Gonadal, adrenal, and neuroactive steroids' role in ictal activity

Abstract

Of the many people that have epilepsy, only about 70% achieve seizure control with traditional pharmacotherapies. Steroids have long been known to influence ictal activity and may have a therapeutic role. This review summarizes recent investigations that have enhanced knowledge of the effects and mechanisms of gonadal, adrenal, and neuroactive steroids on seizure processes. Progesterone, which varies across reproductive cycles, pregnancy, and as a function of aging, has been shown to have anti-seizure effects among women with epilepsy and in animal models of epilepsy. Further, data suggest that progesterone's anti-seizure effects may involve its metabolism to the neuroactive steroid, 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP), and its subsequent actions at GABA(A) receptors. Androgens also have anti-seizure effects. Androgens' anti-seizure effects may be mediated, in part, through actions of the testosterone metabolite, and neuroactive steroid, 5 alpha-androstane-3 alpha,17 alpha-diol (3 alpha-diol) at GABA(A) receptors. Stress can alter seizure susceptibility, suggesting a role of adrenal steroids on seizure processes. In animal models of epilepsy, acute or chronic stress can increase ictal activity. Notably, stress and seizures can alter levels of gonadal, adrenal, and neuroactive steroids, which may then influence subsequent seizure activity. Thus, this review summarizes recent progress in the role of gonadal, adrenal, and/or neuroactive steroids in seizure processes which suggest that greater understanding of these steroids' effects and mechanisms may ultimately lead to improved seizure control for people with epilepsy.