We have previously shown that ACTH and PRL stimulate baboon fetal adrenal dehydroepiandrosterone (DHA) production both in vitro and in vivo and that estrogen diminishes the responsivity of the adrenal to tropic peptides in vitro. In the present study we determined the effects of increasing placental estrogen production by the administration of androstenedione at midgestation on DHA production by the baboon fetus in vivo. Pregnant baboons were untreated (n = 8) or treated (n = 9) with increasing numbers of androstenedione implants inserted in the mother at 8-day intervals between days 70-100 of gestation (term = day 184). On day 100, the fetuses were exteriorized, and a constant infusion of saline (0.1 ml/min) was initiated via a catheter inserted into a femoral vein of the fetus. At 40 min, a bolus injection of either 30 nmol ACTH or 40 nmol ovine PRL was administered to fetuses. ACTH or PRL (0.2 nmol/min.0.1 ml saline) were then infused for an additional 25 min. The concentrations of serum estradiol (E2) in the uterine vein (20.2 +/- 1.5 ng/ml; mean +/- SE) and estrone (E1) in umbilical vein (11.9 +/- 3.1 ng/ml) of androstenedione-treated baboons were 2-fold greater (P less than 0.05) than respective values in untreated baboons. Baseline concentrations of DHA in the femoral vein of the fetus were similar in all treatment groups (overall mean, 120 +/- 20 ng/ml) and greater (P less than 0.05) than values (27 +/- 3) in the mother. In untreated control baboons, basal DHA concentrations in the fetus were increased (P less than 0.05) by 69 +/- 17% and 94 +/- 29% after fetal injection of ACTH (n = 4) or PRL (n = 4), respectively. In contrast, neither PRL (n = 5) nor ACTH (n = 4) had any effect on serum DHA when injected into androstenedione-treated baboons. Regardless of treatment, injection of ACTH or PRL into the fetus had no effect on DHA concentrations in the mother. Collectively, these findings indicate that the ability of the fetal adrenal to increase DHA production in response to an acute infusion of ACTH or PRL was abolished in baboons in which placental estrogen production was increased prematurely at midgestation. Therefore, we suggest that during the second half of gestation in the baboon a regulatory system may exist in utero, in which there is feedback control of the placental product estrogen on the formation of the fetal adrenal precursor DHA.