Elevated levels of insulin-like growth factor binding protein-1 in fetal distress
Department of Obstetrics and Gynaecology and Reproductive Physiology, St Bartholomew's Hospital Medical College, London, UK. British Journal of Obstetrics and Gynaecology
08/1995; 102(7):538-40. DOI: 10.1111/j.1471-0528.1995.tb11356.x
To investigate the association between fetal distress (abnormal cardiotocograph tracing and/or a low fetal pH) and the levels of fetal IGFBP-1.
Prospective comparative study.
Twenty-two women in labour with evidence of fetal distress defined by FIGO criteria and 19 women in uncomplicated labour. The gestation range was 37 to 42 weeks and birthweight range was 2500 to 4240 g. IGFBP-1 was determined by radioimmunoassay.
The umbilical levels of IGFBP-1 were significantly higher in the study group compared with the control group (median 282.5 micrograms/l versus 128 micrograms/l, P = 0.0046; Mann-Whitney U test). There was a significant inverse correlation between fetal IGFBP-1 and cord pH (r = 0.58, P < or = 0.0001). There was no difference between the maternal serum levels of IGFBP-1 in the two groups.
Umbilical IGFBP-1 is elevated in association with fetal distress.
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ABSTRACT: Die vorliegende Arbeit sollte eine mögliche Rolle von Mutationen der Gene IGF-I (Insulin-like Growth Factor-I) und IGF-IR (Insulin-like Growth Factor-I Receptor) in der Pathogenese der intrauterinen Wachstumsretardierung (Intrauterine Growth Retardation/ Restriction, [IUGR]) mit ARED (Absent or Reversed EndDiastolic)-Flow in der Dopplersonographie der A.umbilicalis untersuchen. Die IUGR wird auf Entwicklungsstörungen der Plazenta zurückgeführt. Die Proliferation und Differenzierung des villösen Trophoblasten werden insbesondere von dem Wachstumsfaktor IGF-I und seinem Rezeptor IGF-IR gesteuert. Ausserdem ist das funktionelle IGF-I-System auch in der Angiogenese der Plazentazotten involviert. Die reduzierte Aktivität dieses Systems scheint mit einer eingeschränkten Proliferation des Zytotrophoblasten und einer inadequaten Angiogenese der Plazenta mit der Folge einer postplazentaren Hypoxie einherzugehen. Die geschilderten morphologischen Veränderungen der Plazentazotten sind typisch für Schwangerschaften mit IUGR und ARED-Flow. Bei Schwangerschaften mit IUGR und PED (Preserved EndDiastolic)- Flow bei gleichzeitig pathologischem Dopplerbefund der A.uterina (Notch), zeigt die plazentare Histologie eine Hyperkapillarisierung im Bereich der vermehrt verzweigten Endzotten (uteroplazentare Hypoxie). In der vorliegenden Studie wurden die Gene, die für IGF-I und IGF-IR kodieren, in einem IUGR/ARED-Flow-Kollektiv (19 Mütter und deren 19 Kinder) und einem IUGR/PED-Flow-Kollektiv (14 Mütter und deren 14 Kinder) analysiert. Die DNA wurde aus Frischblut (Mütter und lebende Kinder) und Paraffinblöcken (verstorbene Kinder) isoliert. Das Screening auf genomische Varianten beider Gene erfolgte mittels Einzelstrangkonformationsanalyse (SSCP), Restriktionsanalyse (RFLP) und direkter Sequenzierung. Im IGF-I-Gen konnten bei dem untersuchten Kollektiv keine Mutationen identifiziert werden. Dagegen konnten im IGF-IR-Gen insgesamt fünf Varianten nachgewiesen werden, davon drei bisher noch unbekannte Sequenzveränderungen: eine im 5´- und zwei im 3´-untranslatierten Bereich des Gens, sowie zwei Polymorphismen, die bereits in der Literatur beschrieben worden sind: eine stille Mutation in Exon 16 und eine Deletion in der 3´-untranslatierten Region des Gens. Die neuen Polymorphismen lagen im nicht-kodierenden Bereich des IGF-IR-Gens. Darüber hinaus traten alle genomische Varianten mit etwa gleicher Häufigkeit unter den Patienten und unter den Kontrollen auf. Daraus lässt sich folgern, dass die identifizierten Gen-Polymorphismen keine entscheidende Rolle in der Ätiologie der IUGR mit ARED-Flow spielen. The objective of the present study was to evaluate a possible role of mutations of the genes IGF-I (Insulin-like Growth Factor-I) and IGF-IR (Insulin-like Growth Factor-I Receptor) in the pathogenesis of intrauterine growth retardation/ restriction (IUGR) with ARED (Absent or Reversed EndDiastolic)-flow in the Doppler ultrasonography of the A.umbilicalis. IUGR is caused by abnormal development of the placenta. The proliferation and differentiation of the villous trophoblast are predominantly controlled by growth factor IGF-I and its receptor IGF-IR. The functional IGF-I-system is also involved in the placental angiogenesis. Reduced activity of this system seems to be associated with an impaired proliferation of cytotrophoblastic cells and an inadequate placental angiogenesis, resulting in a postplacental hypoxia. The morphological changes of the placenta, as described above, are characteristic for pregnancies with IUGR and ARED-flow. In pregnancies with IUGR and PED (Preserved EndDiastolic)-flow in the presence of a bilateral abnormal uterine artery Doppler waveform (Notch), the placental histology shows a netlike arrangement of capillaries, forming multiply branched terminal villi (uteroplacental hypoxia). In the present study have been analyzed the genes encoding for IGF-I and IGF-IR in an IUGR/ARED-flow-group (19 mothers and their 19 fetuses) and an IUGR/PED-flow-group (14 mothers and their 14 fetuses). DNA was extracted from blood samples (mothers and alive fetuses) and paraffinblock samples (not-alive fetuses). Both genes were screened for genomic variants by single-strand conformation analysis (SSCP), restriction assays (RFLP) and direct sequencing. In the IGF-I-gene no variants could be identified in the study population. As for the IGF-IR-gene, five variants could be identified, three of them so far unknown: one in the 5´- and two in the 3´-untranslated region of the gene, as well as two polymorphisms that had already been described before in the literature: a silent mutation in exon 16 and a deletion in the 3´-untranslated region of the gene. The new polymorphisms were localized in the non-coding region of the IGF-IR-gene. Furthermore, all genomic variants were detected in similar frequencies in the patient-group and the control-group. Thus we conclude that the identified gene-polymorphisms do not play a relevant role in the aetiology of IUGR with ARED-flow.
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ABSTRACT: The placenta synthesizes insulin-like growth factors (IGFs) and their binding proteins (IGFBPs), which are believed to regulate its growth and development in an autocrine/paracrine manner. To delineate the cellular sites of expression of IGP and IGFBP messenger ribonucleic acids (mRNAs) in human placenta throughout pregnancy, we used in situ hybridization histochemistry with 35S-labeled IGF and IGFBP complementary RNA probes on human placentas and fetal membranes of gestational ages 6 weeks to term (40 weeks). In placental regions where trophoblasts (fetal) or decidua (maternal) coexist (e.g. basal plate), the identity was delineated by their cytokeratin or vimentin immunoreactivity, respectively. Except for IGF-II, mRNAs encoding peptides of the IGF system were expressed in a similar spatial pattern and relative abundance throughout gestation. Both IGF mRNAs showed similar tissue distribution, but the IGF-II mRNA was more abundant than IGF-I mRNA at all gestational ages. IGF-II mRNA was expressed in the chorionic mesoderm of placental villi and chorionic plate in moderate abundance, and it decreased with gestation. It was also expressed in the trophoblasts of the cytotrophoblastic shell and Langhan's layer of placental villi only in the first trimester, suggesting an autocrine role for IGF-II in early cytotrophoblastic proliferation and/or differentiation. IGF-II mRNA was expressed most abundantly in the columns of intermediate trophoblasts in the anchoring villi and chorionic and basal plates. A gradient of IGF-II mRNA abundance was observed in the trophoblasts of the cytotrophoblastic column, with greater IGF-II mRNA levels in those at the invading front, suggesting a role for IGF-II in trophoblastic invasion. In the fetal membranes, IGF-II mRNA was identified in the amnion and chorion laeve. IGF-I receptor mRNA was expressed in low abundance in all cell types of the placenta. All six IGFBP mRNAs were identified in variable abundance in the decidualized stromal cells of the maternal decidua basalis and parietalis, with IGFBP-1 mRNA being expressed in the greatest abundance. The spatial pattern of expression of each IGFBP mRNA also differed among decidual cells, with IGFBP-1, IGFBP-2, IGFBP-4, and IGFBP-6 mRNAs being expressed in most cells, whereas IGFBP-3 and IGFBP-5 mRNAs were expressed in only some cells. IGFBP-1 mRNA was expressed initially in the epithelium of endometrial glands and in a population of decidualized stromal cells in early gestation, and subsequently in the majority of decidualized stromal cells. IGFBP-3 mRNA was expressed in both the decidua and certain intermediate trophoblasts of the basal plate and anchoring villi of placenta and in amnion and chorion laeve of fetal membranes. IGFBP-4 and IGFBP-5 mRNA were expressed additionally in low abundance in the chorionic mesoderm. IGFBP-6 was expressed in greater abundance in the decidua parietalis than in decidua basalis, although the general level of expression was low. The spatial pattern and relative abundance of expression of IGFBP mRNAs suggest IGFBP-1 to be the predominant IGFBP synthesized by the maternal decidual cells, interacting with the IGF-II that synthesizes fetal intermediate trophoblasts. Presumably, IGF-II and IGFBPs are used for cell to cell communication between fetal trophoblasts and maternal decidual cells at the feto-maternal interface for placental development and/or function.
Journal of Clinical Endocrinology & Metabolism 08/1996; 81(7):2680-93. DOI:10.1210/jc.81.7.2680 · 6.21 Impact Factor
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ABSTRACT: Our purpose was to examine the regulation of fetal serum concentrations of insulin (C-peptide), insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding protein-1, which are growth-regulating factors in the fetus, in monozygotic and dizygotic twin pairs.
Cord serum samples were collected from 110 twin pairs and compared with 178 nonsibling singleton pairs with the same gestational age. Five twin pairs were excluded from the statistical analyses because of severe intrauterine growth restriction and placental abnormalities in one. Zygosity was assigned by histologic examination of the placenta and by a questionnaire sent to the mother when the twins were > or = 6 months old. Analyses included the calculation of correlation coefficients, between-pair variation, and univariate genetic analysis.
Cord serum C-peptide concentrations were highly correlated in monozygotic (r = 0.94) and dizygotic twins (r = 0.79) but not in singleton pairs (r = -0.05); the between-pair variation was also smaller in twins than in singletons. Genetic analysis demonstrated a large contribution of the common environment to the variance in C-peptide concentrations (80%) and a smaller genetic contribution (12%). Insulin-like growth factor-I concentrations were better correlated in monozygotic (r = 0.82) than in dizygotic twins (r = 0.42), with a smaller between-pair variation in the former group (22% +/- 4% vs 51% +/- 5%). Univariate genetic analysis indicated that insulin-like growth factor-I levels were regulated predominantly by genetic mechanisms (93% in boys and 77% in girls). The regulation of insulin-like growth factor-II was more complex, with a gender-specific genetic contribution (50% for both sexes combined, 63% for girls but only 5% for boys). Insulin-like growth factor binding protein-1 was regulated by genetic mechanisms (41%) and the common environment (32%) but also by the specific or unique environment of each fetus (27%). In all five twins with intrauterine growth restriction of one member insulin-like growth factor binding protein-1 concentrations were markedly higher in the growth-restricted fetus.
Insulin secretion in twin fetuses is determined primarily by their common, probably maternal, environment, whereas insulin-like growth factor-I production is predominantly genetically regulated. Insulin-like growth factor-II and insulin-like growth factor binding protein-1 are regulated by both genetic and environmental factors. Of these growth-regulating factors, insulin-like growth factor binding protein-1 appears to be the best marker of intrauterine growth restriction in the individual case.
American Journal of Obstetrics and Gynecology 11/1996; 175(5):1180-8. DOI:10.1016/S0002-9378(96)70025-X · 4.70 Impact Factor
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