The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation

Estetrol (E(4)) is a natural estrogen with a long half-life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor α (ERα) ligand-binding domain bound to 17β-estradiol (E(2)) and E(4) are very similar, as well as their capacity to activate the two activation functions AF-1 and AF-2 and to recruit the coactivator SRC3. In vivo administration of high doses of E(4) stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ERα actions. However, E(4) failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane-initiated steroid signaling (MISS). Furthermore, E(4) antagonized E(2) MISS-dependent effects in endothelium but also in MCF-7 breast cancer cell line. This profile of ERα activation by E(4), uncoupling nuclear and membrane activation, characterizes E(4) as a selective ER modulator which could have medical applications that should now be considered further.