Biosynthesis of estetrol in human pregnancy: Potential pathways

• Published in: The Journal of steroid biochemistry and molecular biology 2023-09, Vol.232, p.106359-106359, Article 106359
• Main Authors: Stanczyk, Frank Z., Archer, David F.
• Format: Article
• Language: English
• Subjects: Estetrol; Estrogens; Fetus; Placenta; Pregnancy
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2023.106359

Estetrol (E4) has emerged as a novel and highly promising estrogen for therapeutic use. E4 is a weak natural estrogen produced only in pregnancy. Because of its novelty, there is considerable interest by clinicians in how it is produced in pregnancy. Although the fetal liver plays a key role in its production, the placenta is also involved. A current view is that estradiol (E2) formed in the placenta enters the fetal compartment and is then rapidly sulfated. E2 sulfate then undergoes 15α-/16α-hydroxylation in the fetal liver thereby forming E4 sulfate (phenolic pathway). However, another pathway involving 15α,16α-dihydroxy-DHEAS formed in the fetal liver and converted to E4 in the placenta also plays a significant role (neutral pathway). It is not known which pathway predominates, but both pathways appear to be important in E4 biosynthesis. In this commentary, we summarize the well-established pathways in the formation of estrogens in the nonpregnant and pregnant female. We then review what is known about the biosynthesis of E4 and describe the 2 proposed pathways involving the fetus and placenta. •Estetrol (E4) biosynthesis in pregnancy is usually attributed to a phenolic pathway.•This pathway involves E4 formation in fetal liver from placental estradiol.•A neutral pathway contributes significantly to E4 biosynthesis as well.•It involves placental aromatization of fetal 15α-/16α-hydroxylated androgens.