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R S Gilmour
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Our perception of insulin-like growth factor-I (IGF-I) as a growth promoter stems from the original proposal of Salmon & Daughaday (1957) that it mediates the biological actions of pituitary growth hormone (GH). The primary target for GH, it was proposed, is the liver which is stimulated to synthesize IGF-I. The resultant increase in circulating levels of IGF-I promotes cell division and constitutes a major component of the growth response. There is a large body of evidence which relates serum IGF-I concentrations to growth rates; moreover, the liver is the major source of the hormone since it has the highest tissue level of IGF-I mRNA (Murphy et al. 1987) and its synthesis of IGF-I peptide can account, in theory, for the known turnover of IGF-I in the circulation (Schwander et al. 1983).

Subsequently it was shown that IGFs are synthesized to varying degrees in many other tissues. While these observations indicate

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A L Fowden
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J Szemere
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P Hughes
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R S Gilmour
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A J Forhead
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Abstract

Using indwelling crown–rump length (CRL)-measuring devices, the growth rate of sheep fetuses was monitored during late gestation and after experimental manipulation of fetal plasma cortisol by exogenous infusion and fetal adrenalectomy. In intact control fetuses, the increment in CRL declined progressively during the last 20–25 days of gestation: mean ± s.e.m. values fell from 5·5 ± 0·4 mm/day (n=12) at 21–25 days before delivery to 2·5 ± 0·3 mm/day (n=12) in the last 5 days before birth (P<0·01). These changes closely parallelled the normal prepartum increase in fetal plasma cortisol which rose from 19·3 ±3·3 nmol/l (n=10) at 21–25 days before birth to 177·4 ± 19·0 nmol/l (n=10) in the final 5 days before delivery (P<0·01). When this cortisol surge was prevented by fetal adrenalectomy, there was no decrease in CRL increment towards normal term: mean CRL increment in the 5 days before normal term (4·8 ± 0·6 mm/day, n=5) was similar to that observed at 21–25 days before term (4·7 ± 0·4 mm/day, n=5). At delivery at term, the body weight (4·116 ± 0·280 kg, n=5) and CRL (51·9 ± 1·7 cm, n=5) of the adrenalectomized fetuses were significantly greater than the corresponding values in their sham-operated controls (2·877 ± 0·070 kg and 47·1 ±1·6 cm, n=6, respectively). In contrast with the sham-operated controls, plasma glucose and insulin levels in the adrenal-ectomized fetuses decreased towards term. Infusion of cortisol into the preterm fetus for 5 days increased fetal plasma cortisol to term levels and decreased the CRL increment to a value (1·8 ± 0·5 mm/day, n=8) which was similar to that observed in untreated controls during the last 5 days before spontaneous delivery at term (2·1 ± 0·3 mm/day, n=6). There were no significant alterations in the fetal arterial concentrations of plasma glucose or insulin in response to fetal cortisol infusion. When all the data were combined irrespective of treatment or proximity to delivery, the fetal plasma concentrations of cortisol (P<0·001) and glucose (P<0·04), but not insulin (P>0·05), had a significant effect on the fetal CRL increment measured over 5-day periods during the last 25–30 days of gestation. These findings show that cortisol inhibits growth of the axial skeleton in the sheep fetus during late gestation. They also indicate that the prepartum cortisol surge may be responsible for the normal decline in fetal growth rate observed towards term in this species.

Journal of Endocrinology (1996) 151, 97–105

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J M Brameld
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P A Weller
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J C Saunders
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P J Buttery
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R S Gilmour
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Abstract

The effects of various hormones commonly added to hepatocyte culture media upon the expression of the GH receptor (GHR) and insulin-like growth factor-I (IGF-I) genes in cultured porcine hepatocytes were investigated. Preliminary investigations indicated that there was an absolute requirement only for insulin, with high losses of cell viability upon long term exclusion of insulin from the culture medium. The decline in GHR expression with time in culture was found to be less when high levels of glucose were included in the medium. Therefore the basal culture medium used in these studies was Williams' medium E supplemented with 0·2% (w/v) BSA, 5000 mg glucose/l and 100 nmol porcine insulin/l. The addition of dexamethasone (100 nmol/l) increased the expression of both GHR and IGF-I (class 1 transcripts only) mRNA (P<0·001 and P<0·05 respectively), and resulted in an increased responsiveness of IGF-I mRNA expression to GH (1 μg/ml), when the two were added in combination (although only class 1 transcripts were shown to be statistically significant, P<0·01). The addition of either thyroid hormone (1 nmol/l T3 or T4) alone also increased the expression of GHR mRNA (P<0·01) in addition to the dexamethasone stimulated expression, with T4 appearing to decrease IGF-I expression slightly (P<0·05) (either on its own or with T3). As with dexamethasone, the thyroid hormones increased the response of IGF-I mRNA expression to GH (1 μg/ml) when added in combination with GH (P<0·001). These observations demonstrate one possible mechanism for the interactions of glucocorticoids and thyroid hormones with the GH–IGF axis.

Journal of Endocrinology (1995) 146, 239–245

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K L Kind
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J A Owens
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J S Robinson
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K J Quinn
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P A Grant
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P E Walton
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R S Gilmour
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P C Owens
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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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S Shaikh Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand

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F H Bloomfield Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand

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M K Bauer Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand

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H H Phua Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand

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R S Gilmour Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand

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J E Harding Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand

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We have previously reported that chronic intra-amniotic supplementation of the late gestation growth-restricted (IUGR) ovine fetus with IGF-I (20 μg/day) increased gut growth but reduced liver weight and circulating IGF-I concentrations. Here we report mRNA and protein levels of IGF-I, the type 1 IGF receptor (IGF-1R) and IGF-binding proteins (IGFBP)-1, -2 and -3 in fetal gut, liver, muscle and placenta from fetuses in that earlier study in an attempt to explain these contrasting results. mRNA and protein were extracted from tissues obtained at post mortem at 131 days of gestation (term, 145 days) from three groups of fetuses (control, IUGR+saline and IUGR+IGF-I, n=9 per group). Control fetuses were unembolised and untreated. In the IUGR groups, growth restriction was induced from 113 to 120 days by placental embolisation; from 120 to 130 days fetuses were treated with daily intra-amniotic injections of either saline or 20 μg IGF-I. mRNA was measured by RT-PCR or real-time RT-PCR, and protein by Western blot. In liver, muscle and placenta, IGF-I mRNA and protein levels were reduced by between 8 and 30% in IGF-I-treated fetuses compared with saline-treated fetuses and controls with no change in IGF-1R mRNA or protein levels. In contrast, in the gut, IGF-I mRNA and protein levels were not significantly altered with IGF-I treatment, but IGF-1R levels were increased, especially in the jejunum. Immunolocalisation demonstrated that IGF-1R expression was confined to the luminal aspect of the gut. mRNA levels of all three IGFBPs were reduced in the gut of IGF-I-treated fetuses, but hepatic expression was significantly increased. These data demonstrated tissue-specific regulation of IGF-I, IGF-1R and IGFBPs-1, -2 and -3 in response to intra-amniotic IGF-I supplementation, though the underlying mechanisms remain obscure.

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C. L. van Papendorp
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I. T. Cameron
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A. P. Davenport
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A. King
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P. J. Barker
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N. S. Huskisson
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R. S. Gilmour
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M. J. Brown
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S. K. Smith
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ABSTRACT

The aim of this study was to investigate the localization of endothelin-like immunoreactivity (ET-IR) in human placenta, chorion and amnion and to compare the endogenous concentration of immunoreactive endothelin (ET) in these tissues before and after the onset of labour. ET-IR was detected in the endothelium of stem vessels in placental villi, as well as in decidual stromal cells in the basal maternal plate, by immunocytochemistry using a primary polyclonal rabbit antibody. A specific radioimmunoassay was used to detect endogenous concentration of ET in homogenized placental tissues. The endogenous concentration of ET-IR was significantly greater in amnion than in chorion and placenta (amnion 249 ±13 fmol/g; chorion 190 ±11 fmol/g; placenta 169±14 fmol/g; means ± s.e.m.; n = 12; P < 0·01). No significant difference was seen before or after the onset of labour. The detection of ET-IR in placenta, chorion and amnion suggests that the ETs may play a role in the paracrine control of human uterine function.

Journal of Endocrinology (1991) 131, 507–511

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