Effects of levetiracetam and valproate on reproductive endocrine function studied in human ovarian follicular cells

Purpose:   Recent animal studies have indicated possible reproductive endocrine effects of levetiracetam (LEV). The aim of the present study was to investigate possible reproductive endocrine effects of LEV compared to valproate (VPA) using human ovarian follicular cells.
Methods:   Cell cultures of human granulosa cells were prepared. First, the effect of the drugs on basal and follicle-stimulating hormone (FSH)–stimulated estradiol secretion was investigated at different concentrations of LEV (12, 20, 50, or 80  μ g/ml) or VPA (75, 100, 250, or 350  μ g/ml). Second, the effect of the drugs on CYP19 aromatase activity was studied. Third, the possible effect of the drugs on cell apoptosis was investigated by measuring caspase-3 activity.
Results:   VPA significantly and concentration-dependently decreased basal and FSH-stimulated estradiol secretion. No effects on estradiol secretion were observed for LEV. Neither VPA nor LEV had any effect on CYP19 aromatase activity under basal conditions, but both drugs reduced CYP19 aromatase activity in FSH-stimulated cells at the higher concentrations (VPA 100, 250, and 350 μg/ml; LEV 20, 50, and 80 μg/ml). Both drugs significantly increased caspase-3 activity, the proapoptotic effect of LEV being more pronounced than VPA.
Discussion:   LEV acts differently from VPA on reproductive endocrine function when studied in human ovarian follicular cells. LEV does not affect estradiol secretion, although both drugs affect CYP19 aromatase activity after gonadotropin stimulation. Both drugs act as apoptotic agents in ovarian cells. The proapoptotic effect of LEV was more pronounced than that of VPA.