Regulation of 1lβ-Hydroxysteroid Dehydrogenase Activity in the Baboon Placenta by Estrogen*

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Abstract
We have previously shown that the change in transuteroplacental cortisol (F)-cortisone (E) metabolism in vivo from preferential reduction (E to F) at midgestation to oxidation by term (F to E) does not occur in baboons in which the production or action of estrogen have been blocked. Moreover, because the administration of androstenedione (.DELTA.4A) to baboons increased estradiol (E2) production at midgestation and induced a pattern of F-E metabolism similar to that at term, we suggested that estrogen regulates placental F-E interconversion. The present study was designed to ascertain whether estrogen regulates the activity of the placental 11.beta.-hydroxysteroid dehydrogenase (11.beta.HSD) enzyme catalyzing the oxidation of F to E. Placentas were obtained on day 100 (n = 10) and day 165 (n = 10) of gestation (term = day 184) from untreated baboons, on day 100 from animals (n = 7) treated with .DELTA.4A between days 70-100 of gestation, and on day 165 from animals in which placental estrogen was decreased by fetectomy (n = 5) on day 100 of gestation. Tissue was homogenized in phosphate buffer (pH 7.4) and microsomal fractions (105,000 .times. g) incubated (37 C; 2 min) in buffer containing 2.7 mM NAD+ and 0.03-1.0 .mu.M [3H]F. Serum concentrations of E2 (nanograms per ml) in untreated baboons on day 100 (0.7 .+-. 0.2) were 3-fold lower than those at term, increased (P < 0.05) by .DELTA.4A treatment (2.4 .+-. 0.3), and decreased (0.12 .+-. 0.01; P < 0.05) by fetectomy. The specific activity (picomoles of E per min/mg protein) of placental 11.beta.HSD in untreated baboons at midgestation (134 .+-. 17) was increased (P < 0.01) 3-fold by .DELTA.4A treatment. Enzyme activity at term (148 .+-. 29) was similar to that at midgestation, but markedly decreased (P < 0.01) by fetectomy (16 .+-. 4). Placental capacity to oxidize F to E (micromoles per min/placenta) in untreated baboons was 3-fold greater (P < 0.01) at term (88 .+-. 15) than at midgestation and was markedly reduced (P < 0.01) by fectectomy (3 .+-. 1). Collectively, these findings indicate that the activity of the placental 11.beta.HSD enzyme catalyzing the oxidation of F to E is increased in baboons in which placental estrogen production was elevated at midgestation and decreased in animals when estrogen formation was inhibited by fetectomy. Based on the results of our previous in vivo studies and the present study, we suggest that estrogen produced in the placenta from androgen precursors regulates, in a paracrine/autocrine fashion, corticosteroid metabolism in the placenta by stimulating the synthesis of the enzyme protein(s) catalyzing the oxidation of F to E.