Role of extra-ovarian oestrogens in the regulation of gonadotropin releasing hormone mRNA expression in the rat brain

To further understand the role of oestrogens in the regulation of gonadotro pin releasing hormone (GnRH) mRNA expression in the female rat brain, the e ffect of EM-652.HCl, a pure anti-oestrogen, was studied in intact and ovari ectomized rats as well as in rats chronically treated with a GnRH agonist D -trp(6), des-Gly-NH210 GnRH ethylamide (GnRH-A), a treatment which blocks o varian steroidogenesis. Quantitative in situ hybridization was used to meas ure GnRH mRNA at the cellular level in the preoptic-anterior hypothalamic a rea. It was found that, 49 weeks after ovariectomy (OVX), the number of sil ver grains per cell corresponding to GnRH mRNA was increased by 34%. Long-t erm administration (49 weeks) of EM-652.HCl to OVX rats resulted in a furth er increase (11% over the levels measured in OVX rats) in the hybridization signal. By contrast, in intact female rats, treated during 52 weeks with E M-652.HCl, a 49% increase in the GnRH hybridization signal was detected. In rats treated with GnRH-A during the same period, a 20% decrease in GnRH mR NA was observed. When EM-652.HCl was administered concomitantly with GnRH-A , a further 63% increase over the mRNA levels recorded in GnRH-A treated ra ts was found. Thus, long-term treatment with the anti-oestrogen EM-652.HCl can upregulate GnRH mRNA expression in intact female rats, OVX rats and fem ale rats chronically treated with a GnRH-A. It is suggested that the pure a nti-oestrogen EM-652.HCl can exert an influence on the oestrogen feedback m echanism involved in the regulation of GnRH neuronal activity by neutralizi ng the action of locally produced or low circulating levels of oestrogens r emaining after OVX or GnRH-A treatment.