title: Tissue-specific regulation of genes by estrogen receptors.
abstract: Estrogens are frequently used in reproductive medicine. The Women's Health Initiative trial found that the risks of menopausal hormone therapy (MHT) exceed the benefits. The estrogens in MHT, however, were introduced prior to our understanding of the mechanism of action of estrogens. Estrogen signaling is highly complex, involving various DNA regulatory elements to which estrogen receptors bind. Numerous transcription factors and co-regulatory proteins modify chromatin structure to further regulate gene transcription. With a greater understanding of estrogen action, the major problem with the current estrogens in MHT appears to be that they are nonselective. This produces beneficial effects in bone, brain, and adipose tissue but increases the risk of breast and endometrial cancer and thromboembolism. Resurrecting MHT for long-term therapy will require the development of more selective estrogens, such as estrogen receptor (ER)β-selective estrogens and tissue-selective ERα agonists. These compounds will offer the best prospects to expand the indications of MHT and thus prevent the chronic conditions associated with menopause.
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, California 94720, USA. dale@leitmanlab.com
authors.forename: Dale C
authors.initials: DC
authors.lastname: Leitman
authors.forename: Sreenivasan
authors.initials: S
authors.lastname: Paruthiyil
authors.forename: Chaoshen
authors.initials: C
authors.lastname: Yuan
authors.forename: Candice B
authors.initials: CB
authors.lastname: Herber
authors.forename: Moshe
authors.initials: M
authors.lastname: Olshansky
authors.forename: Mary
authors.initials: M
authors.lastname: Tagliaferri
authors.forename: Isaac
authors.initials: I
authors.lastname: Cohen
authors.forename: Terence P
authors.initials: TP
authors.lastname: Speed
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control; D044127:Epigenesis, Genetic / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000517:prevention & control; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000517:prevention & control; D009765:Obesity / Q000517:prevention & control; D009928:Organ Specificity; D020218:Response Elements / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D016588:Anticarcinogenic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens