The benefits and risks of testosterone replacement therapy …

Abstract

Increased longevity and population aging will increase the number of men with late onset hypogonadism. It is a common condition, but often underdiagnosed and undertreated. The indication of testosterone-replacement therapy (TRT) treatment requires the presence of low testosterone level, and symptoms and signs of hypogonadism. Although controversy remains regarding indications for testosterone supplementation in aging men due to lack of large-scale, long-term studies assessing the benefits and risks of testosterone-replacement therapy in men, reports indicate that TRT may produce a wide range of benefits for men with hypogonadism that include improvement in libido and sexual function, bone density, muscle mass, body composition, mood, erythropoiesis, cognition, quality of life and cardiovascular disease. Perhaps the most controversial area is the issue of risk, especially possible stimulation of prostate cancer by testosterone, even though no evidence to support this risk exists. Other possible risks include worsening symptoms of benign prostatic hypertrophy, liver toxicity, hyperviscosity, erythrocytosis, worsening untreated sleep apnea or severe heart failure. Despite this controversy, testosterone supplementation in the United States has increased substantially over the past several years. The physician should discuss with the patient the potential benefits and risks of TRT. The purpose of this review is to discuss what is known and not known regarding the benefits and risks of TRT.

Keywords: hypogonadism, testosterone replacement therapy, erectile dysfunction, osteoporosis, cardiovascular disease

Hypogonadism is a clinical condition in which low levels of serum testosterone are found in association with specific signs and symptoms. When hypogonadism occurs in an older man, the condition is often called andropause or androgen deficiency of the aging male or late onset hypogonadism (LOH).1 The most easily recognized clinical signs of relative androgen deficiency in older men are a decrease in muscle mass and strength, a decrease in bone mass and osteoporosis, and an increase in central body fat. However, symptoms such as a decrease in libido and sexual desire, forgetfulness, loss of memory, anemia, difficulty in concentration, insomnia, and a decreased sense of well-being are more difficult to measure and differentiate from hormone-independent aging. This condition may result in significant detriment to quality of life and adversely affect the function of multiple organ systems.13 A health factor-independent, age-related longitudinal decrease in serum testosterone levels has been reported.4 This LOH is important since it features many potentially serious consequences that can be readily avoided or treated, and the affected sector of the population is currently expanding in number. Prospective population-based studies reported in the past decade indicate that low testosterone levels are associated with an increase in the risk for developing type 2 diabetes mellitus and metabolic syndrome and possibly a reduction in survival. Results were similar for bioavailable testosterone.57 In men, endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes. Low testosterone may be a predictive marker for those at high risk of cardiovascular disease.8 Also, low testosterone levels were associated with increased mortality in male veterans9 but this association could not be confirmed in the Massachusetts Male Aging Study10 or the New Mexico Aging Study.11

As the clinical symptoms of hormone deficiency in older males may be nonspecific, and since a substantial number of relatively asymptomatic elderly men have testosterone levels outside the normal range for young adults, investigators have suggested that testosterone replacement therapy is only warranted in the presence of both clinical symptoms suggestive of hormone deficiency and decreased hormone levels.12 Restoring serum testosterone levels to the normal range using testosterone replacement therapy results in clinical benefits in some of these areas. Successful management of testosterone replacement therapy requires appropriate evaluation and an understanding of the benefits and risks of treatment.

Due to the baby boom that occurred after World War II, the percentage of population in the older age group in developed countries is increasing. Testosterone deficiency is a common disorder in middle-aged and older men but it is underdiagnosed and often untreated. Clinicians tend to overlook it, and the complaints of androgen-deficient men are merely considered part of aging. Hypogonadism affects an estimated 2 million to 4 million men in the United States. Many patients can derive significant benefits from treatment. Testosterone supplementation in the United States has increased substantially over the past several years.13 However, it has been estimated that only 5% of affected men currently receive treatment.

The decline of serum testosterone levels appears to be a gradual, age-related process resulting in an approximate 1% annual decline after age 30. In cross-sectional and longitudinal studies of men aged 30 or 40 years and above, total, bioavailable and free testosterone concentrations fall with increasing age with a steeper decline in bioavailable and free compared with total testosterone concentrations.4,14,15 In older men above the age of 65 or 70 years, the changes in total testosterone are overshadowed by a more significant decline in free testosterone levels.16,17 This is a consequence of the age-associated increase of the levels of sex hormone binding globulin (SHBG) demonstrated by cross-sectional studies, and has now been confirmed by longitudinal studies.18,19 Although the fall is gradual, by the eighth decade, according to the Baltimore Longitudinal Study, 30% of men had total testosterone values in the hypogonadal range, and 50% had low free testosterone values. The rate of age-related decline in serum testosterone levels varies in different individuals and is affected by chronic disease and medications.20 There is evidence that many of these men are not symptomatic.21

Multiple mechanisms are likely to influence the decline in testosterone levels in aging men.22 Lower testosterone levels may result from reduced testicular responses to gonadotrophin stimuli with aging, coupled with incomplete hypothalamopituitary compensation for the fall in total and free testosterone levels.23,24 Whether the age-dependent decline in androgen levels leads to health problems in older men is being debated vigorously.21,25

At present, the diagnosis of hypogonadism requires the presence of symptoms and signs suggestive of testosterone deficiency.1,26 The symptom most associated with hypogonadism is low libido.2729 Other manifestations of hypogonadism include erectile dysfunction, decreased muscle mass and strength, increased body fat, decreased bone mineral density and osteoporosis, mild anemia, breast discomfort and gynecomastia, hot flushes, sleep disturbance, body hair and skin alterations, decreased vitality, and decreased intellectual capacity (poor concentration, depression, fatigue).30 The problem is many of the symptoms of late life hypogonadism are similar in other conditions31,32 or are physiologically associated with the aging process.33 One or more of these symptoms must be corroborated with a low serum testosterone level.21,25,34 Depression, hypothyroidism and chronic alcoholism should be excluded, as should the use of medications such as corticosteroids, cimetidine, spironolactone, digoxin, opioid analgesics, antidepressants and antifungal drugs. Of course, diagnosis of LOH should never be undertaken during an acute illness, which is likely to result in temporarily low testosterone levels ().

Approach to the diagnosis and treatment of late onset hypogonadism (ADAM = St. Louis University Androgen Deficiency in Aging Males Questionnaire).

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