The present study tests the hypothesis that estrogen regulates the alteration in baboon placental cortisol (F)/cortisone (E) interconversion from preferential reduction (E----F) at midgestation to oxidation (F----E) near term. Five pregnant baboons (Papio anubis) received increasing numbers of 50-mg implants of androstenedione inserted sc at 8-day intervals between days 70 and 100 of gestation (term = day 184) to elevate the production of estrogen. Five animals served as controls at midgestation and received implants containing no steroid, while four baboons were studied near term between days 164-170 of gestation. All animals were bled from a maternal saphenous vein at 2-day intervals, and the serum was assayed for estradiol. On days 100 or 170 of gestation, transuterofetoplacental corticosteroid dynamics were determined by the constant infusion method. Baboons were anesthetized with ketamine and halothane-nitrous oxide and a constant infusion of [3H]F/[14C]E initiated via a maternal saphenous vein. At 60 min, animals were laparotomized and at 70, 80, and 90 min, blood samples were obtained from right and left uterine veins and from a maternal saphenous vein. At 95 min, an incision was made in the uterus, and blood samples were obtained from the umbilical vein and artery. Radiolabeled F and E were extracted from serum and purified by paper chromatography. Maternal serum E2 concentrations (nanograms per ml; mean +/- SE) were greater (P less than 0.01) between days 94 and 100 of gestation in androstenedione-treated baboons (2.4 +/- 0.3) than in untreated animals at midgestation (0.7 +/- 0.2), but lower than those near term (4.5 +/- 1.0). On day 100 of gestation, conversion of E to F across the uterus in control animals (30%) was similar to that of the reverse reaction (23%). In androstenedione-treated baboons at midgestation the conversion of E----F (8%) was lower (P less than 0.05) than the oxidation of F----E (27%) and not different from that in untreated baboons at term (E----F = 13%; F----E = 28%). The dominance of transuterofetoplacental conversion of F----E over the conversion of E----F in term and in androstenedione-treated animals at midgestation was maintained when transfer constants were corrected for fetal metabolic contributions. We conclude that the increase in placental estrogen production induced by androstenedione administration at midgestation alters the pattern of transuterofetoplacental F-E metabolism, supporting the hypothesis that estrogen regulates placental corticosteroid metabolism.