In vivo characterization of estrogen receptor modulators with reduced genomic versus nongenomic activity in vitro.
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.
Otto
Christiane
C
Research Laboratories, Bayer Schering Pharma AG, D-13353 Berlin, Germany. christiane.otto@bayerhealthcare.com
Fuchs
Iris
I
Altmann
Helga
H
Klewer
Mario
M
Schwarz
Gilda
G
Bohlmann
Rolf
R
Nguyen
Duy
D
Zorn
Ludwig
L
Vonk
Richardus
R
Prelle
Katja
K
Osterman
Thua
T
Malmström
Chira
C
Fritzemeier
Karl-Heinrich
KH
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
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