Higher Risk of Cardiovascular Events with Testosterone Injection

Just a few weeks after the publication of a research review that declared testosterone injections safer than testosterone gels, JAMA Internal Medicine has published a large analysis that reaches the opposite conclusion.

Researchers used records from Medicare, commercial insurers in the U.S. and general practitioners in the United Kingdom to identify 544,115 men who began testosterone replacement therapy at some point between 2000 and 2012. Of those men, 37.4% received treatment via injection, while 6.9% used patches and 55.8% used gels.

Men who began their treatment with injections faced higher risks of cardiovascular events such as myocardial infarction, unstable angina, and stroke (hazard ratio [HR], 1.26; 95% confidence interval [CI] 1.18-1.35) compared with men who used gels.

Multivariable analysis also found them to be at greater risk for hospitalization (HR, 1.16; 95% CI, 1.13-1.19), and death (HR, 1.34; 95% CI, 1.15-1.56) but not venous thromboembolism (VTE) (HR, 0.92; 95% CI, 0.76-1.11).

Compared with gels, patches were not associated with a higher risk of cardiovascular events (HR, 1.10; 95% CI 0.94-1.29), hospitalization (HR, 1.04; 95% CI, 1.00-1.08), death (HR, 1.02; 95% CI, 0.77-1.33), or VTE (HR, 1.08; 95% CI, 0.79-1.47).

The study authors noted that their analysis provided no information about whether testosterone therapy, as a whole, has any effect on patient health, either positive or negative, for there was no comparison between men who used testosterone and men who did not.

They also warned of a number of potential limitations in the study beyond its retrospective nature, most notably their inability to distinguish between patients who met all criteria for the use of testosterone replacement and those who did not.

Still, they wrote, the size of the finding suggests a real effect, perhaps created by the large spike in testosterone that comes with each injection but not from the daily application of small amounts of testosterone gel.

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An accompanying editorial in JAMA Internal Medicine argues that the results of the study support Endocrine Society guidelines that recommend therapy as a treatment for genuine hypogonadism rather than for every man with symptoms of hypogonadism or testosterone levels that fall below an arbitrary cutoff.

“Careful evaluation of each patient for a cause that might be reversible is needed, as well as treatment with physiologic testosterone replacement strategies with close monitoring and follow-up to evaluate risk and benefit,” wrote Margaret E. Wierman, MD, from the Veterans Affairs Medical Center in Denver.

The results of the new study contradicted those from a research review and meta analysis that recently appeared in the American Journal of Physiology—Endocrinology and Metabolism.

The authors of that paper, who found very strong evidence that injections of testosterone provided significantly greater benefits than transdermal applications, also found what they believed to be significant evidence that injections were safer than gels.

The authors of that paper had conducted a meta-analysis of 35 different randomized controlled trials that had linked testosterone replacement and cardiovascular health.

That last analysis found that oral testosterone significantly increases the risk of adverse events (relative risk [RR], 2.20; p = 0.015), while transdermal therapy produces a non-significant directional trend toward cardiovascular risk (RR = 1.27) and injection produces a non-significant directional trend toward protection (RR = 0.66).

“A possible explanation for the latter phenomenon is that transdermal testosterone causes greater elevation of serum dihydrotestosterone, due to significant expression of 5α-reductase in skin, but not in muscle,” they wrote.