Precursor role of 15α-hydroxyestradiol and 15α-hydroxyandrostenedione in the formation of estetrol

Abstract

Studies were designed to elucidate the origin of estetrol (15α-hydroxyestriol (estra-1,3,5(10)-triene-3,15α,17β-tetrol) or E4) during late human pregnancy. 3H-Labelled 15α-hydroxy-estradiol (3,15α-dihydroxyestra-1,3,5(10)-trien-17-one or 15E2) and 14C-labelled 17β-estradiol (estra-1,3,5(10)-triene- 3,17β-diol or E2) were infused into the fetus during transfusion in utero for erythroblastosis fetalis, and in another study the same substrates were injected intravenously into the maternal circulation. In a third study, 3H-labelled 15α-hydroxyandrostenedione (15α-hydroxyandrost-4-ene-3,17-dione or 15Δ4) and 14C-labelled E2 were infused into the fetus. Maternal urine was collected for 5-6 days, and after Glusulase hydrolysis, the following metabolites were isolated: estriol (estra-1,3,5(10)- triene-3,16α,17β-triol or E3) containing 14C only and 15α-hydroxyestrone (3,15α-dihydroxyestra-1,3,5(10)-trien-17-one or 15E1), 15E2, and E4, all containing both labels. From the isotope content of these metabolites, it was concluded that E4 was derived from both fetal E2 and 15Δ4 and only partially via 15E2. When administered to the fetus, E2 and 15Δ4 contributed approximately equal amounts to urinary E4. The yield of 15α-hydroxylated estrogens from E2 injected into the mother was very low indicating the predominantly fetal origin of the 15α-hydroxylase. 15Δ4 was a better precursor than E2 for urinary 15E2.