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Endocrinology Vol. 143, No. 11 4172-4177
Copyright © 2002 by The Endocrine Society

ARTICLE

Characterization of the Biological Roles of the Estrogen Receptors, ER{alpha} and ERß, in Estrogen Target Tissues in Vivo through the Use of an ER{alpha}-Selective Ligand

Heather A. Harris, John A. Katzenellenbogen and Benita S. Katzenellenbogen

Women’s Health Research Institute (H.H.), Wyeth Research, Collegeville, Pennsylvania 19426; and Departments of Chemistry (J.A.K.) and Molecular and Integrative Physiology (B.S.K.), University of Illinois, Urbana, Illinois 61801

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

Estrogens elicit many biomedically important responses in different target tissues, and the respective roles of the two estrogen receptors, ER{alpha} and ERß, in mediating these bioactivities is incompletely understood. In this study, we investigated the activity of an ER{alpha}-selective agonist ligand, propyl pyrazole triol (PPT), in several rat animal models to define the involvement of ER{alpha} in these biological responses. In a short-term (4 d) uterotrophic assay, PPT was found to be as efficacious as 17{alpha}-ethinyl-17ß-estradiol in stimulating uterine weight gain and up-regulating complement 3 gene expression. In a 6-wk chronic model, PPT completely prevented the ovariectomy-induced body weight increase and loss of bone mineral density. It also increased uterine weight and markedly reduced plasma cholesterol levels in these mature animals. PPT was also effective in the brain. It increased progesterone receptor mRNA in the arcuate and ventromedial nuclei of the hypothalamus and prevented experimentally induced hot flushes. Our findings indicate that several physiologically relevant estrogen-induced tissue responses can be effectively evoked via ER{alpha} alone. By providing an approach that is complementary to that of analyzing the phenotype and response of ER knockout animals, our findings also demonstrate that ER subtype-selective ligands can play a valuable role in enhancing our understanding of how estrogens work through the two ER subtypes.




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