{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T07:49:03Z","timestamp":1778831343661,"version":"3.51.4"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats: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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a bidirectional two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of major sex hormones including testosterone (<jats:italic>N<\/jats:italic> = 425,097), estradiol (<jats:italic>N<\/jats:italic> = 311,675) and progesterone (<jats:italic>N<\/jats:italic> = 2,619), together with epilepsy (<jats:italic>N<\/jats:italic> = 44,889). We further performed sex-stratified analysis, and verified the significant results using summary statistics from another study on estradiol in males (<jats:italic>N<\/jats:italic> = 206,927).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Genetically determined higher estradiol was associated with a reduced risk of epilepsy (OR: 0.90, 95% CI: 0.83\u20130.98, <jats:italic>P<\/jats:italic> = 9.51E-03). In the sex-stratified analysis, the protective effect was detected in males (OR: 0.92, 95% CI: 0.88\u20130.97, <jats:italic>P<\/jats:italic> = 9.18E-04), but not in females. Such association was further verified in the replication stage (OR: 0.44, 95% CI: 0.23\u20130.87, <jats:italic>P<\/jats: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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats: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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnmol.2023.1153907","type":"journal-article","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T05:39:50Z","timestamp":1681191590000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Sex hormones and risk of epilepsy: A bidirectional Mendelian randomization study"],"prefix":"10.3389","volume":"16","author":[{"given":"Bin","family":"Ke","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huifang","family":"Shang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yfrne.2019.100787","article-title":"Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. 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