Placental restriction alters the functional development of the pituitary-adrenal axis in the sheep fetus during late gestation

We have experimentally restricted placental growth in the sheep to investigate the impact of reduced substrate delivery on fetal pituitary proopiomelanocortin (POMC) mRNA levels and on circulating ACTH 1-39, immunoreactive ACTH, and cortisol concentrations during late gestation. Endometrial caruncles were removed in nine ewes before mating to reduce the number of placentomes formed [placental restriction group (PR)]. Fetal arterial PO2 and O2 saturation were reduced in the PR group (2.0 +/- 0.1 kPa and 42.8 +/- 1.1%, n = 9) when compared with control fetuses (3.1 +/- 0.1 kPa and 66.4 +/- 0.9%, n = 10). The ratio of anterior pituitary POMC mRNA:18 S ribosomal RNA was also lower (p < 0.05) in the PR group (0.49 +/- 0.05) when compared with the control group (0.80 +/- 0.12) after 140 d of gestation. In contrast, plasma concentrations of ACTH 1-39 and immunoreactive ACTH were similar in the PR and control groups throughout late gestation. Plasma ACTH 1-39 concentrations increased (p < 0.006) between 128 and 134 d of gestation, in both the PR (122-128 d: 2.70 +/- 0.34 pmol/L: 134-141 d; 7.07 +/- 1.57 pmol/L) and control (122-128 d; 3.36 +/- 0.56 pmol/L: 134-141 d; 10.78 +/- 2.88 pmol/L) groups. Combined adrenal weight was higher (p < 0.005) in the PR group (130 +/- 10 mg/kg) compared with controls (80 +/- 1 mg/kg) at 140 d of gestation, and plasma cortisol concentrations were also higher (p < 0.02) in PR than control fetuses between 127 and 141 d of gestation. These changes imply that the fetal hypothalamopituitary-adrenal axis is operating at a new central set point in the growth-restricted fetus.