Long-term valproate treatment induces changes in ovarian morphology and serum sex steroid hormone levels in female Wistar rats

Long-term valproate treatment is associated with polycystic ovaries and end ocrine disorders in women with epilepsy. The mechanisms responsible for the se effects are unknown, but both the epilepsy itself and the drug per se ma y be of importance. The aim of this study was to investigate possible effec ts of the dug on gonadal structure and function in animals with no epilepti c disorders. Three groups, each of 15 female Wistar rats, were fed perorall y with a valproate mixture (50 mg/kg or 200 mg/kg) or central solution once daily for 90 days, giving mean valproate concentrations within the normal human range. A significant, 20% increase in ovary weight was found in both low- (P = 0.027) and high- (P < 0.001) dose animals together with a signifi cantly increased number of ovarian follicular cysts. Mean serum testosteron e concentration was significantly reduced in both low- and high-dose animal s. There was a non-significant trend towards reduced estrogen levels, while progesterone levels were unchanged. Even if the hormonal changes are somew hat different from those in humans, the findings demonstrate that changes i n gonadal structure and endocrine function also occur in intact animals ind icating a drug-specific effect. Our findings encourages further studies usi ng animal models to elucidate possible mechanisms involved in the:endocrine side-effects of antiepileptic drugs. (C) 1999 BEA Trading Ltd.