Genetically determined sex hormones and functional outcome after ischemic stroke: A Mendelian randomization study

Abstract

Abstract Background and purpose Sex hormones may affect functional outcome after ischemic stroke (IS). However, the effects reported in previous studies were inconsistent, and randomized data were absent. We performed a two-sample Mendelian randomization analysis to explore the causal effects of genetically determined sex hormones on the 3-month functional outcome after IS. Methods Using genome-wide association studies, we obtained sex-specific genetic instruments for evaluating serum estradiol and bioavailable testosterone levels. The sex-specific functional outcome after IS were estimated via inverse-variance weighted Mendelian randomization analysis. Mendelian randomization-Egger regression, weighted median leave-one-SNP-out analysis, Mendelian randomization-Pleiotropy Residual Sum, and Outlier methods were used for sensitivity analyses. To validate our primary results, we also performed independent repeated and bidirectional Mendelian randomization analyses. Results Genetic predisposition to high levels of bioavailable testosterone was associated with excellent functional outcome in males (OR = 0.41, 95% CI: 0.21–0.79, P = 0.008), but worse outcome in females (OR = 2.49, 95% CI: 1.24–4.99, P = 0.009). Females with genetically predicted higher estradiol levels tend to have excellent and favorable functional outcome (excellent functional outcome, OR = 0.53; 95% CI: 0.41–0.85, P = 0.005); (favorable functional outcome, OR = 0.69; 95% CI: 0.48–0.98, P = 0.036). There was limited evidence that genetically predicted estradiol levels affect functional outcome in men (P > 0.05). Conclusions Our findings suggested that bioavailable testosterone and estradiol were promising neuroprotectants that could respectively improve the functional outcome of IS in males and females.