Reproductive endocrine side effects of antiepileptic drugs

RATIONALE: There is a complex interplay between epilepsy, antiepileptic drugs, and reproductive endocrine disorders. Epilepsy itself may influence on the hormonal balance, hormones may affect epilepsy, hormones may influence on the efficacy and metabolism of antiepileptic drugs and antiepileptic drugs may alter the hormone levels.To better understand the interaction of antiepileptic drugs and production of steroid hormones, we investigated possible effects of valproate, carbamazepine and levetiracetam using the H295R steroidogenesis model. METHODS: H295R human adrenal carcinoma cells are capable of full steroidogenesis. Cells were exposed to three different antiepileptic drugs (valproate, carbamazepine and levetiracetam) for 48 hr. Medium was collected and analyzed for hormone production (estradiol, testosterone, progesterone and cortisol). RESULTS: We observed a significant, dose-dependent reduction in the production of estradiol in cells exposed to valproate (300 – 1500 μM). At a drug concentration of 600 μM, estradiol levels were reduced to 40% compared with controls. Testosterone levels were not significantly changed. This resulted in a dose-dependent increase of the testosterone to estradiol ratio. No significant dose-response effect on hormone production was seen with carbamazepine or levetiracetam. CONCLUSIONS: H295R cells exposed to valproate, carbamazepine, or levetiracetam showed different patterns of hormone production. The most prominent finding was a significant dose-dependent increase of the testosterone/estradiol ratio in cells exposed to valproate. This suggests valproate is capable of inhibiting conversion of testosterone to estradiol. No effects on sex steroid hormone production were observed with carbamazepine or levetiracetam.