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

Abstract

SUMMARYPurpose: 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 lg/ml) or VPA (75, 100, 250, or 350 lg/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 concentrationdependently 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 lg/ ml; LEV 20, 50, and 80 lg/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.

The Anti-Epileptic Drug Valproic Acid (VPA) Inhibits Steroidogenesis in Bovine Theca and Granulosa Cells In Vitro

“…However, VPA completely reversed FSH-induced expression of CYP19A1 and HSD17B1 and partially reversed IGF-induced CYP19A1 and HSD17B1 expression. An inhibitory effect of VPA on CYP19A1 in FSH-treated human GC was also observed by Tauboll et al [38]. As discussed below the enzymes encoded by CYP19A1 and HSD17B1 both play key roles in the synthesis of estradiol-17β by GC.…”

“…Using GC harvested from women undergoing laparotomy procedures for infertility treatment Tauboll et al [38] recently reported that VPA suppressed basal and FSH-induced estradiol secretion. Similarly, in the porcine TC/GC co-culture study of Tauboll et al [23] VPA reduced basal and FSH-induced estrogen secretion.…”

Reproductive toxicity after levetiracetam administration in male rats: Evidence for role of hormonal status and oxidative stress

“…In our study, decreased serum FSH, LH, and testosterone levels were observed in our high-dose group. Studies showed that LH and FSH levels were not altered [44, 45], while testosterone levels were increased [44–46] in male epileptic patients due to LEV treatment. Epilepsy treatment with LEV in prepubertal children did not cause a meaningful change in hormone levels [47].…”

Cancer risk in people with epilepsy using valproate-sodium

“…A trend towards reduced HRs for breast carcinoma and the absence of ovarian and testicular carcinomas in the exposed group are worth mentioning in view of the effect of valproate on endocrine tissue, which might make hormonal‐responsive tumours more sensitive to the antitumour effects of valproate (30). Although purely speculative, the possibility of an inverse association between valproate use and hormone‐responsive tumours merits further study using a larger sample.…”