Men with low testosterone whose levels normalize with testosterone replacement therapy (TRT) may enjoy lower risks of heart attack, stroke, and early death, a new study suggests.

The research provides valuable information amid recent studies that found increased cardiovascular risks for particular TRT users. Following the concerning findings, the FDA issued a safety alert.

For the study, investigators led by Rajat Barua, MD, from the VA Medical Center in Kansas City, Mo., examined the medical records of 83,010 male veterans with low total testosterone levels confirmed by repeat testing. They defined low testosterone as the lower limit of normal reported on laboratory tests to avoid an arbitrary cutoff and to reduce disparities in ranges used by various reporting units. Importantly, the men had no history of myocardial infarction or ischemic stroke.

The researchers categorized the men into 3 groups according to whether they received a TRT prescription (injection, gel, or patch). Group 1 received TRT and subsequently saw normalization of their testosterone levels (confirmed by repeat testing). Group 2 took TRT but experienced no such normalization. And group 3 did not receive TRT. The investigators used propensity score matching to account for covariates, such as age, body mass index, diabetes, hypertension, coronary artery disease, and use of aspirin or statins.

Men who took TRT and also saw their levels normalize (group 1) had lower risks of all-cause mortality (56%), myocardial infarction (24%), and ischemic stroke (36%) compared with men who did not take TRT (group 3) after an average 6.2 years of follow up, the investigators reported in the European Heart Journal.

Similarly, men with normalized testosterone levels (group 1) fared better than those who took TRT but failed to see normalization of testosterone (group 2). They had lower risks of early death, myocardial infarction, and ischemic stroke by 57%, 18%, and 30%, respectively. The researchers observed no difference in heart attack or stroke risk between groups 2 and 3, neither of which achieved testosterone normalization.

“It is the first study to demonstrate that significant benefit is observed only if the dose is adequate to normalize the [total testosterone] levels,” the investigators stated. “Patients who failed to achieve the therapeutic range after TRT did not see a reduction in [myocardial infarction] or stroke and had significantly less benefit on mortality.” In this study, normalization of testosterone was used as a marker of adequate therapy using TRT.

The mechanisms underlying these effects “remain speculative,” the investigators noted. Normalized testosterone levels may have beneficial effects on adipose tissue, insulin sensitivity, and lipid profiles or exert anti-inflammatory and anticoagulant effects. Conversely, adverse mechanisms that increase cardiovascular risks—such as sodium retention, congestive heart failure, increased platelet aggregation, or changes in high density lipoprotein—may account for the observed effects.

The investigators noted that off-label use of TRT remains a concern. They urge randomized controlled trials with long-term follow-up to obtain definitive conclusions. In the meantime, they point to a need for guidelines on TRT use and active surveillance of patients.

1. Sharma, R; Oni, OA; Gupta, K; et al. European Heart Journal; doi: 10.1093/eurheartj/ehv346.

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