Testosterone therapy was associated with adverse cardiovascular (CV) outcomes in a large observational study. The findings raise questions about the potential safety of testosterone use in men, wrote Rebecca Vigen MD, and her colleagues in the Journal of the American Medical Association (2013;310:1829-1836).

Dr. Vigen’s group assessed the association between testosterone therapy and all-cause mortality, myocardial infarction (MI), or stroke among male veterans and determined the effect of underlying coronary artery disease (CAD) on the relationship. The researchers conducted a retrospective national cohort study of men with low testosterone levels (less than 300 ng/dL) who had undergone coronary angiography in the Veterans Affairs health system from 2005 to 2011. Average follow-up was approximately 840 days (27.5 months).

Of the 8,709 study subjects with low testosterone, 1,223 (14%) started testosterone therapy after a median of 531 days following coronary angiography. Those patients tended to be younger (mean age 61 years) than the testosterone non-users (mean age 64 years) and tended to have lower rates of congestive heart failure, renal failure, and other comorbidities.

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Approximately one of every five men not taking testosterone died and/or had a heart attack or a stroke, compared with approximately one out of four testosterone users. Testosterone therapy was associated with a 29% greater risk of these events.

The absolute rate of events among the no-testosterone group versus the testosterone group was 10.1% versus 11.3% at one year post-angiography, 15.4% versus 18.5% at two years, and 19.9% versus 25.7% at three years, for an absolute risk difference of 5.8% at three years after angiography. Even after adjustments for the presence of CAD and other factors, testosterone therapy was associated with adverse outcomes—an effect that was consistent among men with and without CAD.

The investigators noted some potential mechanisms through which testosterone therapy may increase CV risk. For example, other research has indicated that intramuscular testosterone can increase platelet aggregation, and that the testosterone metabolite dihydrotestosterone can promote atherosclerosis.

Having pointed out potential limitations of their study, the investigators emphasized the need for more research, including randomized controlled trials, to properly characterize the risks of testosterone therapy in men with comorbidities.