Study Finds No Convincing Evidence of Increased Cardiovascular Risk with Testosterone Therapy

A review of research conducted over the past 75 years finds no definitive answers about the link between testosterone supplements and cardiovascular health, but it does find far more evidence of benefit than harm.

The review, which appears in Mayo Clinic Proceedings, comes from a group of researchers who made news last year by criticizing the methodology of 2 studies that linked hormone replacement with cardiovascular disease.

Group members collected studies published between 1940 and mid-2014, evaluated the strength of the findings from each, and used all that data toassign level-of-evidence (LOE) ratings to various statements about testosterone’s effects on health.

“Only 4 articles were identified that suggested increased cardiovascular risks with testosterone prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events,” the authors wrote.

“In contrast, several dozen studies have reported a beneficial effect of normal testosterone levels on cardiovascular risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa).”

The authors merely list many of those studies in footnotes or in the various tables that accompany their paper, but they provide narrative summaries of more than a dozen of the largest works, particularly those that consider mortality risk.

A study that followed more than 1,000 veterans for an average of 40.5 months, for example, found that the mortality rate among testosterone users (10.3%) was half that of comparable non-users. (Even after researchers adjusted for potential confounders, the hazard ratiowas 0.61.)

A smaller but longer study that followed 581 diabetic men for an average of 5.8 years found much the same thing. The mortality rate for hypogonadal men was 8.4% among testosterone users and 19.2% among others.

Focusing specifically on cardiovascular mortality, a meta-analysis of more than 16,000 men found that low testosterone levels were associated with a 35% greater risk of fatal heart problems over an average follow-up of 9.7 years.

Such retrospective analyses can never provide the same degree of certainty as a large and lengthy randomized trial, but the review concludes that they provide IIa LOE that low levels of testosterone are associated with overall mortality and cardiovascular disease.

“That's not to say [supplementation is] perfectly safe,” said lead author Abraham Morgentaler, MD. “But we cannot find evidence, and the headlines that jumped out on recent retrospective studies appear to be too strong.”

Later sections of the review find evidence that justifies stronger conclusions in other areas.

There is, for example, top-tier evidence that boosting testosterone into normal ranges boosts muscle mass and muscle strength while reducing body fat and (in diabetics) HBA1C. It also found Ia LOE to support the claim that testosterone therapy increases exercise capacity in men with congestive heart failure.

The review authors, who called themselves “The Androgen Study Group” last year when they attacked the methodology of the studies that created the testosterone health scare, affirmed their earlier criticisms and added to them.

Of the JAMA study that used VA records, for example, they noted, “the actual rate of adverse events was only half as great in the T group as in the untreated group. The authors failed to acknowledge this fact and came to an opposite interpretation of the data based on complex statistics that included adjustment for more than 50 variables.”

They also said that when the article was being corrected — for the second time — the authors revealed they had made “a series of errors… Most astonishingly, the all-male study group was found to include nearly 10% women.”

All of the review authors disclosed ties to pharmaceutical companies.