We determined the role of the fetus and estrogen on transuteroplacental cortisol (F)-cortisone (E) metabolism in the baboon (Papio anubis). The interconversion of F-E at mid-gestation (day 100; term = day 184) was compared with that in animals near term (day 170) in which the fetus, but not the placenta, was removed (fetectomy) on day 100 and that in baboons treated daily between days 140 and 170 of gestation with the antiestrogen ethamoxytriphetol [1-(p-diethylamino-ethoxyphenol)1-phenyl-2-p-methoxyphenolethan ol (MER-25)]. In fetectomized animals at term, transuteroplacental conversion of E to F (30%) exceeded (P less than 0.05) that of the reverse reaction (7%). This pattern of metabolism was significantly different from that measured in intact pregnant animals at term, in which oxidation of F to E (28%) exceeded reduction of E to F (4%). In contrast, placental metabolism in fetectomized baboons at term was similar to that in pregnant animals at mid-gestation, in which conversion of F to E (20%) was lower (P less than 0.05) than reduction of E to F (39%). Treatment of intact pregnant baboons with MER-25 also resulted in a pattern of F-E metabolism across the placenta at term which was similar to that measured at midgestation but different from that in untreated baboons at term. Collectively, our findings show that the striking alteration in F-E interconversion from reduction (E to F) at midgestation to oxidation (F to E) by term, as measured across the placenta in vivo during the second half of baboon pregnancy, does not occur in animals lacking a fetus or in intact baboons in which the action of estrogen was inhibited. Therefore, we suggest that the fetus and/or the hormones of pregnancy that are dependent upon the fetus (i.e. estrogen) regulate transuteroplacental corticosteroid metabolism.