Human Fetal Adrenal Definitive and Fetal Zone Metabolism of Pregnenolone and Corticosterone: Alternate Biosynthetic Pathways and Absence of Detectable Aldosterone Synthesis*

Abstract

In the rhesus monkey and ovine fetus in utero, aldosterone concentrations do not rise in response to surgical stress, ACTH, or angiotensin-II, all of which are secretagogues for this mineralocorticoid in the adult. To assess the mechanism of this phenomenon in the human fetus, metabolism of pregnenolone and corticosterone by second trimester human fetal adrenal definitive zone and fetal zone tissue was studied. After incubation of fresh tissue with trace amounts of [3H]pregnenolone or [3H]corticosterone, the products of metabolism were separated using high performance liquid chromatography and quantified. The Δ5-3β-hydroxysteroids 17-hydroxypregnenolone and dehydroepiandrosterone and their sulfates comprised 85–90% of metabolized pregnenolone. In the fetal zone, cortisol was the predominant secreted Δ4-3-ketosteroid, accounting for 6–8% of the metabolized pregnenolone. In the definitive zone, progesterone and corticosterone were the predominant secreted Δ4-3-ketosteroids, each accounting for about 2% of the metabolized pregnenolone. 11-Dehydrocorticosterone and sulfates were the only metabolites detected after incubation of fetal adrenal tissue with corticosterone. 11-Dehydrocorticosterone accounted for more than 80% of the metabolized corticosterone in the definitive zone and 50% in the fetal zone. Incubations with secretagogues or antioxidants (10 nmol/L ACTH, 10 nmol/L angiotensin-II, 21 mmol/L potassium, 100 mmol/L dimethylsulfoxide, 5 μmol/L metyrapone, or 100 μmol/L butylated hydroxyanisole) did not change the pattern or extent of precursor metabolism. No aldosterone, 18-hydroxycorticosterone, or 18-hydroxydeoxycorticosterone was detected in baseline or stimulated incubations of human fetal tissue. In contrast, adult human zona glomerulosa metabolized corticosterone to aldosterone, 18-hydroxycorticosterone, and 11-dehydrocorticosterone under similar conditions. ACTH (10 nmol/L) increased the relative production of aldosterone from 29% to 45% of the metabolized corticosterone, while 18-hydroxycorticosterone decreased from 41% to 26%, and 11-dehydrocorticosterone remained unchanged at 30%. These results indicate that, in the second trimester human fetal adrenal, the non-17-hydroxylated steroid metabolic pathway is localized to the definitive zone, and mineralocorticoid secretion is very low and unresponsive to secretagogues known to be active in the adult.