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Endocrinology Vol. 139, No. 3 1108-1114
Copyright © 1998 by The Endocrine Society

ARTICLES

Regulation of Gonadotropin-Releasing Hormone (GnRH) Gene Expression by 5{alpha}-Dihydrotestosterone in GnRH-Secreting GT1–7 Hypothalamic Neurons1

Denise D. Belsham, Andreas Evangelou, Deboleena Roy, Duc Vinh Le and Theodore J. Brown

Departments of Physiology (D.D.B.) and Zoology (A.E., T.J.B.), Institute of Medical Sciences (D.R.) and Division of Reproductive Science, University of Toronto and Toronto Hospital Research Institute, Toronto, Ontario, Canada M5G 2C4

Address all correspondence and requests for reprints to: Denise D. Belsham, Ph.D., Department of Physiology/Division of Reproductive Science, University of Toronto/Toronto Hospital Research Institute, 200 Elizabeth Street, CCRW 3–831, Toronto, Ontario, Canada M5G 2C4. E-mail: d.belsham{at}utoronto.ca

Hypothalamic GnRH secretory neurons are precisely regulated by circulating gonadal steroids. However, the question of whether these cells are directly responsive to steroid hormones remains a central and controversial issue in reproductive science. In the present study, we demonstrate the expression of androgen receptor (AR) in a mouse hypothalamic GnRH-secreting cell line, GT1–7. AR messenger RNA was detected by Northern blot analysis of 10 µg total cellular RNA. Western blot analysis revealed a 110K AR immunoreactive band, and saturation binding analysis confirmed the presence of a high affinity low capacity androgen binding entity (Kd = 0.06 nM; Bmax = 12.4 fmol/mg protein). In addition, GT1–7 cells were found to express ARA70, an AR-specific coactivator that has been reported to enhance transactivational activity of the AR. GT1–7 cells transiently transfected with an androgen responsive MMTV-luciferase reporter construct displayed a 4.2-fold induction of luciferase reporter gene activity by 1 nM 5{alpha}-dihydrotestosterone (DHT), further demonstrating the presence of a functional AR. Treatment of GT1–7 cells with 1 or 10 nM DHT resulted in approximately 55% reduction in GnRH messenger RNA measured at 24 and 36 h after treatment. This repression was completely blocked by hydroxyflutamide, an AR antagonist. These results provide the first demonstration that androgen acts directly through an AR-mediated pathway to repress GnRH gene expression in hypothalamic GnRH-secreting neurons.




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