AUTHOR=Ke Bin , Li Chunyu , Shang Huifang 

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=16

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2023.1153907

DOI=10.3389/fnmol.2023.1153907

ISSN=1662-5099

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>We conducted a bidirectional two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of major sex hormones including testosterone (<italic>N</italic> = 425,097), estradiol (<italic>N</italic> = 311,675) and progesterone (<italic>N</italic> = 2,619), together with epilepsy (<italic>N</italic> = 44,889). We further performed sex-stratified analysis, and verified the significant results using summary statistics from another study on estradiol in males (<italic>N</italic> = 206,927).</p></sec><sec><title>Results</title><p>Genetically determined higher estradiol was associated with a reduced risk of epilepsy (OR: 0.90, 95% CI: 0.83–0.98, <italic>P</italic> = 9.51E-03). In the sex-stratified analysis, the protective effect was detected in males (OR: 0.92, 95% CI: 0.88–0.97, <italic>P</italic> = 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, <italic>P</italic> = 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.</p></sec><sec><title>Conclusion</title><p>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.</p></sec>