Biosynthesis of estetrol in human pregnancy: Potential pathways

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.