[Anti-estrogens, selective estrogen receptor modulators (SERM), tibolone: modes of action]

The regulation of estrogen-induced cellular effects is a multistep molecular process. The diversity of estrogen and anti-estrogen effects on cellular functions is also modulate by tissue and gene specificity. This diversity may be explained by different levels of molecular regulation, including the presence of two distinct estrogen receptor isoforms (ER alpha and ER beta), their binding to activator or corepressor transcriptional proteins, and their affinity to different DNA binding domains of target genes (estrogen responsive element or API). These mechanisms may account for the specific responses to estrogens or anti-estrogens according to tissue, cell or gene level. The anti-estrogen tamoxifen, in vitro, inhibits the estrogen-induced proliferation of breast cancer cells and, in vivo, enhances long-term prognosis of patients having ER positive breast cancer when it is used as an adjuvant treatment. The partial agonist effect of anti-estrogens such as raloxifene, is observed only on bones and vessels but not in endometrium. Tibolone is another class of ER modulators which acts as a prodrug. It is metabolized in compounds activating nuclear receptors (androgen and progesterone receptors) which modify the ER level and estrogen metabolism. The improvement of current knowledge on the cellular mechanisms of estrogen and anti-estrogens action should allow the elaboration new therapeutic approaches on specific functions involved in estrogen-dependent pathologies.