Modulation of Estetrol Bioavailibility in Fetal and Maternal Circulation in Pregnancy

Le résumé fourni par la source

Introduction Estetrol (E4), a natural estrogen uniquely synthesized prenatally by the fetal liver, preferentially binds estrogen receptor α (ESR1). Unlike other estrogens, E4 does not bind to the sex hormone-binding globulin (SHBG). Its estrogenic function is disabled by conjugation with glucuronic acid and sulfonyl groups. Its physiological role remains unknown. This study examines the E4 bioavailability in the fetus, and mother, as well as the potential regulation of its activity by the placenta. Methods Active and glucuronidated estradiol (E2), estriol (E3), and E4 were quantified in 89 matched maternal and umbilical cord (fetal) plasma samples using liquid chromatography-tandem mass spectrometry. Expression of genes involved in E4 metabolism, and estrogen receptors (ESR1, ESR2, GPER1) was assessed by qPCR in patient-matched tissues: umbilical cord (n=22), placenta (n=25), decidua (n=23), and myometrium (n=18). Results In fetal plasma, E3 (475±80 nM) was the predominant estrogen, followed by E4 (41±26 nM) and E2 (39±31 nM). Surprisingly, only 51% of E4 was present in the active, unglucuronidated form. In contrast, E2 and E3, reportedly binding SHBG, were mainly active (89% E2; 67% E3). In maternal plasma, E3 (73±10 nM) and E4 (8±4 nM) were lower than in cord blood, whereas E2 (78±30 nM) was enriched. 95% of E2, 37% of E3, and 25% of E4 were unglucuronidated. Active and total levels of E4 and E2 (but not E3) correlated positively between fetal and maternal circulation. Higher fetal active and total E4, fetal total E3, and maternal active and total E2 were found in pregnancies with female fetuses. UDP-glucuronosyltransferase 2B7 was not detected in any tissue, suggesting minimal glucuronidation at the feto-maternal interface. In contrast, the activating β-glucuronidase (GUSB) was widely expressed, particularly in the placenta. Placental GUSB levels correlated inversely with fetal total and active E4. Further, fetal total E4 correlated with placental ESR2 expression, while maternal free and total E4 levels correlated with placental expression of its preferential receptor ESR1. Discussion Glucuronidation was higher in E4 compared to E2 and E3, and increased in maternal compared to fetal circulation, suggesting that conjugation plays a prominent role in regulating E4 bioactivity. The high placental β-glucuronidase expression supports that local reactivation of E4 may occur. The correlations between fetal and maternal E4 concentrations, as well as of E4 with placental β-glucuronidase and target receptors support the placenta"s role as a regulatory interface, mediating estrogen transfer and metabolism between fetus and mother. Elucidating these mechanisms is key to grasping E4 physiology in pregnancy. Publication History Article published online: 10 December 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.