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A study of genetic variants that predict endogenous testosterone levels provided additional evidence that the hormone is linked with cardiovascular disease in men.

The mendelian randomization study, which included nearly 400,000 middle-age men and women, found that for each unit increase of endogenous testosterone predicted by variants of the JMJD1C gene, the risk of heart failure in men increased nearly eight-fold (OR 7.81, 95% CI 2.56-23.8, P<0.001), reported C. Mary Schooling, PhD, of the City University of New York, and colleagues.

The risk of thromboembolism in men doubled for each unit increase in testosterone (OR 20.9, 95% CI 1.27-3.46, P=0.004), but the risk for myocardial infarction was not significant (OR 1.17, 95% CI 0.78-1.75, P=0.44). In women, testosterone was not associated with significant risk for any cardiovascular outcome, Schooling's group wrote online in .

In an additional validation analysis that included more than 171,000 men and women, a unit increase of testosterone was nominally associated with risk for myocardial infarction (OR 1.37, 95% CI 1.03-1.82, P=0.03).

"Our study suggests that endogenous testosterone could have a role in thromboembolism, heart failure, and myocardial infarction in men. It might be worth considering whether existing treatments that modulate endogenous testosterone could be used for these conditions," the researchers wrote.

They noted that exploring a testosterone-cardiovascular disease link is important because sales of supplemental testosterone increased by 12-fold globally from 2000 to 2011, especially in North America. Prescriptions for testosterone-replacement therapy in the U.S. dropped by half from 2013 to 2016, "but remain well above the levels needed to treat pathological hypogonadism," Schooling's group said.

Previous observational studies have been difficult to interpret and are open to various types of confounding, and randomized, placebo-controlled trials have been limited in size and scope, the team noted, adding that mendelian randomization offers a unique way to address these limitations.

"Mendelian randomization is less susceptible to confounding than traditional observational studies because genetic variants are randomly allocated at conception," they explained. "Therefore, mendelian randomization is at the interface of experimental and observational studies, and can be used to obtain evidence in support of a potential causal effect or of potential targets of interventions."

Schooling's group performed three interrelated analyses. The first included 3,225 European men ages 50-75 from the REDUCE trial, and it identified genetic variants, including variants of JMJD1C, that could be used predict endogenous testosterone levels.

The second analysis included 392,038 white British men and women ages 40-69 from the a prospective cohort study with detailed genetic, physical, and health data. In this study, the researchers used logistic regression analysis, adjusted for age, sex, and other factors, and mendelian randomization analysis to explore links between the genetic variants identified in the first analysis and cardiovascular outcomes over the lifetimes of participants.

Finally, they conducted a validation analysis that included 171,875 patients, mostly European, from the CARDIoGRAMplusC4D 1000 study, a meta-analysis of 48 myocardial infarction studies.

An important limitation of the current study, Schooling and co-authors noted, was that it examined genetic variants, which are associated with small but lifelong changes in endogenous testosterone, and therefore the results might not be fully applicable to testosterone replacement therapy, which occurs at a specific time and increases testosterone by a relatively large amount.

However, previous studies have suggested several mechanisms by which testosterone could be linked with cardiovascular disease, Schooling and colleagues indicated, including the following:

• Raising estrogen in men, which is a known cause of thromboembolism

• Promoting platelet aggregation through thromboxane A2, which could underlie any effects on thromboembolism

• Inducing cardiac myocyte hypertrophy

• Raising endothelin levels, which can lead to ischemic heart disease

"From a clinical perspective, our study suggests that lifelong endogenous testosterone could have a role in thromboembolism, heart failure, and possibly myocardial infarction, particularly among men. These findings provide another strand of evidence consistent with the cardiovascular warnings about testosterone replacement therapy issued by regulators," the team wrote.

"Further evidence is needed to clarify whether our findings are relevant to the higher rates of these diseases in men than in women, or suggest that agents that lower testosterone would be protective. Additional research is also required comparing the effects of endogenous testosterone with those of exogenous testosterone," the researchers added.

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