Origin of deoxycorticosterone sulfate (DOC-SO4) in plasma of pregnant women: pregnenolone-3,21-disulfate is a placental precursor of DOC-SO4.

The plasma levels of deoxycorticosterone sulfate (DOC-SO4) in near-term pregnant women are approximately 100 times those in plasma of men or non-pregnant women. Yet, neither the tissue site of synthesis nor the precursor of DOC-SO4 that enters maternal plasma is known. Several potential sources have been excluded: plasma DOC-SO4 is not derived from plasma DOC; and the secretion of C21-steroids (other than aldosterone) from the maternal adrenals during human pregnancy is not increased. Similarly, the transfer of DOC-SO4 from fetal plasma cannot account for the high level of DOC-SO4 in the maternal compartment, and a reduced clearance of plasma DOC-SO4 during pregnancy cannot account for the high levels of DOC-SO4. Indeed, the rate of clearance of DOC-SO4 from plasma is 10-100 times that of most other steroid sulfates. To address this question further, we evaluated the possibility that fetal plasma pregnenolone-3,21-disulfate serves as a precursor for DOC-SO4 formation in the placenta. The preferential hydrolysis of the 3beta-sulfate of pregnenolone-3,21-disulfate in placenta would give rise to pregnenolone-21-monosulfate, which, if acted upon by placental 3beta-hydroxysteroid dehydrogenase/delta5 --> 4 isomerase, could give DOC-SO4. [3H]Pregnenolone-3,21-disulfate was incubated with minces of human placental tissue for 5, 20, 60 and 120 min. Radiolabelled DOC-SO4, DOC, and pregnenolone-21-monosulfate were isolated from the incubation media and quantified. After a 5 min incubation, 7.5% of substrate was converted to DOC-SO4; and after 20, 60 and 120 min approximately 30% of the [3H]pregnenolone-3,21-disulfate was recovered from the media of these incubations as [3H]DOC-SO4. [3H]DOC was also present in the incubation media and the concentrations of this product increased as a function of incubation time. Therefore, pregnenolone-3,21-disulfate, which is present in very high concentrations in fetal plasma (approximately 1000 ng/ml), is metabolized in the placenta to DOC-SO4. Because of the fetal and maternal vascular arrangements of the hemochorioendothelial placenta of human pregnancy, steroids produced in syncytiotrophoblasts preferentially enter the intervillous space; thus, fetal plasma pregnenolone-3,21-disulfate may serve as a placental precursor of maternal plasma DOC-SO4.