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A new genetic study led by Distinguished Professor Mary Schooling lends fresh evidence to an evolutionary idea known as antagonistic pleiotropy; the notion that a trait can boost reproductive success while quietly shortening lifespan. Using Mendelian randomization, the researchers found that higher testosterone in men is linked to greater fertility but a shorter life, a trade-off that was not seen in women.
Testosterone supplementation is widely prescribed in men, often on the basis of observational studies tying low testosterone to chronic conditions such as kidney disease. Yet robust evidence from randomized trials remains limited, and the U.S. Food and Drug Administration recently warned that testosterone supplements may raise blood pressure. That safety signal raised a deeper, evolutionary question: could testosterone, as a driver of male fertility and virility, be enhancing reproduction at the cost of survival?
Drawing on large genome-wide association studies from the UK Biobank, Dr. Schooling and Dr Zhu Liduzi Jiesisibieke of the University of Hong Kong used identified genetic variants that predict testosterone, i.e., bioavailable testosterone in men (184,205 participants) and total testosterone in women (199,569 participants). They then tested how genetically predicted testosterone related to three outcomes: fertility (number of offspring), lifespan (proxied by maternal and paternal attained age), and blood pressure (included as a control outcome). Body mass index (BMI) was treated as a potential confounder and adjusted for using multivariable analysis.
After adjusting for BMI, each standard-deviation increase in genetically predicted bioavailable testosterone was associated with about 0.74 fewer years of life in men (95% confidence interval (CI): −1.32 to −0.16), with no equivalent effect in women. The same higher-testosterone profile was linked to a small increase in the number of children fathered (0.03 additional children, 95% CI: 0.01 to 0.05) again, only in men. Testosterone was tied to elevated diastolic blood pressure in men after BMI adjustment, a result the authors say establishes a plausible mechanistic pathway from the hormone to cardiovascular risk and, ultimately, to shorter lifespan.
The authors suggest the cardiovascular toll of testosterone, particularly its effect on diastolic blood pressure possibly via peripheral vascular resistance, may help explain why men, on average, live shorter lives than women.
“Given current interest in offering testosterone screening and replacement to U.S. military personnel, our findings, consistent with established biological thinking, suggest caution,” says Dr. Schooling.
