Treating Aging with Testosterone.

Although some off-label medication use is justified, the use of testosterone for nonspecific symptoms of aging is not. Using testosterone to treat older men with decreased energy, decreased strength, low libido, erectile dysfunction, mood disorders, sleep disorders, or poor memory is inappropriate because symptoms do not correlate with testosterone levels, testosterone supplementation is unimpressive in clinical trials, and inappropriate testosterone therapy is not safe. Many nonspecific symptoms treated with testosterone are due to normal aging or pathologies for which there are more effective, safer therapies. For example, depression should be treated with antidepressants, not testosterone, and erectile dysfunction is appropriately treated with phosphodiesterase inhibitors. A systematic review of 40 studies found only weak correlations between low testosterone and any symptoms.1 Symptoms associated with low testosterone are also associated with chronic disease, psychogenic factors, and substance use. Erectile dysfunction, for example, is associated with diabetes mellitus, vascular dysfunction, and neurologic impairment— all of which are common in older men. Although there are more than 100 trials of testosterone therapy, there is little evidence that testosterone works for any symptoms. Evidence from randomized controlled trials2 and a systematic review conducted by our team3 found that testosterone does not benefit physical function, mood, cognition, or cardiovascular health. A recent set of testosterone studies that included men 65 years or older with a serum testosterone level less than 275 ng per mL (9.5 nmol per L) found that topical testosterone therapy over one year improved bone density 4 and anemia5 but had no effect on age-associated memory impairment.6 Evidence on sexual function is mixed. Out of 47 studies, 24 found no benefit of testosterone over placebo on any sexual function end point. Although 23 studies found a benefit on at least one end point, most end points were negative.3 About one-half (16 out of 31) of erectile dysfunction studies found a benefit.3 Testosterone levels vary hourly, daily, weekly, and seasonally.7 There is no reliable evidence that raising testosterone levels prevents or treats any disease. Although many persons with chronic diseases have low testosterone levels,8 it is much more likely to be an effect rather than a cause of chronic disease. Our systematic review found no evidence of benefit for any clinical end points of cardiovascular disease. Although trials have occasionally found a benefit for a marker of cardiovascular disease, clinical end points are more important, and evidence must be considered as a whole.3 Adverse effects of testosterone therapy are a concern. Testosterone may increase prostate cancer rates, and it is also linked to thromboembolic events, especially in those with thrombophilia-hypofibrinolysis.9 Testosterone probably increases cardiovascular risks, especially soon after treatment commences.10-12 It bears noting that long-term observational studies showing no increased cardiovascular risk censored short-term events.13,14 All prevalence studies will have this bias; it is vital to study new users prospectively, and in the case of testosterone therapy, long-term prospective trials would contribute to a more accurate understanding of all-cause adverse effects. Studies of testosterone and cardiovascular risk have received attention recently. One trial found that in a subset of 170 men (mean age of 71.2 years; one-half with severe atherosclerosis), testosterone treatment significantly increased noncalcified plaque volume over a year compared with placebo, Editorials