scholarly journals Chronic pulsatile infusion of growth hormone to growth-restricted fetal sheep increases circulating fetal insulin-like growth factor-I levels but not fetal growth

2003 ◽  
Vol 177 (1) ◽  
pp. 83-92 ◽  
Author(s):  
MK Bauer ◽  
BB Breier ◽  
FH Bloomfield ◽  
EC Jensen ◽  
PD Gluckman ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Blood Glucose ◽  
Growth Factor ◽  
Fetal Growth ◽  
Fetal Blood ◽  
Gh Treatment ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Igf I ◽  
Blood Glucose Concentrations

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.

The effects of ovine placental lactogen infusion on metabolites, insulin-like growth factors and binding proteins in the fetal sheep

1995 ◽  
Vol 144 (2) ◽  
pp. 333-338 ◽  
Author(s):  
M H Oliver ◽  
J E Harding ◽  
B H Breier ◽  
P C Evans ◽  
B W Gallaher ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Binding Proteins ◽  
Amino Nitrogen ◽  
Late Gestation ◽  
Placental Lactogen ◽  
Fetal Blood ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Igf I ◽  
Igfbp 3

Abstract It has been suggested, but not shown, that in the fetus placental lactogen (PL) may affect the regulation of the IGFs and fetal metabolism. To examine the effects of PL on the circulating concentrations of the IGFs, IGF-binding proteins (IGFBPs), glucose, free fatty acids (FFAs) and amino nitrogen (AN), we infused late gestation sheep fetuses with recombinant ovine PL (roPL). Five chronically-catheterised sheep fetuses were infused intravenously with three 24 h infusions of saline, roPL (100 μg bolus then 500 μg over 24 h) and then saline again. Fetal roPL infusion increased plasma oPL from 0·4 ± 0·1 to 3·3 ± 0·5 nm (mean ± s.e.m.; P<0·05; factorial analysis of variance and Scheffé's test). Fetal plasma IGF-I, IGF-II, insulin, FFAs and blood glucose were unaffected by the roPL infusion. Fetal plasma IGFBP-3, as measured by Western ligand blotting, decreased by 30% during fetal roPL infusion while other fetal plasma IGFBPs were unaffected. Fetal roPL infusion decreased fetal blood AN from 7·3 ± 0·5 to 6·6 ± 0·2 mm (P<0·05). Maternal plasma IGF-I, IGF-II, IGFBPs, insulin, FFAs, blood glucose and AN were unaffected by the fetal roPL infusion. Saline infusion had no effect on any parameter. The data suggest that PL is not a significant determinant of plasma IGFs in the late gestation sheep fetus although there may be an indirect effect via alterations in levels of IGFBP-3. The effect of fetal roPL infusion on fetal blood AN concentrations may suggest some role for PL in the regulation of fetal amino acid metabolism. Journal of Endocrinology (1995) 144, 333–338

Fetal plasma insulin-like growth factor-binding protein-3 concentrations are elevated following bilateral nephrectomy in fetal sheep

1995 ◽  
Vol 7 (3) ◽  
pp. 345
Author(s):  
C Beanland ◽  
C Browne ◽  
R Young ◽  
J Owens ◽  
P Walton ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Bilateral Nephrectomy ◽  
Fetal Sheep ◽  
Factor Binding ◽  
Fetal Plasma ◽  
Igf I ◽  
Igf Binding ◽  
Igfbp 3

Insulin-like growth factors mediate many of the effects of growth hormone and are important in the regulation of growth, especially in the fetus where growth is less dependent on circulating growth hormone. In the ovine fetus, insulin-like growth factor-I (IGF-I) is bound mainly to the low molecular weight insulin-like growth factor-binding proteins (IGFBP), IGFBP-1 and IGFBP-2, with little binding to IGFBP-3 until near term at 147 days gestation. To determine if there was any difference in plasma IGF-I and IGFBP-3 concentrations in growth-retarded fetal sheep with altered renal status, concentrations were measured by specific radioimmunoassay from bilaterally nephrectomized fetal sheep between Days 113 and 135 gestation. Plasma IGFBP-3 concentrations were significantly (P < 0.001) increased in bilaterally nephrectomized fetuses (4.19 +/- 0.19 micrograms mL-1, n = 7) compared with control fetuses (2.33 +/- 0.10 micrograms mL-1, n = 7). There was no change in plasma IGFBP-3 concentration with gestational age in either experimental group. Maternal plasma IGFBP-3 concentrations did not differ between the bilateral nephrectomy group (3.11 +/- 0.09 micrograms mL-1, n = 7) and the control group (3.25 +/- 0.11 micrograms mL-1, n = 7) and showed no change within groups over the experimental period. Total plasma IGF-I concentrations in bilaterally nephrectomized fetuses and ewes were similar to those in control fetuses and ewes. The results indicate that the profile of IGF binding in fetal plasma is altered in the anephric fetal sheep. In nephrectomized fetal sheep, increased IGFBP-3 concentrations, and therefore increased IGF-binding capacity in fetal plasma, may have contributed to a decrease in free IGF in plasma and decreased IGF-I bioactivity. This would provide a possible mechanism for the growth retardation reported in bilaterally nephrectomized fetal sheep.

scholarly journals Effects of acute hypoxemia on insulin-like growth factors and their binding proteins in fetal sheep

2006 ◽  
Vol 263 (6) ◽  
pp. E1151-E1156 ◽  
Author(s):  
H. S. Iwamoto ◽  
M. A. Murray ◽  
S. D. Chernausek
Keyword(s):  
Fetal Growth ◽  
Recovery Period ◽  
Fetal Blood ◽  
Fetal Sheep ◽  
Oxyhemoglobin Saturation ◽  
Subsequent Recovery ◽  
Factor I ◽  
Igf I ◽  
Vascular Catheters ◽  
Insulin Like Growth Factors

It has been proposed that insulin-like growth factor I (IGF-I) regulates fetal growth and differentiation. Plasma IGF-I concentrations correlate positively with fetal nutrient availability and newborn birth weights. To explore the hypothesis that hypoxemia decreases fetal growth by decreasing fetal IGF-I availability, we instrumented 14 fetal sheep with vascular catheters. At least 4 days after surgery, 10 fetuses were made acutely hypoxemic by infusing nitrogen into the maternal trachea for 3 h. Fetal blood oxyhemoglobin saturation decreased from 53 +/- 6 (SD) to 31 +/- 9%. Concomitantly, plasma IGF-I concentrations decreased from 91 +/- 11 to 67 +/- 10 ng/ml and IGF-I binding protein-1 concentration increased significantly, as assessed by ligand and Western blot analysis. Fetal IGF-I concentrations remained below control values throughout a subsequent recovery period (68 +/- 12 ng/ml at 6 h). In four control fetuses and in the ewes, plasma IGF-I concentrations were not significantly different from control values (97 +/- 18 and 181 +/- 18 ng/ml, respectively). These data support the hypothesis that decreases in fetal oxygen availability may decrease fetal growth by decreasing IGF-I production and availability.

Circulating insulin-like growth factors-I and -II and substrates in fetal sheep following restriction of placental growth

1994 ◽  
Vol 140 (1) ◽  
pp. 5-13 ◽  
Author(s):  
J A Owens ◽  
K L Kind ◽  
F Carbone ◽  
J S Robinson ◽  
P C Owens
Keyword(s):  
Growth Factors ◽  
Blood Glucose ◽  
Fetal Growth ◽  
Fetal Liver ◽  
Liver Weight ◽  
Fetal Weight ◽  
Fetal Sheep ◽  
Arterial Blood ◽  
Igf I ◽  
Insulin Like Growth Factors

Abstract To determine the relationship between placental delivery of oxygen and glucose, circulating insulin-like growth factors (IGFs) and fetal growth, the effect of variable restriction of placental growth was determined in sheep in late gestation. Arterial blood was obtained via indwelling catheters at 120 and 127 days of gestation, prior to necropsy at 130 days to measure fetal and placental weights. Plasma was acidified and subjected to size-exclusion high-performance liquid chromatography at pH 2·8 to dissociate and separate IGFs from their binding proteins. The acid-dissociated IGF fraction was analysed by sensitive and highly specific radioligand assays for IGF-I and IGF-II, previously defined using ovine IGFs. Fetal weight and blood pO2 and glucose at 120 and 127 days of gestation correlated positively with placental weight. Plasma IGF-I was positively associated with fetal weight and fetal liver weight, and with blood pO2 and glucose at both ages. Plasma IGF-II levels also correlated positively with fetal weight, fetal liver weight and with blood glucose and pO2, but only at 127 days of gestation. In the most severely growth-retarded fetal sheep, blood glucose and pO2 and plasma IGF-I were significantly reduced when compared with normal fetuses at 120 days. All decreased further by 127 days of gestation as did plasma IGF-II in severely growth-retarded fetal sheep compared with normal fetuses. These observations are consistent with the hypothesis that both IGF-I and IGF-II are chronically regulated by oxygen and nutrition in utero and mediate part of the influence of placental supply of substrate over fetal growth. Journal of Endocrinology (1994) 140, 5–13

Endotoxin attenuates growth hormone-induced hepatic insulin-like growth factor I expression by inhibiting JAK2/STAT5 signal transduction and STAT5b DNA binding

2007 ◽  
Vol 292 (6) ◽  
pp. E1856-E1862 ◽  
Author(s):  
Yu Chen ◽  
Difei Sun ◽  
Vidya M. R. Krishnamurthy ◽  
Ralph Rabkin
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Janus Kinase ◽  
Cytokine Gene Expression ◽  
Cytokine Signaling ◽  
Insulin Like Growth Factor ◽  
Gh Treatment ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Gram-negative sepsis with release of endotoxin is a frequent cause of cachexia that develops partly because of resistance to growth hormone (GH) with reduced insulin-like growth factor-I (IGF-I) expression. We set out to more fully characterize the mechanisms for the resistance and to determine whether in addition to a defect in the janus kinase 2 (JAK2)-signal transducer and activator of transcription (STAT) 5b pathway, required for GH-induced IGF-I expression, there might also be a more distal defect. Conscious rats were given endotoxin and studied 4 h later. In liver of these animals, GH-induced JAK2 and STAT5 phosphorylation was impaired and appeared to be caused, at least in part, by a marked increase in hepatic tumor necrosis factor-α and interleukin-6 mRNA expression accompanied by elevated levels of inhibitors of GH signaling, namely cytokine-inducible suppressors of cytokine signaling-1 and -3 and cytokine-inducible SH2 protein (CIS). Nuclear phosphorylated STAT5b levels were significantly depressed to 61% of the control values and represent a potential cause of the reduced GH-induced IGF-I expression. In addition, binding of phosphorylated STAT5b to DNA was reduced to an even greater extent and averaged 17% of the normal control value. This provides a further explanation for the impaired IGF-I gene transcription. Interestingly, when endotoxin-treated rats were treated with GH, there was a marked increase in proinflammatory cytokine gene expression in the liver. If such a response were to occur in humans, this might provide a partial explanation for the adverse effect of GH treatment reported in critically ill patients.

scholarly journals Effects of Short-Term Insulin-Like Growth Factor-I (IGF-I) or Growth Hormone (GH) Treatment on Bone Metabolism and on Production of 1,25-Dihydroxycholecalciferol in GH-Deficient Adults1

1998 ◽  
Vol 83 (1) ◽  
pp. 81-87 ◽  
Author(s):  
Tarcisio Bianda ◽  
Yvonne Glatz ◽  
Roger Bouillon ◽  
Ernst Rudolf Froesch ◽  
Christoph Schmid
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Bone Formation ◽  
Bone Turnover ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Gh Treatment ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Administration of insulin-like growth factor-I (IGF-I) or growth hormone (GH) is known to stimulate bone turnover and kidney function. To investigate the effects of IGF-I and GH on markers of bone turnover, eight adult GH-deficient patients (48 ± 14 yr of age) were treated with IGF-I (5 μg/kg/h in a continuous sc infusion) and GH (0.03 IU/kg/daily sc injection at 2000 h) in a randomized cross-over study. We monitored baseline values for three consecutive days before initiating the five-day treatment period, as well as the wash-out period of ten weeks. Serum osteocalcin, carboxyterminal and aminoterminal propeptide of type I procollagen (PICP and PINP, respectively) increased significantly within 2–3 days of both treatments (P &lt; 0.02) and returned to baseline levels within one week after the treatment end. The changes in resorption markers were less marked as compared with formation markers. Total 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) rose significantly, whereas PTH and calcium levels remained unchanged during either treatment. Conclusions: Because the rapid increase in markers of bone formation was not preceded by an increase in resorption markers, IGF-I is likely to stimulate bone formation by a direct effect on osteoblasts. Moreover, because PTH, calcium, and phosphate remained unchanged, IGF-I appears to stimulate renal 1α-hydroxylase activity in vivo.

Insulin-like growth factor I promotes growth selectively in fetal sheep in late gestation

1996 ◽  
Vol 270 (5) ◽  
pp. R1148-R1155 ◽  
Author(s):  
F. Lok ◽  
J. A. Owens ◽  
L. Mundy ◽  
J. S. Robinson ◽  
P. C. Owens
Keyword(s):  
Growth Factor ◽  
Fetal Growth ◽  
Late Gestation ◽  
Skeletal Maturation ◽  
Long Bones ◽  
Insulin Like Growth Factor ◽  
Fetal Sheep ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Insulin-like growth factor I (IGF-I) is required for normal fetal growth and skeletal maturation in late gestation, because null mutations of the IGF-I gene in mice reduce fetal weight and retard ossification of bones. To determine if, conversely, increased abundance of IGF-I promotes fetal growth and skeletal maturation, fetal sheep were infused intravascularly with recombinant human IGF-I (n = 7) (26 +/- 3 micrograms. h-1.kg-1) from 120 to 130 days gestation and compared with controls (n = 15). IGF-I infusion increased plasma IGF-I concentrations by 140% (P = 0.002) and weights of fetal liver, lungs, heart, kidneys, spleen, pituitary, and adrenal glands by 16-50% (P < 0.05). Weights and/or lengths of the fetus, placenta, gastrointestinal tract, individual skeletal muscles, and long bones were unchanged by IGF-I. However, IGF-I increased the percentage of proximal epiphyses of long bones present (P < 0.05) and their cross-sectional areas by 15 to 38% (P < 0.05). These results show that IGF-I promotes growth of major fetal organs, endocrine glands, and skeletal maturation in vivo, consistent with IGF-I actively controlling and not merely facilitating fetal growth. The variable response of different tissues may partly reflect tissue specificity in growth requirements for additional factors.

Effect of restriction of placental growth on expression of IGFs in fetal sheep: relationship to fetal growth, circulating IGFs and binding proteins

1995 ◽  
Vol 146 (1) ◽  
pp. 23-34 ◽  
Author(s):  
K L Kind ◽  
J A Owens ◽  
J S Robinson ◽  
K J Quinn ◽  
P A Grant ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fetal Growth ◽  
Fetal Weight ◽  
Ribonuclease Protection Assay ◽  
Fetal Blood ◽  
Fetal Sheep ◽  
Fetal Tissues ◽  
Arterial Blood ◽  
Igf I ◽  
Igfbp 3

Abstract To determine whether tissue production of the IGFs is altered when fetal growth is retarded, IGF-I and -II mRNAs were measured in tissues of fetal sheep subjected to placental restriction and the relationships between IGF gene expression, circulating IGF protein and fetal growth were examined. The majority of potential placental attachment sites were surgically removed from the uterus of 12 non-pregnant ewes to restrict placental size in a subsequent pregnancy. Blood and tissues were collected at 121 days of gestation (term=150) in 12 fetuses with restricted placental size and eight normal fetuses. IGF-I and IGF-II mRNA was detected by solution hybridization/ribonuclease protection assay in placenta and all fetal tissues studied. IGF-I mRNA was most abundant in skeletal muscle and liver and IGF-II mRNA was highest in kidney and lung. Restriction of placental size reduced fetal weight by 17% and reduced the pO2 (18%) and glucose concentration (23%) of fetal blood. Placental restriction also reduced IGF-I mRNA in fetal muscle (P<0·002), lung (P<0·05) and kidney (P<0·01) but had no significant effect on IGF-II mRNA in any tissue. IGF-I mRNA in fetal liver, kidney and skeletal muscle correlated positively with the concentration of IGF-I protein in fetal blood (P<0·01). There was no relationship between the concentration of IGF-II protein in fetal blood and IGF-II mRNA in any fetal tissue examined. The concentration of IGF-binding protein-3 (IGFBP-3) in fetal arterial blood plasma measured by RIA correlated positively with fetal weight and with plasma IGF-I. This study shows that restriction of placental growth in sheep reduces circulating levels of IGF-I and IGFBP-3 in the sheep fetus and reduces the capacity of the fetus to produce IGF-I at a number of tissue sites. Altered production of IGF-I, but not IGF-II, by fetal tissues may contribute to retarded fetal growth. Journal of Endocrinology (1995) 146, 23–34

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