Plasma levels of ACTH and cortisol in fetal sheep increase progressively during late pregnancy, providing the stimulus for birth. However, little information is available concerning either sources of pro-opiomelanocortin (POMC, the precursor to ACTH) or changes in POMC gene expression, which may be responsible for the elevated fetal plasma ACTH concentrations. We therefore studied the relative amount of POMC mRNA in fetal sheep hypothalami, anterior pituitaries and adrenals at discrete times of pregnancy between day 60 and term (approximately 145 days) and from newborn lambs. Total RNA from these tissues was analysed by Northern blot hybridization using a human POMC DNA probe, and the amount of POMC mRNA was expressed relative to the signal obtained for 18S ribosomal RNA. A single 1.2 kb transcript was detected by day 60 in the anterior pituitary, and its relative amount did not change significantly until after days 125-130. Pituitary POMC mRNA levels increased significantly at days 138-143, remained elevated at term and increased further in newborn lambs. In contrast, POMC mRNA was undetectable in hypothalami and adrenal glands of fetuses at all ages. The results suggested that the prepartum rise in plasma ACTH concentrations in fetal sheep is due to increased POMC biosynthesis in the fetal pituitary. The increase in POMC mRNA occurs at a time when fetal plasma cortisol concentrations are elevated, indicating that the negative feedback effects of circulating glucocorticoids on the fetal hypothalamic-pituitary axis may be obscured by other mechanisms that increase pituitary POMC mRNA accumulation during the last week of gestation.