In mammals, survival both before and after birth depends on a number of key physiological processes such as the provision of 02, a supply of oxidative substrates and a means of removing the waste products of metabolism. In adults these processes are carried out by a number of different tissues, whereas in the fetus they are carried out primarily by the placenta. The successful transition from intrato extra-uterine life, therefore, depends on the ability of specific tissues and organ systems to take over the functions of the placenta at birth. Consequently, organs such as the lungs, liver, kidneys and gut undergo maturational changes during late gestation in preparation for extra-uterine life. Most of these changes are glucocorticoid dependent and can be induced prematurely by exogenous glucocorticoid administration (Silver, 1990; Liggins, 1994; Fowden, 1995). As a consequence, synthetic glucocorticoids are now routinely administered to women in threatened preterm labour to improve neonatal viability (NIH Consensus Development Conference, 1995). In all species studied so far, there is an increase in the circulating glucocorticoid concentration in the fetus towards term (Fig. 1). The magnitude and timing of this cortisol surge vary between species, as does the precise mechanism by which it occurs (Fig. 1; Fowden & Silver, 1995; Wood & Cudd, 1997). In most species, the prepartum cortisol surge is due to increased adrenal cortisol output, but in certain animals, such as the rat and horse, its effect is enhanced by a fall in the level of plasma corticosteroidbinding globulin (Challis et al. 1993; Wood & Cudd, 1997). In normal conditions, therefore, fetal tissues are exposed to increasing levels of bioactive glucocorticoid for periods of up to 10-15 d before delivery.

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Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance?

The glucocorticoids, cortisol and corticosterone, have a unique function in the fetus in inducing a wide range of enzymes before birth that have little or no function during fetal life but on which survival after birth is dependent. The loss of the placenta at birth deprives the fetus of a source of oxygen, glucose and heat (among many other things) for which alternatives must be available immediately if survival is to be assured. In anticipation of these needs several organs undergo maturational changes in late pregnancy aimed at meeting these requirements. The lungs mature structurally and functionally, becoming distensible and capable of coping with high surface tension when air enters the alveoli with the first breath. In the liver, glycogen accumulates and gluconeogenesis is initiated to meet the demands for glucose until feeding begins. There is an increase in the production of tri-iodothyronine and catecholamines in preparation for the sharp increase in metabolic rate and thermogenesis associated with breathing and the cold environment. All these dramatic maturational events are regulated by cortisol as are numerous others in most organ systems that contribute to neonatal well-being but on which survival is less dependent. Pharmacological manipulation of these systems before birth has made a substantial contribution to improving human health.

The role of cortisol in preparing the fetus for birth

Many animal studies and human epidemiological findings have shown that impaired growth in utero is associated with physiological abnormalities in later life and have linked this to tissue programming during suboptimal intrauterine conditions at critical periods of development. However, few of these studies have considered the contribution of the placenta to the ensuing adult phenotype. In mammals, the major determinant of intrauterine growth is the placental nutrient supply, which, in turn, depends on the size, morphology, blood supply and transporter abundance of the placenta and on synthesis and metabolism of nutrients and hormones by the uteroplacental tissues. This review examines the regulation of placental nutrient transfer capacity and the potential programming effects of nutrition and glucocorticoid over-exposure on placental phenotype with particular emphasis on the role of the Igf2 gene in these processes.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2005.104141

Programming placental nutrient transport capacity.

Hormones have an important role in the control of fetal growth. They act on both tissue accretion and differentiation and enable a precise and orderly pattern of growth to occur during late gestation. In part, their actions on growth may be mediated by other growth factors such as the insulin-like growth factors (IGFs). Insulin stimulates fetal growth by increasing the mitotic drive and nutrient availability for tissue accretion. It has little effect on tissue differentiation. In contrast, the main effects of cortisol in utero are on tissue differentiation and maturation. Cortisol appears to act directly on the cells to alter gene transcription or post-translational processing of the gene products. Cortisol may also initiate the transition from the fetal to the adult modes of growth regulation by inducing the switch from IGF-II to IGF-I gene expression in the fetal liver. Thyroxine affects both tissue accretion and differentiation in the fetus by a combination of metabolic and non-metabolic mechanisms. Pituitary growth hormone, on the other hand, appears to have little part in the control of fetal growth, unlike its role postnatally. Fetal hormones, therefore, promote growth and development in utero by altering both the metabolism and gene expression of the fetal tissues. These hormonal actions ensure that fetal growth rate is commensurate with the nutrient supply and that prepartum maturation occurs in preparation for extrauterine life.

Endocrine regulation of fetal growth

/pdf/hormonal-control-of-lactation-39bekhhu1g.pdf

Hormonal Control of Lactation

1 The changes in liver glycogen concentration in normal, adrenalectomized and hypophysectomized foetal lambs have been examined during the last third of gestation using a biopsy technique to remove one or more samples of liver from the same foetus at different gestational ages 2 The rate of glycogen deposition increased sharply from about 130 days' gestation in normal lamb foetuses whereas after hypophysectomy or adrenalectomy liver glycogen concentrations remained low even when gestation was prolonged 3 IV infusions of cortisol (4-10 mg/day) for 52 hr resulted in four- to fivefold increases in liver glycogen in all three groups of foetuses The level of glycogen in the liver appeared to be related to log plasma corticosteroid concentration in all foetuses whether they had received cortisol infusions or not 4 Little or no change occurred in glycogen concentration in other foetal tissues apart from a decrease in the glycogen levels in peri-renal fat of adrenalectomized and hypophysectomized foetuses after cortisol infusion There were also no detectable changes in foetal plasma lactate, urea or alpha amino nitrogen following the cortisol infusions Foetal plasma glucose values rose slightly but this change was significant only in the adrenalectomized group 5 The 52 hr cortisol infusions to the foetus resulted in a slight but significant fall in maternal plasma progesterone in the last few hours of the infusion period

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1978.sp012209

Effect of cortisol on liver glycogen concentrations in hypophysectomized, adrenalectomized and normal foetal lambs during late or prolonged gestation.

Prostaglandins in the foetal pig and prepartum endocrine changes in mother and foetus

1. Foetal hypophysectomy or bilateral adrenalectomy, carried out in utero at about 100 or 125 days gestation respectively, increased the length of gestation in sheep. It was confirmed that pregnancy was not prolonged significantly if hypophysectomy or adrenalectomy was carried out on one of a pair of twins. The hypophysectomized foetus was, however, smaller and the adrenalectomized foetus larger, than the unoperated twin. 2. In about half of the previously operated foetuses intravascular catheters were inserted into both mother and foetus, either at about 125 days, for a comparison with normal catheterized foetuses, or during the post-mature period. Both adrenalectomized and hypophysectomized foetuses appeared to have little resistance to stress or infection and the majority survived only 1-2 weeks after the insertion of catheters. 3. Maternal peripheral plasma oestrogen, progesterone and corticosteroid concentrations did not appear to be altered by either foetal hypophysectomy or adrenalectomy and were maintained in the normal range during prolonged gestation. 4. Foetal plasma oestrogen concentrations were significantly lower after hypophysectomy or adrenalectomy than values found in control lambs. Plasma progesterone values were low in all three groups of foetuses. 5. Plasma corticosteroid concentrations after foetal hypophysectomy (12-6 ng/ml.) or adrenalectomy (14-7 ng/ml.) were in the same range as the values for control lambs before the pre-partum rise (14-6 ng/ml.). However, there was a small but significant maternal-to-foetal plasma corticosteroid gradient in the two operated groups whereas this difference was not found in the control animals. 6. Tissue glycogen concentrations were measured in non-catheterized adrenalectomized and hypophysectomized foetuses. In these two groups, whether examined before 149 days or after prolonged gestation, liver glycogen concentrations were 30-40% of those in non-catheterized control foetuses at term. In other respects there was little apparent difference between adrenalectomized and control foetuses. 7. Hypophysectomized foetuses had significantly higher glycogen concentrations in heart, skeletal muscle and lung compared with control or adrenalectomized lambs. Plasma glucose and fructose values were also low in this group compared with control foetuses.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1977.sp011676

The effects of bilateral adrenalectomy or hypophysectomy of the foetal lamb in utero

Placental blood flow: some fetal and maternal cardiovascular adjustments during gestation.

The concentrations of 13, 14-dihydro-15-oxo-prostaglandin F(PGFM), the stable metabolite of prostaglandin F, were measured in the plasma of catheterized mares and foetuses and non-catheterized thoroughbred mares and ponies during the last months of gestation. The plasma concentration of PGFM increased gradually towards term in all groups of animals. During the operation for insertion of catheters, maternal and foetal concentrations of PGFM were high, but the values fell to basal levels 24--48 h after the operation. It was found the preoperative starvation (24 h) led to a rise in the concentration of PGFM in the maternal plasma. The raised concentrations of PGFM during the operation were associated with low progestogen and high oestrogen concentrations in umbilical venous plasma. The subsequent survival period of the catheterized foal was inversely related to the maximum concentration of PGFM were studied during normal parturition in thoroughbred mares, during oxytocin-induced delivery in non-catheterized ponies and during premature delivery or abortion in the catheterized animals. The greatest increase in the concentration of PGFM was seen in the thoroughbred animals during second-stage labour; oxytocin also resulted in a very rapid rise in the level of PGFM, which remained high until delivery. In the catheterized animals, the birth of live foetuses was associated with a rise in the concentration of PGFM in both foetal and maternal plasma during the last 2 h before delivery. Less consistent changes were found during abortion.

Barnes Rj

Papers

Effect of cortisol on liver glycogen concentrations in hypophysectomized, adrenalectomized and normal foetal lambs during late or prolonged gestation.

Prostaglandins in the foetal pig and prepartum endocrine changes in mother and foetus

The effects of bilateral adrenalectomy or hypophysectomy of the foetal lamb in utero

Placental blood flow: some fetal and maternal cardiovascular adjustments during gestation.

Foetal and maternal plasma concentrations of 13, 14-dihydro-15-oxo-prostaglandin F in the mare during late pregnancy and at parturition.