Mendelian randomization studies of testosterone exposure: A systematic review.

[BACKGROUND] Testosterone impacts reproductive health, cardiovascular function, and metabolism. Considering the use of testosterone therapy and anabolic steroid misuse, understanding its health effects is important. While randomized clinical trials provide short-term insights, and observational studies struggle with confounding factors, Mendelian randomization offers an alternative by using genetic variations to explore causal relationships.

[METHOD] A systematic search was performed using MEDLINE to identify studies published from inception to October 2024. We included studies that conducted a Mendelian randomization analysis to evaluate associations between testosterone exposure and any health outcomes in males.

[RESULTS] Twenty-nine Mendelian randomization studies were included, examining a broad spectrum of health outcomes linked to testosterone exposure. Cardiovascular and metabolic health, alongside prostate cancer risk, were the most frequently studied areas. Most studies indicated that higher testosterone levels were associated with adverse cardiovascular outcomes, such as increased risks of thromboembolism, ischemic heart disease, and heart failure. Elevated levels of genetically predicted free testosterone consistently showed a correlation with increased prostate cancer risk. The relationship between testosterone and type 2 diabetes remained inconclusive. Neuropsychiatric and musculoskeletal outcomes received less attention, while dermatological, infectious, and respiratory health were minimally explored.

[CONCLUSION] This review provides information about the causal relationships between testosterone exposure and health outcomes, contributing to the ongoing discourse on testosterone-related health risks and benefits. The included studies exhibit great heterogeneity.