Neurosteroid regulation of GABAA receptors: A role in catamenial epilepsy

Abstract The female reproductive hormones progesterone and estrogen regulate network excitability. Fluctuations in the circulating levels of these hormones during the menstrual cycle cause frequent seizures during certain phases of the cycle in women with epilepsy. This seizure exacerbation, called catamenial epilepsy, is a dominant form of drug-refractory epilepsy in women of reproductive age. Progesterone, through its neurosteroid derivative allopregnanolone, increases γ-aminobutyric acid type-A receptor (GABAR)-mediated inhibition in the brain and keeps seizures under control. Catamenial seizures are believed to be a neurosteroid withdrawal symptom, and it was hypothesized that exogenous administration of progesterone to maintain its levels high during luteal phase will treat catamenial seizures. However, in a multicenter, double-blind, phase III clinical trial, progesterone treatment did not suppress catamenial seizures. The expression of GABARs with reduced neurosteroid sensitivity in epileptic animals may explain the failure of the progesterone clinical trial. The expression of neurosteroid-sensitive δ subunit-containing GABARs is reduced, and the expression of α4γ2 subunit-containing GABARs is upregulated, which alters the inhibition of dentate granule cells in epilepsy. These changes reduce the endogenous neurosteroid control of seizures and contribute to catamenial seizures.