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Harrison’s Manual of Medicine



Androgen Deficiency
Male Infertility
Erectile Dysfunction
The testes produce sperm and the steroid hormones that regulate male sexual development and function. Inadequate production of sperm can occur as an isolated defect, whereas inadequate formation of testosterone by the Leydig cells reduces virilization and libido and often impairs spermatogenesis secondarily. Classification of testicular function in adults is found in Table 174-1.

Table 174-1 Abnormalities of Adult Testicular Function

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 are high. Klinefelter’s syndrome is the most common cause and is due to the presence of one or more extra X chromosomes, usually a 47, XXY karyotype. Acquired primary testicular failure usually results from viral orchitis, but may be due to trauma, 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 a polyglandular autoimmune failure syndrome in which multiple primary endocrine deficiencies coexist. Malnutrition, AIDS, renal failure, liver disease, myotonic dystrophy, paraplegia, and toxins such as alcohol, marijuana, heroin, methadone, lead, and antineoplastic and chemotherapeutic agents can also lead to testicular failure. Testosterone synthesis may be blocked by ketoconazole, or testosterone action may be diminished by competition at the androgen receptor by spironolactone and cimetidine.
Secondary hypogonadism is diagnosed when levels of both testosterone and gonadotropins are low (hypogonadotropic hypogonadism). Kallmann’s syndrome is due to impairment of the synthesis and/or release of gonadotropin- releasing hormone (GnRH) and is characterized by low levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and anosmia. Other individuals present with idiopathic congenital GnRH deficiency without anosmia. Critical illness, Cushing’s syndrome, congenital adrenal hyperplasia, hemochromatosis, and hyperprolactinemia (due to pituitary adenomas or drugs such as phenothiazines) are other causes of isolated hypogonadotropic hypogonadism. Destruction of the pituitary gland by tumors, infection, trauma, or metastatic disease causes hypogonadism in conjunction with disturbances in the production of other pituitary hormones.
Clinical Features   If insufficient androgens are present before the onset of puberty, failure of sexual maturation (eunuchoidism) is evidenced by an infantile amount and distribution of body hair, poor development of skeletal muscles, and delayed closure of the epiphyses. In Klinefelter’s syndrome, the testes are small and firm, gynecomastia is common, and azoospermia is usually present. Testosterone levels are low, and the gonadotropins are increased (FSH > LH). Variable features include eunuchoid habitus, mild mental deficiency, and diabetes mellitus.
Men who present with hypogonadism that occurred after puberty may report diminished libido, sexual function, general strength, and energy level. A decreased rate of beard growth may signify decreased virilization. On physical exam, gynecomastia and small or soft testes may be present.
Males without androgen deficiency may have isolated testosterone levels that are below the normal range during the day, particularly in the afternoon, so that repeat or pooled samples may be required to document testosterone deficiency. Levels of LH and FSH can be used to differentiate between primary (increased gonadotropins) and secondary hypogonadism (decreased gonadotropins).

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). 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 parenteral administration of a long-acting testosterone ester (100–200 mg testosterone enanthate at 1- to 3-week intervals) or daily application of transdermal testosterone patches or gel.

Etiology   Male infertility plays a role in one-third of infertile couples (couples who fail to conceive after 1 year of unprotected intercourse). Secondary impairment of spermatogenesis by androgen deficiency may occur, as described above. Isolated spermatogenic tubule dysfunction is usually idiopathic. However, known causes include Y chromosome microdeletions and substitutions, alterations of temperature of the testes as in varicocele, cryptorchidism, or immotile cilia syndrome. Ejaculatory obstruction can be a congenital (cystic fibrosis, in utero DES exposure, or idiopathic) or acquired (tuberculosis, leprosy, or gonorrhea) etiology of male infertility. Defects of the androgen receptor and disorders of sperm transport may also cause infertility. Radiation, chemotherapeutic agents, and environmental toxins have all been associated with isolated impaired spermatogenesis. Androgen abuse by male athletes can lead to testicular atrophy and a low sperm count.
Clinical Features   Evidence of hypogonadism may 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 <20 million/mL, with a motility of <40%, are associated with infertility. Testosterone levels should be measured if the sperm count is low on repeated exam or if there is clinical evidence of hypogonadism.

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.

Etiology   Erectile dysfunction (ED) is the failure to achieve erection, ejaculation, or both. It affects 10–25% of middle-aged and elderly men. Sexual dysfunction can be psychogenic but often has an organic component related to a systemic disease, urogenital disorders, or endocrinopathy. Some organic causes of ED are listed in Table 174-2.

Table 174-2 Some Organic Causes of Erectile Dysfunction in Men

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. 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 artiography, electromyography, or penile Doppler ultrasound is occasionally performed.

An approach to the evaluation and treatment of ED is summarized in Fig. 174-1. Correction of the underlying disorders or discontinuation of responsible medications should be attempted. Oral sildenafil enhances erections after sexual stimulation, with an onset of approximately 60–90 min. It is contraindicated in men receiving any form of nitrate therapy and should be avoided in those with congestive heart failure. Injection of alprostadil into the corpora cavernosa or urethra or vacuum constriction devices may also be effective. The insertion of penile prosthesis is rarely indicated.

FIGURE 174-1. Algorithm for the evaluation and management of patients with ED.


For a more detailed discussion, see Griffin JE, Wilson JD: Disorders of the Testes, Chap. 335, p. 2143; Hall JE: Infertility and Fertility Control, Chap. 54, p. 301; McVary KT: Erectile Dysfunction, Chap. 51, p. 291, in HPIM- 15.


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