Effect of Contraceptive Estradiol on Hippocampus Kindling Seizure Activity

Abstract

Contraceptive management is critical in women with epilepsy because of the potential for maternal and fetal risks if unexpected pregnancy develops while on AED treatment. Although oral contraceptives (OCs) are widely used by many women with epilepsy, there has been little investigation into how interactions among circulating hormones and antiepileptic drugs (AEDs) impact both epileptic seizures and contraception. Ethinyl estradiol (EE) is the primary component of combined OC pills which are used by several million women worldwide. The present study was undertaken to investigate the potential adverse effect of EE on epileptogenesis and seizure activity using the hippocampus kindling model in female mice. Animals were stimulated daily without or with EE, given daily for 14 days, at 125% afterdischarge (AD) threshold until a fully-kindled state where stage 5 seizures could be elicited consistently. EE impacted the development of kindling by acceleration of rate of epileptogenesis. Fully-kindled mice were treated with various doses of EE and seizure susceptibility was assessed by seizure stage, seizure severity, AD duration, and AD threshold. In acute studies, the AD current threshold was dose-dependently reduced by EE treatment. The highest dose tested caused a ~50% decrease in AD threshold and increased the incidence and severity of seizures in kindled mice. In chronic studies, EE treatment caused greater susceptibility to kindling seizures. These results provide strong evidence that EE exacerbates seizures, lowers seizure threshold, and promotes epileptogenic responses, which are consistent with its proconvulsant effects. Such excitatory effects may underlie an increase in seizure risk in women with epilepsy using oral contraceptives.