Fetal and maternal plasma insulin-like growth factors and binding proteins in pregnancies with appropriate or retarded fetal growth

Holmes, Robert; Montemagno, R.; Jones, Jessica; Preece, M A; Rodeck, Charles H.; Soothill, Peter

doi:10.1016/s0378-3782(97)01867-7

Cited by 92 publications

(62 citation statements)

References 27 publications

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“…There are no data in humans with which we can make comparisons. Cord serum IGF-II was significantly reduced in the FGR newborns as reported earlier by Holmes et al (33) and Leger et al (34), but in contrast with the study on serum from direct puncture of umbilical cords, which showed unchanged IGF-II in FGR (35).…”

Section: Discussionsupporting

confidence: 66%

Changes in interleukin-6 and IGF system and their relationships in placenta and cord blood in newborns with fetal growth restriction compared with controls

et al. 2006

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Objectives: The IGF system is central to fetal growth. Recently, the relationships between cytokines and the IGF system have been shown in specific tissues. It is unknown whether these occur in the placenta. The aim of this study was to assess whether interleukin-6 (IL-6) modulated the IGF system. Methods: Whole villous tissue and cord serum were collected from fetal growth restriction (FGR) neonates diagnosed before birth with altered Doppler velocimetry and controls. Sixteen FGR and 20 controls, born after week 32 of gestation from elective Caesarean sections, were compared. Total RNA was extracted from the placenta samples, reverse transcribed, and real-time quantitative reverse transcriptase (RT)-PCR was performed to quantify cDNA for IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-2, and IL-6. The same proteins were assayed in placenta lysates and cord serum using specific commercial kits and western immunoblotting. Results: FGR subjects had significantly more IGFBPs-1 and -2, and IL-6 mRNA and corresponding proteins in the placenta. In particular, the less phosphorylated isoforms of IGFBP-1 were highly increased. IL-6 and IGFBPs-2 mRNA, and IL-6 and IGFBP-1 peptides were positively and significantly correlated in the placenta. The IGF-II peptide was also significantly increased in FGR placentas. In cord serum, IGFBPs-1 and -2 were significantly more elevated in the FGR neonates. Serum IL-6 was significantly and positively correlated with both IGFBP-1 and IGFBP-2. Conclusions: The placenta of FGR neonates has higher IGF-II, IGFBP-1, IGFBP-2, and IL-6 contents compared with controls. At birth, IGFBPs-1 and -2 are increased in the cord blood of FGR neonates. IL-6 and IGFBP-2 gene expressions are closely related in the placenta. We suggest that the increase in IL-6 and IGFBP-2 could be subsequent to hypoxia and nutrient deficiency. As IGFBP-2 has a strong affinity for IGF-II, which is crucial for fetal growth, it could be an important bioregulator of IGF-II in the placenta.European Journal of Endocrinology 155 567-574

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Section: Discussionsupporting

confidence: 66%

Changes in interleukin-6 and IGF system and their relationships in placenta and cord blood in newborns with fetal growth restriction compared with controls

et al. 2006

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“…Although IGF-II is involved in the regulation of fetal growth, the correlation of IGF-II levels in the maternal circulation with fetal growth is not consistent (31,32). However, serum IGF-II levels in these reported studies were determined by the immunoassays that could not distinguish between mature IGF-II, big IGF-II, and pro-IGF-II.…”

Section: Discussionmentioning

confidence: 92%

Role of pro-IGF-II processing by proprotein convertase 4 in human placental development

Qiu

Basak

Mbikay

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Fetal growth restriction (intrauterine growth restriction, IUGR) is a leading cause of perinatal mortality. However, the causes of aberrant development of the placenta and, thus, of the fetus, are not currently known. Insulin-like growth factor II (IGF-II) has been shown to be an important regulator of fetoplacental growth. This growth factor must undergo posttranslational processing, and, thus, we hypothesized that aberrant processing of pro-IGF-II to IGF-II may be a cause of IUGR. Here, we have found that the proprotein convertase PC4 is expressed in the human placenta and that it cleaves pro-IGF-II to generate the intermediate processed form, IGF-II (1-102) and, subsequently, mature IGF-II (1-67), which are accounted for by the removal of terminal basic residues by carboxypeptidases. This processing confers the ability of IGF-II to activate invasive trophoblast cells through AKT phosphorylation, whereas inhibition of PC4 by a PC4-specific inhibitor blocks pro-IGF-II processing and reduces trophoblast cell migration, which can be partly restored by addition of mature IGF-II. Consistent with the hypothesis that IGF-II processing is implicated in IUGR, sera of patients carrying IUGR fetuses displayed elevated levels of pro-IGF-II. Thus, abnormal processing of IGF-II by PC4 may represent a previously uncharacterized mechanism involved in the pathophysiology of fetoplacental growth restriction, and elevated pro-IGF-II may be a useful clinical marker for risk of IUGR.insulin-like growth factor II ͉ intrauterine growth restriction

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“…However, controversy exists with regard to the relation between fetal serum IGF-II levels and fetal growth. Some studies report reduced cord blood IGF-II levels in IUGR babies (38)(39)(40), while others report similar levels of IGF-II in IUGR and normal fetuses (41). Human mutations in the gene encoding IGF-II, located on 11p15, have not been identified so far.…”

Section: Intrauterine Growthmentioning

confidence: 99%

“…In addition, maternal IGFBP-1 excess is associated with reduced fetal growth indicating placental insufficiency (69). In human, there is a striking inverse correlation between maternal and fetal circulating levels of IGFBP-1 and fetal size (39,44,70,71). It is postulated that IGFBP-1 inhibits the growth-promoting effect of IGF-I by binding fetal IGFs in IUGR.…”

Section: Regulation Of Gh Secretionmentioning

confidence: 99%

Genetic disorders in the GH–IGF-I axis in mouse and man

Walenkamp

Wit²

2007

eur j endocrinol

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Animal knockout experiments have offered the opportunity to study genes that play a role in growth and development. In the last few years, reports of patients with genetic defects in GH-IGF-I axis have greatly increased our knowledge of genetically determined causes of short stature. We will present the animal data and human reports of genetic disorders in the GH-IGF-I axis in order to describe the role of the GH-IGF-I axis in intrauterine and postnatal growth. In addition, the effects of the GH-IGF-I axis on the development and function of different organ systems such as brain, inner ear, eye, skeleton, glucose homeostasis, gonadal function, and immune system will be discussed. The number of patients with genetic defects in the GH-IGF-I axis is small, and a systematic diagnostic approach and selective genetic analysis in a patient with short stature are essential to identify more patients. Finally, the implications of a genetic defect in the GH-IGF-I axis for the patient and the therapeutic options will be discussed.European Journal of Endocrinology 157 S15-S26

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Fetal and maternal plasma insulin-like growth factors and binding proteins in pregnancies with appropriate or retarded fetal growth

Cited by 92 publications

References 27 publications

Changes in interleukin-6 and IGF system and their relationships in placenta and cord blood in newborns with fetal growth restriction compared with controls

Changes in interleukin-6 and IGF system and their relationships in placenta and cord blood in newborns with fetal growth restriction compared with controls

Role of pro-IGF-II processing by proprotein convertase 4 in human placental development

Genetic disorders in the GH–IGF-I axis in mouse and man

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