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Type:	Artigo de Periódico
Title:	Estetrol (E4): the new estrogenic component of combined oral contraceptives
Authors:	Giovanni Grandi Maria Chiara Del Savio Agnaldo Lopes da Silva Filho Fabio Facchinetti
Abstract:	Estetrol (E4) is a natural fetal estrogenic steroid discovered in 1965 at the Karolinska Institutet in Stockholm (Sweden). It was studied for a period of 20 years originally as a biomarker of fetal wellbeing during pregnancy [2] before being abandoned as a weak estrogen: research into the potential physiological effects and applications of E4 resumed in 2001. E4 is a steroid hormone with four -OH groups, two more than estradiol (E2), the estrogen physiologically produced by the granulosa cells of human ovaries (Figure 1). The fetal liver is the exclusive site responsible for 15α- and 16α-hydroxylation: for this reason, E4 is only present during pregnancy from 9 weeks of gestation until only shortly after birth but its physiological role is still unknown. The two additional -OH groups have a crucial impact on the oral pharmacokinetics: the half-life of E4 is 20–28 hours, compared with only 10–20 minutes for estriol (E3), 1–2 hours for natural E2 and 10–12 hours formicronized E2. E4 is minimally, if at all,metabolized and not reconverted to E3 or E2. Receptor binding and target interaction studies showed E4 to have high selectivity for the estrogen receptors (ER), indicating a potential for low risk of side effects. No specific toxicity for E4 has been observed to date. The estrogen dose in COCs has gone from micrograms (50 to 15) in the age of EE, to a few milligrams (1.5–3) in the E2 era, to several milligrams (15) in the age of E4, as the estrogenic component became weaker and weaker: during evolution the emphasis has shifted from the crude mass of steroids administered to their real biological activity. In terms of safety, mainly the lowest E4 doses seems to be associated to a favorable hemostatic profile and impact on lipids, low drug-drug interaction and a limited stimulation of breast tissue. The 10 mg E4 dose potency at endometrial level seems similar to that of the 2 mg E2 V dose: for this reason it seems that at the highest doses of E4 used and studied (≥ 15mg), E4 COCs can guarantee more satisfactory cycle control in comparison to E2-based COCs (i.e. lowrate of unscheduled bleeding and/or spotting and the absence of withdrawal bleeding). Unfortunately, at these E4 doses (≥ 15 mg) the hemostatic and metabolic effects of this combination have not been deeply studied and it has not been clearly demonstrated to be weaker than during traditional EE-based COCs. However, this third estrogenic generation of COCs could provide additional benefits to women’s health and in the coming years will be a topic for great interest and further personalization in hormonal contraception technology.
Subject:	Contracepção hormonal Estetrol Metabolismo Hemostasia Fatores de risco de doenças cardíacas Hormônios Esteroides
language:	eng
metadata.dc.publisher.country:	Brasil
Publisher:	Universidade Federal de Minas Gerais
Publisher Initials:	UFMG
metadata.dc.publisher.department:	MED - DEPARTAMENTO DE GINECOLOGIA OBSTETRÍCIA
Rights:	Acesso Aberto
metadata.dc.identifier.doi:	https://doi.org/10.1080/17512433.2020.1750365
URI:	http://hdl.handle.net/1843/54691
Issue Date:	7-Apr-2020
metadata.dc.url.externa:	https://www.tandfonline.com/doi/full/10.1080/17512433.2020.1750365
metadata.dc.relation.ispartof:	Expert Review of Clinical Pharmacology
Appears in Collections:	Artigo de Periódico

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