In the present study, we used an in vivo approach to determine whether the fetus and estrogen have direct effects on placental production and serum concentrations of insulin-like growth factor I (IGF-I) in baboons. On day 100 of gestation, fetuses were removed and placentas left in situ (fetectomy). On days 100-155 of gestation after fetectomy, baboons received 50 mg androstenedione pellets sc in increasing numbers (1-3 every 10 days, n = 8), were injected sc with estradiol (E2) benzoate (0.50-2.5 mg/day, n = 8), or were not further treated (n = 6). Placentas were obtained on day 160, and cells were dispersed in 0.1% collagenase, isolated on 50% Percoll, then incubated for 24 h at 37 C in medium 199. Mean (+/- SE) peripheral serum E2 (nanograms per ml) in untreated baboons (n = 5) was 1.33 +/- 0.06 on days 101-160. Fetectomy decreased (P less than 0.001) E2 to 0.28 +/- 0.04, and androstenedione and E2 after fetectomy increased serum E2 to 0.75 +/- 0.08 and 2.51 +/- 0.23, respectively. Serum IGF-I (nanograms per ml) determined by RIA was 182 +/- 6 on days 101-160 in controls. Serum IGF-I increased (P less than 0.001) rapidly after fetectomy to 403 +/- 22 on days 101-160 and fell precipitously to 185 +/- 8 after placental delivery. Androstenedione and E2 treatment after fetectomy decreased IGF-I to 291 +/- 16 and 239 +/- 6, respectively, values similar to those before fetectomy. Uterine vein concentrations of IGF-I were similar to those in peripheral maternal serum, and the same relative treatment effects were observed. IGF-I secretion (picograms per ml/24 h) by placental trophoblasts of fetectomized baboons (80.1 +/- 9.8) was 242% greater (P less than 0.001) than controls (23.4 +/- 4.7) and decreased after fetectomy by androstenedione (56.7 +/- 15.1) and E2 (62.3 +/- 12.8). Thus, removal of the fetus decreased serum E2 and markedly elevated placental production and maternal serum levels of IGF-I, and these effects were largely reversed by androstenedione or E2. We suggest that the fetus, via secretion of estrogen precursors, regulates placental IGF-I production and consequently maternal serum concentrations of IGF-I during primate pregnancy.