The experiments described in this thesis investigated the effects of low doses of insulin-like growth factor (IGF)-I on fetal growth and metabolism in normally growing and growth-restricted (IUGR) late-gestation ovine fetuses. Intra-amniotic and intravenous routes of administration were studied. The aim of the first experiment was to investigate the effects of daily intra-amniotic injections of IGF-I for l0 days to fetuses with IUGR induced by placental embolisation. Embolisation produced asymmetrical IUGR with moderately severe effects on the gut. Gut weight, gut wall thickness and crypt mitoses were reduced. Villus enterocytes in the ileum contained numerous vacuoles, suggesting either functional adaptation or delayed maturation. IGF-I treatment increased amniotic fluid IGF-I concentrations 5-fold, but decreased plasma concentrations. The effects of embolisation on the gut were reversed, except for the enterocyte vacuolation in the ileum which was more pronounced with IGF-I treatment. Fetal gut uptake of glutamine from the circulation was reduced in IGF-I treated animals, but uptake from amniotic fluid may have increased. Fetal liver and spleen size were reduced. The distribution of placentome types was also altered with IGF-I treatment. The aim of the second experiment was to investigate the clearance of 125I-IGF-I from amniotic fluid. The half-life of 125I-IGF-I in amniotic fluid was 24 hours. Significant amounts of 125I-IGF-I remained unbound for up to 144 hours in both amniotic fluid and plasma. The predominant binding protein in amniotic fluid was IGFBP-3, and the proportion of 125I-IGF-I that was bound in amniotic fluid was strongly correlated with relative levels of IGFBP-3. Uptake of intact 125I-IGF-I across the fetal gut was clearly demonstrated, and continued for at least 36 hours following injection. A preliminary pharmacokinetic model of intra-amniotic dosing with IGF-I is presented. The aim of the final experiment was to investigate the effects of a chronic intravenous infusion of a low dose of IGF-I to normally growing late-gestation fetuses. There were no effects of IGF-I treatment on fetal growth or metabolism. Five fetuses were found to be IUGR at post mortem due to the effects of facial eczema in the ewe. A post hoc analysis of the effects of intravenous IGF-I in IUGR fetuses was therefore performed. IGF-I treatment significantly increased growth rate of IUGR fetuses and increased fetal blood aminonitrogen levels. Mean placentome weight was increased and the distribution of placentome types was altered. IGF-I treatment of IUGR fetuses reduced fetal lactate production. There were no differences in measures of fetal body or organ size at post mortem. The data from these investigations into the experimental manipulation of fetal growth provide clear evidence of the reversal of some of the effects of established IUGR, demonstrate uptake of intact and free IGF-I across the fetal gut, and, for the first time, suggest that IGF-I may increase the rate of fetal growth in IUGR. Amniotic fluid is the most readily accessible fetal compartment. The experiments described in this thesis suggest that fetal supplementation with IGF-I via the amniotic route may be a feasible, efficacious and clinically applicable therapeutic stratagem for the IUGR fetus. / Whole document restricted, but available by request, use the feedback form to request access.
| Identifer | oai:union.ndltd.org:ADTP/275480 |
| Date | January 2000 |
| Creators | Bloomfield, Francis Harry |
| Publisher | ResearchSpace@Auckland |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Whole document restricted but available by request. Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated., http://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm, Copyright: The author |
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