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¹ Division of Clinical and Reproductive Sciences, Department of Clinical Sciences, University of Kentucky, Lexington, Kentucky 40536, USA ² Department of Anatomy and Neurobiology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, South Korea Departments of ³ Biology and ⁴ Animal Sciences, University of Kentucky, Lexington, Kentucky 40536, USA ⁵ Institut de Genetique et de Biologie Moleculaire et Cellulaire (CNRS, INSERM, ULP, College de France) and Institut Clinique de la Souris, BP10142, 67404 Illkirch-Strasbourg, France

(Correspondence should be addressed to C Ko; Email: cko2{at}uky.edu) http://www.mc.uky.edu/CLS/ko/default.htm

Estrogen plays a critical role in inducing LH surge. In the pituitary, estrogen receptor (ER) mediates the action of estrogen, while the downstream pathway of ER activation is yet to be elucidated. Here, we report the finding that cholecystokinin type A receptor (CCK-AR) is an ER downstream gene in the mouse anterior pituitary. In the cycling mouse pituitary, the expression of CCK-AR mRNA is markedly higher in the afternoon of proestrus compared with metestrus. Both ovariectomy (OVX) and null mutation of the ER gene completely abolish CCK-AR mRNA expression. Injection of 17ß-estradiol to OVX wild-type mice induces recovery of CCK-AR mRNA expression to levels observed at proestrus, but no such recovery is induced in OVX ER knockout mice. The same pattern of estrogen dependency in inducing CCK-AR mRNA expression was seen in cultured primary anterior pituitary cells, indicating that estrogen directly acts on pituitary cells to induce CCK-AR expression. Immunohistological analysis revealed that more than 80% of gonadotrophs express CCK-AR in the afternoon of proestrus. To test whether CCK-AR mediated the sensitizing effect of estrogen in GnRH-induced LH secretion, primary pituitary cells were primed with estrogen followed by treatment with GnRH in the presence or absence of lorglumide, a CCK-AR antagonist. While both groups secreted LH upon GnRH treatment, lorglumide treatment significantly decreased LH secretion. Taken together, this study finds CCK-AR to be an ER downstream gene in the pituitary and suggests that CCK-AR may play a role in the estrogen sensitization of the pituitary response to GnRH.