Uteroplacental and fetal metabolism

The relative contribution of different nutrients to feto-placental metabolism varies between species but glucose is the principal metabolite in all livestock species studied to date including sheep, cows, pigs and horses. ^{Reference Fowden41} In late gestation, short-term (<24h) infusions of cortisol or dexamethasone directly into fetal sheep have little apparent effect on the fetal uptake of glucose. ^{Reference Fowden, Vaughan, Murray and Forhead16,Reference Fowden, Forhead, Coan and Burton17} However, when fetal cortisol concentrations are raised within the physiological range by direct infusion for 5 days, fetal glucose uptake decreases by 30% per kg of fetus. ^{Reference Ward, Wooding and Fowden42,Reference Vaughan, De Blasio and Fowden43} Similar reductions in fetal glucose uptake are seen in response to physiological increments in the maternal cortisol concentration for 5 days during the same period of late pregnancy. ^{Reference Vaughan, Davies, Ward, de Blasio and Fowden44} Weight specific rates of fetal glucose uptake also decrease as fetal cortisol levels rise naturally during the prepartum period in sheep and horses (Fig 1). In addition, when data are combined from the several ovine studies in which fetal cortisol concentrations are raised either exogenously or endogenously, there is an inverse correlation between umbilical glucose uptake per kg fetus and the fetal cortisol concentration during late gestation, irrespective of the mechanism by which cortisol concentrations is increased (Fig 2).

Figure 1. Mean values (±SEM) of (A) plasma cortisol concentrations and (B) the rate of umbilical glucose uptake in fetal sheep (filled columns) and horses (open columns) with respect to the stage of gestation (term: sheep, ≥ 145 days, horse approx. 335 days). Data from references. ^{Reference Fowden, Mundy and Silver23,Reference Molina, Carver and Hay45-Reference Fowden, Forhead, White and Taylor47}

Figure 2. Relationship between the plasma cortisol concentration and the rate of umbilical glucose in fetal sheep during late gestation in 11 separate published studies, references. ^{Reference Fowden, Mundy and Silver23,Reference Brown, Rozance and Bruce25,Reference Ward, Wooding and Fowden42-Reference Vaughan, Davies, Ward, de Blasio and Fowden44,Reference Fowden, Mapstone and Forhead48-Reference Davis, Camacho and Anderson53} Data points are the mean values for each group of fetuses with respect to their mean cortisol concentration caused by fetal cortisol infusion, placental growth restriction or by the natural prepartum increment in fetal cortisol towards term. (All animals≥130 days, term≥145 days). Statistical analysis was carried out using sigma-stat (Statistical software version 3.5; San Jose, CA, USA).

While maternal and fetal cortisol exposure appear to have similar effects on umbilical glucose uptake in fetal sheep, their effects on uteroplacental glucose metabolism and the supply of lactate to the fetus differ. ^{Reference Ward, Wooding and Fowden42-Reference Vaughan, Davies, Ward, de Blasio and Fowden44} Uteroplacental glucose consumption per kg placenta increases with fetal but not maternal cortisol treatment while uteroplacental lactate production rises with maternal but not fetal treatment. ^{Reference Vaughan, De Blasio and Fowden43,Reference Vaughan, Davies, Ward, de Blasio and Fowden44} This leads to an increase in fetal lactate delivery with maternal but not fetal treatment, despite the similar decrements in umbilical glucose uptake with the two routes of placental cortisol overexposure. Fructose is also produced and used oxidatively by ovine uteroplacental and fetal tissues and its fetal concentration rises with maternal but not fetal hypercortisolaemia. ^{Reference Ward, Wooding and Fowden42-Reference Vaughan, Davies, Ward, de Blasio and Fowden44} In part, these differences in carbohydrate handling appear to relate to the direction and/or degree of the transplacental GC gradient. Longer term maternal infusions of cortisol for 30 days in late pregnancy are known to alter amino acid metabolism and biosynthesis in the term ovine placenta using multiomics analyses. ^{Reference Joseph, Walejko, Zhang, Edison and Keller-wood54} In addition, both maternal and fetal GC administration have been shown to affect fetal amino acid uptake and catabolism with increased proteolysis and/or reduced protein synthesis by the fetus, depending on the origin, timing and duration of the GC overexposure in late gestation. ^{Reference Fowden and Forhead55} Significant feto-placental shuttling of nutrients, therefore, occurs in response to raised cortisol levels, whether of maternal or fetal origin, and appears to reflect altered enzyme activities and nutrient transporter abundance in tissues like the placenta and fetal liver. ^{Reference Fowden, Forhead, Coan and Burton17,Reference Brown, Kohn, Rozance, Hay and Wesolowski51,Reference Fowden and Forhead55}

In normoxic conditions, the fetal and uteroplacental rates of oxygen consumption vary little with variations in either fetal or maternal cortisol concentrations, ^{Reference Ward, Wooding and Fowden42-Reference Vaughan, Davies, Ward, de Blasio and Fowden44} although the oxidative substrates used for energy production alter with the cortisol-induced changes in the type and origin of substrates available to the tissues. ^{Reference Davies, Camm and Smith56} For example, the increase in urea production seen in fetal sheep in response to maternal cortisol infusion suggests that amino acids become a more prominent fetal oxidative fuel as the umbilical supply of glucose declines. ^{Reference Jensen, Gallaher, Brier and Harding57} Other substrates like the volatile fatty acids (VFAs) also make a contribution to fetal oxidative metabolism and carbon accumulation in ruminants, compared to other livestock species with hind gut fermentation. ^{Reference Vaughan and Fowden58} However, little is known about the effects of GCs on the fetal supply or utilization of VFAs in ruminants.

Collectively, these observations suggest that ovine feto-placental metabolism adapts to maternal hypercortisolaemia by diverting glucose into lactate and possibly fructose as well as altering fetal amino acid provision and metabolism. This diversifies the fetal carbon supply and allows the fetus more options for carbon utilization during maternal stressful conditions. In contrast, when fetal cortisol levels rise independently of maternal levels, ovine uteroplacental tissues use more glucose on a weight specific basis and transfer less to the fetus. There is also an increase in the fetal to placental glucose and pyruvate clearance when cortisol level rise in response to stressful concentrations on either side of the placenta. ^{Reference Vaughan, De Blasio and Fowden43,Reference Vaughan, Davies, Ward, de Blasio and Fowden44,Reference Kyllo, Wang and Lorca59} This suggests that, in certain circumstances, the fetus may prioritise placental glucose requirements over its own needs to ensure survival of the placenta on which its own survival in utero depends. ^{Reference Vaughan, De Blasio and Fowden43,Reference Kyllo, Wang and Lorca59}

Tissue specific metabolic effects

A wide range of fetal tissues, in addition to the placenta, are affected metabolically by rising fetal cortisol levels including the liver, skeletal and cardiac muscle, adipose tissue and gastrointestinal tract as well as several endocrine axes involved in controlling metabolism. ^{Reference Fowden, Vaughan, Murray and Forhead16,Reference Fowden and Forhead55} In fetal sheep and pigs, cortisol increases the hepatic glycogen content and the activity of glucose-6-phosphatase (G6P), the final enzyme in both the gluconeogenic and glycogenolysis pathways of glucose production (Fig 3). In fetal sheep, GCs also increase phosphoenolpyruvate carboxykinase (PEPCK) activity which controls gluconeogenesis from lactate and amino acids. ^{Reference Fowden, Mijovic and Silver61} In addition, the hepatic activity of lactate dehydrogenase and specific aminotransferases involved in gluconeogenesis increase in response to elevated cortisol concentrations. ^{Reference Vaughan, Davies, Ward, de Blasio and Fowden44,Reference Fowden, Mijovic and Silver61} Similarly, dexamethasone administration to pregnant ewes in late gestation increases the hepatic glycogen content and G6P activity in the fetal liver. ^{Reference Franko, Giussani, Forhead and Fowden62} Increases in hepatic glycogen content and enzyme activities also occur when fetal cortisol concentrations rise naturally towards term in fetal sheep, pigs and horses ^{Reference Fowden, Apatu and Silver60,Reference Fowden, Mijovic and Silver61,Reference Fowden, Mijovic, Ousey, McGladdery and Silver63} and are prevented in fetal sheep when the prepartum cortisol surge is abolished by fetal adrenalectomy (Fig 3). Moreover, increases in the glycogen content and glucogenic enzymes activities are seen in the fetal kidney with increased GC exposure in fetal sheep, pigs and horses. ^{Reference Fowden, Apatu and Silver60-Reference Fowden, Mijovic, Ousey, McGladdery and Silver63}

Figure 3. Mean values (±SEM) of (A) plasm cortisol concentrations, (B) hepatic glycogen content and (C) hepatic glucose-6-phosphatase activity in fetal sheep and pigs with respect to gestational age to term (filled circles), after preterm fetal infusion of either saline (open columns) or cortisol (filled columns) for 5-6 days and in fetal sheep after adrenalectomy (filled triangles). * significantly greater value than in saline infused fetuses (P < 0.01, t-test). Data from references. ^{Reference Fowden, Apatu and Silver60,Reference Fowden, Mijovic and Silver61}

In line with the gestational rise in fetal glucogenic capacity, endogenous glucose production rises naturally towards to term in fetal sheep and is positively related to the cortisol concentration during the prepartum period and in response to intrauterine stress and fetal growth restriction in late gestation. ^{Reference Fowden, Mundy and Silver23,Reference Brown, Kohn, Rozance, Hay and Wesolowski51,Reference Brown, Rozance and Wang64} Conversely, when cortisol increments are prevented in fetal sheep by adrenalectomy, glucose production does not occur in response to maternal fasting close to term, despite normal fetal circulating catecholamine concentrations. ^{Reference Fowden and Forhead49} More specifically, hepatic glucose production from lactate and amino acids has been shown to be activated in fetal sheep by short term GC exposure close to term, although not earlier in gestation when hepatic glycogen storage and gluconeogenic enzyme activities are still low. ^{Reference Fowden and Forhead55,Reference Townsend, Rudolph, Wood and Rudolph65} The role of GCs in regulating hepatic glucose production during late gestation is amplified by their actions in increasing hepatic abundance of both the β-adrenoreceptors which bind catecholamines and the enzyme 11βHSD1 which increases availability of cortisol from cortisone. ^{Reference Fowden, Vaughan, Murray and Forhead16,Reference Vaughan, De Blasio and Fowden43,Reference Fowden, Apatu and Silver60,Reference Sloboda, Newnham and Challis66} Collectively, these findings suggest that GCs first increase the fetal glucogenic capacity before activating endogenous glucose production per se. This will maintain a glucose supply to key fetal tissues as the weight specific rate of umbilical glucose uptake declines towards term and then ceases at birth.

In skeletal muscle, direct cortisol infusion into fetal sheep for 5 days in late gestation increases the content and respiratory capacity of the mitochondria in a manner that depends on the specific oxidative substrate and muscle studied. ^{Reference Davies, Camm and Smith56} Similar increases in muscle oxidative phosphorylation (OXPHOS) capacity are also seen in fetal sheep as cortisol concentrations rise naturally towards term and are abolished by fetal adrenalectomy. ^{Reference Davies, Camm and Smith56,Reference Davies, Camm and Atkinson67} This cortisol induced upregulation of muscle OXPHOS capacity is associated with changes in the mitochondrial abundance of specific electron transfer system (ETS) and adenine translocator proteins. ^{Reference Davies, Camm and Smith56,Reference Davies, Camm and Atkinson67} However, longer term cortisol administration to pregnant ewes in late gestation reduces the mitochondrial OXPHOS transcriptomics of fetal cardiac and skeletal muscle, consistent with sustained reductions in the fetal nutrient supply. ^{Reference Joseph, Alava and Antolic68} Fetal cortisol also regulates the relative proportions of the slow twitch (oxidative) and fast twitch (more glycolytic) fibres in specific skeletal muscles. ^{Reference Davies, Camm and Smith56} Since OXPHOS produces more ATP per molecule of glucose utilized than glycolysis, changes in the proportion of the different muscle fibres has implications for whole body energetics and metabolic phenotype. ^{Reference Davies, Camm and Smith56} In addition, there are changes in glucose transporter abundance in certain fetal muscles GC overexposed during late gestation, with an increase in the insulin-responsive transporter (GLUT4) and a relative reduction in insulin-unresponsive GLUT1, thereby allowing insulin to assume tighter glucoregulatory control of metabolism postnatally. ^{Reference Jellyman, Martin-Gronet and Cripps69}

Like fetal liver and muscle, there are also GC induced changes in the metabolic profile of fetal adipose tissue and the gastrointestinal tract during late gestation. ^{Reference Fowden, Vaughan, Murray and Forhead16,Reference Fowden and Forhead55} In sheep near term, both fetal cortisol infusion and maternal dexamethasone administration increase the abundance of mitochondrial ETS, uncoupling and voltage dependent anion channel proteins in fetal perirenal adipose tissue, in line with the need for non-shivering thermogenesis at birth. ^{Reference Gnanalingham, Hyatt and Bispham70,Reference Mostyn, Pearce and Budge71} Similarly, in fetal pigs and sheep, specific pancreatic, stomach and small intestine enzymes involved in postnatal digestion increase in activity in response to pre-term fetal cortisol infusion and the natural prepartum rise in cortisol concentrations. ^{Reference Sangild, Sjoström, Nexø, Fowden and Silver33,Reference Trahair and Sanglid72} GC exposure during late gestation, therefore, affects the metabolic characteristics of many somatic tissues with important consequences for the nutrient demands for both intrauterine growth and the onset of new functions essential for neonatal survival.

Other metabolic hormones

Not all the metabolic outcomes of increased GC exposure are likely to be due directly to the GCs as fetal availability of several other metabolic hormones are affected in these circumstances. ^{Reference Fowden, Vaughan, Murray and Forhead16,Reference Fowden and Forhead55} In late gestation fetal sheep, GCs regulate the circulating concentrations of tri-iodothyronine (T ₃), adrenaline, insulin-like growth factor-1 (IGF1), leptin and ovine placental lactogens (oPL), all of which have metabolic actions in utero. ^{Reference Fowden and Forhead55,Reference Braun, Li and Moss73} For instance, fetal cortisol infusion and maternal dexamethasone administration are known to reduce the number of binucleate cells producing oPL in the placenta and lower maternal and fetal oPL concentrations. ^{Reference Braun, Li and Moss73,Reference Ward, Wooding and Fowden74} Indeed, the changes in placental oPL availability may mediate, in part, the effects of GCs on umbilical glucose uptake as recent studies have shown that reducing placental oPL protein abundance directly using RNAi technology lowers umbilical glucose uptake at any given maternal-fetal glucose concentration gradient. ^{Reference Tanner, Lynch and Ali75} In late gestation GCs increase adrenaline, IGF1 and leptin availability in fetal sheep. ^{Reference Fowden and Forhead55} Adrenaline can stimulate fetal glucose production while IGF1 has organ specific effects on glucose and amino acid utilization in fetal sheep ^{Reference Fowden, Mundy and Silver23,Reference Davis, Camacho and Anderson53,Reference Stremming, Heard and White76} . Fetal leptin affects growth and development of a range of fetal tissues including the lungs, pancreatic β cells and bones in addition to its potential role in programming appetite regulation. ^{Reference Forhead, Lamb and Franko77,78}

Similarly, the actions of GCs on fetal gluconeogenic and OXPHOS capacity are mediated, in part, by the fetal thyroid hormones and upregulation of the tissue deiodinases producing the more biologically active T₃ from circulating thyroxine. ^{Reference Forhead, Curtis, Kapstein, Visser and Fowden79,Reference Forhead, Jellyman and Gardner80} Thyroidectomy of fetal sheep impairs the normal prepartum increments in both mitochondrial density and OXPHOS capacity in skeletal muscle and the glycogen content and gluconeogenic enzyme activities in the liver. ^{Reference Davies, Camm and Atkinson67,Reference Forhead, Cutts, Matthews and Fowden81,Reference Forhead, Poore, Mapstone and Fowden82} It also prevents activation of endogenous glucose production by the fetus in response to maternal fasting in late gestation. ^{Reference Fowden, Mapstone and Forhead48} However, pre-term T₃ infusion is less effective than cortisol at increasing hepatic glycogen content in fetal sheep. ^{Reference Forhead, Poore, Mapstone and Fowden82} This suggests that the actions of T₃ in mediating the effects of cortisol also depend on concomitant changes in other circulating factors and/or cellular pathways, such as tissue thyroid hormone receptor abundance. ^{Reference Forhead, Poore, Mapstone and Fowden82} Feto-placental hormones, therefore, interact widely in controlling feto-placental metabolism through actions on the development of the fetal endocrine axes per se. ^{Reference Fowden, Vaughan, Murray and Forhead16,Reference Challis, Sloboda and Matthews29,Reference Fowden and Forhead55} Indeed, in fetal sheep, pre-term GC overexposure influences functioning of the HPA axis. ^{Reference Fowden and Forhead6,Reference Challis, Sloboda and Matthews29} Depending on timing of the overexposure, there are alterations in fetal HPA stress responsiveness and the trajectory of the normal prepartum cortisol surge together with molecular changes at all levels of the axis from the brain to tissue GR abundance. ^{Reference Fletcher, Ma and Wu83-Reference Sloboda, Moss and Li86}

Intrauterine growth

In sheep, maternal but not fetal treatment with synthetic GC during the last third of gestation reduces fetal body weight with symmetrical reductions in the weight of most fetal organs. ^{Reference Newnham, Evans and Godfrey87} By birth, lamb body weight is reduced by 10 to 30% in ewes receiving synthetic GCs in late gestation but not with treatment before 80 days pregnancy. ^{Reference Li, Sloboda and Moss88} The degree of prenatal growth restriction is more pronounced when maternal synthetic GC treatment is closer to term, longer in duration and at higher doses. ^{Reference Newnham, Evans and Godfrey87-Reference Moss, Sloboda and Gurrin89} Similarly, maternal dexamethasone treatment in late gestation reduces piglet birthweight and the height but not the weight of newborn foals. ^{Reference Schiffner, Rodriguez-Gonzalez and Rakers90,Reference Valenzuela, Jellyman, Allen, Holdstock and Fowden91} In contrast, treatment of ewes with cortisol for 30 days before term has little effect on lamb body weight but increases the rate of stillbirth. ^{Reference Keller-wood, Feng and Wood92} In sows in late gestation, ACTH-induced increments in maternal cortisol increase birthweight of their piglets with no effect on stillbirth rates. ^{Reference Kanitz, Otten and Tuchscherer93} With shorter maternal or direct fetal cortisol infusions of ≤ 10 days duration in late gestation, there is also little effect on lamb body weight before or at birth, despite reductions in the fetal growth rate measured as the increment in girth or crown-rump length. ^{Reference Jensen, Gallaher, Brier and Harding57,Reference Fowden, Szemere, Hughes, Gilmour and Forhead94} Growth of fetal bone and specific somatic tissues may, therefore, be affected differentially by prenatal GC overexposure. The differing intrauterine growth trajectories seen with the various GC dosing regimens are, therefore, likely to reflect the specific alterations in a range of factors including feto-placental nutrient handling, concentrations of other metabolic hormones and tissue expression of receptors, transporters and growth factors like the IGFs, in addition to variations in the size and/or gross morphology of the placenta. ^{Reference Fowden, Vaughan, Murray and Forhead16,Reference Fowden, Forhead, Coan and Burton17,Reference Fowden, Li and Forhead30,Reference Fowden and Forhead55,Reference Stremming, Heard and White76}

Metabolism

The effects of prenatal GC overexposure on adult glucose tolerance and insulin sensitivity in sheep appear to be less pronounced than in rodents, guinea pigs or human populations. ^{Reference Cottrell and Ozanne2,Reference Lee4,Reference Reynolds7,Reference Tegethoff, Pryce and Meinlschmidt116} This is consistent with adult ruminants being less dependent on glucose metabolism than simple monogastric animals or monogastric, hind gut fermentors. ^{Reference Fowden41,Reference Judson, Filsett and Jarrett117} However, pre-weaning lambs are purely monogastric and depend more heavily on glucose as a metabolic substrate than adult sheep. ^{Reference Fowden41,Reference Judson, Filsett and Jarrett117} There is, therefore, a natural decline in glucose tolerance, relative insulin secretion and insulin sensitivity with ageing in sheep, irrespective of the prenatal environmental or endocrine conditions, as they switch to using VFA and free fatty acids as more prominent primary sources of energy. ^{Reference Gatford, De Blasio and Thavaneswaran118}

After prenatal GC overexposure in late gestation, juvenile (pre-pubertal) sheep and horses have improved glucose-stimulated insulin secretion compared to controls irrespective of the type or route of GC administered (Table 1). There is also increased insulin sensitivity in neonatal and juvenile sheep after maternal GC treatment (Table 1), which may reflect persisting upregulation of muscle GLUT4 expression in utero. ^{Reference Jellyman, Martin-Gronet and Cripps69} By 3 years of age, there is little, if any, effect of fetal or maternal treatment with betamethasone in late gestation on ovine glucose tolerance or insulin sensitivity, although basal hyperinsulinaemia is seen after maternal betamethasone treatment in the older offspring (Table 1). In contrast, treatment of ewes with dexamethasone in late gestation is associated with glucose intolerance and reduced insulin secretion in the 2-3 year-old offspring and in their subsequent progeny. ^{Reference Long, Shasa, Ford and Nathanielsz103} In horses, short-term maternal administration of dexamethasone in late gestation had no effect on glucose tolerance or glucose-stimulated insulin secretion in the foals 2 weeks after birth but reduced their β cell response to arginine 10 weeks later. ^{Reference Valenzuela, Jellyman, Allen, Holdstock and Fowden91} When synthetic GCs are given to ewes early in pregnancy or directly to the fetus late in gestation, there are only minor effects on glucose tolerance or insulin sensitivity in their postnatal offspring compared to maternal treatment (Table 1). There is also little evidence for altered metabolism of substrates other than glucose with either early or late gestation overexposure to synthetic GCs, although insulin is less effective at suppressing lipolysis in adult sheep after maternal dexamethasone treatment in early pregnancy. ^{Reference Gatford, Wintour, De Blasio, Owens and Dodic102}

In growth restricted lambs that had high endogenous cortisol concentrations during late gestation due to placental restriction by pre-pregnancy carunclectomy, glucose-stimulated insulin secretion and whole-body insulin sensitivity are impaired 1 month after birth but are normalized at 1 year of age. ^{Reference De Blasio, Gatford, Robinson and Owens119,Reference De Blasio, Gatford, McMillen, Robinson and Owens120} Similarly, in sheep at 10 months, there are no changes in insulin secretion or sensitivity after direct intrauterine infusion of cortisol during late gestation. ^{Reference Davies, Miles and Camm112} In addition, in newborn foals, a short period of neonatal cortisol overexposure induces only minor increases in glucose-stimulated insulin secretion during the suckling period with no persisting effects on glucose tolerance, insulin secretion or insulin sensitivity at weaning or in early adulthood. ^{Reference Jellyman, Allen, Holdstock and Fowden114,Reference Valenzuela, Jellyman and Allen115} However, there were muscle specific differences in insulin receptor abundance in adult horses 2 years after neonatal cortisol overexposure, which may affect insulin sensitivity later in life. ^{Reference Valenzuela, Jellyman and Allen115} Collectively, these observations suggest that early-life overexposure to cortisol may be less effective at programming glucose-insulin dynamics in later life than the synthetic GCs.

Tissue specific metabolic effects

Prenatal GC overexposure is known to alter the postnatal metabolome of ovine liver, heart, skeletal muscle and adipose tissue. ^{Reference Vaughan and Fowden58,Reference Sloboda, Moss and Li105,Reference Walejko, Antolic and Koelmel106,Reference Davies, Miles and Camm112} In addition to changes in expression of the muscle GLUT transporters and insulin receptors ^{Reference Jellyman, Martin-Gronet and Cripps69,Reference De Blasio, Gatford, Harland, Robinson and Owens121} , there are also alterations in the abundance of mitochondrial ETS complexes, OXPHOS capacity and uncoupling proteins in a range of postnatal ovine tissues after prenatal GC overexposure in late gestation induced either experimentally or by adverse intrauterine conditions. ^{Reference Gnanalingham, Hyatt and Bispham70,Reference Antolic, Li and Richards107,Reference Davies, Camm and Smith113} The upregulation of the hepatic glucogenic capacity induced in fetal sheep by early GC overexposure also persists into adult life with sustained increases in key gluconeogenic enzyme activities. ^{Reference Franko, Giussani, Forhead and Fowden62,Reference Sloboda, Newnham and Challis66,Reference Sloboda, Moss and Li105} In contrast, the cortisol-induced changes in muscle fibre composition in fetal sheep did not persist into early adulthood. ^{Reference Davies, Camm and Smith113} However, the changes in gut structure and enzyme activity induced by early GC overexposure are associated with altered intestinal nutrient uptake postnatally. ^{Reference Trahair and Sanglid72} For instance, treatment of newborn pigs with synthetic GCs advances postnatal development of intestinal amino acid uptake by at least 4 weeks. ^{Reference James, Smith, Tivey and Wilson110} The tissue specific changes in nutrient handling induced by early-life GC overexposure alter the balance of nutrients available for glycolytic and oxidative metabolism postnatally with implications for heat and energy production essential for pre-weaning survival.

Other Metabolic Hormones

In addition to pancreatic β cell function (Table 1), early-life GC exposure alters postnatal activity of several other endocrine axes involved in regulating metabolism. Basal concentrations of T₃ and IGF-I are lower than control values in young sheep after prenatal GC overexposure. ^{Reference Li, Sloboda and Moss88,Reference Gatford, Owens and Li122} Similarly, leptin concentrations are suppressed in sucking calves for 2 weeks after giving cortisol for the first 24h after birth. ^{Reference Lewis, Ricks and Long123} In contrast, in juvenile sheep, postnatal levels of leptin are elevated or unaffected by prenatal GC overexposure depending on its cause. ^{Reference Li, Sloboda and Moss88,Reference De Blasio, Blache, Gatford, Robinson and Owens124} Basal ACTH and cortisol concentrations, and the sensitivity of the HPA axis to stressful stimuli and exogenous CRH/ACTH administration, are also altered following prenatal GC overexposure in sheep, pigs and horses after birth (Table 2). In general, prenatal GC overexposure tends to increase pituitary-adrenal responses pre-weaning but leads to adrenal hypo-responsiveness in older animals, particularly after maternal treatments later in gestation (Table 2). These changes are accompanied by molecular alterations at all levels of the HPA axis as well as in adrenal morphology (Table 2). In both sheep and pigs, there is a relative expansion of adrenal medullary cells at the expense of the cortex after prenatal cortisol overexposure^{Reference Kanitz, Otten and Tuchscherer93,Reference James, Smith, Tivey and Wilson110} . Furthermore, there are changes in plasma CBG and in tissue abundance of the GC receptors in adult sheep following prenatal overexposure to synthetic GCs, which will influence the overall metabolic outcomes of the programmed HPA activity.^{Reference Li, Moss and Matthews85,Reference Sloboda, Moss and Li86,Reference Kanitz, Otten and Tuchscherer93,Reference Li, Nitsos and Polglase126,Reference Long, Ford and Nathanielsz127} Indeed, the relative hypo-responsiveness of the adult HPA axis after prenatal GC overexposure may reduce the risk of developing dysfunctional glucose-insulin dynamics with ageing. However, collectively, the changes in postnatal endocrine function induced by prenatal GC overexposure are likely to influence postnatal growth and body composition.

Table 2. Postnatal outcomes of prenatal glucocorticoid overexposure on the HPA axis in livestock. (dGA = days gestational age, dPN = days postnatal age)

Postnatal growth

Low birthweight neonates of ewes, sows and mares treated with synthetic GCs in late gestation often undergo catch-up growth after birth. ^{Reference Kranendork G.Hopster and Fillerup109,Reference Gaines, Carroll, Allee and Yi111,Reference De Blasio, Gatford, McMillen, Robinson and Owens120,Reference Long, Ford and Nathanielsz127,Reference Lay, Kattesh and Cunnick135-Reference Moss, Doherty and Nitsos137} Offspring body weight tends to be normalized by the time of weaning or puberty. Similar postnatal increases in the fractional growth rate are also seen in growth restricted lambs that had high endogenous cortisol concentrations during late gestation due to placental restriction induced by pre-pregnancy carunclectomy. ^{Reference De Blasio, Gatford, Robinson and Owens119,Reference De Blasio, Gatford, McMillen, Robinson and Owens120} In part, the catch-up growth probably reflects the increased insulin secretion and the changes in tissue insulin receptors and mitochondrial function seen in early postnatal life (Table 1). It may also reflect postnatal alterations in appetite and feeding behaviour as increased sucking frequency and more rapid intake of the food ration are observed in low birthweight lambs and piglets following prenatal GCs overexposure. ^{Reference De Blasio, Blache, Gatford, Robinson and Owens124,Reference Kranendork, HopseterMulder and Fillerup131,Reference Lay, Kattesh and Cunnick135,Reference Moss, Doherty and Nitsos137} In both piglets and lambs, the increased postnatal growth rate is associated with increased fat deposition and a reduced relative lean or muscle mass by young adulthood. ^{Reference Kranendork G.Hopster and Fillerup109,Reference De Blasio, Gatford, Robinson and Owens119,Reference Moss, Doherty and Nitsos137,Reference Liu, Schultz and Blasio138} Together, the GC-induced changes in postnatal appetite regulation and fat deposition may eventually lead to more pronounced insulin resistance and glucose intolerance in aged ruminants as occurs in other species.