Abstracts

Rationale: Clinical data suggest that chronic seizures in women with epilepsy can have adverse effects on reproductive function, such as polycystic ovarian syndrome (PCOS), but it has been difficult to dissociate the effects of epilepsy per se from the potential role of antiepileptic drug (AED) therapy. To distinguish the effects of chronic seizures alone, we used the laboratory rat, where an epileptic condition can be induced experimentally, without AEDs. Methods: Adult female Sprague-Dawley rats (2-3 months old) were administered atropine methylbromide (1 mg/kg, s.c.), followed 30 min later by the cholinergic chemoconvulsant pilocarpine hydrochloride (350 mg/kg, s.c.), to initiate a state of severe continuous seizures (status epilepticus; SE), which developed within 60 min of pilocarpine injection. SE severity was decreased by administration of diazepam (5 mg/kg, i.p.) 1 hr after the onset of SE. Rats that had SE developed spontaneous seizures in the ensuing weeks, and are therefore termed “epileptic.” Comparisons were made to animals treated with saline instead of pilocarpine (saline controls), or animals that were injected with pilocarpine and had seizure-associated motor behavior, but never developed SE (pilocarpine controls). Ovarian cyclicity and weight gain were evaluated for 2-3 months after treatment. Serum hormone levels were assayed from trunk blood that was collected at the time of euthanasia, which was 10:00-11:30 a.m. on the first day of diestrus for cycling rats, and during a diestrous period for acyclic rats. Paraformaldehyde-fixed ovaries were sectioned serially, and evaluated quantitatively. Results: Rats that experienced pilocarpine-induced seizures, whether they had SE or not, exhibited an increased incidence of acyclicity by the end of the study, relative to rats without any seizure-related behaviors and saline controls. Outcome appeared to be independent of the cycle stage at the time of pilocarpine or saline treatment. Ovarian cysts and weight gain were significantly greater in epileptic rats than saline or pilocarpine controls, whether they maintained cyclicity throughout the study or not. Serum levels of estrogen, progesterone and prolactin were not significantly different among epileptic rats, saline controls and pilocarpine controls, but serum testosterone values were significantly elevated in epileptic rats. Testosterone values were increased whether epileptic rats maintained regular estrous cycles or not. Conclusions: The results suggest that an epileptic condition leads to symptoms of PCOS, including increased body weight, cystic ovaries and elevated testosterone levels. In addition, even a cluster of seizures in a normal rat appears to have long-term consequences, increasing the incidence of female rats that develop irregular estrous cycles before the normal age of reproductive senescence. Although caution is required when basing conclusions on one animal model, or comparing female rats to women, the data suggest that chronic seizures may be sufficient to induce some of the symptoms of PCOS. Supported by NIH NS37562, NIH HD047890, and NSERC.