Endogenous Testosterone, Testosterone Treatment, and Cardiovascular Health Outcomes in Men

Whether lower testosterone concentrations in aging men predispose to poorer health, particularly cardiovascular disease (CVD), remains controversial. This narrative review summarizes the relationships between testosterone and cardiovascular health outcomes, based on observational and interventional studies. Cross-sectional analyses show that lower endogenous testosterone concentrations are found in men with preexisting CVD, but larger influences are age > 70 years, higher body mass index, and medical comorbidities such as diabetes or cancer. In the United Kingdom Biobank, the largest prospective cohort study to date, lower endogenous testosterone concentrations were associated with higher risk of all-cause mortality, but not incident cardiovascular events or CVD deaths. In an individual participant data meta-analysis of prospective cohort studies with testosterone measured using mass spectrometry, there were nonlinear associations of baseline testosterone concentrations with higher all-cause and cardiovascular mortality, with these risks increasing below thresholds of testosterone < 7.4 nmol/L (213 ng/dL) and < 5.3 nmol/L (153 ng/dL), respectively. In the randomized, placebo-controlled T4DM trial involving men with dysglycemia, testosterone treatment on a background of lifestyle intervention reduced risk of type 2 diabetes mellitus after 2 years. The TRAVERSE cardiovascular safety trial, conducted in men with CVD or multiple risk factors, found no increased risk of major adverse cardiovascular events in men randomized to testosterone treatment vs placebo, with average follow-up of 3 years. Based on epidemiological studies, and the results of T4DM and TRAVERSE, additional studies are needed to confirm long-term cardiovascular safety, and explore possible cardiovascular benefits related to changes in body composition and cardiometabolic risk.