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 factors in children with end-stage liver disease before and after liver transplantation: a review

Growth failure is a common observation in children with end-stage liver disease (ESLD). The liver is an important endocrine organ producing potent anabolic growth factors such as IGF-I (insulin-like growth factor-I) and its major binding-proteins, called IGFBP-1, -2 and -3. Circulating IGF-I and IGFBP-3 levels are low in children with chronic liver failure despite increased GH secretion. This discrepancy suggests that GH resistance is present in chronic liver failure and is mainly due to the associated malnutrition. The advent of orthotopic liver transplantation (OLT) has dramatically improved the life expectancy of children with ESLD. Nevertheless, the growth of 15-20% of the children in recent studies remains poor after successful transplantation. Several factors such as age and height deficit at the time of OLT, etiology of the liver disease and graft function as well as the dose and mode of administration of glucocorticoids have been implicated in the lack of complete catch-up growth following surgery. Few studies have explored the possibility that anomalies in the GH-IGF-I cascade could explain growth retardation. However, it is unlikely that major anomalies of the GH-IGF-I axis contribute to impaired growth. Treatment with GH alone or in combination with IGF-I before or after OLT may improve the growth of children. Randomized multi-center studies are needed to address this issue.     

Effects of insulin-like growth factor I treatment on the molecular distribution of insulin-like growth factors among different binding proteins

The molecular distribution of insulin-like growth factor I (IGF-I) and IGF-II among the IGF binding proteins (IGFBPs) was studied before and during IGF-I therapy in Ecuadorean adults with growth hormone receptor deficiency (GHRD). Of the total circulating IGF-I and IGF-II, 70% was carried by the 150 kDa complex in normal subjects, while in patients with GHRD, 50% of serum IGF-I, but only 30–35% of serum IGF-II, was measured within the 150 kDa IGFBP-3 region. Administration of IGF-I altered the concentration of IGF-I and IGF-II, although the percentage of total IGF measured within each IGFBP region was not affected, as the increase in IGF-I and the decrease in IGF-II were proportional. Similarly, serum concentrations of IGFBP-3 and the acid-labile subunit, measured by radioimmunoassay, were unaltered. Thus, administration of IGF-I to patients with GHRD was unable to correct the aberrant distribution of IGFs among the IGFBPs.     

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.     

The insulin-like growth factor axis in children with inflammatory bowel disease

BACKGROUND: The insulin-like growth factor (IGF) axis consists of two IGFs and six IGF-binding proteins (IGFBPs) that regulate proliferation and differentiation of many cell types. Malnutrition and inflammation alter the IGF axis. The authors evaluated circulating IGFs and IGFBPs in patients with inflammatory bowel disease (IBD) at the time of presentation and compared them with values obtained during remission. METHODS: Seventeen newly diagnosed pediatric IBD patients were studied on presentation and during remission. Nutritional status was assessed by body mass index (BMI) and serum protein assay. The Lloyd-Still and Green IBD clinical scoring system was used. IGF-I and IGF-II levels were measured by radioimmunoassay, and IGFBP-3 levels were measured by immunoradiometric assay. IGFBPs were quantified on ligand blots with a PhosphorImager. RESULTS: Body mass index and IBD clinical scores improved after treatment: 18.7 +/- 3.0 versus 21.3 +/- 3.0 kg/m (P = 0.023) and 74.6 +/- 16.7 versus 93.1 +/- 7.4 (P< 0.001), respectively. Protein changes were insignificant. IGFBP-3 levels increased from time of first evaluation to remission: 3,470 +/- 850 versus 4,700 +/- 473 ng/mL (P< 0.001). The ratio of IGFBP-3 to IGFBP-2 increased from first evaluation to remission: 1.7 +/- 1.9 versus 3.9 +/- 1.9 (P= 0.003). IGF-I and IGF-II levels also increased: 139 +/- 167 versus 223 +/- 118 ng/mL (P= 0.011) and 307 +/- 111 versus 386 +/- 73 ng/mL (P= 0.007), respectively. CONCLUSIONS: Circulating IGFBP-3 levels were low during active IBD and increased at remission in parallel with the IGF-I levels. The IGFBP-3 to IGFBP-2 ratio was altered in the presence of active disease in a manner that would reduce IGF-I action. This abnormality improved after treatment.     

Early developmental changes in IGF-I, IGF-II, IGF binding protein-1, and IGF binding protein-3 concentration in the cerebrospinal fluid of children

IGF-I and IGF-II are ubiquitously expressed growth factors that have profound effects on the growth and differentiation of many cell types and tissues, including cells of the CNS. In biologic fluids, most IGFs are bound to one of six IGF binding proteins (IGFBPs 1-6). Increasing evidence strongly supports a role for IGF-I in CNS development, as it promotes neuronal proliferation and survival. However, little is known about IGF-I and its homolog IGF-II and their carrier proteins, IGFBPs, during the neonatal period in which brain size increases dramatically, myelination takes place, and neurons show limited capacity to proliferate. Herein, we have determined the concentrations of IGF-I, IGF-II, IGFBP-1, and IGFBP-3 in cerebral spinal fluid (CSF) samples that were collected from children who were 1 wk to 18 y of age. The concentrations of IGF-I, IGFBP-1, and IGFBP-3 in CSF from children <6 mo of age were significantly higher than in older children, whereas IGF-II was higher in the older group. This is in contrast to what is observed in the peripheral circulation, where IGF-I and IGFBP-3 are low at birth and rise rapidly during the first year, reaching peak levels during puberty. Higher concentrations of IGF-I, IGFBP-1, and IGFBP-3 in the CSF of very young children suggest that these proteins might participate in the active processes of myelination and synapse formation in the developing nervous system. We propose that IGF-I and certain IGFBPs are likely necessary for normal CNS development during critical stages of neonatal brain growth and development.     

Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity

Burren CP, Wanek D, Mohan S, Cohen P, Guevara-Aguirre J, Rosenfeld RG. Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity. Acta Pædiatr 1999; Suppl 428: 185–91. Stockholm. ISSN 0803–5326
Although insulin-like growth factor binding proteins (IGFBPs) are known to be important modulators of the action of insulin-like growth factors (IGFs), regulation of their production in vivo is not completely understood. Serum concentrations of IGFBP-3, -4 and -5 and acid-labile subunit (ALS) were therefore examined in 20 children with growth hormone (GH) insensitivity before and after 6 months of therapy with recombinant human IGF-I (80 or 120 ug/kg twice daily). The IGFBP concentrations in these children were compared with those in 62 GH-deficient children receiving GH therapy for 3 months. Serum levels of IGFBP-3, -4 and -5 and ALS all increased significantly ( p < 0.0001) in GH-deficient children in response to GH therapy, whereas no significant increases occurred in the children with GH insensitivity. These findings indicate that GH is responsible for the regulation of serum levels of IGFBP-3, -4 and -5 and ALS, and that IGF-I does not directly regulate the concentrations of these circulating IGFBPs. □ Growth hormone, growth hormone insensitivity, insulin-like growth factor I, insulin-like growth factor binding protein     

Serum levels of insulin-like growth factor-I,-II and insulin-like growth factor binding proteins-2 and-3 in children with acute lymphoblastic leukaemia

Abstract The insulin-like growth factor (IGF) signaling pathway may be of importance for the proliferation of different tumours (e.g. breast cancer and Wilms tumour). The bioavailability of both IGF-I and IGF-II is regulated by specific IGF-binding proteins (IGFBPs). IGFBP-2 is the predominant binding protein during fetal life, where it is expressed in most tissues. In contrast, postnatally it is mainly released by specific cell types (hepatocytes, astroglia, kidney cells, prostate cells) and a range of tumour cell lines. Furthermore, phytohaemagglutinin stimulated normal lymphoblasts and malignant lymphoblasts express IGFBP-2. In order to investigate the IGF regulatory pathway in leukaemia serum levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were determined in 28 leukaemic children. Whereas serum levels of IGF-I (mean/range: –2.7/–0.1 to –6.7 SDS), IGF-II (–3.6 SDS/–1.3 to –8.7) and IGFBP-3 (–2.0/+2.2 to –7.1 SDS) were significantly decreased comparable to levels in growth hormone deficiency, IGFBP-2 levels (+4.0/–0.45 to +7.4 SDS) were found to be markedly elevated and inversely correlated to IGF-I (r=–0.51,P=0.013). After haematological remission upon chemotherapy all four parameters had normalized in the 16 re-investigated children. Similar findings have been observed in one boy with a relapse including CNS leukaemia.Conclusion This study demonstrates that the proliferation of malignant lymphoblasts (at diagnosis vs treatment) occurs in the presence of decreased serum levels of IGF-I, IGF-II and IGFBP-3 and that diminished production of these peptides may contribute to impaired growth. It further indicates that serum levels of IGFBP-2 may be directly related to the proliferation of lymphoblasts.     

Plasma insulin-like growth factors (IGFs), IGF-Binding proteins (IGFBPs), acid-labile subunit (ALS) and IGFBP-3 proteolysis in individuals with clinical characteristics of Sotos syndrome

OBJECTIVE: Sotos syndrome is an overgrowth syndrome of poorly understood aetiology. We investigated whether this syndrome is related to alterations in plasma insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), acid-labile subunit (ALS) and serum IGFBP-3 proteolysis. DESIGN: Based on clinical criteria, 32 patients with clinical characteristics of Sotos syndrome (median age 8.4 years, range 1.8-48.4) were categorised into three groups: typical (n = 10, group 1), dubious (n = 12, group 2) and atypical (n = 10, group 3). Blood samples were obtained from 29 patients. MEASUREMENTS: Plasma IGF-I, IGF-II, E-II (pro-IGF-II and E-domain fragments), IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-6 and ALS were measured by specific radioimmunoassays (RIAs). Except for E-II immunoreactivity, the concentrations were compared with those of age references, and expressed as standard deviation scores (SDS). IGFBP-3 proteolysis was assessed by incubation of serum with [125I]-IGFBP-3, followed by gel electrophoresis and was then compared with that in normal serum and third trimester pregnancy serum. RESULTS: Patients in group 1 showed significantly reduced plasma levels of IGF-II (median -0.9 SDS; p = 0.01), IGFBP-4 (-0.5 SDS; p = 0.02) and IGFBP-3 (-1.0 SDS; p = 0.01). Mean IGFBP-3 proteolysis was higher than in normal standard serum (61% vs 37%; p < 0.01) but lower than in third trimester pregnancy serum (94%; p < 0.01). Plasma IGF-I showed a tendency towards low values (median -0.9 SDS; p = 0.09), IGFBP-6 and ALS a tendency towards elevated levels (median values +0.8 SDS; p = 0.07 and +2.3 SDS; p = 0.09), and IGFBP-2 was normal. The mean value of E-II immunoreactivity was 8.7 nmol/l, similar to that in pooled normal plasma (8.6 nmol/l). Plasma and serum parameters in groups 2 and 3 were similar to reference values with the exception of plasma IGFBP-3 (in groups 2 and 3 median < or = -1.1 SDS; p < or = 0.02) and ALS (in group 3 median +1.3 SDS; p < 0.01). CONCLUSIONS: Patients with typical Sotos syndrome show low plasma IGF-II, IGFBP-3, IGFBP-4, and increased proteolysis of IGFBP-3 in serum. The extent to which these findings are associated with the pathophysiology of Sotos syndrome remains uncertain.     

Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity

Although insulin-like growth factor binding proteins (IGFBPs) are known to be important modulators of the action of insulin-like growth factors (IGFs), regulation of their production in vivo is not completely understood. Serum concentrations of IGFBP-3, -4 and -5 and acid-labile subunit (ALS) were therefore examined in 20 children with growth hormone (GH) insensitivity before and after 6 months of therapy with recombinant human IGF-I (80 or 120 micrograms/kg twice daily). The IGFBP concentrations in these children were compared with those in 62 GH-deficient children receiving GH therapy for 3 months. Serum levels of IGFBP-3, -4 and -5 and ALS all increased significantly (p < 0.0001) in GH-deficient children in response to GH therapy, whereas no significant increases occurred in the children with GH insensitivity. These findings indicate that GH is responsible for the regulation of serum levels of IGFBP-3, -4 and -5 and ALS, and that IGF-I does not directly regulate the concentrations of these circulating IGFBPs.     

Insulin-Like Growth Factors (IGFs) and IGF Binding Proteins in Chronic Renal Failure: Evidence for Reduced Secretion of IGFs

To test the hypothesis that growth hormone (GH) insensitivity is responsible, amongst other mechanisms, for impaired growth in uraemic children, insulin-like growth factor I (IGF-I), IGF-II, IGF binding protein-1 (1GFBP-1), IGFBP-2 and IGFBP-3 were measured by radioimmunoassay in normal control children, in patients with end-stage renal failure (n = 51) and in patients with preterminal chronic renal failure (n = 11) and the production rate of IGF was calculated. A unique pattern of normal IGF-I and IGF-II levels and markedly increased levels of all three IGFBPs was present in uraemia. Measurement of free IGF-II binding capacity, and affinity cross-linking experiments showed that the excess immuno-reactive IGFBP was able to bind IGFs. To explain the excess of unoccupied IGF binding sites in uraemia, a mathematical model was developed which describes the production of IGFs and their interaction with IGFBP. Calculations of IGF secretion rates suggested that production of IGF is two orders of magnitude lower in uraemic children than in control children, despite normal GH secretion. It is concluded that in uraemia there is a relative GH insensitivity with respect to IGF production.     

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.     

营养肾病和糖皮质激素对大鼠肝肾组织IGF-I/IGFBPs mRNA表达的影响

目的：探讨营养不良、肾病本身和糖皮质激素作为各自独立因素对大鼠肝肾组织胰岛素样生长因子I/胰岛素样生长因子结合蛋白(IGF-I/IGFBPs) mRNA表达和血清浓度的影响。方法：24只周龄相同体重相近的雄性SD大鼠被随机分成正常对照、食物对照、阿霉素肾病和地塞米松治疗肾病4组。血清IGF-I/IGFBPs和肝肾组织IGF-I/IGFBPs mRNA表达分别采用RIA,Western ligand blot和RT-PCR法检测。结果：①营养不良大鼠血清IGF-I减低,肝肾组织IGF-I mRNA表达增高;肾病本身对血清IGF-I,肝脏IGF-IA mRNA表达无影响,肾脏表达减低;激素治疗使血清IGF-I,肝肾组织IGF-IA mRNA表达均下降。②营养不良大鼠血清IGFBP-2,肝脏IGFBP-2 mRNA表达减低,肾脏表达正常;肾病本身使大鼠血清IGFBP-2,肝脏IGFBP-2 mRNA表达增高,肾脏表达减低;激素治疗使肝肾组织IGFBP-2 mRNA表达均下降,但对血清浓度无影响。③营养不良大鼠血清IGFBP-3减低,肝脏IGFBP-3 mRNA表达正常;肾病本身使血清IGFBP-3,肝脏IGFBP-3 mRNA表达均下降;激素治疗使血清IGFBP-3增高,但肝脏IGFBP-3 mRNA表达下降。肾脏IGFBP-3 mRNA表达仅在激素治疗组大鼠能检测到。结论：营养、肾病和糖皮质激素对大鼠肝肾组织IGF-I/IGFBPs mRNA表达的调节具有器官特异性;除血清IGF-I减低部分源于肾脏合成下降外,血清IGFBPs紊乱主要与肝脏合成有关;肾病时IGFBPs可能在不同的水平对IGF-I生物效应发挥调节作用。     

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.     

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.     

Endocrine and bone metabolic complications in chronic liver disease and after liver transplantation in children

With improved survival of orthotopic liver transplantation (OLT) in children, prevention and treatment of pre- and posttransplant complications have become a major focus of care. End-stage liver failure can cause endocrine complications such as growth failure and hepatic osteodystrophy, and, like other chronic illnesses, also pubertal delay, relative adrenal insufficiency, and the sick euthyroid syndrome. Drug-induced diabetes mellitus post-OLT affects approximately 10% of children. Growth failure is found in 60% of children assessed for OLT. Despite optimisation of nutrition, rarely can further stunting of growth before OLT be prevented. Catch-up growth is usually observed after steroid weaning from 18 months post-OLT. Whether growth hormone treatment would benefit the 20% of children who fail to catch up in height requires testing in randomised controlled trials. Hepatic osteodystrophy in children comprises vitamin D deficiency rickets, low bone mass, and fractures caused by malnutrition and malabsorption. Vitamin D deficiency requires aggressive treatment with ergocalciferol (D2) or cholecalciferol (D3). The active vitamin D metabolites alphacalcidol or calcitriol increase gut calcium absorption but do not replace vitamin D stores. Prevalence of fractures is increased both before OLT (10%-28% of children) and after OLT (12%-38%). Most fractures are vertebral, are associated with low spine bone mineral density, and frequently occur asymptomatically, but they may also cause chronic pain. Fracture prediction in these children is limited. OLT in children is also associated with a greater risk of developing avascular bone necrosis (4%) and scoliosis (13%-38%). This article reviews the literature on endocrine and skeletal complications of liver disease and presents preventive screening recommendations and therapeutic strategies.     

Serum Levels of Free Insulin-Like Growth Factor (IGF)-I in Normal Children

Serum levels of free insulin-like growth factor (IGF)-I were measured by immunoradiometric assay (IRMA) in fasting sera of 137 normal boys and 120 normal girls aged from 8 to 15 yr to study relationships between free IGF-I levels and ages, total IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit (ALS) levels. In both sexes, serum free IGF-I levels and the ratios of free IGF-I to total IGF-I were significantly higher in the pubertal age groups than in the prepubertal age groups. Serum levels of free IGF-I showed a significant positive correlation with those of total IGF-I, IGFBP-3 and ALS, while they showed a significant negative correlation with those of IGFBP-1. These observations suggest that increase in serum free IGF-I levels during puberty is caused by a dramatic increase in total IGF-I, rather than IGFBP-3, and a decrease in IGFBP-1. Also, high free IGF-I levels may play an important role in pubertal growth spurt.     

Insulin-like growth factor serum concentrations reflect insufficient growth in a hypoplastic infant with partial trisomy 9q in the 12th week of life

This report presents changes of IGFs and IGFBPs in a female infant with partial trisomy 9q in the 12th week of life. Studying deficient growth in this hypoplastic infant (birth weight 1405 g, birth length 36 cm) with dysmorphic features, the following changes in IGFs and IGFBPs were detected (microg/l): IGF-I: 26.5 vs 48.1 in healthy infants; IGF-II: 420 vs 728; IGFBP-2: 931 vs 524; IGFBP-3: 800 vs 1070. This demonstrates that IGFs and IGFBPs may reflect individual insufficient growth even at this early age.     

Markers of type I and type III collagen turnover, insulin-like growth factors, and their binding proteins in cord plasma of small premature infants: relationships with fetal growth, gestational age, preeclampsia, and antenatal glucocorticoid treatment

Disorders affecting fetal growth are commonly associated with premature birth. IGFs and their binding proteins (IGFBPs) are potent regulators of fetal growth. In vitro evidence suggests that they regulate collagen turnover. Collagen turnover can be monitored by serum markers of type I collagen synthesis (PINP) and degradation (ICTP) and a marker of type III collagen synthesis (PIIINP). We examined whether these markers in fetal circulation reflect intrauterine growth and maturity, and whether any interrelationship exists between them and fetal IGFs and IGFBPs in preterm infants before 32 wk of gestation. Cord plasma PINP, ICTP, PIIINP, IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were determined for 98 preterm infants. To express birth weight in units adjusted for gestational age, a birth weight SD score (SDS) was calculated. Negative correlations existed between gestational age and PINP (r = -0.43; p < 0.0001), ICTP (r = -0.34; p = 0.002), and PIIINP (r = -0.34; p = 0.0001). Positive correlations existed between birth weight SDS and PINP (r = 0.40; p = 0.0002) and ICTP (r = 0.48; p < 0.0001) but not PIIINP. Moreover, birth weight SDS was positively correlated with IGF-I (r = 0.58; p < 0.0001) and IGFBP-3 (r = 0.44; p < 0.0001) and negatively correlated with IGF-II (r = -0.36; p = 0.003) and IGFBP-1 (r = -0.50; p < 0.0001). Gestational age correlated with IGFBP-3 (r = 0.25; p = 0.03). In preeclampsia, IGF-I was lower (p = 0.002) and IGFBP-1 higher (p < 0.0001), also after adjustment for fetal size. The number of antenatal glucocorticoid treatments was associated with lower ICTP (p = 0.04), higher IGF-I (p = 0.002), lower IGF-II (p = 0.02), lower IGFBP-1 (p = 0.05), and higher IGFBP-3 (p = 0.004), also after adjustment for potential confounders. In multiple regression analysis, the factors significantly associated with PINP (R:(2) = 0.47) were gestational age and IGF-I, and those associated with ICTP (R:(2) = 0.54) were IGF-I, gestational age, and antenatal glucocorticoid treatment. We conclude that IGF-I may be involved in regulation of type I collagen turnover in the growing fetus. Cord blood PINP and ICTP reflect both fetal growth and maturity and deserve evaluation as potential indicators of postnatal growth velocity in preterm infants, whereas PIIINP reflects fetal maturity.     

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.