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.Le texte complet de cet article est disponible en PDF.