Changes in glucocorticoid receptor number in the hypothalamus and pituitary of the sheep fetus with gestational age and after adrenocorticotropin treatment.

The concentrations of ACTH and cortisol both rise in the plasma of fetal lambs during late pregnancy, reflecting maturation of the fetal hypothalamic-pituitary-adrenal axis and providing the stimulus for parturition. The failure of rising cortisol to suppress plasma ACTH may be due to altered sensitivity of glucocorticoid negative feedback. To examine the possibility that this effect might be mediated through changes in the number of glucocorticoid receptors (GR) in the fetal hypothalamus and pituitary, we measured changes in GR number in these tissues from fetuses at discrete times of pregnancy between day 60 and term (day 145) and from newborn lambs and adult sheep. We also determined the effect of intrafetal ACTH administration in amounts known to produce premature parturition on GR number in fetuses at days 125-130 of gestation. Binding of [1,2,4-N-3H]triamcinolone acetonide to dispersed cell preparations of fetal pituitary and hypothalamus was saturable, temperature dependent, glucocorticoid specific, and of high affinity (2-3 X 10(-9) M). The number of GR in the pituitary always exceeded that in the hypothalamus. In both tissues GR number rose between days 60-70 to highest values on days 100-110, then decreased until day 125. GR number in the pituitary rose again at term, paradoxically at a time of rising endogenous glucocorticoid levels. However, after ACTH administration, there was a significant decrease in GR number in both hypothalamus and pituitary. These results indicate that altered efficacy of glucocorticoid negative feedback in term fetuses is not due to a decrease in pituitary or hypothalamic GR number. The rise in GR number at term and the fall after intrafetal ACTH treatment raises the possibility that mechanisms exist in the fetus allowing normal autoregulation of GR to be overridden at term.