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EC Jensen, JE Harding, MK Bauer, and PD Gluckman

It has been shown that IGF-I has an anabolic effect in the normal fetus. However, there is evidence to suggest that there may be IGF-I resistance in the growth retarded fetus. Therefore, we investigated the effects of acute IGF-I infusion to chronically catheterised fetal sheep. At 128 days gestation, fetuses underwent a 4 h infusion of IGF-I (50 microg/kg/h). Three groups of animals were studied. Nine normally grown fetuses were studied as controls. Embolised animals (n=8) received microspheres into the uterine vasculature, and animals with spontaneous intra-uterine growth retardation (IUGR animals) (n=6) were fetuses found at post mortem to be spontaneously growth restricted. The effects of IGF-I infusion on feto-placental carbohydrate and protein metabolism were similar in our control group to previous similar experiments. IGF-I infusion decreased fetal blood glucose, oxygen, urea and amino-nitrogen concentrations, and inhibited placental lactate production. The same fetal blood metabolite concentrations also fell during IGF-I infusion in the embolised fetuses, but the effect on placental lactate production was not seen. The only effect of IGF-I infusion in the spontaneous IUGR animals was a fall in fetal blood amino-nitrogen concentrations. We conclude that fetal IGF-I infusion does not have the same anabolic effects in the growth retarded fetus as the normal fetus. In addition, the effects of IGF-I were different in the two growth retarded groups. Our data support previous evidence that the growth retarded fetus has altered IGF-I sensitivity, and this may vary depending on the cause, severity and duration of growth retardation.

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EC Jensen, BW Gallaher, BH Breier, and JE Harding

Exposure of the fetus to excess maternal glucocorticoids has been postulated to alter fetal growth and development, and thus provide a possible mechanism for the link between impaired fetal growth and altered postnatal physiology. However, the effects of exposure to excess maternal glucocorticoids on fetal physiology and metabolism in utero have not been described. We therefore studied the effects of chronic maternal cortisol infusion on fetal growth, blood pressure, metabolism and endocrine status in chronically catheterised fetal sheep. We infused hydrocortisone (80 mg/day, n=6) or saline (n=8) for 10 days into the pregnant ewes beginning at 119 days of gestation. Maternal cortisol infusion reduced fetal growth rate by 30% (girth increment 2.9+/-0.3 vs 1.8+/-0.4 mm/day, P=0.03). Maternal cortisol infusion increased fetal heart weight by 15% relative to body weight and increased ventricular wall thickness by 30% in the left and 50% in the right ventricle. The weight of the spleen was reduced by 30% and placental weight reduced by 25%. Fetal blood pressure increased by approximately 10 mmHg (20%) during maternal cortisol infusion. Maternal cortisol infusion did not alter amino-nitrogen concentrations. However, maternal lactate concentrations increased by 80% and fetal lactate concentrations increased by 74% with maternal cortisol infusion, and both maternal and fetal urea concentrations increased by 40%. Circulating maternal IGF-binding protein (IGFBP)-3 levels had increased by 20% by the end of the maternal cortisol infusion. Fetal IGF-I concentrations decreased during cortisol infusion and fetal IGFBP-1 concentrations were negatively correlated with fetal weight (r=-0.76, P=0.02). We conclude that even a modest elevation of maternal cortisol levels affects fetal growth, cardiovascular function, metabolism and endocrine status which may have long-term consequences.

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EC Jensen, P van Zijl, PC Evans, and JE Harding

Acute infusion of IGF-I to the fetus has been shown to inhibit amino acid oxidation and appears to increase fetoplacental amino acid uptake. This study was designed to investigate further the effects of IGF-I on fetal amino acid metabolism. Radiolabeled serine was used to test the hypothesis that fetal IGF-I infusion enhances serine uptake into the fetus and/or placenta and inhibits serine oxidation. Eight fetal sheep were studied at 127 days of gestation before and during a 4-h infusion of IGF-I (50 microg/h per kg). During the infusion there was no change in uptake of serine or its oxidation by fetus or placenta. However, both uptake and oxidation of serine and glycine decreased in the fetal carcass. There was also a decrease in fetal blood serine and glycine concentrations which could indicate a decrease in protein breakdown, although reduced amino acid synthesis cannot be excluded. Thus IGF-I appeared to influence the distribution of these amino acids as oxidative substrates between different fetal tissues. In addition, fetal IGF-I infusion increased the conversion of serine to glycine which is likely to have increased the availability of one-carbon groups for biosynthesis. Our data provide further evidence that IGF-I plays a role in the regulation of fetoplacental amino acid metabolism.

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MK Bauer, BB Breier, FH Bloomfield, EC Jensen, PD Gluckman, and JE Harding

Intra-uterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity. Postnatally, growth hormone (GH) increases growth, increases circulating insulin-like growth factor (IGF)-I levels, and alters metabolism. Our aim was to determine if GH infusion to IUGR fetal sheep would alter fetal growth and metabolism, and thus provide a potential intra-uterine treatment for the IUGR fetus. We studied three groups of fetuses: control, IUGR+ vehicle and IUGR+GH (n=5 all groups). IUGR was induced by repeated embolisation of the placental vascular bed between 110 and 116 days of gestation (term=145 days). GH (3.5 mg/kg/day) or vehicle was infused in a pulsatile manner from 117 to 127 days of gestation. Embolisation reduced fetal growth rate by 25% (P<0.01) and reduced the weight of the fetal liver (20%), kidney (23%) and thymus (31%; all P<0.05). GH treatment further reduced the weight of the fetal kidneys (32%) and small intestine (35%; both P<0.04), but restored the relative weight of the fetal thymus and liver (P<0.05). Embolisation decreased fetal plasma IGF-I concentrations (48%, P<0.001) and increased IGF binding protein 1 (IGFBP-1) concentrations (737%, P<0.002). GH treatment restored fetal plasma IGF-I concentrations to control levels, while levels in IUGR+vehicle fetuses stayed low (P<0.05 vs control). IGFBP-1 and IGFBP-2 concentrations were about sevenfold lower in amniotic fluid than in fetal plasma, but amniotic and plasma concentrations were closely correlated (r=0.75, P<0.0001 and r=0.55 P<0.0001 respectively). Embolisation transiently decreased fetal blood oxygen content (40%, P<0.002), and increased blood lactate concentrations (213%, P<0.04). Both returned to pre-embolisation levels after embolisation stopped, but blood glucose concentrations declined steadily in IUGR+vehicle fetuses. GH treatment maintained fetal blood glucose concentrations at control levels. Our study shows that GH infusion to the IUGR fetal sheep restores fetal IGF-I levels but does not improve fetal growth, and further reduces the fetal kidney and intestine weights. Thus, fetal GH therapy does not seem a promising treatment stratagem for the IUGR fetus.