Intrauterine Growth Retardation: Evidence for the Activation of the Insulin-Like Growth Factor (IGF)-Related Growth-Promoting Machinery and the Presence of a Cation-Independent IGF Binding Protein-3 Proteolytic Activity by Two Months of Life

Abstract

Thirty-seven children with intrauterine growth retardation (IUGR) were enrolled in a 3-mo longitudinal study. Weight, length, and knee-heel length (by knemometry) were measured at birth and at 7, 14, 30, 60, and 90 d. GH, IGF-I, IGF binding protein (BP)-3, IGFBP-1, and C-peptide were measured at birth and at 2 mo. IGFBP-3 Western immunoblotting and proteolytic activity assay were also performed. Twenty-five newborns with birth weight appropriate for gestational age were chosen as controls. At birth IUGR newborns showed levels of GH and IGFBP-1 significantly higher, and IGF-I, IGFBP-3, and C-peptide significantly lower than control subjects. At 2 mo GH and IGFBP-1 levels decreased, whereas IGF-I, IGFBP-3, and C-peptide rose, attaining the concentrations found in control subjects at birth. Baseline peptide levels as well as their 2-mo variations did not correlate with the gain in weight, supine length, and knee-heel length recorded at 3 mo. Fourteen of nineteen IUGR cord blood samples showed the presence of the intact approximately 42-39-kD IGFBP-3 doublet and the major approximately 29-kD fragment. At 2 mo the IGFBP-3 band pattern was characterized by the predominance of a approximately 18-kD fragment in 6 of 19 tested IUGR infants. The incubation of 2-mo IUGR samples with normal adult serum induced the appearance of the approximately 18-kD band, which was not modified by the addition of EDTA. These results suggest that: 1) the IGF-related growth-promoting mechanism is impaired in IUGR children at birth but is fully restored at 2 mo; 2) the cord blood levels of GH, IGF-I, IGFBP-3, IGFBP-1, and C-peptide are not predictive of the weight and length gain during the first 3 mo of life; 3) IUGR children have at least two different IGFBP-3 proteases, one cation-dependent protease that is present at birth and able to yield the major approximately 29-kD IGFBP-3 fragment and a second one, with a different activation timing, which exhibits cation independence and induces the formation of a approximately 18-kD IGFBP-3 form.

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

“…Cord serum IGF-I was not significantly different in FGR and controls, which reflects the findings in animal model studies (30), but is in contrast with the data published earlier in humans (31). However, these authors studied subjects delivered after the 38th week of gestation by both CS and vaginal delivery.…”

Endocrine Disruptors and Fetal Programming

“…The SGA (Small for Gestational Age) child demonstrates a reorganization of the endocrine system at birth with low insulin concentrations, insulin-like growth factor 1 (IGF-1) and IGF-1 binding protein type 3 (IGFBP-3) in addition to high levels of growth hormone IGFBP-1 and IGFBP-2 [27]. During the first trimester of postnatal life, as nutritional statues improves, insulin and IGF concentrations increase by exposing the fetus to the development of insulin resistance [27]. Na excessive gain of weight and consequent increase of adipose tissue in childhood would increase the risk of developing insulin resistance [28].…”

“…Fetal, maternal or environmental factors during pregnancy would affect the development of the fetus, promoting permanent changes in morphology and physiology, inducing a predisposition to the appearance of pathologies such as metabolic syndrome and cardiovascular diseases [26]. The SGA (Small for Gestational Age) child demonstrates a reorganization of the endocrine system at birth with low insulin concentrations, insulin-like growth factor 1 (IGF-1) and IGF-1 binding protein type 3 (IGFBP-3) in addition to high levels of growth hormone IGFBP-1 and IGFBP-2 [27]. During the first trimester of postnatal life, as nutritional statues improves, insulin and IGF concentrations increase by exposing the fetus to the development of insulin resistance [27].…”

Insulin Sensitivity in Children Born Small for Gestational Age (SGA)

“…Normalization of these parameters occurs early during the first trimester of life [12,13]. On the basis of this rapid adaptation to the extra-uterine environment, we have formulated the 'catch-up growth' hypothesis, suggesting that tissues chronically depleted of nutrients and, consequently, insulin and insulin-like growth factors (IGFs) during fetal life, in early postnatal life, being suddenly exposed to increased concentrations of the two hormones after normalization of nutrient supply, may counteract the additive insulin-like actions by developing insulin resis-tance [36].…”

“…Approximately 10% of SGA children will remain permanently < -2 SD for height [6,7]. The mechanisms that allow catch-up growth in SGA children or, on the other hand, prevent them from achieving a normal height are still unknown [12,13]. We have suggested that catch-up growth in SGA children might be, at least in part, affected by intrauterine reprogramming of hypothalamic-pituitary-adrenal axis, children with increased cortisol secretion being at higher risk of growth failure.…”