Female sex steroids and epilepsy: Part 1. A review of reciprocal changes in reproductive systems, cycles, and seizures

Abstract

Seizures, antiseizure medications, and the reproductive systems are reciprocally entwined. In Section 2 of this review, we outline how seizures may affect the hypothalamic–pituitary–gonadal axis, thereby altering sex steroids, and changes in sex steroids across the menstrual cycle and changes in pharmacokinetics during pregnancy may alter seizure susceptibility. The literature indicates that females with epilepsy experience increased rates of menstrual disturbances and reproductive endocrine disorders. The latter include polycystic ovary syndrome, especially for females on valproate. Studies of fertility have yielded mixed results. We aim to summarize and attempt to detangle the existing knowledge on these reciprocal interactions. The menstrual cycle causes changes in seizure intensity and frequency for many females. When this occurs perimenstrually, during ovulation, or in association with an inadequate luteal phase, it is termed catamenial epilepsy. There is a clear biophysiological rationale for how the key female reproductive neurosteroids interact with the brain to alter the seizure threshold, and Section 3 outlines this important relationship. Critically, what remains unknown is the specific pathophysiology of catamenial epilepsy that describes why not all females are affected. There is a need for mechanism‐focused investigations in humans to uncover the complexity of the relationship between reproductive hormones, menstrual cycles, and the brain.