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Estrogen Response Element-Independent Estrogen Receptor (ER)- Signaling Does Not Rescue Sexual Behavior but Restores Normal Testosterone Secretion in Male ER Knockout Mice

Department of Neurobiology and Physiology (M.A.M., J.E.L.), Northwestern University, Evanston, Illinois 60208; Department of Endocrinology, Metabolism, and Molecular Medicine (C.G.-K., J.W., J.L.J.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; and Institut de Génétique et de Biologie Moléculaire et Cellulaire (P.C.), Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, Collège de France, 67404 Illkirch Cedex, France

Address all correspondence and requests for reprints to: Jon E. Levine, Ph.D., Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, Illinois 60208. E-mail: jlevine{at}northwestern.edu.

Estrogen receptor (ER)- mediates estradiol (E₂) actions in the male gonads and brain and is critical for normal male reproductive function. In the classical pathway, ER binds to estrogen response elements (EREs) to regulate gene transcription. ER can also regulate gene transcription independently of EREs via protein-protein interactions with transcription factors and additionally signal via rapid, nongenomic pathways originating at the cell membrane. This study assessed the degree to which ERE-independent ER signaling can rescue the disrupted masculine sexual behaviors and elevated serum testosterone (T) levels that have been shown to result from ER gene deletion. We utilized male ER null mice that possess a ER knock-in mutation (E207A/G208A; AA), in which the mutant ER is incapable of binding to DNA and can signal only through ERE-independent pathways (ER^–/AA mice). We found that sexual behavior, including mounting, is virtually absent in ER^–/– and ER^–/AA males, suggesting that ERE-independent signaling is insufficient to maintain any degree of normal sexual behavior in the absence of ERE binding. By contrast, ERE-independent signaling in the ER^–/AA mouse is sufficient to restore serum T levels to values observed in wild-type males. These data indicate that binding of ERs to EREs mediates most if not all of E₂’s effects on male sexual behavior, whereas ERE-independent ER signaling may mediate E₂’s inhibitory effects on T production.

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