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?

Epidemiological findings and experimental studies in animals have shown that individual tissues and whole organ systems can be programmed in utero during critical periods of development with adverse consequences for their function in later life. Detailed morphometric analyses of the data have shown that certain patterns of intrauterine growth, particularly growth retardation, can be related to specific postnatal outcomes. Since hormones regulate fetal growth and the development of individual fetal tissues, they have a central role in intrauterine programming. Hormones such as insulin, insulin-like growth factors, thyroxine and the glucocorticoids act as nutritional and maturational signals and adapt fetal development to prevailing intrauterine conditions, thereby maximizing the chances of survival both in utero and at birth. However, these adaptations may have long-term sequelae. Of the hormones known to control fetal development, it is the glucocorticoids that are most likely to cause tissue programming in utero. They are growth inhibitory and affect the development of all the tissues and organ systems most at risk of postnatal pathophysiology when fetal growth is impaired. Their concentrations in utero are also elevated by all the nutritional and other challenges known to have programming effects. Glucocorticoids act at cellular and molecular levels to alter cell function by changing the expression of receptors, enzymes, ion channels and transporters. They also alter various growth factors, cytoarchitectural proteins, binding proteins and components of the intracellular signalling pathways. Glucocorticoids act, directly, on genes and, indirectly, through changes in the bioavailability of other hormones. These glucocorticoid-induced endocrine changes may be transient or persist into postnatal life with consequences for tissue growth and development both before and after birth. In the long term, prenatal glucocorticoid exposure can permanently reset endocrine systems, such as the somatotrophic and hypothalamic-pituitary-adrenal axes, which, in turn, may contribute to the pathogenesis of adult disease. Endocrine changes may, therefore, be both the cause and the consequence of intrauterine programming.

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Endocrine mechanisms of intrauterine programming.

Since the first mention of fetal programming of adult health and disease, a plethora of programming events in early life has been suggested. These have included intrauterine and postnatal events, but limited attention has been given to the potential contribution of the birth process to normal physiology and long-term health. Over the last 30 years a growing number of studies have demonstrated that babies born at term by vaginal delivery (VD) have significantly different physiology at birth to those born by Caesarean section (CS), particularly when there has been no exposure to labour, i.e. pre-labour CS (PLCS). This literature is reviewed here and the processes involved in VD that might programme post-natal development are discussed. Some of the effects of CS are short term, but longer term problems are also apparent. We suggest that VD initiates important physiological trajectories and the absence of this stimulus in CS has implications for adult health. There are a number of factors that might plausibly contribute to this programming, one of which is the hormonal surge or "stress response" of VD. Given the increasing incidence of elective PLCS, an understanding of the effects of VD on normal development is crucial.

The health implications of birth by Caesarean section.

There is increasing epidemiological evidence in humans which associates low birthweight with later metabolic disorders, including insulin resistance and glucose intolerance. There is evidence that nutritional and hormonal factors (e.g. maternal protein restriction, exposure to excess maternal glucocorticoids) markedly influence intra-uterine growth and development. A picture is also emerging of the biochemical and physiological mechanisms that may underlie these effects. This review focuses on recent research directed towards understanding the molecular basis of the relationship between indices of poor early growth and the subsequent development of glucose intolerance and Type 2 diabetes mellitus using animal models that attempt to recreate the process of programming via an adverse intra-uterine or neonatal environment. Emphasis is on the chain of events and potential mechanisms by which adverse adaptations affect pancreatic-β-cell insulin secretion and the sensitivity to insulin of key metabolic processes, including hepatic glucose production, skeletal-muscle glucose disposal and adipose-tissue lipolysis. Unravelling the molecular details involved in metabolic programming may provide new insights into the pathogenesis of impaired glucoregulation and Type 2 diabetes.

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Early-life programming of susceptibility to dysregulation of glucose metabolism and the development of Type 2 diabetes mellitus.

Gluconeogenesis in the fetus and neonate.

In the present study, the ontogenic changes in gluconeogenic enzyme activities and in hepatic glycogen and beta-adrenergic receptor levels were investigated in fetal pigs from 70 days of gestation until delivery at term (114 +/- 2 days). The values were compared with those observed in fetuses infused subcutaneously with cortisol for 6 days beginning at 82-84 or 92-94 days of gestation. Tissue glucose-6-phosphatase (G6Pase) activity increased with increasing gestational age in the liver, kidney and duodenum of control fetal pigs. At birth, there was a further increase in G6Pase activity in the liver but not in the kidney or duodenum. In the kidney, there was a similar gestational increase in phosphoenolpyruvate carboxykinase (PEPCK) activity. These changes in enzyme activities closely paralleled the prepartum increase in fetal plasma cortisol and were accompanied by increases in hepatic glycogen content and beta-adrenergic receptor density. At 98-100 days, there were significant increases in G6Pase activity in the liver, kidney and duodenum of the cortisol-infused fetuses, whereas at 88-90 days only renal G6Pase was significantly elevated by cortisol infusion. Cortisol infusion also increased hepatic beta-receptor density at 88-90 days and hepatic glycogen content at both gestational ages. There were no changes in hepatic PEPCK, hepatic or renal fructose diphosphatase and aspartate amino transferase activities during cortisol infusion or with increasing gestational age. When the data from all the piglets were combined, irrespective of age or treatment, there were significant positive correlations between log plasma cortisol and G6Pase activity in the liver, kidney and duodenum. Similar positive correlations were observed between hepatic beta-adrenoceptor density and log plasma cortisol and between the latter values and the hepatic glycogen content. These findings show that cortisol induces tissue G6Pase activity in the fetal pig and suggest that the prepartum rise in endogenous cortisol may be responsible for the increase in fetal glucogenic capacity observed towards term in this as in other species.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/expphysiol.1995.sp003860

R. S. K. Apatu

Papers

The glucogenic capacity of the fetal pig: developmental regulation by cortisol