Perspectives in Pharmacology Molecular Mechanisms of Selective Estrogen Receptor Modulator (SERM) Action

In females, estrogens play a key role in reproduction and have beneficial effects on the skeletal, cardiovascular, and central nervous systems. Most estrogenic responses are mediated by estrogen receptors (ERs), either ERa or ERb, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues act like estrogens, but block estrogen action in others. Thus, SERMs may exhibit an agonistic or antagonistic biocharacter depending on the context in which their activity is examined. For example, the SERMs tamoxifen and raloxifene both exhibit ER antagonist activity in breast and agonist activity in bone, but only tamoxifen manifests agonist activity in the uterus. Numerous studies have examined the molecular basis for SERM selectivity. Collectively they indicate that different ER ligands induce distinct structural changes in the receptor that influence its ability to interact with other proteins (e.g., coactivators or corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and of its target gene promoter affect SERM biocharacter. Taken together, SERM selectivity reflects the diversity of ER forms and coregulators, cell type differences in their expression, and the diversity of ER target genes. This model provides a basis for understanding the molecular mechanisms of SERM action, and should help identify new SERMs with enhanced tissue or target gene selectivity. Selective Estrogen Receptor Modulators (SERMs): Puzzling Pharmacological Agents In addition to their key role in female reproductive function, estrogens have beneficial actions on unrelated tissues, as demonstrated by the effects of estrogen replacement therapy in postmenopausal women (Mitlak and Cohen, 1997; Cosman and Lindsay, 1999). Estrogens inhibit bone resorption and can prevent osteoporosis. In addition, many studies suggest that estrogens, in part through effects on hepatic lipid metabolism, have beneficial effects on the cardiovascular system and decrease the incidence of coronary heart disease. Although further investigations are required, estrogen exposure also has been associated with improvements in cognitive function and a delay in the onset of Alzheimer’s disease. In contrast, estrogen exposure is associated with an increase in the incidence of breast cancer and of various uterine lesions, including tumors (Cosman and Lindsay,