RESUMEN
Estetrol (E4) 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 17ß-estradiol (E2) and E4 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 E4 stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ERα actions. However, E4 failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane-initiated steroid signaling (MISS). Furthermore, E4 antagonized E2 MISS-dependent effects in endothelium but also in MCF-7 breast cancer cell line. This profile of ERα activation by E4, uncoupling nuclear and membrane activation, characterizes E4 as a selective ER modulator which could have medical applications that should now be considered further.
Asunto(s)
Membrana Celular/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Estetrol/farmacología , Receptor alfa de Estrógeno/metabolismo , Útero/efectos de los fármacos , Animales , Western Blotting , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Endotelio Vascular/metabolismo , Estetrol/química , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/genética , Femenino , Expresión Génica/efectos de los fármacos , Células HeLa , Células Hep G2 , Humanos , Inmunohistoquímica , Células MCF-7 , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Moleculares , Estructura Molecular , Ovariectomía , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Útero/metabolismoRESUMEN
Estetrol (E(4)) is an estrogenic steroid molecule synthesized exclusively by the fetal liver during human pregnancy and reaching the maternal circulation through the placenta. Its function is presently unknown. After its discovery in the mid-1960s, E(4) research revealed rather unique properties of this steroid and spawned a large body of state-of-the art publications. Nevertheless, 20 years later experimental work was virtually abandoned. In recent years based on new data, E(4) has experienced a vita nova, a revival of preclinical and clinical research activities with the goal to elucidate its physiological function and explore its potential for therapeutic use in humans. This review is intended to offer an historical account of the discovery of E(4) and the preclinical studies conducted during the heyday of E(4) research that ended in the mid-1980s.
