Foetal endocrine maturation

Abstract

In domestic ruminants such as the sheep, birth is effected through sequential maturation of the foetal hypothalamicpituitary-adrenal (HPA) axis, leading to the increased output of cortisol. Factors regulating foetal pituitary adrenocorticotrophin (ACTH) secretion have been delineated, and these include corticotrophin releasing hormone (CRH), arginine vasopressin, prostaglandin (PG) E2 and endogenous opioids. The pre-partum increase in foetal plasma ACTH is associated with a rise in pro-opiomelanocortin (POMC) mRNA in the foetal pars distalis, and with an altered pattern of POMC post-translational processing. Foetal adrenal activation results from an increase in ACTH receptors and enhanced coupling through the Gs protein to adenylate cyclase, and increased expression of key steroidogenic enzymes including P45OC1p Cortisol modulates the mechanism by which ACTH activates foetal adrenal function, through specific glucocorticoid receptors (GR) in the foetal adrenal cortex. Although the numbers of GR change with gestation, the relative abundance of GR mRNA does not, pointing to post-translational regulatory mechanisms. Cortisol also stimulates an increase in the concentration of its own high affinity binding protein (corticosteroid binding globulin; CBG) in the foetal circulation, apparently by increasing CBG gene expression in the foetal liver, and by altering the extent of foetal CBG glycosylation in a manner that would be expected to decrease the metabolic clearance of this glycoprotein. Clear evidence for placental CRH and ACTH production is lacking in sheep, but PGE2, produced in increasing amounts by the placenta during late pregnancy, may augment the drive to HPA maturation. Aspects of the maturational pathway of cortisol biosynthesis have been described in other species, including the horse, and some comparison is made with the more detailed information currently available from species such as the sheep.

Improving pregnancy outcomes in humans through studies in sheep

“…5). The magnitude and timing of this preparturient surge in fetal plasma glucocorticoid vary between species and may be a result of activation of the fetal HPA axis (67) and/or reductions in levels of plasma corticosteroid-binding proteins (66,472) and/or an increased transplacental flux of glucocorticoids from the maternal to the fetal circulation (250). The preparturient surge in fetal plasma glucocorticoid concentration is important for regulation of structural and functional maturation of a number of fetal organs, promoting a switch from tissue accretion and cellular proliferation to tissue differentiation (130,132).…”

Nutritional regulation of uteroplacental prostaglandin production and metabolism in pregnant ewes and mares during late gestation

“…These changes in plasma oestrogen and progesterone in the ewe may have been related to increased adrenocortical activity in the fetus, particularly in the animals close to term. Increases in fetal plasma cortisol occur in response to maternal fasting in this species and cortisol has been shown to induçe the enzymes responsible for conversion of progesterone to oestrogen in the ovine placenta (Fowden & Silver, 1983;Mason et al, 1989;Challis et al, 1993). Thus, steroid hormone changes may contribute to the increased uteroplacental production of primary PGs found during fasting in ewes close to term.…”

“…The rise in fetal plasma PGE during fasting may also be involved in stimulating cortisol secretion by the fetus. Fetal cortisol levels rise during maternal fasting and PGE2 is known to cause cortisol secretion in the sheep fetus, even at a gestational age when the fetal adrenal is relatively unresponsive to exogenous ACTH (Challis et al, 1993;Fowden & Silver, 1985;Thorburn, 1992). PGE evoked cortisol secretion may therefore accelerate maturation of the fetus during fasting and maximize its changes of survival should delivery occur.…”

Fifty years of the British Equine Veterinary Association as a facilitator of progress in equine clinical science

“…The relationship of fetal/adrenal cortex development and secretion in relation to maturity was addressed by Silver et al . (1984), Challis et al . (1993) and Han et al .…”