Effects and mechanisms of progestogens and androgens in ictal activity

Steroid hormones, such as progestogens and androgens, influence seizures. Progestogens and androgens exert organizational and/or activational effects that may mitigate vulnerability to, and/or expression of, some seizure disorders. Progestogens, such as progesterone (P(4)) and its 5alpha-reduced metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), which vary across the reproductive cycle and lifespan, may protect against seizures through actions at intracellular progestin receptors (PRs) and membrane receptors, such as gamma-aminobutyric acid (GABA)(A) receptors. Similarly, androgens, such as testosterone (T), which also vary across the reproductive cycle and the lifespan, can have antiseizure effects. Some of these effects of T may be due to aromatization to estrogen and/or 5alpha-reduction to dihydrotestosterone (DHT), and its subsequent conversion through 3alpha-hydroxysteroid dehydrogenase to 5alpha-androstane-3alpha,17alpha-diol (3alpha-diol). Sensitivity to steroids in some individuals may be mitigated by differences in stress, developmental phase, reproductive status, endocrine status, and treatments, such as antiepileptic drugs (AEDs), which alter levels of these ligands and/or function of their target sites. The evidence implicating sex steroids in differences associated with hormonal, reproductive, developmental, stress, seizure type, and/or therapeutics are discussed.