LAUSR

O spemifene, raloxifene, bazedoxifene, lasofoxifene, clomiphene, and tamoxifen are unique molecules that are active via the estrogen receptor. Estrone, estradiol, and estriol are classic endogenous estrogens whose estrogenic efficacy is related to both concentration and binding affinity to the cellular estrogen receptor. Estrogens bind to the cytoplasmic estrogen receptor, translocate to the nucleus, attach at the estrogen response element of the gene which initiates recruitment of nuclear co-activators and co-inhibitors that modify the cellular gene transcriptional activity. The terms selective estrogen receptor modulator (SERM) and the Food and Drug Agency preferred term estrogen receptor agonist/antagonist (ERAA) are both descriptive assessments of their mechanism of action. Each ERAA binds to the estrogen receptor resulting in a unique conformational change to the ligand-estrogen receptor complex. The subsequent recruitment of nuclear co-activators and co-inhibitors that alter the downstream translational activity are tissue specific. Each tissue then manifests estrogen agonistic or antagonistic outcomes. The tissue specific changes are modulated since each ERAA elicits subtle differences in the recruited co-activators and co-repressors. SERM/ERAA were heralded as the answer to the unwanted estrogen stimulation of breast and endometrium in postmenopausal women with an indication for hormone therapy. The ERAAs did not stimulate breast or endometrium while maintaining a positive effect on bone. A problem was that none of the ERAAs reduced menopausal hot flushes and often increased the incidence of hot flushes. Ospemifene followed this general rule with one exception an increase in vaginal estrogen agonistic activity. The clinical trials documenting ospemifene efficacy as an oral treatment for postmenopausal