. Gonadotropin therapy for secondary hypogonadism should be reserved for fertility induction.

MALE INFERTILITY

Etiology

Male infertility plays a role in 25% of infertile couples (couples who fail to conceive after 1 year of unprotected intercourse). Known causes of male infertility include primary hypogonadism (30–40%), disorders of sperm transport (10–20%), and secondary hypogonadism (2%), with an unknown etiology in up to half of men with suspected male factor infertility (see Fig. 186-3). Impaired spermatogenesis occurs with testosterone deficiency but may also be present without testosterone deficiency. Y chromosome microdeletions and substitutions, viral orchitis, tuberculosis, STDs, radiation, chemotherapeutic agents, and environmental toxins have all been associated with isolated impaired spermatogenesis. Prolonged elevations of testicular temperature, as in varicocele, in cryptorchidism, or after an acute febrile illness, may impair spermatogenesis. Ejaculatory obstruction can be a congenital (cystic fibrosis, in utero diethylstilbestrol exposure, or idiopathic) or acquired (vasectomy, accidental ligation of the vas deferens, or obstruction of the epididymis) etiology of male infertility. Androgen abuse by male athletes can lead to testicular atrophy and a low sperm count.

Clinical Features

Evidence of hypogonadism may or may not be present. Testicular size and consistency may be abnormal, and a varicocele may be apparent on palpation. When the seminiferous tubules are damaged prior to puberty, the testes are small (usually <12 mL) and firm, whereas postpubertal damage causes the testes to be soft (the capsule, once enlarged, does not contract to its previous size). The key diagnostic test is a semen analysis. Sperm counts of <13 million/mL, motility of <32%, and <9% normal morphology are associated with subfertility. Testosterone levels should be measured if the sperm count is low on repeated exam or if there is clinical evidence of hypogonadism.

TREATMENT Male Infertility

Men with primary hypogonadism occasionally respond to androgen therapy if there is minimal damage to the seminiferous tubules, whereas those with secondary hypogonadism require gonadotropin therapy to achieve fertility. Fertility occurs in about half of men with varicocele who undergo surgical repair. In vitro fertilization is an option for men with mild to moderate defects in sperm quality; intracytoplasmic sperm injection (ICSI) has been a major advance for men with severe defects in sperm quality.

ERECTILE DYSFUNCTION

Etiology

Erectile dysfunction (ED) is the failure to achieve erection, ejaculation, or both. It affects 10–25% of middle-aged and elderly men. ED may result from three basic mechanisms: (1) failure to initiate (psychogenic, endocrinologic, or neurogenic); (2) failure to fill (arteriogenic); or (3) failure to store adequate blood volume within the lacunar network (venoocclusive dysfunction). Diabetic, atherosclerotic, and drug-related causes account for >80% of cases of ED in older men. The most common organic cause of ED is vasculogenic; 35–75% of men with diabetes have ED due to a combination of vascular and neurologic complications. Psychogenic causes of ED include performance anxiety, depression, relationship conflict, sexual inhibition, history of sexual abuse in childhood, and fear of pregnancy or sexually transmitted disease. Among the antihypertensive agents, the thiazide diuretics and beta blockers have been implicated most frequently. Estrogens, GnRH agonists and antagonists, H2 antagonists, and spironolactone suppress gonadotropin production or block androgen action. Antidepressant and antipsychotic agents—particularly neuroleptics, tricyclics, and selective serotonin reuptake inhibitors—are associated with erectile, ejaculatory, orgasmic, and sexual desire difficulties. Recreational drugs, including ethanol, cocaine, and marijuana, also may cause ED. Any disorder that affects the sacral spinal cord or the sensory nerves or autonomic fibers innervating the penis may lead to ED.

Clinical Features

Men with sexual dysfunction may complain of loss of libido, inability to initiate or maintain an erection, ejaculatory failure, premature ejaculation, or inability to achieve orgasm, but frequently are too embarrassed to bring up the subject unless specifically asked by the physician. Initial questions should focus on the onset of symptoms, the presence and duration of partial erections, the progression of ED, and ejaculation. Psychosocial history, libido, relationship issues, sexual orientation and sexual practices should be part of the clinical assessment. A history of nocturnal or early morning erections is useful for distinguishing physiologic from psychogenic ED. Relevant risk factors should be identified, such as diabetes mellitus, coronary artery disease, lipid disorders, hypertension, peripheral vascular disease, smoking, alcoholism, and endocrine or neurologic disorders. The pt’s surgical history should be explored, with an emphasis on bowel, bladder, prostate, or vascular procedures. Evaluation includes a detailed general as well as genital physical exam. Penile abnormalities (Peyronie’s disease), testicular size, and gynecomastia should be noted. Peripheral pulses should be palpated, and bruits should be sought. Neurologic exam should assess anal sphincter tone, perineal sensation, and bulbocavernosus reflex. Serum testosterone and prolactin should be measured. Penile arteriography, electromyography, or penile Doppler ultrasound is occasionally performed.

TREATMENT Erectile Dysfunction

An approach to the evaluation and treatment of ED is summarized in Fig. 185-2. Correction of the underlying disorders or discontinuation of responsible medications should be attempted. Oral inhibitors of phosphodiesterase-5 (sildenafil, tadalafil, and vardenafil) enhance erections after sexual stimulation, with an onset of approximately 60–120 min. They are contraindicated in men receiving any form of nitrate therapy and should be avoided in those with congestive heart failure. Vacuum constriction devices or injection of alprostadil into the urethra or corpora cavernosa may also be effective. The insertion of a penile prosthesis is reserved for pts with refractory ED.

Image

FIGURE 185-2 Algorithm for the evaluation and management of pts with ED. PDE, phosphodiesterase.

Image

For a more detailed discussion, see Bhasin S, Jameson JL: Disorders of the Testes and Male Reproductive System, Chap. 346, p. 3010; Hall JE: The Female Reproductive System, Infertility, and Contraception, Chap. 347, p. 3028; and McVary KT: Sexual Dysfunction, Chap. 48, p. 374, in HPIM-18.