No Evidence of Testosterone Harm

A group of researchers who have long been defending the benefits of testosterone has published a large-scale review showing there’s no evidence that testosterone therapy increases cardiovascular risk.

“That’s not to say it’s perfectly safe,” lead author Abraham Morgentaler, MD, of Harvard, said in a statement. “But we cannot find evidence, and the headlines that jumped out on recent retrospective studies appear to be too strong.”

Only four studies have suggested increased cardiovascular risk with testosterone, and Morgentaler said these studies were low-quality, with “serious methodological limitations.”

That includes the two studies — one by Vigen et al., the other by Finkle et al. — that sparked an FDA investigation into testosterone-heart risks last year.

On the other hand, Morgentaler said, “several dozen” studies have found a beneficial effect of normal testosterone levels on cardiovascular risk and death, and that low testosterone levels are tied to worse mortality and complications such as atherosclerosis and heart disease.

Morgentaler told MedPage Today that the report, published online in Mayo Clinic Proceedings, is an expanded version of findings submitted to the FDA ahead of a September meeting evaluating the cardiovascular risks of testosterone therapy.

The Vigen and Finkle studies, along with stories and editorials published in the New York Times, had sparked concern among patients that their testosterone therapy could be harming their hearts, Morgentaler and colleagues wrote, prompting many to discontinue their treatment, and some physicians to stop prescribing it.

Last September, the FDA advisory committee called for a tightening of the drug’s label indications and renewed efforts to curb off-label use. It also recommended that testosterone companies conduct a clinical trial of cardiovascular risk.

To assess the full literature on testosterone therapy, Morgentaler and colleagues searched the archives from 1940 to 2014.

Overall, they found “no large, long-term, placebo-controlled, randomized clinical trials in the field of therapy to provide definitive conclusions about cardiovascular risk.”

They noted, however, that the balance of the evidence shows that testosterone therapy works and is safe.

Low testosterone levels have been strongly associated with increased mortality, as well as with atherosclerosis and coronary artery disease, the researchers said.

The evidence also shows that replacing testosterone in deficient patients is associated with increases in lean mass, reduced fat mass, improved insulin sensitivity, diminished carotid intima-media thickness, and reduced risk of mortality, they wrote.

“We are unaware of any compelling evidence that T therapy is associated with increased CV risk,” they wrote.

Karl Nadolsky, DO, an endocrinology fellow at Walter Reed Medical Center, noted that it “may be worth noting the differences in patient characteristics” when it comes to treating with testosterone.

“Maybe we should exercise much more caution when treating older males with chronic disease and heart disease who have had very low T for likely a long time,” Nadolsky told MedPage Today.

“We also need to focus on making the appropriate diagnosis and then treating the underlying cause when possible,” he added. “For many patients who have obesity, obstructive sleep apnea, or metabolic syndrome-related secondary hypogonadism, lifestyle measures and supportive treatment have evidence of benefit.”

When asked about subgroup analyses for cardiovascular risk with testosterone therapy among older patients and longer-term use, Morgentaler said he has “seen no data to support either.”