Estetrol (E₄) is an estrogen produced by the human fetal liver only during pregnancy. A recent clinical phase II study evaluating its contraceptive properties revealed that E₄ did not change the levels of hepatic-derived proteins, including coagulation factors. Thus, at variance to classically used estrogens, it might not increase thrombo-embolic events. The molecular mechanism of action of E₄ is essentially unknown, and the goal of this study was to define the nuclear/transcriptional actions versus the membrane/rapid actions in comparison to E2.

In this study, we show that E₄ is less potent than E2 to activate estrogen receptor alpha (ERα), but a high dose is able to modulate the transcriptional activity of ERα in the uterus, the proliferation of endometrial epithelium and to prevent atheroma. In contrast, E₄ was not only devoid of effects on endothelial healing and NO production, but it antagonized these E2 effects that are purely membrane ERα-dependent.

Thus, E₄ appears not only as less potent estrogen than E2 but behaves as a natural Selective ER Modulator, and its spectrum of action as safe oral contraceptive or hormonal treatment of menopause should now be considered.