In vivo characterization of estrogen receptor modulators with reduced genomic versus nongenomic activity in vitro

• Published in: The Journal of steroid biochemistry and molecular biology 2008-07, Vol.111 (1), p.95-100
• Main Authors: Otto, Christiane, Fuchs, Iris, Altmann, Helga, Klewer, Mario, Schwarz, Gilda, Bohlmann, Rolf, Nguyen, Duy, Zorn, Ludwig, Vonk, Richardus, Prelle, Katja, Österman, Thua, Malmström, Chira, Fritzemeier, Karl-Heinrich
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bone; Cell Proliferation; Cohort Studies; Dose-Response Relationship, Drug; Epithelial Cells - physiology; Estradiol - pharmacology; Estrenes - pharmacology; Estrogen receptor; Estrogen Receptor Modulators - metabolism; Estrogens - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Genome - drug effects; Hormone metabolism and regulation; In Vitro Techniques; Ligands; Mammalian female genital system; Mammary gland; Mammary Glands, Animal - cytology; Mammary Glands, Animal - metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Organ Size; Ovariectomy; Pathway-selective estrogens; Receptors, Estrogen - metabolism; Selective Estrogen Receptor Modulators - pharmacology; Time Factors; Uterus; Uterus - cytology; Uterus - growth & development; Uterus - metabolism; Vertebrates: reproduction
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2008.05.003

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.