Thanks to unique mouse models, we demonstrated that the estrogen receptor alpha (ERa), but not ERb, is absolutely necessary for most of the arterial and metabolic actions of 17b-estradiol (E2). Estrogens also elicit deleterious effects on the uterus and breast (partly via their proliferative effect which increases the risk of cancer) as well as increased risk of venous thromboembolism, which are the two main limitations of classic estrogen therapies. ER contains two independent transactivation functions AF-1 and AF-2, and our team dissected for the first time in vivo the roles of functions ERaAF-1 and AF-2, allowing to define the key role of these nuclear actions in several tissues. More recently, we reported the key role of the ERa fraction localized to the plasma membrane which is absolutely necessary for the protective endothelial actions of E2 as well as, more unexpectedly, for female fertility. One mystery of estrogens biology is that selective ER modulators (SERMs, such as tamoxifen, raloxifen) have a highly tissue-specific action, behaving as agonists in some tissues (such as bone) and as antagonist in others (breast). We will report how these mouse models allowed us to characterize:

The author declares a conflict of interest: JF Arnal’team received a financial support from Uteron/Mithra to study the mechanisms of action of Estetrol.