Men with genetic predisposition to high endogenous testosterone levels might be at greater risk for thromboembolism and heart failure, according to study results published in the BMJ.

It is difficult to interpret the results of previous observational studies exploring endogenous testosterone levels and cardiovascular outcomes because they are subject to various confounders. In addition, there are few randomized controlled trials. Therefore, the current study sought to assess the effect of endogenous testosterone on thromboembolism, heart failure, and myocardial infarction (MI) in participants from the UK Biobank.

The study cohort included British and European descent participants, age 50 to 75 years. Using mendelian randomization, the researchers analyzed genetic variants that predict endogenous testosterone levels and the association with thromboembolism, heart failure, and MI.

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Of 392,038 UK Biobank participants (mean age, 56.9 years; 179,929 men), 13,691 had thromboembolism, 1688 had heart failure, and 12,882 had MI.

The results indicated that serum testosterone level, as predicted by 9 genetic variants from the JMJD1C gene region in men, was associated with a 2-fold increased risk for thromboembolism (odds ratio [OR], 2.09; 95% CI, 1.27-3.46) and more than 7-fold increased risk for heart failure (OR, 7.81; 95% CI, 2.56-23.81) for each unit increase in testosterone. Serum testosterone level was not associated with an increased risk for MI, and testosterone was not associated with these outcomes in women.

Although this analysis of UK Biobank participants found no significant association with risk for MI, a validation analysis with >170,000 men and women from the CARDIoGRAMplusC4D 1000 study found that a unit increase of genetically predicted testosterone was nominally associated with a 37% percent greater risk for MI (OR 1.37; 95% CI, 1.03-1.82).

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Testosterone predicted by 21 genetic variants from the SHBG gene region was not associated with the risk for thromboembolism, heart failure, or MI.

The study had several limitations, including a possible bias secondary to recruitment of generally healthier participants from the UK Biobank, with a relatively low number of patients with heart failure. Furthermore, although endogenous testosterone decreases with poor health, no adjustment for health status was done.

“Our study suggests that endogenous testosterone could have a role in thromboembolism, heart failure, and myocardial infarction in men,” concluded the researchers, adding that “[i]t might be worth considering whether existing treatments that modulate endogenous testosterone could be used for these conditions.”

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Luo S, Au Yeung SL, Zhao JV, Burgess S, Schooling CM. Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank. BMJ. 2019;364:I476.