The role of neurosteroids in the pathophysiology and treatment of catamenial epilepsy

Abstract

Catamenial epilepsy is a multifaceted neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around perimenstrual or periovulatory period. Generally, a twofold or greater increase in seizure frequency during a particular phase of the menstrual cycle could be considered as catamenial epilepsy. Based on this criteria, recent clinical studies indicate that catamenial epilepsy affects 31-60% of the women with epilepsy. Three types of catamenial seizures (perimenstrual, periovulatory and inadequate luteal) have been identified. However, there is no specific drug available today for catamenial epilepsy, which has not been successfully treated with conventional antiepileptic drugs. Elucidation of the pathophysiology of catamenial epilepsy is a prerequisite to develop specific targeted approaches for treatment or prevention of the disorder. Cyclical changes in the circulating levels of estrogens and progesterone play a central role in the development of catamenial epilepsy. There is emerging evidence that endogenous neurosteroids with anticonvulsant or proconvulsant effects could play a critical role in catamenial epilepsy. It is thought that perimenstrual catamenial epilepsy is associated with the withdrawal of anticonvulsant neurosteroids. Progesterone and other hormonal agents have been shown in limited trials to be moderately effective in catamenial epilepsy, but may cause endocrine side effects. Synthetic neurosteroids, which enhance the tonic GABA-A receptor function, might provide an effective approach for the catamenial epilepsy therapy without producing hormonal side effects.

Fig. 1. Temporal relationship between ovarian hormones and occurrence of catamenial seizures during the menstrual cycle

The upper panel illustrates the strong relationship between seizure frequency and estradiol/progesterone levels. The lower panel illustrates the three types of catamenial epilepsy. The vertical gray bars (left and right) represents the likely period for the perimenstrual (C1) type, while the vertical gray bar (middle) represent the likely period for the periovulatory (C2) type. The horizontal dark gray bar (bottom) represent the inadequate luteal (C3) type that likely occur starting early ovulatory to menstrual phases.

Fig. 2. Molecular mechanisms of progesterone and neurosteroids in the brain

The two mechanisms by which progesterone affects seizure susceptibility are (i) binding to progesterone receptors (PRs) (left panel) and (ii) metabolism to GABA_A receptor-modulating neurosteroids (right panel). Progesterone binding to PRs could lead to activation of neural gene expression in the brain. Neurosteroid allopregnanolone is synthesized from progesterone by two sequential A-ring reductions both in peripheral tissues and in the brain. Allopregnanolone binds and potentiate the GABA_A receptor function leading protective effects against seizures. GABA-A receptors are believed to be pentameric with five protein subunits that form the chloride ion channel pore. The allopregnanolone binding site is thought to be at the “neurosteroid binding site”, which is distinct from sites for GABA, benzodiazepines and barbiturates. There are seven different classes of subunits with multiple variants; most GABA_A receptors are believed to be composed of α, β and γ or δ subunits. Although allopregnanolone binds poorly to PRs, it could indirectly activate PRs by re-conversion to dihydroprogesterone, which is a moderately potent PR agonist. Moreover, progesterone and neurosteroids are shown to affect GABA-A receptor expression. Thus, there may be an interaction between genomic and non-genomic actions of progesterone in modulation of seizure activity.

Fig. 3. Mean serum concentrations of two major GABA-A receptor-modulating neurosteroids, allopregnanolone and THDOC, during menstrual cycle in women with catamenial epilepsy and in control subjects

Allopregnanolone levels are similar, but THDOC levels are significantly (p < 0.05) reduced in women with catamenial epilepsy during periovulatory, perimenstrual period and throughout the menstrual cycle (data from Tuveri et al., 2008).

Fig. 4. Neurosteroid withdrawal-induced spontaneous seizures in female epilepsy rats

The protocol for the catamenial model is illustrated in the top panel. Chronic epilepsy with spontaneous recurrent seizures was induced in rats by pilocarpine treatment. Pilocarpine-induced status epilepticus was terminated after 2 h with diazepam (5 mg/kg, ip) injections and animals with frequent spontaneous seizures (average 2 seizures daily) after 5 months post pilocarpine were utilized for neurosteroid withdrawal cycles. To simulate the hormonal state of the luteal-phase (high progesterone) and menstruation (withdrawal) in epilepsy rats, pseudopregnancy, which is associated with sustained secretion of progesterone and neurosteroids, was induced by gonadotropin regimen. Neurosteroid withdrawal was induced by treatment with finasteride, a 5α-reductase inhibitor that blocks the synthesis of allopregnanolone. Rats undergoing neurosteroid withdrawal exhibited significant (p<0.01) increase in daily seizure frequency as compared to control, non-withdrawing group (bottom panel), which is consistent with perimenstrual type catamenial epilepsy.