Reproductive endocrine effects of antiepileptic drugs - with special reference to valproate

Abstract Previous observations have indicated that reproductive endocrine disorders are common among patients with epilepsy. Valproate (VPA) treatment is associated with hyperandrogenism, polycystic ovaries, and obesity in women. Carbamazepine (CBZ) may also induce endocrine disorders, while the hormonal effects of oxcarbazepine (OXC) are poorly known. The aim of this study was to elucidate the effects of antiepileptic drugs on reproductive hormones, linear growth and pubertal maturation in patients with epilepsy. Altogether 223 patients taking VPA, CBZ, or OXC monotherapy for epilepsy and 103 healthy age- and sex-matched volunteers participated in the study. Seventy-eight girls and 90 men with epilepsy participated in the cross-sectional parts of the study. Thirty-nine adult patients with newly diagnosed epilepsy participated in a 3-month longitudinal study and VPA was replaced with lamotrigine (LTG) in 16 women with VPA-related endocrine disorders in a 1-year longitudinal study. The girls were between 8-18 years, the women 17-41 years and the men 17-51 years of age. None of the antiepileptic drugs studied significantly influenced linear growth or pubertal development in girls with epilepsy, but hyperandrogenemia, increased number of ovarian follicles, and weight gain were observed in prepubertal, pubertal and postpubertal girls taking VPA for epilepsy. Increased serum testosterone levels were observed in half of the women after the first 3 months of VPA medication, and high serum concentrations of androgens were common (prevalence 57 %, p < 0.001) in men taking long-term VPA treatment. The women with VPA-related hyperandrogenism and polycystic ovaries were also found to present other features of insulin resistance (i.e. hyperinsulinemia, centripetal obesity, and an unfavorable serum lipid profile). Reproductive endocrine disorders associated with VPA treatment in women began to normalize after VPA was replaced by LTG. CBZ reduced the bioactivity of androgens, whereas OXC did not have similar effects. Serum concentrations of sex hormone-binding globulin (SHBG) were increased and dehydroepiandrosterone sulfate decreased already during the first months of CBZ treatment. Serum hormone levels were normal in patients with low OXC doses (< 900 mg/d), but serum concentrations of testosterone, gonadotropins and SHBG were high in men with a daily OXC dose ≥ 900 mg. The adverse reproductive endocrine effects of antiepileptic drugs should be considered at the beginning of and during antiepileptic medication