5α-dihydroprogesterone formation in human placenta from and 5-pregnan-3β-yl-20-one sulfate

5α-Dihydroprogesterone (5α-DHP) is the immediate precursor of 5α-pregnan-3α-ol-20-one, a potent anxiolytic/anesthetic agent in all vertebrate animals tested, including humans. The levels of 5α-DHP in the plasma of pregnant women are very high; and during the third trimester of pregnancy, the blood production rate of this steroid may exceed 100 mg/24 h. 5α-DHP in maternal plasma, however, cannot be accounted for totally by the metabolism of maternal plasma progesterone. This study was conducted to evaluate the possibility that 5α-DHP is synthesized in placenta from delivered to the trophoblast via the fetal umbilical blood. In incubations of placental minces with radiolabelled , there is extensive epimerization and the intermediate, 5α-DHP, is the major product. In other incubations, 5α-pregnan-3β-ol-20-one-sulfate was hydrolysed and the liberated 5α-pregnan-3β-ol-20-one was converted to 5α-DHP by homogenates of placental tissue, but 5α-pregnan-3β-ol-20-one-sulfate was not. The oxidation of was concentrated in microsome-enriched preparations of placental tissue and the apparent Kms for 5α-pregnan-3α-ol-20-one and 5α-pregnan-3β-ol-20-one were 3.6 μM and 78 nM, respectively. The Vmaxs for 5α-DHP formation from 5α-pregnan-3α-ol-20-one and 5α-pregnan-3β-ol-20-one were, respectively, 336 pmol/min/mg protein and 9.7 nmol/min/mg protein. These oxidation reactions were supported by both NAD+ and NADP+. We suggest that progesterone, which enters the umbilical circulation from its site of synthesis in the syncytiotrophoblast, is metabolized in the fetus to and to sulfates. These metabolites of progesterone, and 5α-pregnan-3β-yl-20-one sulfate, formed in the fetus, serve as plasma-borne substrates for trophoblast formation of 5α-DHP. Because of the hemochorioendothelial nature of human placentation, 5α-DHP secreted from the trophoblast will preferentially enter the maternal compartment, thus constituting a maternal plasma progesteroneindependent source of 5α-DHP.