Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause

Céline Gerard, Jean-François Arnal, Maud Jost, Jonathan Douxfils, Françoise Lenfant, Coralie Fontaine, René Houtman, David F Archer, Robert L Reid, Rogerio A Lobo, Ulysse Gaspard, Herjan J T Coelingh Bennink, Mitchell D Creinin, Jean-Michel Foidart

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Introduction: Estrogens used in women’s healthcare have been associated with increased risks of venous thromboembolism (VTE) and breast cancer. Estetrol (E4), an estrogen produced by the human fetal liver, has recently been approved for the first time as a new estrogenic component of a novel combined oral contraceptive (E4/drospirenone [DRSP]) for over a decade. In phase 3 studies, E4/DRSP showed good contraceptive efficacy, a predictable bleeding pattern, and a favorable safety and tolerability profile. Areas covered: This narrative review discusses E4ʹs pharmacological characteristics, mode of action, and the results of preclinical and clinical studies for contraception, as well as for menopause and oncology. Expert opinion: Extensive studies have elucidated the properties of E4 that underlie its favorable safety profile. While classical estrogens (such as estradiol) exert their actions via both activation of nuclear and membrane estrogen receptor α (ERα), E4 presents a specific profile of ERα activation: E4 binds and activates nuclear ERα but does not induce the activation of membrane ERα signaling pathways in specific tissues. E4 has a small effect on normal breast tissue proliferation and minimally affects hepatic parameters. This distinct profile of ERα activation, uncoupling nuclear and membrane activation, is unique.

Original languageEnglish
Pages (from-to)121-137
Number of pages17
JournalExpert review of clinical pharmacology
Issue number2
Early online date22 Mar 2022
Publication statusPublished - 2022


  • Combined oral contraception
  • contraception
  • E4
  • estetrol
  • estrogen
  • estrogen receptor
  • hemostasis
  • menopause
  • venous thrombosis


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