0218: The uterine and vascular actions of estetrol delineate an original distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation

Estetrol (E4) is a natural estrogen produced by the human fetal liver only during pregnancy. Its distinctive biological profile offers potential benefits in women's health, such as contraception and hormone replacement therapy. The crystal structures of the estrogen receptor α (ERα) ligand binding domain with 17beta-estradiol (E2) and E4 were very similar, whereas these two estrogens showed distinct positioning within phospholipid bilayers. Using in vivo approaches, we demonstrated that high doses of E4 stimulate genomic, ERα-dependent effects in the uterus leading to epithelial proliferation and prevent atheroma in hypercholesterolemic mice to a similar extent as E2. In contrast to E2, however, E4 failed to promote membrane-initiated ERα signaling such as acceleration of endothelial healing. Moreover, E4 antagonized this endothelial effect of E2. We conclude that E4 is a weak estrogen able to modulate the nuclear/transcriptional activity of ERα, and is not only devoid of membrane-initiated steroid signal, but also able to antagonize the membrane effects of E2, thereby delineating a distinctive profile of ERα activation.