Male Hypogonadism

Inadequate testicular androgen production resulting in a bioavailable testosterone level < 70 ng/dL (2.4 nmol/L), which can be associated with loss of libido, diminished muscle mass and muscle strength, and altered energy and well-being.

Androgen deficiency in the aging male (ADAM syndrome) is common; at least half of men >= 50 have levels of bioavailable testosterone well below those of healthy younger men. Testosterone declines with age (by about 100 ng/dL [3.5 nmol/L] per decade after age 50), but bioavailable testosterone (nonsex hormone-binding globulin [non-SHBG] bound testosterone) as well as free testosterone (non-SHBG, non-albumin-bound testosterone) decline far more dramatically. Sex hormone-binding globulin increases with age.

Although a decreased number of Leydig's cells and decreased testosterone production and clearance rate occur with age, the decline in male hormones is generally not accompanied by the expected rise in luteinizing hormone (LH), suggesting a defect at the level of the hypothalamus or pituitary rather than at the testicular level. Loss of diurnal rhythmicity occurs for LH, testosterone, and bioavailable testosterone with age. Both pulse amplitude and frequency decrease with age. Decreased feedforward stimulation by LH and delayed feedback inhibition by testosterone occur in elderly men. Thus, the majority of elderly men with hypogonadism have secondary, rather than primary, gonadal deficiency. Alterations in gonadotropin-releasing hormone appear to play a key role in the hormonal changes. An age-related increase in prolactin can result in inhibition of gonadotropins at the hypothalamic and pituitary levels.

Relatively rare causes of hypogonadism may include drug use, exposure to toxins, and medical disorders (see Table 115-3). With Sertoli cell failure associated with age, follicle-stimulating hormone levels rise, unlike the response to changes in Leydig's cells. Loss of sperm quality and quantity can be noted with age.

Symptoms and Signs

Hypogonadism in elderly men generally has few or nonspecific symptoms or physical findings. The most common symptom is decreased libido, which is directly related to testosterone (and bioavailable testosterone) levels. Although potency is not dependent on testosterone levels, severe impairment of libido causes erectile dysfunction. Male hypogonadism can also lead to fatigue, loss of energy, muscle weakness, and a decreased sense of well-being, which may manifest as depression. Although animal studies suggest that male hypogonadism reduces coronary artery blood flow, the effect in humans is unknown.

Muscle mass, which decreases with age (resulting in sarcopenia), can be associated with weakness, immobility, and impaired gait and balance. Muscle mass and balance correlate with the level of bioavailable or free testosterone. Severe prolonged hypogonadism leads to loss of body hair and masculine habitus; small, soft testes; and a loss of scrotal pigmentation and rugae. Bone loss has been associated with hypogonadism; however, an independent non-age-related link of testosterone and bone mass is difficult to demonstrate. It is possible that the lack of substrate (testosterone) for aromatization to estrogen plays a role in osteoporosis in aging men.

Laboratory Findings

Bioavailable testosterone levels < 70 ng/dL (< 2.4 nmol/L) or total testosterone levels < 300 ng/dL (< 10.4 nmol/L) are diagnostic of male hypogonadism. Measuring bioavailable or free testosterone is more sensitive than measuring total testosterone because the sex hormone-binding globulin bound fraction increases with age.

LH levels are normal or low in most hypogonadal men. Dynamic testing with gonadotropin-releasing hormone adds little information, because the response is usually proportional to the basal LH level. A normal prolactin level helps exclude a pituitary tumor as the cause of male hypogonadism. Laboratory findings may show anemia.

Treatment

Male hypogonadism is treated with testosterone therapy. Other androgens, such as dehydroepiandrosterone, are not recommended for therapy. The type and dose of testosterone are somewhat controversial. However, intramuscular formulations are generally preferred. The oral testosterones available in the USA (17- alkylated compounds) may cause hepatotoxicity, with elevation of hepatic enzymes, and occasionally cholestatic jaundice and hepatic tumors. Oral 17- testosterone (eg, testosterone undecenoate) has less hepatotoxicity than oral 17- alkylated compounds, but it is not available in the USA. Thus, testosterone injections--given by a visiting nurse, the patient, or a family member--are a mainstay of treatment. Long-acting esters of testosterone (eg, enanthate, cypionate) are usually given IM in dosages of 200 mg every 2 weeks.

Transdermal testosterone patches (applied to the scrotum or elsewhere) are effective. However, skin rashes and high cost make this modality a second choice.

In most cases, testosterone therapy clearly improves libido, muscle strength, sense of well-being, and mood. Cognitive performance is highly linked to bioavailable testosterone levels, and testosterone therapy has been shown to improve visual spatial memory in middle-aged men. Testosterone therapy stimulates erythropoietin secretion, increasing the Hct. The polycythemia that may occur with testosterone therapy is independent of the baseline erythropoietin level and is neither dose-dependent nor duration-dependent. Use of testosterone may raise the prostate-specific antigen level, but development or exacerbation of obstructive prostatic symptoms is rare. Patients with elevated or borderline levels of prostate-specific antigen probably should not be treated with testosterone until prostate cancer has been ruled out. However, for many patients, the benefit may outweigh the risk, so therapy may be appropriate after careful consideration and with close monitoring. Gynecomastia (due to aromatization to estrogen) and water retention may occur. A negative effect on the lipid profile has not been found with testosterone replacement for hypogonadism in elderly men. Studies showing benefit and safety are continuing to accrue, and the risk/benefit ratio for each patient must be assessed.