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

• Published in: EMBO molecular medicine 2014-10, Vol.6 (10), p.1328-1346
• Main Authors: Abot, Anne, Fontaine, Coralie, Buscato, Mélissa, Solinhac, Romain, Flouriot, Gilles, Fabre, Aurélie, Drougard, Anne, Rajan, Shyamala, Laine, Muriel, Milon, Alain, Muller, Isabelle, Henrion, Daniel, Adlanmerini, Marine, Valéra, Marie‐Cécile, Gompel, Anne, Gerard, Céline, Péqueux, Christel, Mestdagt, Mélanie, Raymond‐Letron, Isabelle, Knauf, Claude, Ferriere, François, Valet, Philippe, Gourdy, Pierre, Katzenellenbogen, Benita S, Katzenellenbogen, John A, Lenfant, Françoise, Greene, Geoffrey L, Foidart, Jean‐Michel, Arnal, Jean‐François
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Analysis; Animals; Blotting, Western; Breast cancer; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Proliferation - drug effects; EMBO45; Endocrinologie, métabolisme & nutrition; Endocrinology, metabolism & nutrition; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; estetrol; Estetrol - chemistry; Estetrol - pharmacology; estrogen receptor; Estrogen Receptor alpha - chemistry; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Ethinyl estradiol; Experiments; Female; Fetuses; Gene expression; Gene Expression - drug effects; HeLa Cells; Hep G2 Cells; Human health sciences; Humans; Immunohistochemistry; Life Sciences; Ligands; Low density lipoprotein receptors; MCF-7 Cells; Menopause; Mice, Inbred C57BL; Mice, Knockout; Models, Molecular; Molecular Structure; Nitric-oxide synthase; Ovariectomy; Phenols; Physiology; Pregnancy; Prevention; Protein Structure, Secondary; Protein Structure, Tertiary; Research Article; Reverse Transcriptase Polymerase Chain Reaction; Sciences de la santé humaine; Uterus; Uterus - drug effects; Uterus - metabolism
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.201404112

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. Synopsis Estetrol (E 4 ) is shown to be a less potent estrogen than E 2 but with the features of a natural Selective ER Modulator suggesting its application as a safe oral contraceptive or for the hormonal treatment of menopause. The nuclear transcriptional activity of ERα in the mouse uterus leading to the proliferation of the endometrial epithelium is modulated by E 4 . The prevention of atheroma, another process recognized to be nuclear ERα‐dependent, is promoted by E 4 in hypercholesterolemic mice. At variance with E 2 , neither acceleration of endothelial healing nor activation of endothelial NO synthase, two ERα membrane‐dependent effects, are affected by E 4 . The ERα membrane‐dependent effects of E 2 are antagonized by E 4 , not only in the endothelium, but also in MCF‐7 breast cancer cells. E 4 acts as a natural Selective Estrogen Receptor Modulator (SERM) uncoupling nuclear and membrane activation, and its medical potential should now be fully explored. Graphical Abstract Estetrol (E 4 ) is shown to be a less potent estrogen than E 2 but with the features of a natural Selective ER Modulator suggesting its application as a safe oral contraceptive or for the hormonal treatment of menopause.