Effect of hyperthyroidism on insulin-like growth factor-I (IGF-I) and IGF-binding proteins in adolescent children

A study was performed on adolescent hyperthyroid patients to determine the effects of hyperthyroidism on insulin-like growth factor (IGF)-I and its binding proteins. Serum concentrations of immunoreactive total and free IGF-I, and IGF binding protein (IGFBP)-2 and IGFBP-3 were determined before and after correction of hyperthyroidism in eight patients with Grave's disease and compared to control patients matched for age, sex and pubertal stage. The concentration of serum total IGF-I was not significantly different in the hyperthyroid state and euthyroid state, and did not differ significantly from euthyroid controls. IGFBP-2 levels were elevated three-fold in hyperthyroid patients at the time of diagnosis of hyperthyroidism compared to control subjects, and fell significantly during treatment. There was also a significant positive correlation between serum IGFBP-2 concentrations and thyroxine (T4) concentrations in all subjects. Serum IGFBP-3 concentrations were also elevated in hyperthyroid subjects and normalized with correction of the hyperthyroidism. There was also a positive correlation between serum T4 and IGFBP-3 concentrations in all subjects. Despite the hyperthyroid-induced elevations in IGFBP-2 and -3, no significant difference in the serum concentration of free IGF-I before or after correction of the hyperthyroid condition was observed. We conclude that hyperthyroidism does not cause alterations in the serum concentrations of either free or total IGF-I. However, both serum IGFBP-2 and IGFBP-3 concentrations were elevated during hyperthyroidism and correlated with serum T4 levels. These abnormalities reversed with normalization of thyroid function.     

Serum concentrations of insulin, insulin-like growth factor-I and insulin-like growth factor binding proteins are different between white and African American girls.

OBJECTIVES: To determine whether serum insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP) concentrations are different between African American and white girls. STUDY DESIGN: Serum glucose and hormone concentrations were measured in blood samples collected after a 12-hour fast from 79 white and 57 African American healthy girls between 9 and 17 years of age. Tanner stages of pubic hair development were evaluated by physical examination, and body composition by dual energy x-ray absorptiometry. RESULTS: The African American girls were older and sexually more mature and had higher fat mass, higher serum insulin and free IGF-I concentrations, higher serum free IGF-I to total IGF-I ratio, but lower serum IGFBP-1 concentrations than the white girls. After controlling for sexual maturation and fat mass, the serum concentrations of total IGF-I, bound IGF-I, and IGFBP-3 in the white girls became significantly higher than those in the African American girls. The higher concentrations of total IGF-I in the white girls were due to a proportional increase in the concentrations of bound IGF-I that coincided with a similar increase in serum IGFBP-3 concentrations. CONCLUSIONS: Higher serum insulin concentrations in the African American girls are associated with lower serum IGFBP-1 concentrations and increased bioavailability of free IGF-I, which may contribute to their accelerated growth compared with their white counterparts.     

Leptin, insulin-like growth factor (IGF)-I and IGF binding protein-3 levels in children with constitutional delay of growth

This study was planned in order to investigate the role of insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) and leptin, the product of the ob gene synthesized by fat tissue cells, in constitutional delay of growth and puberty (CDGP) which is the most frequent cause of short stature in children. This study was conducted on 80 children with CDGP aged 6-15 years, and 60 healthy children served as controls. Serum IGF-I, IGFBP-3, insulin and plasma leptin levels were measured by immunoradiometric assay. Mean IGF-I and leptin levels were significantly lower in the CDGP group compared with the controls, but the mean IGFBP-3 level was not different in the two groups. Mean leptin levels were 3.72 +/- 2.29 in CDGP and 4.68 +/- 3.08 in the control group (p <0.05). There was a statistically significant relationship between leptin levels and height, weight, and body mass index. Leptin levels were also correlated with chronological age, bone age and height age. When evaluated according to pubertal status, a significant difference was found in IGF-I, leptin and IGFBP-3 levels between prepubertal and pubertal groups. Leptin levels were significantly different in the prepubertal CDGP group compared with controls but in the pubertal CDGP group only IGF-I levels were significantly different from controls. As the weight of children with CDGP was lower than in the control group, it is postulated that the reason for short stature and pubertal delay may be this decrease in weight which is also the cause of low levels of leptin and IGF-I.     

Serum profiles of insulin-like growth factors and their binding proteins in adults with growth hormone receptor deficiency treated with insulin like growth factor I

Six adult patients with growth hormone receptor deficiency (GHRD) (2 men, 4 women) with an identical defect in the growth hormone receptor (GHR) gene, were treated with recombinant human insulin-like growth factor I (IGF-I), 40 μgikg S.C. twice daily, for 7 days. Serum concentrations of IGF peptide and IGF binding protein-3 (IGFBP-3) were measured by specific radioimmunoassays; serum IGFBPs were also measured by Western ligand blotting. The size distribution of both IGF-I and IGF-II was measured in serum following size-exclusion fast-performance liquid chromatography. IGF-I treatment resulted in a normalization of serum IGF-I levels on days 1–7 of treatment and a decrease in serum IGF-II levels. The fall in IGF-II levels and the simultaneous rise in IGF-I levels, however, resulted in an unchanged total serum IGF level. The low IGFBP-3 values did not significantly change during treatment, whereas there was a slight increase in IGFBP-2 levels. Preliminary analysis of size-fractionated sera suggested an increase in IGF-I levels in the 40 and 150 kDa regions at the expense of IGF-II levels. The results suggest that despite the failure of IGF-I treatment to increase IGFBPs significantly, serum IGFBP concentrations were sufficient to maintain normal levels of IGF-I. 0 Laron syndrome, growth hormone receptor deficiency, insulin-like growth factors, insulin-like growth factor binding protein     

Growth hormone and insulin-like growth factor I axis and growth of children with different sickle cell anemia haplotypes

BACKGROUND: The purpose of this study was to examine the relationships between growth in children with sickle cell anemia and the different beta-globin haplotypes, as well as components of the insulin-like growth factor (IGF)/insulin-like growth factor binding protein (IGFBP) axis. PATIENTS AND METHODS: Growth parameters and plasma concentrations of growth hormone (GH), IGF-I, and IGFBP-3 were studied in 41 children with sickle cell anemia whose haplotypes were defined. RESULTS: Plasma concentrations of IGF-I (total, free, and free/total fraction) and IGFBP-3 were significantly reduced in all patients with sickle cell anemia compared with the healthy children. Patients with the CAR/CAR haplotype had significantly lower mean growth velocity compared with those with Ben/Ben. When the GH/IGF axis elements were compared in relation with the different haplotypes, total IGF-I levels in CAR/CAR patients were significantly lower compared with levels in patients with Ben/Ben. A positive correlation was found between hematocrit and total IGF-I and between fetal hemoglobin percentages and the z-scores for total IGF-I and IGFBP-3. There was a positive correlation between age, weight, height, bone age, and the various elements of the GH/IGF-I axis when all groups were considered, although the correlation was lost when the auxologic data were expressed as standard deviation score for age. Growth velocity and the z-score for growth velocity were not correlated with any element of the axis. CONCLUSIONS: The positive relationship between hematocrit and fetal hemoglobin percentages with total IGF-I, free/total IGF-I, and IGFBP-3 in patients with sickle cell anemia could show that the delayed growth of these patients may be linked to intrinsic factors of the disease, which also determine the low circulating concentrations of the various elements of the GH/IGF-I axis. It is reasonable to assume that decrease of total IGF-I concentrations in patients with CAR/CAR haplotype is secondary to the severity of the disease.     

Growth hormone insensitivity syndromes: a preliminary report on changes in insulin-like growth factors and their binding proteins during treatment with recombinant insulin-like growth factor I

Serum levels of insulin-like growth factor (IGF) binding proteins (IGFBPs) 1, 2 and 3 were studied by radioimmunoassay in 29 patients with growth hormone (GH) insensitivity syndromes (GHIS) before and during treatment with IGF-I. As in normal subjects, there was a highly significant correlation between IGFs and IGFBP-3 but not between IGFs and the other binding proteins, though IGFBP-3 represented only about one-third of the total IGFBP concentration. In 6 patients with GH deficiency and in 5 patients with GHIS, the pharmacokinetic profile of IGF-I after a single injection was strongly dependent on the IGFBP-3 concentration. A slight but significant increase in IGFBP-3 was observed coincident with the IGF-I peak, whereas IGFBP-2 increased after a delay of about 10 hours. In the patients with GHIS, chronic IGF-I treatment, with twice-daily injections for 6 months, caused a significant steady decline of IGF-II and an increase in IGFBP-2, but had no effect on IGFBP-1 and IGFBP-3 levels. During IGF-I treatment, an inverse relationship between baseline IGF-I and GH levels was observed. The data suggest that total IGF-I and IGF-IL serum levels are determined mainly by IGFBP-3, even in extreme situations such as GHIS, while other IGFBPs are less important. The IGFBP-3 concentration seems to be a major regulator of the pharmacokinetics of exogenous IGF-I, which, in turn, influences IGFBP-3 levels. This effect of IGF-I on IGFBP-3 is not through induction of IGFBP-3 synthesis, but possibly by reduction of IGFBP-3 clearance. Finally, IGF-I administration suppresses GH secretion.     

Serum zinc, insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels in children with type 1 diabetes mellitus

BACKGROUND: Growth is impaired during the course of diabetes mellitus (DM). Derangement of the growth hormone/insulin-like growth factor (IGF) axis, insulinopenia and zinc deficiency are the possible causative factors of this impairment. Zn supplementation is proven to attenuate hyperglycemia in mice but its use to ameliorate impaired height is still a matter of discussion. OBJECTIVE: To investigate serum Zn, IGF-I and IGF binding protein-3 (IGFBP-3) levels and to emphasize the potential beneficial effects of Zn supplementation for the prevention of growth failure in children with type 1 DM (DM1). Patients and Methods: Twenty-eight patients with DM1 and 15 control children were included in the study. Zn levels were measured by flame atomic absorption spectrophotometry; IGF-I and IGFBP-3 levels were measured by immunoradiometric assay. RESULTS: Mean serum Zn levels were significantly lower in diabetic children taken as a whole and as their pubertal subgroup compared to the controls. Mean serum IGF-I and IGFBP-3 levels were significantly lower in both prepubertal and pubertal diabetic groups compared to those of control groups. CONCLUSION: From the results of our study, it can be hypothesized that serum Zn levels should be closely monitored during the course of DM1 and supplementation may be given to patients, especially at the time of puberty. This hypothesis needs to be confirmed by further studies.     

Differential impact of simple childhood obesity on the components of the growth hormone-insulin-like growth factor (IGF)-IGF binding proteins axis

Simple childhood obesity is characterized by normal or even accelerated growth in spite of reduced growth hormone (GH) secretion. There are conflicting reports on the effects of obesity upon components of the GH-insulin-like growth factor-I (IGF-I)-IGF binding proteins (IGFBPs) system. In the present study we aimed to determine GH, IGF-I, IGFBP-3 and IGFBP-2 as well as some of the less explored components of this axis (IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments, and total acid labile subunit [ALS]) in 22 obese and 17 age-matched control children. We also evaluated not only total GH binding protein (GHBP) serum levels but also GHBP bound to GH (complexed) in both groups. Obese and control groups strongly differed in BMI (obese: 4.7 +/- 0.36 vs control: 0.37 +/- 0.25 SDS, p <0.0001). In the obese group, we found lower GH serum levels, but normal serum levels of GH-GHBP complex, IGF-I, IGFBP-3, IGF-I/IGFBP-3 molar ratio, IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments and total ALS. Obese children presented higher total circulating GHBP (6.0 +/- 0.44 vs 2.9 +/- 0.29 nmol/l, p <0.001) and insulin levels (10.5 +/- 1.5 vs 5.1 +/- 0.8 mU/l, p <0.001), while IGFBP-2 (4.6 +/- 0.5 vs 6.6 +/- 0.7%, p <0.05) and the ratio IGFBP-2/IGF-I (0.032 +/- 0.019 vs 0.095 +/- 0.01, p = 0.013) were lower than in controls. BMI and insulin were directly, and IGFBP-2 serum levels inversely, correlated to total GHBP serum levels when multiple regression analysis was performed (r = 0.74, p <0.001). By stepwise regression analysis, insulin (r = -0.37, p <0.05) and BMI (r = -0.52, p <0.01) inversely determined IGFBP-2. In summary, obese children present normal growth in spite of reduced GH secretion, probably because the combination of increased total GHBP and normal GH-GHBP complex serum levels (suggesting increased GH receptor [GHR] number and a normal serum GH reservoir, respectively) allow for the achievement of normal levels of IGF-I, IGFBP-3, IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments and total ALS. Reduced IGFBP-2 serum levels and a lower ratio of IGFBP-2/IGF-I in obese children may suggest an increase of tissue IGF-I bioavailability, thus promoting its action. Normal IGF-I and GH availability may be contributing to maintain normal growth in obese children.     

Insulin-like growth factor binding protein-3 proteolysis and growth of athyreotic infants in the first weeks of life

To gain a better understanding of the growth of athyreotic newborns in the first weeks of life, we evaluated auxological parameters and determined the serum levels of growth hormone (GH), insulin-like growth factor I (IGF-I) and free IGF-I, and IGF-binding protein-3 (IGFBP-3) in 15 hypothyroid infants (10 females) at a mean age of 25 d of life, immediately before the beginning of L-thyroxine therapy, and at 3 and 6 mo of life. Fourteen normal infants (9 females) of the same age were studied as controls. IGFBP-3 proteolytic activity was evaluated in 8 patients and in 8 controls at 25 d and 6 mo of life. There was no significant difference concerning weight and length between the patients and controls at birth, 25 d, 3 and 6 mo of life. The blood GH, IGF-I and IGFBP-3 levels were significantly lower in patients at diagnosis than in controls of the same age (p < 0.01 for all parameters), as well as IGFBP-3 studied by Western blotting. At diagnosis, the patients' free IGF-I level was within the control range, but the free IGF-I percentage of total IGF-I was higher than in the controls (p < 0.01). IGFBP-3 proteolytic activity was found to be greater in the patients (p < 0.01). At 6 mo of life, after therapy, none of these parameters was different from those of the controls. CONCLUSION: Increased IGFBP-3 proteolytic activity in our patients at diagnosis, favouring IGF-I bioavailability, could account for normal free IGF-I levels and in turn for their normal growth pattern during the first weeks of life and before the start of treatment.     

Reduced levels of growth hormone, insulin-like growth factor-I and binding protein-3 in patients with shunted hydrocephalus

OBJECTIVE: Children with hydrocephalus are characterised by slow linear growth in prepuberty, accelerated physical maturation during puberty, and reduced final height. We aimed to study the possible roles of growth hormone, insulin-like growth factor-I (IGF-I), and IGF binding protein-3 (IGFBP-3) in this growth pattern. STUDY DESIGN: One hundred and fourteen patients with shunted hydrocephalus (62 males) aged 5 to 20 years, of whom 17 had spina bifida (six males), and 73 healthy controls (38 males) were studied. Anthropometric measures, body mass index, and body fat mass were assessed and the stage of puberty was determined. Serum growth hormone and plasma IGF-I and IGFBP-3 concentrations were measured. RESULTS: The patients comprised 44 (26 males) who were prepubertal and 70 (36 males) pubertal or postpubertal, while 32 of the controls (19 males) were prepubertal and 41 (19 males) pubertal or postpubertal. The prepubertal children with hydrocephalus had lower IGF-I (p = 0.002) and IGFBP-3 concentrations (p < 0.001) than the controls, and the pubertal children had four times lower basal growth hormone concentrations (p < 0.001). There was a correlation between height SD score and IGF-I levels in the total patient population (r = 0.23; p = 0.01). Peripheral IGF-I concentrations peaked at pubertal stages 2-3 in the female patients and at stage 4 in the controls. The prepubertal patients on antiepileptic treatment, carbamazepine in most cases (73%), had higher IGF-I (p = 0.01) and IGFBP-3 concentrations (p = 0.03) than those who had never been treated with antiepileptic drugs, but still lower IGFBP-3 levels than the controls (p = 0.01). CONCLUSION: Based on these findings, it can be concluded that reduced growth hormone secretion may contribute to the pattern of slow linear growth and reduced final height observed in these patients.     

The insulin-like growth factor and binding protein axis in children with end-stage liver disease before and after orthotopic liver transplantation

Over 50% of children with established cirrhosis have evidence of growth failure and malnutrition. Orthotopic liver transplantation (OLT) is a successful treatment for many children and leads to improved growth and nutrition. Most of the anabolic actions of GH are mediated through the generation of the mitogenic polypeptide insulin-like growth factor-I (IGF-I). Although this is synthesised ubiquitously, the bulk of circulating IGF-I is derived from the liver. The actions of IGF-I are modulated by a family of at least six high-affinity binding proteins (IGFBPs). Growth failure in end-stage liver disease, both before and after OLT, may result from abnormalities in the IGF-IGFBP axis. Children who had undergone successful OLT were studied before and after OLT. Anthropometry was measured by standard techniques. Serum IGFs, IGFBPs and acid labile subunit (ALS) were measured by RIA, IRMA, ELISA, Western ligand and immunoblotting. The most severely affected anthropometric parameters were skin fold thickness and mid-arm circumference. After OLT there was a marked improvement in these parameters. Chronic liver disease was characterised by low serum IGF-I, IGF-II, IGFBP-3 and ALS levels with raised IGFBP-1 and -2 levels. Serum IGFBP-1 and -2 were negatively correlated with pre-OLT anthropometric parameters. After OLT, there was a rapid normalisation of serum IGF-I, while IGF-II and IGFBP-3 overshot to supranormal levels. ALS levels post-OLT remained below control levels. By 3 years post-OLT, IGFBP-3 had fallen to levels which were insignificantly different from controls. IGFBP-1 fell but remained above normal, while there was no significant change in IGFBP-2. Growth post-OLT correlated positively with serum IGF-I and negatively with IGFBP-1. In conclusion, chronic liver disease is associated with marked changes in body composition. These changes are associated with and may be caused by an impaired generation of IGF-I and altered production of IGFBPs. After OLT there is a marked improvement in growth associated with partial normalisation of the IGF-IGFBP axis. However, there are persistent abnormalities in this axis which may explain growth failure post-OLT.     

Insulin-like growth factors in childhood-onset Gaucher disease

There is a high prevalence of growth retardation in children with type 1 Gaucher disease. The cause of this poor growth is not yet known; however, studies have shown acceleration of growth with enzyme replacement therapy (ERT). IGF are recognized as important determinants of somatic growth. It has been proven that chronic diseases with liver involvement might cause IGF deficiency. The aim of this study was to assess the IGF system in patients with childhood-onset Gaucher disease, before and after ERT, and its association with other clinical and analytical parameters. Twenty-two patients with type I Gaucher disease were included. The diagnosis was established before 14 y of age in all patients. Baseline determinations of total IGF-I, free IGF-I, and IGF binding protein 3 (IGFBP-3) were obtained in 19 patients before starting ERT at a mean age of 13.8 +/- 11.2 y. A Spearman test was performed to establish the association with other clinical and analytical parameters. In a group of 13 patients receiving IGF, changes were evaluated during the initial 2 y of treatment. A Wilcoxon test was performed for the statistical analysis. Total IGF-I, free IGF-I, and IGFBP-3 were expressed as SD scores (SDS). We found low levels of IGF and its binding proteins before ERT. A significant association was found between the total IGF-I SDS before treatment and the age-adjusted severity score index: r = -0.62, p < 0.05. Total IGF-I and IGFBP-3 SDS correlated negatively with the presence of the L444P mutation (r = -0.53 and -0.5, respectively, p < 0.05). Height SDS correlated with total IGF-I and IGFBP-3 SDS in eight children (r = 0.84 and 0.78, respectively, p < 0.05). Total IGF-I SDS increased from -1.8 +/- 0.8 to -0.8 +/- 1.4 (p = 0.005) and free IGF-I increased from -1.2 +/- 1 to 1.1 +/- 2.1 after 12 +/- 6.8 mo (p = 0.011) of ERT. IGFBP-3 SDS increased from -1.3 +/- 0.6 to -0.2 +/- 1.2 (p = 0.012) after 12 +/- 4.5 mo of ERT. Type 1 Gaucher disease is associated with low levels of IGF and its binding proteins, which could be a consequence of liver involvement. Total IGF-I deficiency is associated with the severity of the illness. Growth retardation in pediatric patients with Gaucher disease is related to the alterations in IGF axis. Total IGF-I and IGFBP-3 are the two parameters that better correlate with height before treatment. ERT results in significant increase of total IGF-I, free IGF-I, and IGFBP-3 during the first year of treatment.     

Insulin-like growth factor axis parameters in sick hospitalized neonates

The circulating insulin-like growth factor (IGF) axis consists of the IGF peptides, the IGF binding proteins (IGFBPs), and the IGFBP proteases. Little is known about the IGF axis in newborns, its possible perturbations in sick neonates, and the effect of nutrition on the IGF axis of such patients. The aims of this study were to define IGF axis parameters in the sera of hospitalized newborns and to correlate these parameters with the nutritional status of the infants. Serum samples obtained from twenty four hospitalized infants in the intensive care nursery were analyzed for IGF axis parameters. Insulin-like growth factor-I and IGFBP-3 by RIA were mostly within the normal range for age and were only minimally affected by gestational age. In comparison, 8 newborn infants with congenital growth hormone deficiency had IGFBP-3 levels which were below the normal range. Two infants on ECMO had elevated levels of IGFBP-3 by RIA. Western ligand blotting (WLB) demonstrated that IGFBP-2 was the major binding protein in infant serum and the 44 kDa IGFBP-3 in critically ill neonatal serum was approximately 10% of adult serum levels. IGFBP-3 by RIA in neonatal serum averaged approximately 25% of adult serum levels. Compatible with this discrepancy, a number of sick neonates had detectable levels of IGFBP-3 proteolytic activity and higher levels of IGFBP-3 fragments compared to normal adult serum in both the protease assays and Western immunoblotting. There was no correlation between any IGF axis parameter and nutritional status. In summary, sick hospitalized neonates display mostly normal IGF and IGFBP-3 levels, which are not correlated to nutritional intake. Thus serum IGFBP-3 levels maintain their diagnostic utility for growth hormone deficiency in critically ill neonates.     

IGF-I, IGF-II, free IGF-I and IGFBP-1, -2 and -3 levels in venous cord blood: relationship to birthweight, length and gestational age in healthy newborns

Abstract The insulin-like growth factors (IGF-I and IGF-II) and their binding proteins (IGFBPs) have been implicated in regulating fetal growth and development. The aim of this study was to determine whether fetal IGFs correlate with auxologic data at birth and/or gestational age. Venous cord blood was obtained from 138 healthy newborns immediately after birth and clinical data were recorded using a standardized data sheet. For the determination of IGF-I and IGF-II, IGFBP-blocked radioimmunoassays were used. A coated-tube immunoradiometric assay was applied for the measurement of free IGF-I. IGFBP-1, -2, and -3 were measured using specific radioimmunoassays. IGF-I levels were 61 ± 21 ng ml^-1, median 61 ng ml^-1, range 19-114ng ml^-1: IGF-II levels were 466 ± 80ng ml^-1, median 457 ng ml^-1, range 311–701 ng ml^-1; free IGF-I levels were 2.4 ± 1.8ng ml^-1, median 1.8 ng ml^-1, range 0.4–7.8ng ml^-1. The concentration of IGFBP-1 was 144± 110 ng ml^-1, median 113 ng ml^-1, range 20–626 ng ml^-1; that of IGFBP-2 was 1165 ± 455ng ml^-1, median 1119ng ml^-1, range 440–3466 ng ml^-1. IGFBP-3 levels were 1272 ± 280 ng ml^-1, median 1272ng ml^-1, range 600–1966 ng ml^-1. IGF-I levels correlated significantly with IGFBP-3 levels (r= 0.71). birthweight (r= 0.48) and birth length (r= 0.37). There were significant inverse correlations between IGF-I and both IGFBP-I (r= - 0.45) and IGFBP-2 (r= - 0.62). Although free IGF-I levels correlated (r= 0.71) with total IGF-I, only marginally significant correlations were found between free IGF-I and birthweight (r= 0.25). According to multiple regression analysis free IGF-I levels were only dependent upon total IGF-I, IGFBP-2 and IGFBP-1, whereas IGFBP-3 levels did not contribute to the variance of free IGF-1 concentrations in venous cord blood. There was no significant correlation between IGF-II and auxologic data at birth. When IGF-I and IGFBP-3 levels were analysed with respect to gestational age a biphasic pattern with maxima at 270 d was observed. IGFBP-2 exhibited a reversed pattern with a minimum at 265 d of gestation. In conclusion, these data suggest that IGF-I and the IGFBPs, but not IGF-II, play a role in the regulation of late fetal growth and development.     

Maternal and fetal serum insulin-like growth factor-I (IGF-I) IGF binding protein-3 (IGFBP-3), leptin levels and early postnatal growth in infants born asymmetrically small for gestational age

This study was planned to investigate the relationship between birth weight and insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), and leptin levels in neonates with normal growth (appropriate for gestational age: AGA) and retarded growth (small for gestational age: SGA); and to evaluate these growth factors' effects in early postnatal growth. All newborns were full-term: gestational age 3,841 weeks. Of 50 neonates, 25 were SGA. IGF-I, IGFBP-3 and leptin levels were measured in maternal serum and venous cord blood at birth and at 15 days of life of neonates using specific RIAs. Maternal serum leptin concentrations were significantly higher than cord blood leptin concentrations (p < 0.001). Maternal serum IGF-I, IGFBP-3 and leptin levels did not show correlations with birth weight. In contrast, there were significantly positive correlations between birth weight and venous cord blood IGF-I, IGFBP-3 and leptin levels (p < 0.001). In the SGA group, the newborns with a slow postnatal growth pattern had lower umbilical cord serum IGF-I levels compared with newborns with a normal growth pattern. A similar result was also found in the AGA group. Similar results were not found for serum leptin and IGFBP-3. In conclusion, cord blood IGF-I, IGFBP-3 and leptin levels play an important role in the regulation of fetal and neonatal growth. It is likely that IGF-I has a more important role than the other factors in early postnatal growth.     

Improvement of diagnostic criteria in growth hormone insensitivity syndrome: solutions and pitfalls

A survey to identify children and adolescents with primary growth hormone insensitivity syndrome (GHIS) yielded 38 patients who were positively identified using a scoring system that included five criteria: height, basal growth hormone (GH), GH binding protein, basal insulin-like growth factor 1 (1GF-I) and the increase of IGF-I after 4 days of GH administration (IGF generation test). Because of an overlap of the accepted and excluded groups with respect to points scored, an attempt was made to improve the scoring system. The new criteria were: height below –3 SDS, basal GH 4 mU/I or above, GH binding below 10%, basal IGF-I and basal IGF binding protein-3 (IGFBP-3) below the 0.1 centile for age, an increase of IGF-I in the IGF generation test less than 15 μg/1, and the increase of IGFBP-3 less than 0.4 mg/1. With this scoring system, a clear separation between the accepted and the excluded groups was obtained. IGFBP-3 was included to give the GH-dependent parameters of the IGF system more weight and because the accuracy of IGFBP-3 in the IGF generation tests was greater than the accuracy of IGF-I, when the group of patients with GHIS was compared with a group of patients with GH deficiency. Unexpectedly, the IGF generation test was unable to segregate both cohorts completely. In the GHIS-positive group, a significant correlation was found between basal IGF-I or IGFBP-3 levels corrected for age (SDS) and height SDS ( r = 0.49, p < 0.002 and r = 0.61, p < 0.0001, respectively). There was also a significant correlation between the changes of IGF-I or IGFBP-3 in the IGF generation test and height SDS. That is, the patients with a slight response to GH were those with the least growth retardation, suggesting the existence of partial GH insensitivity.     

Diagnosis of idiopathic growth hormone deficiency: contributions of data on the acid-labile subunit, insulin-like growth factor (IGF)-I and-II, and IGF binding protein-3

The diagnosis of non-organic growth hormone (GH) deficiency (GHD) remains difficult. OBJECTIVE: To evaluate the value of measuring plasma insulin-like growth factor (IGF)-I and -II, IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS) as criteria for diagnosing GHD. PATIENTS: 120 prepubertal patients having at least one of the main auxological criteria defined by the GH Research Society for initiating GH exploration were classified as (1) certain GHD (n = 40), (2) transient GHD (n = 18), (3) idiopathic short stature (n = 27), or (4) extreme short stature (n = 35). RESULTS: All the patients with certain GHD had low (< or = -2 z-score) plasma concentrations of IGF-I and ALS, but only 35.1% had low IGF-II, and 48.6% had low IGFBP-3. All the patients but three (83.3%) with transient GHD had low IGF-I, but only 44.4% had low ALS, and only one had low IGF-II or IGFBP-3. The data for patients with idiopathic and extreme short stature and normal GH peak were similar to each other and to those for patients with transient GHD, except that IGF-I was less frequently low (49.2%, p <0.05). CONCLUSIONS: All the patients with certain GHD had both IGF-I and ALS z-scores < or = -2, unlike those with transient GHD, and idiopathic or extreme short stature. Almost all the patients with short stature and normal GH peak had normal serum IGF-II and IGFBP-3 concentrations.     

Reduced levels of growth hormone,insulin-like growth factor-I and binding protein-3 in patients with shunted hydrocephalus

Accepted 25 March 1997
OBJECTIVE—Children with hydrocephalus are characterised by slow linear growth in prepuberty, accelerated physical maturation during puberty, and reduced final height. We aimed to study the possible roles of growth hormone, insulin-like growth factor-I (IGF-I), and IGF binding protein-3 (IGFBP-3) in this growth pattern.
STUDY DESIGN—One hundred and fourteen patients with shunted hydrocephalus (62 males) aged 5 to 20 years, of whom 17 had spina bifida (six males), and 73 healthy controls (38 males) were studied. Anthropometric measures, body mass index, and body fat mass were assessed and the stage of puberty was determined. Serum growth hormone and plasma IGF-I and IGFBP-3 concentrations were measured.
RESULTS—The patients comprised 44 (26 males) who were prepubertal and 70 (36 males) pubertal or postpubertal, while 32 of the controls (19 males) were prepubertal and 41 (19 males) pubertal or postpubertal. The prepubertal children with hydrocephalus had lower IGF-I (p = 0.002) and IGFBP-3 concentrations (p< 0.001) than the controls, and the pubertal children had four times lower basal growth hormone concentrations (p< 0.001). There was a correlation between height SD score and IGF-I levels in the total patientpopulation (r = 0.23; p = 0.01). Peripheral IGF-I concentrations peaked at pubertal stages 2-3 in the female patients and at stage 4 in the controls. The prepubertal patients on antiepileptic treatment, carbamazepine in most cases (73%), had higher IGF-I (p = 0.01) and IGFBP-3 concentrations (p = 0.03) than those who had never been treated with antiepileptic drugs, but still lower IGFBP-3 levels than the controls (p = 0.01).
CONCLUSION— Based on these findings, it can be concluded that reduced growth hormone secretion may contribute to the pattern of slow linear growth and reduced final height observed in these patients.

• Prepubertal children with shunted hydrocephalus have reduced circulating IGF-I and IGFBP-3 concentrations • Pubertal children with shunted hydrocephalus have reduced basal serum growth hormone concentrations • Reduced growth hormone secretion may contribute to slow linear growth and reduced final height in hydrocephalic children • Carbamazepine treatment may increase IGF-I and IGFBP-3 concentrations in the peripheral circulation     

Serum levels of insulin-like growth factor (IGF)-I, free IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3 and insulin in obese children.

In simple obesity, spontaneous and stimulated growth hormone (GH) secretions are diminished. However, this diminished GH secretion does not result in decreased somatic growth in obese children. Although the increased insulin level, low insulin-like growth factor binding protein (IGFBP)-1 and the resulting increase of bioavailability of insulin-like growth factor I (IGF-I) have been suggested as being involved, the exact mechanism has not yet been established. We investigated serum IGF-I, free IGF-I, IGFBP-1, IGFBP-3 and insulin levels in 36 obese and 39 non-obese healthy children. Insulin and IGFBP-3 were significantly higher in the obese group than in the control group (p < 0.05, p = 0.001, respectively). IGF-I, free IGF-I, free IGF-I/IGF-I and IGFBP-1 levels in the obese children were not significantly different from those in the control group. A positive correlation was found between body mass index (BMI) and IGF-I in the obese children (r = 0.30, p = 0.05). IGFBP-3 levels correlated positively with IGF-I (r = 0.44, p < 0.005), and free IGF-I levels (r = 0.37, p = 0.05) in the obese children. A negative correlation was found between IGFBP-1 and insulin levels (r = -0.30, p = 0.05) in the obese children. We concluded that normal growth in obese children might be maintained through normal IGF-I and increased IGFBP-3 levels, which are stimulated by increased insulin levels or nutritional factors or by increased responsiveness to GH.     

Serum insulin-like growth factor-I (IGF-I), IGF-binding protein-3, and growth hormone levels in collodion babies: a case-control study

AIM: Because growth failure occurs in many collodion babies, we investigated serum growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) levels in collodion babies admitted to Gevher Nesibe Hospital, Kayseri, Turkey between 1999 and 2006. PATIENTS AND METHOD: The newborns diagnosed clinically as 'collodion baby' were included in the study group (group 1). Because collodion babies are usually born small for gestational age (SGA) and/or premature, a control group (group 2) was formed by selecting the first infant admitted immediately after each study infant who matched for gestational age (+/- 7 days) and birth weight (+/- 100 g). All infants' blood samples were collected within the first 2 h of life for measurements of serum GH, IGFBP-3 and IGF-I levels. RESULTS: Group 1 consisted of 23 collodion babies (13 males and 10 females) with gestational ages ranging from 32 to 42 weeks, and birth weights ranging from 1,300 to 3,600 g. Ten were born premature and 16 were SGA. Serum IGF-I and IGFBP-3 levels were lower but serum GH levels were higher in collodion babies than in controls. Birth weight was positively correlated with serum IGF-I (r = 0.310, p = 0.046) and IGFBP-3 (r = 0.389, p = 0.011) levels. Serum GH level was negatively correlated with birth weight (r = -0.376, p = 0.014), serum IGF-I (r = -0.567, p <0.001) and IGFBP-3 (r = -0.444, p = 0.003). CONCLUSION: Collodion babies had lower serum IGF-I and IGFBP-3 levels but higher serum GH levels than controls in the present case-control study. The underlying mechanism needs to be explored.