By Steven E. Nissen, MD

If you turn on your television set or read the popular press, you can't miss clever and seductive advertisements directed at middle-aged and older men. If you don't have the energy or sexual performance of your youth, you may have "low T," a medical condition with a simple and effective treatment: testosterone replacement therapy (TRT). Low T treatment centers are appearing around the country that promise men a nearly magical cure for their lost youth—a safe and effective treatment with few, if any, adverse effects. These advertisements and treatment centers take advantage of the natural desire (and vanity) of aging men who want to feel stronger and regain the "performance" they enjoyed when they were young. As a consequence of these marketing efforts, in recent years, a variety of testosterone products have enjoyed an astonishing increase in sales and profitability for drug makers.

To physicians with a sense of history, the rush toward hormone replacement therapy (HRT) for men, in the immortal words of Yogi Berra, seems like "déjà vu all over again." Two decades ago, women were routinely treated with estrogen-containing therapies to maintain a youthful appearance and ostensibly ward off diseases of aging, including cardiovascular disease. When the late Director of the NIH, Bernadine Healy, proposed conducting a randomized controlled trial of HRT, most members of the medical community were supremely confident about the benefits of hormone treatment for women.

Indeed, some physicians opined that a placebo-controlled trial would be unethical because it would deny 50% of the participants the cardiovascular benefits of HRT. Fortunately, Dr. Healy prevailed and pursued the Women's Health Initiative, which eventually demonstrated cardiovascular harm, rather than benefit, for HRT.

The lessons learned about HRT in women should serve as a warning to the medical community about the potential risks of testosterone replacement therapy in men. In recent months, these concerns have transitioned from theoretical to tangible. Two important observational studies provide considerable evidence that TRT may represent a serious cardiovascular risk to men's health. In November 2013, a study performed in the Veteran's Affairs system reported on outcomes for 8,709 men with testosterone levels less than 300 ng/dL who underwent coronary angiography.¹ The risk of death, myocardial infarction (MI), or stroke was higher in men treated with testosterone compared with men who were not treated: 25.7% vs. 19.9% (hazard ratio = 1.29; 95% CI 1.04–1.58).

In January 2014, an unrelated cohort study examined outcomes in 55,593 men in a health care database after an initial prescription for TRT.² This study compared the incidence of MI in the 90 days following an initial prescription with the rate in the 1 year prior to the prescription. This analysis showed a relative risk of 1.36 (95% CI 1.03–1.81) following initiation of TRT compared with the period prior to treatment. This study also examined the risk of MI in a cohort of 167,279 men prescribed phosphodiesterase type 5 (PDE5) inhibitors and compared pre- and post treatment risk for MI to pre- and post-treatment risk for TRT initiation. In men >65 years, the risk ratio was 2.19 (95% CI 1.27–3.77) for TRT, but not significantly increased for PDE5 treatment (risk ratio = 1.15; 95% CI 0.83–1.59).

It should be noted that neither of these observational studies represents definitive evidence of harm, but they must not be ignored. Indeed, there is solid biological plausibility for the hypothesis that TRT might increase adverse cardiovascular outcomes. Testosterone administration has extraordinarily widespread biological effects, including a reduction in levels of high-density lipoprotein cholesterol.³ TRT increases hemoglobin and hematocrit and regulates expression of platelet thromboxane A2 receptors, which may contribute to thrombogenicity. Use of anabolic steroids to enhance performance by young athletes has been associated with MI and stroke.

In the wake of the recent publications, the US Food and Drug Administration (FDA) announced in January 2014 that the Agency is investigating the risk of stroke, MI, and death in men taking testosterone products. Unfortunately, once again on a drug safety issue, the FDA is too late and too slow to recognize an important public health concern. The FDA unwisely approved TRT products based upon short-term data showing that the products raise testosterone levels, but without requiring evidence of cardiovascular safety. History has repeatedly shown that approving products based upon "surrogate endpoints" (biochemical effects) is risky and may lead to unintended consequences.

Given these concerns about the safety of TRT, what is the best course of action for the cardiovascular community? In my opinion, we should counsel our patients that TRT is not a panacea and warn that the cardiovascular effects are uncertain and potentially catastrophic. We should insist that the FDA require marketers of testosterone products to conduct proper randomized controlled trials to determine the long-term effects of these drugs on cardiovascular outcomes. Anything less exposes American men to a gigantic uncontrolled experiment that may ultimately result in serious damage to public health.

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References

1. Vigen R, O'Donnell CI, Barón AE, et al. JAMA. 2013;310(17):1829-36.
2. Finkle WD, Greenland S, Ridgeway GK, et al. PLoS One. 2014;9(1):e85805.
3. Ruige JB, Ouwens DM, Kaufman JM. J Clin Endocrinol Metab. 2013;98(11):4300-10.

Steven E. Nissen, MD, is Chair of the Department of Cardiovascular Medicine at the Cleveland Clinic and co-author of Heart411: The Only Guide to Heart Health You'll Ever Need.

Keywords: Athletes, Myocardial Infarction, Public Health, Veterans, United States Food and Drug Administration, Cardiovascular Diseases, Women's Health, Risk Factors, Marketing, Hormone Replacement Therapy, Testosterone, CardioSource WorldNews, ACC Publications

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