Abstracts

RATIONALE: Chronic valproate treatment has been shown to induce hyperandrogenism and polycystic ovaries in women with epilepsy. There is an intense, ongoing debate on whether this is related to the drug itself or to the epileptic activity. The aim of the study was to investigate the possibility of a drug-induced effect of valproate on steroidogenesis by studying the effect of valproate on steroid secretion from isolated follicular cells.
METHODS: Small and medium follicles were obtained from pig ovaries collected respectively at days 8-10 and 14-16 of oestrus cycle. Theca and granulosa cells were collected from follicles and cultured as a co-culture in one well. Cells were cultured for 24, 48 or 72 hrs with valproate 100 or 250 [mu]g/ml. To show whether the effect of valproate was reversible, the medium was changed to fresh medium without drugs for an additional 24, 48 or 72 hrs.
RESULTS: Valproate added to the culture medium caused a significant reduction of estradiol secretion with concomitant increase in both testosterone and progesterone secretion by small follicles. In medium sized follicles, 100 [mu]g/ml of valproate was without effect on estradiol secretion while 250 [mu]g/ml caused a small, but statistically significant decrease. The effects of valproate on steroid secretion patterns were irreversible independent of concentration, exposure time and time of restoration after drug exposure up to 72 hrs in both small and medium follicles.
CONCLUSIONS: The study shows a direct effect of valproate on steroidogenesis in isolated ovarian follicular cells resulting in increased testosterone and progesterone, and decreased estradiol secretion. The effects are achieved at therapeutic serum concentrations. It was not possible to reverse the steroidogenic effects of valproate by removing the drug from the cell cultures.