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 alpha (ER alpha) ligand-binding domain bound to 17 beta-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 ER alpha 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 ER alpha 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.