Comparison of reproductive effects of levetiracetam and valproate studied in prepubertal porcine ovarian follicular cells

PURPOSE: Long-term valproate (VPA) treatment has been associated with reproductive endocrine disorders characterized by hyperandrogenism and polycystic changes in the ovaries in women with epilepsy. Levetiracetam (LEV) is a promising, new antiepileptic drug that may represent an alternative to VPA for many patients. Here the effect of LEV and VPA on basal and gonadotropin-stimulated steroid secretion from prepubertal porcine ovarian follicular cells was compared and the conversion of testosterone to estradiol is measured. METHODS: Ovarian follicles were obtained from prepubertal pigs. Follicular theca and granulosa cells were cocultured and different concentrations of LEV or VPA added to the control or gonadotropin-stimulated cultures. RESULTS: VPA, but not LEV, caused a significant increase of LH-stimulated testosterone secretion and decreased FSH-stimulated estradiol secretion. VPA decreased conversion of testosterone to estradiol in both basal and FSH-stimulated cultures, while LEV only decreased testosterone to estradiol conversion after FSH stimulation and only at the highest, nontherapeutic drug concentration. Both drugs increased basal testosterone secretion at therapeutic drug levels. VPA also reduced basal estradiol secretion, while LEV decreased basal estradiol secretion only at nontherapeutic drug levels. CONCLUSION: Both LEV and VPA affect endocrine function in the prepubertal ovary. But while VPA alters both basal and gonadotropin-stimulated testosterone and estradiol secretion at therapeutic drug concentrations, LEV only affects basal hormone secretion at this concentration level. The possibility that LEV could be an alternative treatment to VPA if reproductive endocrine problems emerge in adult women, is discussed. However, extrapolation to the clinical situation is problematic and particular emphasis is placed on the need for further studies.