Allopregnanolone levels and seizure frequency in progesterone-treated women with epilepsy

To determine whether allopregnanolone (AP) may mediate seizure reduction in progesterone-treated women with epilepsy.

The NIH Progesterone Trial compared the efficacy of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects, randomized 2:1 to progesterone or placebo, stratified by catamenial vs noncatamenial designation. Treatments were compared on proportions of 50% responders, and changes in seizure frequency from 3 baseline to 3 treatment cycles. Serum AP levels were measured by radioimmunoassay from 155 women with intractable focal-onset seizures who had baseline and treatment-phase midluteal serum samples drawn each cycle for hormone measurements.

There was no significant correlation between percentage changes in AP levels and seizure frequencies from baseline to treatment for either the catamenial or noncatamenial stratum. There was a significant correlation for the subset of subjects who showed a significantly greater responder rate in the post hoc analysis of the trial, i.e., subjects who had a 3-fold or greater increase in average daily seizure frequency perimenstrually compared with the midfollicular and midluteal phases (C1 ≥ 3: r = -0.442, p = 0.013, and specifically for C1 ≥ 3 progesterone-treated subjects [r = -0.452, p = 0.035], but not other groups [C1 ≥ 3 placebo: r = -0.367; C1 <3 progesterone: r = 0.099; C1 <3 placebo: r = 0.131; p = not significant]).

The findings support AP as a mediator of seizure reduction in progesterone-treated women who have a substantial level of perimenstrually exacerbated seizures.