Is there evidence for side effects of testosterone supplementation in men with low or low-normal testosterone levels?
Common adverse events reported with testosterone supplementation include acne, oily skin, and breast tenderness. Small decreases in high-density lipoprotein cholesterol (HDL-C) may also occur with testosterone therapy. A rise in hematocrit and frank erythrocytosis are dose-related, more common in older than younger men and are exacerbated in the setting of sleep apnea. Worsening of benign prostatic hyperplasia is also relatively common. There is a consistent lack of evidence of increased prostate cancer risk in studies of men on testosterone therapy, but there is evidence that testosterone administration is associated with an increased risk of detecting subclinical prostate cancer in older men; this is likely a result of increased surveillance and testosterone-induced increases in PSA levels that may lead to an increased likelihood of a prostate biopsy.
Although observational studies have consistently reported an association between low testosterone and increased cardiovascular risk and mortality, recent studies have suggested possible cardiovascular harm in older men receiving testosterone therapy. This has led to cautions against testosterone use in older men. In 2010, researchers from the Testosterone in Older Men with Mobility Limitations (TOM) trial published data on adverse events associated with testosterone administration, which led to early termination of the study. The original purpose of the study was to determine the effects of testosterone administration on lower extremity strength and physical function in older men with significant mobility limitations and low serum levels of either total or free testosterone. The participants were men aged ≥ 65 years with limitations in mobility and a high prevalence of chronic disease (e.g., diabetes, hypertension, obesity). During the 6-month intervention, men who were randomized to testosterone gel therapy with a goal of attaining a serum total testosterone level > 500 ng/dL unexpectedly had a higher prevalence of cardiovascular, respiratory, and dermatologic adverse events, even after adjustment for baseline risk factors. The increased frequency of cardiovascular events led to trial termination. However, this has not been confirmed in other studies or in meta-analyses of testosterone intervention trials. Furthermore, a recently completed study demonstrated a reduction in cardiovascular adverse events in a testosterone-supplemented group versus a placebo-supplemented group of generally healthy older men with low-normal serum total testosterone levels at baseline. Taken together, there have been no large, long-term, randomized, placebo-controlled trials of testosterone therapy evaluating cardiovascular outcomes to provide any definitive conclusions about cardiovascular risk with testosterone.