Elevated levels of N-terminal pro-opiomelanocortin peptides in fetal sheep plasma may contribute to fetal adrenal gland development and the pre-parturient cortisol surge.

Abstract

Parturition in sheep is initiated by a rapid rise in fetal plasma cortisol. There is some controversy as to the exact nature of the drive for this pre-partum cortisol surge and it is thought that factors other than ACTH may act in concert to stimulate the development of the fetal adrenal gland. We have investigated the concentrations of ACTH and other peptides derived from pro-opiomelanocortin (POMC) in the circulation of fetal sheep during the final part of gestation, using specific 2-site immunoradiometric assays. The expected rise in fetal cortisol was seen with an 880% (p < 0.01) increase in concentration of this hormone between the initial measurement period (110-119 days gestation) and the final period (139-147 days). Fetal plasma ACTH increased less dramatically (137%; p < 0.03) during this time. The most surprising finding was the presence of very high relative concentrations of the N-terminal POMC peptide N-POMC(1-77) in the fetal circulation. Initially the concentration was 289 +/- 66 pmol/l compared to ACTH concentrations of 6.4 +/- 0.8 pmol/l. In the final week of gestation N-POMC(1-77) levels, although still high, had declined to 188 +/- 35 pmol/l (ACTH having increased to 13.7 +/- 2.2 pmol/l). Fetal plasma 3 yen-MSH was found to increase towards the end of gestation when the concentration of N-POMC(1-77) was declining, suggesting some cleavage of the latter. We postulate that the N-POMC(1-77) and its fragments, acting in concert with ACTH, play a vital role in stimulating the development of the fetal adrenal cortex and provide the additional drive to the adrenal gland required to stimulate parturition.

Extracellular signal-regulated kinases (ERK1/2) signaling pathway plays a role in cortisol secretion in the long-term hypoxic ovine fetal adrenal near term

“…Fassnacht et al (12) noted that NH 2 -terminal proopiomelanocortin (POMC) 1-28 stimulated mitosis in adrenocortical tumor cells (Y-1, NCI-h295) and primary cultures of bovine adrenocortical cells via an ERK-dependent pathway that was associated with decreased steroidogenesis. Elevated levels on NH 2 -terminal POMC-derived peptides have been noted in late-gestation fetal sheep and have been postulated to contribute to fetal adrenal gland development and the prepartum cortisol surge (35). We previously reported that POMC and NH 2 -terminal POMC fragment are elevated in the LTH fetus.…”

Developmental regulation of corticotrophin receptor gene expression in the adrenal gland of the ovine fetus and newborn lamb: effects of hypoxia during late pregnancy

“…Thus altered adrenal responsiveness probably reflects either low levels of ACTH 1-39 in the circulation of the fetal sheep between days 80-115, as suggested by Wintour et al (1995), or a greater proportion of large-molecular-weight peptides, derived from proopiomelanocortin (POMC), that are inhibitory to the adrenal effects of ACTH (Saphier et al 1993, Jones & Roebuck 1980, Schwartz et al 1995. There is diminished expression of P450 C17 in fetal adrenal tissue at days 80-100 of gestation, but the present studies show that the limitation to upregulation of P450 C17 in late pregnancy is apparently not due to the absence of ACTH-R, and reflects more the inadequate or inappropriate stimulus to the fetal adrenal cortical cells.…”

60 YEARS OF POMC: N-terminal POMC peptides and adrenal growth

“…There is some further evidence from sheep to support the notion that the processing of pro-γ-MSH can change (Saphier et al 1993). In the sheep, parturition is initiated by a rapid rise in the levels of fetal plasma cortisol, and measurement of fetal ACTH levels showed them to be low during gestation and to increase moderately toward the end of gestation.…”