Valproate, but not lamotrigine, induces ovarian morphological changes in Wistar rats

Valproate (VPA) medication is associated with development of polycystic ovaries, menstrual disorders and hormonal changes in women with epilepsy. We sought to determine if changes in the ovaries also occurred in an animal model without epilepsy, and whether this effect could be related to a carcinogenic effect expressed by overexpression of p53. A potentially alternative antiepileptic drug, lamotrigine (LTG), was evaluated simultaneously. To this end, female Wistar rats were fed perorally with VPA 400 mg/kg/day (n = 15), VPA 600 mg/kg/day (n = 20), LTG 10 mg/kg/day (n = 15) or control solution (n = 15) for 90-95 days. There was a significant, dose-dependent increase in the number of follicular cysts, reduction in the number of corpora lutea and reduction of ovarian weight in the VPA group. No ovarian pathology was observed in the LTG group. In neither of the groups were morphological changes seen in other organs, nor was there any overexpression of the tumor suppressor gene p53 found. An alternative antiepileptic drug, LTG, showed no ovarian pathology, and there were no light microscopic changes in other organs, or evidence of pathologic p53 overexpression in the LTG-treated animals.