title: In vivo characterization of estrogen receptor modulators with reduced genomic versus nongenomic activity in vitro.
abstract: Estrogen receptor (ER) ligands that are able to prevent postmenopausal bone loss, but have reduced activity in the uterus and the mammary gland might be of great value for hormone therapy. It is well established that the classical ER can activate genomic as well as nongenomic signal transduction pathways. In this study, we analyse the in vivo behaviour of ER ligands that stimulate nongenomic ER effects to the same extent as estradiol, but show clearly reduced activation of genomic ER effects in vitro. Using different readout parameters such as morphological changes, cellular proliferation, and target gene induction, we are able to demonstrate that ER ligands with reduced genomic activity in vitro show a better dissociation of bone versus uterine and mammary gland effects than estradiol that stimulates genomic and nongenomic effects to the same extent. We conclude that pathway-selective ER ligands may represent an interesting option for hormone therapy.
authors.affiliation: Research Laboratories, Bayer Schering Pharma AG, D-13353 Berlin, Germany. christiane.otto@bayerhealthcare.com
authors.forename: Christiane
authors.initials: C
authors.lastname: Otto
authors.forename: Iris
authors.initials: I
authors.lastname: Fuchs
authors.forename: Helga
authors.initials: H
authors.lastname: Altmann
authors.forename: Mario
authors.initials: M
authors.lastname: Klewer
authors.forename: Gilda
authors.initials: G
authors.lastname: Schwarz
authors.forename: Rolf
authors.initials: R
authors.lastname: Bohlmann
authors.forename: Duy
authors.initials: D
authors.lastname: Nguyen
authors.forename: Ludwig
authors.initials: L
authors.lastname: Zorn
authors.forename: Richardus
authors.initials: R
authors.lastname: Vonk
authors.forename: Katja
authors.initials: K
authors.lastname: Prelle
authors.forename: Thua
authors.initials: T
authors.lastname: Osterman
authors.forename: Chira
authors.initials: C
authors.lastname: Malmström
authors.forename: Karl-Heinrich
authors.initials: KH
authors.lastname: Fritzemeier
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D016678:Genome / Q000187:drug effects*; D066298:In Vitro Techniques; D008024:Ligands; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009929:Organ Size; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013997:Time Factors; D014599:Uterus / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism
chemical_list: C468666:4-estren-3,17-diol; D004963:Estrenes; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D008024:Ligands; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D004958:Estradiol