Article Impact Level: HIGH Data Quality: STRONG Summary of The Journal of Clinical Endocrinology & Metabolism https://doi.org/10.1210/clinem/dgaf582 Dr. Emily J Morbey et al.
Points
- Researchers used Mendelian randomization to analyze genetic data from over one million individuals to determine if high circulating testosterone levels causally increase the risk of developing coronary artery disease in men.
- The study found that genetically higher testosterone is associated with a seventeen percent increase in heart disease risk which potentially raises a man’s lifetime risk from seven to eight percent.
- This increased cardiovascular risk is partially explained by the discovery that higher testosterone levels lead to elevated blood pressure which can eventually result in serious events like heart attacks or failure.
- The findings suggest that previous observational studies linking low testosterone to heart disease were likely confounded by metabolic conditions such as obesity and diabetes that independently lower hormone levels in patients.
- While testosterone replacement remains a vital treatment for hypogonadism these results highlight the need for clearer clinical warnings regarding the cardiovascular safety of supplements used for anti-aging or physical performance.
Summary
This study utilized Mendelian randomization to evaluate the causal relationship between higher circulating testosterone and coronary artery disease (CAD) risk in men. To address inconsistencies between observational studies and randomized controlled trials, researchers analyzed genetic data from 425,097 UK Biobank participants and summary statistics from 1,165,690 individuals in the CARDIoGRAMplusC4D consortium. The approach sought to isolate the physiological effects of testosterone from common confounding factors, such as obesity and diabetes, which are typically associated with both low hormone levels and elevated cardiovascular risk.
The analysis revealed that genetically higher testosterone levels are linked to a 17% increase in the risk of CAD among men. While the baseline lifetime risk for coronary artery disease in the general population is approximately 7.3%, the study suggests that exogenous testosterone supplementation could increase this risk to 8.5%. This elevated risk profile is attributed, in part, to testosterone’s hypertensive effect, as higher circulating levels were positively correlated with increased blood pressure. Notably, no significant causal association between testosterone and CAD risk was identified in the female cohort.
These findings suggest that the apparent protective effect of testosterone observed in previous studies may be secondary to metabolic health confounders. While testosterone replacement remains an indicated treatment for medically diagnosed hypogonadism, the study cautions against widespread use for performance enhancement or anti-aging in eugonadal men. Given these results, the authors advocate for more robust clinical warnings regarding the cardiovascular safety of testosterone supplementation, aligning with existing FDA guidance to mitigate the risk of myocardial infarction and heart failure.
Link to the article: https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgaf582/8300597?login=false
References
Morbey, E. J., Day, F. R., Butterworth, A. S., Wareham, N. J., Perry, J. R. B., & Ong, K. K. (2025). Higher circulating testosterone linked to higher cad risk in men: Mendelian randomization and survival analyses. The Journal of Clinical Endocrinology & Metabolism, dgaf582. https://doi.org/10.1210/clinem/dgaf582
