Effects of chronic valproate treatment on reproductive endocrine hormones in female and male Wistar rats.

Valproate (VPA) has been claimed to induce endocrine disorders in both sexes in humans. There is sparse information regarding the mechanisms behind these disturbances. By using an animal model, we wanted to study the effect of valproate on hormonal function in non-epileptic rats. Female rats were given 0 (vehicle control, n=15), 200mg/kg (n=15), or 300 mg/kg (n=20) valproate twice daily by gavage for 90 days, resulting in mean valproate concentrations within the therapeutic range 4-6h after the last dose given. Serum testosterone concentrations remained unchanged, while estradiol levels were significantly reduced in both treatment groups, leading to significantly increased testosterone/estradiol ratios. Follicle stimulating hormone (FSH) levels remained unaltered in valproate treated rats, whereas the luteinizing hormone (LH) concentrations were reduced at the lowest valproate dose. Male rats received 0 (vehicle control, n=15), 200mg/kg (n=15), or 400mg/kg (n=20) valproate twice daily by gavage for 90 days, resulting in mean valproate concentrations within the therapeutic range 4-6h after the last dose. Serum testosterone levels were not significantly changed, but there was a highly significant increase in FSH and LH concentrations at the high dose. In conclusion, the study demonstrates a drug-induced effect of valproate on endocrine function in both male and female rats. The results indicate that the drug exerts its effect primarily at the gonadal level, although a centrally mediated effect cannot be ruled out.