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Endocrinology, doi:10.1210/en.2002-0143
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Endocrinology Vol. 144, No. 7 3159-3166
Copyright © 2003 by The Endocrine Society

Response-Specific and Ligand Dose-Dependent Modulation of Estrogen Receptor (ER) {alpha} Activity by ERß in the Uterus

Jonna Frasor, Daniel H. Barnett, Jeanne M. Danes, Rex Hess, Albert F. Parlow and Benita S. Katzenellenbogen

Departments of Molecular and Integrative Physiology (J.F., J.M.D., B.S.K.), Cell and Structural Biology (D.H.B., B.S.K.), and Veterinary Medicine (R.H.), University of Illinois, Urbana, Illinois 61801; and Department of Obstetrics and Gynecology (A.F.P.), Pituitary Hormone Center, Harbor-University of California, Los Angeles Medical Center, Torrance, California 90509

Address all correspondence and requests for reprints to: Dr. Benita S. Katzenellenbogen, University of Illinois, Department of Molecular and Integrative Physiology, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801-3704. E-mail: katzenel{at}life.uiuc.edu

Estrogen is of great importance in the regulation of uterine function. The aim of this study was to examine the individual physiological roles of each of the two receptors for estradiol, estrogen receptor (ER) {alpha} and ERß, and their potential comodulatory effects on gene expression and uterine growth using recently developed ER subtype-selective agonist ligands. The use of ER subtype-selective ligands provides an alternative, complementary approach to the use of receptor knockout mice. Administration of the ER{alpha}-selective ligand propyl pyrazole triol (PPT) to immature mice resulted in a significant increase in uterine weight, as well as bromodeoxyuridine incorporation and proliferating cell nuclear antigen expression in luminal epithelial cells. PPT also increased complement component 3, lactoferrin, and glucose-6-phosphate dehydrogenase (G6PDH), and decreased androgen receptor (AR) and progesterone receptor (PR) mRNA levels in uterine tissue, as did estradiol (E2). However, when compared with E2, PPT was less effective in stimulating uterine weight, complement component 3, and G6PDH expression but was as effective as E2 in regulating lactoferrin, AR, and PR expression. In contrast to the action of the ER{alpha} agonist PPT, the ERß agonist diarylpropionitrile (DPN) did not increase uterine weight or luminal epithelial cell proliferation at a dose that reduced G6PDH and elicited a decrease in PR and AR mRNA and protein expression. Interestingly, DPN reduced the uterine weight stimulation by PPT, and enhanced the effect of PPT in decreasing uterine PR and AR mRNA. These findings with ER subtype-selective ligands indicate that ER{alpha} is the major regulator of estrogen function in the uterus, but that ERß does exert effects on some uterine markers of estrogen action. In addition, ERß can modulate ER{alpha} activity in a response-specific and dose-dependent manner.




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