Sex hormones and risk of epilepsy: A bidirectional Mendelian randomization study

Multiple evidence has suggested complex interaction between sex hormones and epilepsy. However, whether there exists a causal association and the effect direction remains controversial. Here we aimed to examine the causative role of hormones in the risk of epilepsy and vice versa. We conducted a bidirectional two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of major sex hormones including testosterone ( = 425,097), estradiol ( = 311,675) and progesterone ( = 2,619), together with epilepsy ( = 44,889). We further performed sex-stratified analysis, and verified the significant results using summary statistics from another study on estradiol in males ( = 206,927). Genetically determined higher estradiol was associated with a reduced risk of epilepsy (OR: 0.90, 95% CI: 0.83-0.98, = 9.51E-03). In the sex-stratified analysis, the protective effect was detected in males (OR: 0.92, 95% CI: 0.88-0.97, = 9.18E-04), but not in females. Such association was further verified in the replication stage (OR: 0.44, 95% CI: 0.23-0.87, = 0.017). In contrast, no association was identified between testosterone, progesterone and the risk of epilepsy. In the opposite direction, epilepsy was not causally associated with sex hormones. These results demonstrated higher estradiol could reduce the risk of epilepsy, especially in males. Future development of preventive or therapeutic interventions in clinical trials could attach importance to this.