Testosterone Supplementation

By Peter Galvin, MD

In men, hypogonadism (low testosterone level) generally has readily recognizable clinical manifestations, such as decreased libido and sexual activity, loss of secondary sex characteristics and muscle mass, hot flushes, and anemia. Testosterone preparations have been approved to treat hypogonadism and are effective in correcting the clinical abnormalities associated with this condition in many men. Most men currently treated with these preparations have only moderately decreased testosterone levels, a high burden of chronic diseases, and non-specific symptoms that overlap with age-related symptoms. The risks and benefits of testosterone treatment in this population are less clear and are associated with controversy.

Many of the benefits and some of the risks of testosterone treatment are mediated by the mechanisms through which testosterone acts. Testosterone has anabolic effects on muscle and bone (stimulates growth) and stimulates erythropoiesis (production of red blood cells). It also increases penile blood flow and improves erectile function. Its effects on sexual desire (libido) and bone are largely mediated through its conversion to 17Beta-estradiol. Testosterone is also converted to dihydrotestosterone (DHT) which stimulates prostate growth and has additional effects on muscle and bone.

Placebo-controlled trials done during the 1990s and early 2000s evaluated whether testosterone treatment in older men with low or low-normal testosterone levels would improve sexual function, bone density, and muscle mass and strength. Some studies suggested benefits from treatment, others did not. In 2003, the Institute of Medicine concluded that the evidence was insufficient and recommended a coordinated set of new trials. In response, a set of seven trials, the Testosterone Trials (TTrials) was developed, but even before the TTrials had been completed, the FDA, alarmed about the increasing use of testosterone and questions about its cardiovascular safety, required new trials to assess the risk of major cardiovascular adverse events (MACE) with testosterone treatment. The resulting trial, Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) was conducted.

All these trials had similar results. Overall, they confirmed that testosterone therapy had positive effects in men with low levels of testosterone, but sexual function and desire increased mostly in men with low levels and not in men with low-normal levels. Muscle and bone mass increased in most groups, as did hemoglobin levels. In TRAVERSE, many men reported depressive symptoms at the start and found that with treatment, and not placebo, depressive symptoms improved except in those with a formal diagnosis of major depressive disorder. Also found was that the rates of MACE were similar in both the treatment and placebo groups, which indicates that the risk of heart disease and stroke from testosterone therapy may have been overestimated. Finally, because both the TRAVERSE and TTrials studies excluded, via PSA testing and prostate exam, men who were considered to have BPH or were at high risk for prostate cancer, their results may not apply to the broader population of men with hypogonadism.

Based on these findings, the decision of whether to recommend testosterone treatment should be based on an approach that balances risks and benefits. Improvements in libido and sexual function can only be expected in men with low (<200) testosterone levels. Older men should undergo an evaluation for prostate cancer and BPH before treatment. Men with a history of blood clots should be excluded. And lastly, only those with severe symptoms who are willing to accept both the risk and monitoring should be considered for treatment.

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