Testosterone replacement therapy and the risk of stroke in men: A systematic review

In recent years, questions have been raised regarding the cardiovascular safety of testosterone replacement therapy (TRT). The objective of this study was to systematically review the available evidence on TRT safety in men, specifically with respect to the risk of stroke. We identified publications from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to May 2017. Articles eligible for review included observational studies evaluating TRT and the risk of stroke among men aged 18 or older. Randomized controlled trials (RCTs) comparing testosterone to placebo in men were also eligible, provided stroke was identified as an adverse event. Among seven cohort studies of hypogonadal men, one study reported that TRT was associated with a significant decrease in the risk of ischemic stroke (hazard ratio (HR) 0.64; 95% confidence interval (CI) 0.52-0.80). Another reported a similar decrease in risk (HR 0.64; 95% CI 0.43-0.96) among treated men who achieved normalized levels of testosterone. Limitations in study design, including immortal time bias and residual confounding, may have influenced both of these results. The remaining observational studies did not report measures of association to estimate the independent risk of stroke associated with TRT. Among eight RCTs, a low frequency of stroke events (<5) was observed across both testosterone and control groups, thus precluding any definitive conclusions. Based on these findings, the association between TRT and the risk of stroke in men remains unclear, and further large and methodologically robust studies are needed to establish this relationship.