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Estradiol Coupling to Endothelial Nitric Oxide Stimulates Gonadotropin-Releasing Hormone Release from Rat Median Eminence Via a Membrane Receptor¹

INSERM, U-422, Unité de Neuroendocrinologie et Physiopathologie Neuronale (V.P., D.C., P.P., J.-C.B.), 59045 Lille Cedex, France; Neuroscience Research Institute, State University of New York (C.M.R., G.L.F., G.B.S.), Old Westbury, New York 11568; and the Division of Psychiatry, Harvard Medical School, Brigham and Women’s Hospital (G.L.F., G.B.S.), Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Dr. Vincent Prevot, INSERM, U-422, Unité de Neuroendocrinologie et Physiopathologie Neuronale, place de Verdun, 59045 Lille Cedex, France. E-mail: prevot{at}biserte.lille.inserm.fr

The median eminence (ME), which is the common termination field for adenohypophysiotropic systems, has been shown to produce nitric oxide (NO), a signaling molecule involved in neuroendocrine secretion. Using an ex vivo technique, 17ß-estradiol exposure to ME fragments, including vascular tissues, stimulated NO release within seconds in a concentration-dependent manner, whereas 17-estradiol or testosterone had no effect. 17ß-Estradiol conjugated to BSA (E₂-BSA) also stimulated NO release, suggesting mediation by a membrane surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized the action of both 17ß-estradiol and E₂-BSA. Furthermore, estradiol-stimulated NO stimulates GnRH release. This was demonstrated by hemoglobin (a NO scavenger), N-nitro-L-arginine methyl ester, and L-N⁵-(1-iminoethyl)ornithine (nitric oxide synthase inhibitors) inhibition of estradiol stimulated NO and GnRH release. In this regard, L-N⁵-(1-iminoethyl)ornithine, specific for endotheliol constitutive nitric oxide synthase, was significantly more potent, suggesting that the estradiol-stimulated NO release arose from vascular endothelial cells. Additionally, the NO-stimulated GnRH release occurs via guanylyl cyclase activation in GnRH nerve terminals, as ODQ, a potent and selective inhibitor of NO-sensitive guanylyl cyclase, abolished the estradiol-stimulated GnRH release. The results suggest that at physiological concentrations, 17ß-estradiol may have immediate actions on ME endothelial cells via nongenomic signaling pathways leading to NO-stimulated GnRH release.

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