Characterization of the Biological Roles of the Estrogen Receptors, ERα and ERβ, in Estrogen Target Tissues in Vivo through the Use of an ERα-Selective Ligand
Abstract
Estrogens elicit many biomedically important responses in different target tissues, and the respective roles of the two estrogen receptors, ERalpha and ERbeta, in mediating these bioactivities is incompletely understood. In this study, we investigated the activity of an ERalpha-selective agonist ligand, propyl pyrazole triol (PPT), in several rat animal models to define the involvement of ERalpha in these biological responses. In a short-term (4 d) uterotrophic assay, PPT was found to be as efficacious as 17alpha-ethinyl-17beta-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 ERalpha 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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PPT is a potent ERα agonist.
“we treated mice with either the anti-estrogen ICI 182,780 (ICI), a “pure” anti-estrogen [17], 4,4′,4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), a potent ERα agonist [18], or ditolylguanidine (DTG), a sigma-1 and −2 receptor agonist.”
From Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis (2015) · cites this paper as [18]
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- Authors
- Harris, H. A., Katzenellenbogen, J. A., & Katzenellenbogen, B. S.
- Affiliations
- Wyeth (US)
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Katzenellenbogen, Benita S.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2002-11
- Volume
- 143
- Issue
- 11
- Pages
- 4172-4177
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2011735277
- Cited by
- 357
- References
- 21
- Citations by year
- 2026: 1 · 2024: 13 · 2023: 5 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 5 · 2018: 6 · 2017: 8 · 2016: 7 · 2015: 12 · 2014: 12 · 2013: 19 · 2012: 16
- FWCI
- 13.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA018119)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK015556)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Health Sciences › Medicine › Pathology and Forensic Medicine › Phytoestrogen effects and research
- Keywords
- estrogen receptor alpha, estrogen receptor beta, propyl pyrazole triol, uterotrophic assay, uterine growth, bone mineral density, ovariectomy, serum cholesterol, progesterone receptor, hypothalamus, hot flashes, estrogen target tissues
- MeSH terms
- Animals, Body Weight, Complement C3, Estrogens, Ethinyl Estradiol, Female, Hypothalamus, Ligands, Organ Size, Ovariectomy, Phenols, Pyrazoles, Receptors, Estrogen, Receptors, Progesterone, RNA, Messenger, Skin Temperature, Uterus, Bone Density, Gene Expression, Rats, Sprague-Dawley, Estrogen Receptor alpha, Estrogen Receptor beta, Rats
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