The Medical Letter on Drugs and Therapeutics
Safety of Testosterone Replacement Therapy
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Revised 5/2/16: Footnote 7 has been added to Table 1

Three coordinated double-blind, placebo-controlled clinical trials have evaluated the efficacy of one year of testosterone replacement therapy in improving sexual function, physical function, and vitality in a total of 790 men ≥65 years old with moderately low serum testosterone concentrations and symptoms suggesting hypoandrogenism. Sexual function improved modestly, and there appeared to be marginal benefits in some areas of physical function and vitality as well. The trials were not designed to evaluate the safety of testosterone replacement therapy.1

ADVERSE EFFECTS — Testosterone administration has been associated with development of acne, gynecomastia, peripheral edema, and polycythemia. Injections of testosterone undecanoate rarely have caused pulmonary oil microembolism (POME) and anaphylactic reactions. The main concern with testosterone replacement therapy, however, has been the possibility that it could increase the risk of prostate cancer and cardiovascular disease.

Prostate Cancer – Testosterone replacement therapy has been associated with increases in serum prostate-specific antigen (PSA) concentrations. In the coordinated trials, which excluded men at high risk for prostate cancer, a PSA increase of ≥1.0 ng/mL occurred in 23 men treated with testosterone and 8 treated with placebo. Four men developed prostate cancer during the trials or in the subsequent year; three were in the testosterone group. Large randomized controlled trials are lacking, but recent reviews have found no convincing evidence that higher testosterone levels increase the risk of prostate cancer.2,3

Cardiovascular Disease – Some studies have found an association between testosterone replacement therapy and cardiovascular events. In the coordinated trials, 7 men in each treatment group had a major cardiovascular event.

In an earlier 6-month randomized trial in 209 men ≥65 years old with a high prevalence of cardiac risk factors, 23 treated with testosterone gel had cardiovascular-related adverse events, compared to 5 who received placebo (HR 2.4; p=0.05).4 A meta-analysis of randomized, placebo-controlled trials also found an increased risk of cardiovascular-related adverse events in men treated with testosterone (OR 1.54; 95% CI 1.09-2.18); an analysis by funding source found that the risk was greater in trials not sponsored by the pharmaceutical industry (OR 2.06 vs 0.89).5

Other studies have not found an association between testosterone replacement therapy and cardiovascular risk, and some have found a reduced incidence of myocardial infarction and mortality in men treated with testosterone.6-8

CONCLUSION — The safety of testosterone replacement therapy remains unclear. There is no convincing evidence to date that it increases the risk of prostate cancer. Some studies have found an increased incidence of cardiovascular events in men treated with testosterone, but others have not.

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