Mendelian randomization investigation into testosterone's trade-offs between longevity and reproductive fitness

Background Antagonistic pleiotropy between fertility and survival suggests testosterone may promote fertility at the expense of survival. We investigated sex-specific effects of testosterone on fertility (offspring number) and lifespan (proxied by maternal and paternal attained age), with blood pressure as a control outcome, adjusted for confounders such as body mass index (BMI) using Mendelian randomization.Methods We identified independent (r2 < 0.001) genetic variants strongly (p < 5e-8) predicting testosterone in men (bioavailable) and women (total) from the largest genome-wide association studies (GWAS), and applied them to the largest available sex-specific GWAS summary statistics for maternal and paternal attained age, participant fertility, and blood pressure adjusted for sex-specific BMI.Results Testosterone in men (n = 184,205) was inversely associated with lifespan (−0.74 years per standard deviation increase, 95% confidence interval [CI] −1.32 to −0.16) and was positively associated with fertility (0.03 children, 95% CI: 0.01 to 0.05; n = 209,872) after BMI adjustment. Testosterone was not associated with lifespan or fertility in women. Testosterone was associated with the control outcome in men, i.e. higher diastolic blood pressure after BMI adjustment.Conclusions Our findings in men are consistent with antagonistic pleiotropy, i.e. higher testosterone was associated with greater fertility but shorter lifespan.