Seizure facilitating activity of the oral contraceptive ethinyl estradiol

Abstract

Contraceptive management is critical in women with epilepsy. Although oral contraceptives (OCs) are widely used by many women with epilepsy, little is known about their impact on epileptic seizures and epileptogenesis. Ethinyl estradiol (EE) is the primary component of OC pills. In this study, we investigated the pharmacological effect of EE on epileptogenesis and kindled seizures in female mice using the hippocampus kindling model. Animals were stimulated daily with or without EE until generalized stage 5 seizures were elicited. EE treatment significantly accelerated the rate of epileptogenesis. In acute studies, EE caused a significant decrease in the afterdischarge threshold and increased the incidence and severity of seizures in fully-kindled mice. In chronic studies, EE treatment caused a greater susceptibility to kindled seizures. Collectively, these results are consistent with moderate proconvulsant-like activity of EE. Such excitatory effects may affect seizure risk in women with epilepsy taking OC pills.

Keywords: Epileptogenesis; Ethinyl estradiol; Kindling; Oral contraceptive; Pregnancy.

Figure 1. Effects of acute and chronic EE treatment on seizure activity in fully-kindled female mice

(ABCDE) The acute effects of EE (10–100 μg/g, sc) on kindled seizures. (A) Intensity of ADT current for eliciting generalized (stage 4/5) seizures after EE treatment. (B) Duration of behavior (stage 4/5) seizures after EE treatment. (C) Duration of AD after EE treatment. (D) Percent animals exhibiting generalized seizures at 50% ADT current. (E) Representative traces illustrate EE exacerbation of electrographic seizure activity in a fully-kindled mouse. Control trace was obtained without EE treatment. (FGHI) Effects of chronic EE treatment on kindled seizures. Fully-kindled mice were treated with EE (25 μg/g, sc) for 21 days and then seizure activity measured on day 22 following EE challenge dose (0, 10 and 25 μg/g, sc). (F) Mean ADT current for eliciting generalized (stage 4/5) seizures after EE treatment. (G) Duration of behavior (stage 4/5) seizures after EE treatment. (H) Mean AD duration after EE treatment. (I) Percent animals exhibiting generalized seizures at subthreshold ADT current. Control group represents vehicle-treated, fully-kindled mice that were not exposed to EE therapy. All other groups represent fully-kindled mice chronically-treated with EE and then challenged with an EE dose (0, 10 and 25 μg/g, sc). Values represent the mean ± SEM (n = 6–8 mice per group). *p<0.05 versus control group.

Figure 2. Effect of EE on the development of kindling epileptogenesis in female mice

(A) EE-treated mice displayed enhanced kindling development as expressed by a higher mean seizure stage at the corresponding stimulation session. (B) AD duration was markedly higher in EE-treated mice than in vehicle controls. (C) Rate of kindling development (mean seizure stage per stimulation through stage 5 kindling) was significantly increased in EE-treated mice. (D) Mean number of stimulations to achieve hippocampus kindling stages in control and EE-treated (25 μg/g, sc) mice. (E) Sample traces of electrographic AD activity in EE-treated mice during hippocampus kindling development. The traces show depth recordings from a right hippocampus stimulating-recording electrode after 1^st and 10^th stimulations. Behavioral seizure stages are indicated on the trace. Values represent the mean ± SEM (n = 6–8 mice per group). *p<0.05 versus control group.