Neuroendocrine plasticity in GnRH release is disrupted by valproic acid treatment of cycling rats.

Valproic acid (VPA) has been used for > 30 years in the treatment of epilepsy and is now one of the most frequently prescribed anti-epileptic drugs (AEDs) worldwide. Its chronic use has been associated with hyperandrogenism and polycystic ovaries in women with epilepsy and thus suggests change in normal levels of estrogens--the gonadal steroids in females. We have tested the hypothesis whether AEDs that exert anticonvulsive effects via key molecules of the gamma amino butyric acid (GABAergic) system, have inhibitory effects on the hypothalamo-hypophyseal-gonadal (HPG) axis at the level of hypothalamic gonadotropin releasing hormone (GnRH) synthesis and/or release and thereby affect reproductive health. Three-month old female Wistar rats were given VPA (i.p.) at a dose of 300 mg/Kg once a day for 12 weeks; the control group received an equivalent volume of vehicle. Glutamic acid decarboxylase (GAD), glial fibrillary acidic protein (GFAP) and their mRNA expression in the median eminence arcuate region (ME-ARC) of the hypothalamus were upregulated in the VPA treated group. By contrast, polysialyltransferase (PST) mRNA which is the enzyme responsible for the polysialylation of neural cell adhesion molecule (NCAM), a plasticity marker, was found to be downregulated. These results support our hypothesis that VPA disrupts normal neuronal-glial plasticity in the hypothalamus and can thereby cause reproductive neuroendocrine disorders in female patients treated for epilepsy, bipolar disorder or migraine.