Urinary Bisphenol-A (BPA) and Bis(2-ethylhexyl)phthalate (DEHP) metabolite concentrations in children with obesity: A case-control study.

Introduction Obesity is a worldwide public health problem. Experimental animal and in vitro studies suggest that the exposure to BPA and phthalates are associated to a higher risk of obesity. Objective To determine urinary excretion of bisphenol A and phthalates in obese and normal weight children. Methods A case-control study was conducted in 122 children. Sixty-six obese children 36 girls (mean age 8.41±1.27 years) and 30 boys (mean age 8.51 ± 1.33 years), and 56 normal weight children, 27 girls (mean age 7.64 ± 1.49 years) and 29 boys (mean age 7.77 ± 1.56 years) were studied. Urinary BPA and Bis(2-ethylhexyl) phthalate (DEHP) metabolites (MEHP, MEHHP and MEOHP) were measured respectively by gas chromatography and high-performance liquid chromatography. Individual determinants of exposure were evaluated through "ad hoc" questionnaires. Results BPA and DEHP metabolites were detectable in obese and normal weight children. Obese girls showed significantly higher BPA concentrations in comparison with normal weight girls (means 10.77, 95% CI 7.02-16.53 vs 5.50, 95% CI 3.93-7.71 µg/g creatinine, respectively, p< 0.02). The first step of DEHP metabolic rate was significantly higher in obese girls compared with controls (p<0.05). DEHP metabolites correlated significantly with leptin concentrations in obese girls (p< 0.03). A higher risk of obesity was found in children with BPA levels above the median values with the habit to eat food packaged (OR=11.09, 95% CI=1.28-95.78). Conclusions These findings show that a higher exposure to BPA is associated with the risk of obesity in girls. Further studies are needed to unveil the cause-effect relationship.

Crk Haploinsufficiency Is Associated with Intrauterine Growth Retardation and Severe Postnatal Growth Failure.

BACKGROUND: Children with 17p13.3 microdeletions including the YWHAE gene show intrauterine growth restriction, craniofacial dysmorphisms, postnatal growth failure, and cognitive impairment. This region is characterized by genomic instability and has been associated with isolated lissencephaly sequence and Miller-Dieker syndrome characterized by facial dysmorphisms, microcephaly, short stature, seizures, cardiac malformations, and agyria. Whilst brain abnormalities are secondary to YWHAE deficiency, the cause of pre- and postnatal growth failure has not been identified yet. CASE PRESENTATION: We describe 2 patients (patient 1 15 years and patient 2 11 years and 10 months) referred to our Center of Pediatric Endocrinology for intrauterine growth retardation with de novo 17p13.3 deletion. In vitro assays showed a defect in CRK expression and GH/IGF1 signaling. rhGH therapy was effective in partially reducing the deficit in height in patient 1 and induced catch-up growth in patient 2. CONCLUSION: Our results suggest that 17p13.3 microdeletion involving CRK affects both GH and IGF1 signaling ultimately leading to pre- and postnatal growth retardation, secondary to partial insensitivity to GH/IGF1. rhGH therapy may be considered to reduce the height deficit in these patients, though data on adult height are lacking.

A prospective case-control study on miRNA circulating levels in subjects born small for gestational age (SGA) evaluated from childhood into young adulthood.

OBJECTIVE: microRNAs (miRNAs) associated with metabolic risk have never been extensively investigated in SGA subjects. The aim of the current study was to evaluate miRNAs in SGA and AGA subjects and their relationships with the metabolic status and growth. DESIGN AND METHODS: A prospective longitudinal case-control study was performed in 23 SGA with postnatal catch-up growth and 27 AGA subjects evaluated at the age of 9 and 21 years. Circulating levels of miR-122-5p, miR-16-5p, miR-126-3p, and miR-486-5p were assessed by qPCR. RESULTS: SGA subjects were shorter both at 9 and at 21 years. No significant differences in insulin like growth factors and metabolic profile were found with the exception of basal glycemia at 9 years. miRNA levels did not differ between SGA and AGA subjects, at 9 and 21 years. miR-16-5p and miR-126-3p levels were higher at 9 than at 21 years. In SGA subjects, miR-122-5p at 9 years was inversely related to adiponectin levels at 21 years and miR-486-5p at 9 years was inversely related to whole-body insulin sensitivity at 9 years and directly related to Hb1Ac at 21 years. Regression analyses showed no predictive value of miRNAs for growth parameters in neither SGA nor AGA subjects. CONCLUSIONS: SGA with postnatal catch-up growth did not show any difference in metabolic risk markers or miRNA circulating levels compared to AGA controls in childhood and young adulthood. miR-122-5p during childhood could identify SGA subjects at higher risk of developing insulin resistance and, eventually, type 2 diabetes in adulthood but further studies are needed to confirm it.

Impact of uteroplacental insufficiency on ovarian follicular pool in the rat.

BACKGROUND: A low oxygen supply to the fetus causes intrauterine growth restriction and can affect gonadal development of the offspring, having a potential impact on fertility. We investigated histology and gene expression in the postnatal rat ovary after fetal hypoxia induced by uterine artery ligation. METHODS: Sprague-Dawley rats underwent uterine artery ligation at day 19 of gestation. Offspring were sacrificed at 5, 20 and 40 days post-partum. Follicles were counted and classified in hematoxylin-eosin stained sections. Gene expression of 90 genes was analyzed by TaqMan® Low Density Array. RESULTS: A significantly lower number of total and primordial follicles was detected in 20 days post-partum intrauterine growth restricted animals. Follicle density was not different at 40 days post-partum, suggesting that compensatory mechanisms occurred during the pre-pubertal window. Uterine artery ligation modified the expression of 24 genes involved in different cellular functions, among which proliferation, apoptosis and metabolism. CONCLUSION: Ovarian follicle pool was affected by fetal hypoxia in early life, but this effect did not persist in puberty. Genes involved in cellular processes were affected at all ages, potentially implying long-term genetic alterations. Further analyses are needed to elucidate later effects of fetal hypoxia on ovarian function and fertility.

The exposure to uteroplacental insufficiency is associated with activation of unfolded protein response in postnatal life.

Early life events are associated with the susceptibility to chronic diseases in adult life. Perturbations of endoplasmic reticulum (ER) homeostasis activate the unfolded protein response (UPR), which contributes to the development of metabolic alterations. Our aim was to evaluate liver UPR in an animal model of intrauterine growth restriction (IUGR). A significantly increased expression of X-box binding protein-1 spliced (XBP1s) mRNA (p<0.01), Endoplasmic Reticulum-localized DnaJ homologue (Erdj4) mRNA (p<0.05) and Bip/GRP78-glucose-regulated protein 78 (Bip) mRNA (p<0.05) was observed in the liver of IUGR rats at birth. Furthermore, the expression of gluconeogenesis genes and lipogenesis genes were significantly upregulated (p<0.05) in IUGR pups. At 105 d, IUGR male rats showed significantly reduced glucose tolerance (p<0.01). A significant decreased expression of XBP1s mRNA (p<0.01) and increased expression of double-stranded RNA-dependent protein kinase-like ER kinase (PERK) and Asparagine synthetase (ASNS) (p<0.05) was observed in the liver of IUGR male adult rats. Liver focal steatosis and periportal fibrosis were observed in IUGR rats. These findings show for the first time that fetal exposure to uteroplacental insufficiency is associated with the activation of hepatic UPR and suggest that UPR signaling may play a role in the metabolic risk.

Impact of uteroplacental insufficiency on postnatal rat male gonad.

Prenatal events such as intrauterine growth restriction can affect gonadal development of the offspring and have an impact on reproductive health. To investigate the effects of intrauterine growth restriction induced by uterine artery ligation on the postnatal rat testis. Pregnant rats underwent uterine artery ligation at day 19 of gestation. Offspring were killed at 5, 20 and 40 days post-partum (dpp). At killing, one gonad was snap-frozen in liquid nitrogen and processed for RNA and steroid extraction. The other gonad was formalin-fixed for histology. Gene expression was analyzed by TaqMan Low-Density Array. Intratesticular testosterone, estradiol and serum gonadotrophins were measured. Thirty genes were dysregulated in intrauterine growth-restricted rats compared to controls, among which markers of Sertoli cell and Leydig cell function, cell metabolism and growth factors. Testis weights were significantly reduced at 5 and 20 dpp in intrauterine growth-restricted rats and caught-up by 40 dpp Accordingly, Sertoli cell number was significantly lower in 5 dpp intrauterine growth-restricted rats. At 20 dpp, intratesticular testosterone was significantly increased in intrauterine growth-restricted rats, whereas serum gonadotrophins were unchanged. IUGR altered the gene expression in the rat testes up to peripubertal age and reduced testis size and Sertoli cell number in neonatal age. Multiple mechanisms encompassing genetic changes and steroid production by the testis may be involved in the catch-up growth phase that restored testis size by 40 dpp Permanent consequences on organ function and gamete integrity cannot be excluded and deserve further investigations.

Serum Levels of Polybrominated Diphenyl Ethers in Girls with Premature Thelarche.

BACKGROUND/AIMS: Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants and have shown endocrine disruption properties in experimental studies. The aim of this study was to investigate the association between the exposure to PBDEs and alterations of puberty in girls referred for idiopathic central precocious puberty (ICPP) and premature thelarche (PT). METHODS: A case-control study was conducted in 124 girls: 37 girls with ICPP (mean age 7.4 ± 0.9 years), 56 with PT (mean age 5.7 ± 2.1 years) and 31 controls (mean age 5.4 ± 1.9 years). PBDE serum concentrations, hormone levels and anthropometry were assessed. PBDE concentrations were corrected for total serum lipid content. Individual exposure to PBDEs was evaluated through ad hoc questionnaires. RESULTS: PBDE serum concentrations corrected for total lipid content were significantly higher in girls with PT (mean 1.49 ± 0.63 log ng/g) than in controls (mean 1.23 ± 0.54 log ng/g; p < 0.05). PT girls showed higher levels of PBDE than ICPP girls (1.49 ± 0.63 vs. 1.37 ± 0.49 log ng/g), though this was not significant. An analysis of the questionnaires revealed no significant differences in exposure between the three groups. CONCLUSION: Our findings suggest that higher concentrations of serum PBDEs are associated with PT in girls.

Insulin-like growth factor-I and -II levels are associated with the progression of nonalcoholic fatty liver disease in obese children.

OBJECTIVE: To correlate circulating levels of insulin-like growth factor (IGF)-I, IGF-II, and IGF binding protein (IGFBP)-3 in a population of obese children with biopsy-proven nonalcoholic fatty liver disease (NAFLD) with clinical, biochemical, and histological features. STUDY DESIGN: We conducted a cross-sectional study at the Hepatometabolic Unit of the Bambino Gesù Children's Hospital, Rome, Italy. Obese children (42 girls and 57 boys) underwent liver biopsy, anthropometry, biochemical assessment, and IGF system evaluation. Serum concentrations of IGF-I, IGF-II, and IGFBP-3 were measured. The liver biopsy features of each case were graded according to the NAFLD Activity Scoring system. The degrees of steatosis, inflammation, ballooning, and fibrosis were calculated. RESULTS: Nonalcoholic steatohepatitis was diagnosed in 14/99 obese subjects. Stepwise regression analysis revealed that IGF-I was the major predictor of ballooning (ß = -0.463; P < .0001) and NAFLD activity score (ß = -0.457; P < .0001), IGF-I/IGFBP-3 ratio was the major predictor of liver inflammation (ß = -0.285; P = .005), and IGF-II was the major predictor of liver fibrosis (ß = 0.343; P < .005). CONCLUSION: Circulating levels of IGF-I and IGF-II are associated with the histological stages of NAFLD and may represent novel markers of liver damage progression in obese children.

IGF2 methylation is associated with lipid profile in obese children.

AIM: Our aim was to investigate the relationships between the degree of IGF2 methylation and the metabolic status in obese children and adolescents. SUBJECTS AND METHODS: Eighty-five obese subjects aged 11.6 ± 2.1 years were studied. Anthropometry, metabolic parameters, blood pressure and body composition were assessed. DNA methylation analysis was performed by restriction enzyme digestion assay. The study population was subdivided into two groups according to the percentage of IGF2 cytidine-guanosine (CpG) island methylation. RESULTS: Twenty-two subjects showed intermediate methylation (a percentage of CpG site methylation comprised between 10 and 60%), 56 were hypomethylated (percentage of methylation lower than 10%), and only 1 showed a high rate of hypermethylation (percentage of methylation above 60%). Children with intermediate methylation showed significantly higher levels of triglycerides (107.6 ± 41.99 vs. 76.6 ± 30.18 mg/dl, p < 0.005) and a higher triglyceride/high-density lipoprotein-cholesterol ratio (2.23 ± 0.98 vs. 1.79 ± 0.98, p < 0.02) compared with hypomethylated children. CONCLUSIONS: These preliminary findings show for the first time a relationship between IGF2 methylation pattern and lipid profile in obese children. Although the correlation does not imply causation, if our findings are confirmed in further studies, IGF2 methylation might represent an epigenetic marker of metabolic risk.

Epigenetic changes predisposing to type 2 diabetes in intrauterine growth retardation.

Epidemiologic studies have demonstrated an association between intrauterine growth retardation and a greater risk of chronic disease, including coronary heart disease, hypertension, stroke, and type 2 diabetes in adulthood. An adverse intrauterine environment may affect both growth and development of the organism, permanently programming endocrine and metabolic functions. One of the mechanisms of programming is the epigenetic modification of gene promoters involved in the control of key metabolic pathways. The aim of this review is to provide an overview of the experimental evidence showing the effects of early exposure to suboptimal environment on epigenome. The knowledge of the epigenetic markers of programming may allow the identification of susceptible individuals and the design of targeted prevention strategies.

Exposure to uteroplacental insufficiency reduces the expression of signal transducer and activator of transcription 3 and proopiomelanocortin in the hypothalamus of newborn rats.

IUGR has been linked to the development of type 2 diabetes. Recent data suggest that some of the molecular defects underlying type 2 diabetes reside in the CNS. Disruption of the signal transducer and activator of transcription 3 (STAT3) in the hypothalamic neurons expressing leptin receptor, results in severe obesity, hyperglycaemia, and hyperinsulinemia. Our aim was to investigate the expression of STAT3 and its downstream effector proopiomelanocortin (POMC) in IUGR rats obtained by uterine artery ligation. On day 19 of gestation, time-dated Sprague-Dawley pregnant rats were anesthetized, and both the uterine arteries were ligated. At birth, hypothalamus was dissected and processed to evaluate the expression of STAT3, its phosphorylated form, and POMC. STAT3 mRNA, STAT3 protein, phosphorylated STAT3, POMC mRNA, and POMC protein were significantly reduced in IUGR versus sham animals (p < 0.0001, p < 0.05 and p < 0.001, p < 0.01, p < 0.01, respectively). No significant differences either in serum leptin concentrations or in hypothalamic leptin receptor expression were observed. Our results suggest that an abnormal intrauterine milieu can affect the hypothalamic expression of STAT3 and POMC at birth, altering the hypothalamic signaling pathways that regulate the energy homeostasis.

Uteroplacental insufficiency down regulates insulin receptor and affects expression of key enzymes of long-chain fatty acid (LCFA) metabolism in skeletal muscle at birth.

BACKGROUND: Epidemiological studies have revealed a relationship between early growth restriction and the subsequent development of insulin resistance and type 2 diabetes. Ligation of the uterine arteries in rats mimics uteroplacental insufficiency and serves as a model of intrauterine growth restriction (IUGR) and subsequent developmental programming of impaired glucose tolerance, hyperinsulinemia and adiposity in the offspring. The objective of this study was to investigate the effects of uterine artery ligation on the skeletal muscle expression of insulin receptor and key enzymes of LCFA metabolism. METHODS: Bilateral uterine artery ligation was performed on day 19 of gestation in Sprague-Dawley pregnant rats. Muscle of the posterior limb was dissected at birth and processed by real-time RT-PCR to analyze the expression of insulin receptor, ACCalpha, ACCbeta (acetyl-CoA carboxylase alpha and beta subunits), ACS (acyl-CoA synthase), AMPK (AMP-activated protein kinase, alpha2 catalytic subunit), CPT1B (carnitine palmitoyltransferase-1 beta subunit), MCD (malonyl-CoA decarboxylase) in 14 sham and 8 IUGR pups. Muscle tissue was treated with lysis buffer and Western immunoblotting was performed to assay the protein content of insulin receptor and ACC. RESULTS: A significant down regulation of insulin receptor protein (p < 0.05) and reduced expression of ACS and ACCalpha mRNA (p < 0.05) were observed in skeletal muscle of IUGR newborns. Immunoblotting showed no significant change in ACCalpha content. CONCLUSION: Our data suggest that uteroplacental insufficiency may affect skeletal muscle metabolism down regulating insulin receptor and reducing the expression of key enzymes involved in LCFA formation and oxidation.

Late effects of disturbed IGF signaling in congenital diseases.

The biologic effects of insulin-like growth factor-1 (IGF-1) are mediated by specific cell surface receptors. IGF-1 binding to the extracellular alpha-subunits activates the tyrosine kinase intrinsic to the cytoplasmic portion of the IGF-1 receptor, leading to autophosphorylation of specific tyrosine residues in the receptor beta-subunit. One early molecular event that links the receptor kinase to the biologic actions of IGF-1 is tyrosine phosphorylation of the insulin receptor substrate family (IRS-1 to -4). IRS acts as a multisite 'docking' protein by binding to downstream signal-transducing molecules. Phosphorylation of multiple tyrosine residues results in the association of IRS-1 with the Src homology 2 (SH2) domains of other cytoplasmic signaling proteins, including phosphatidylinositol 3' kinase, Syp, Grb2 and Nck. By binding to Grb2, IRS proteins couple the IGF-1 receptor to the Ras/mitogenactivated protein kinase pathway. This pathway regulates cell growth, differentiation and proliferation. Severe pre- and postnatal growth retardation may arise from abnormalities of IGF-1 signaling such as IGF-1-binding alterations and IGF-1 receptor mutations. Knockout studies have shown severe growth impairment in mice lacking IRS family components or Akt. Finally, in human placentas from pregnancies complicated by intrauterine growth retardation, multiple alterations of IGF-1-signaling molecules have recently been described.

Changes in the expression of hypothalamic lipid sensing genes in rat model of intrauterine growth retardation (IUGR).

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in later life. The mechanisms underlying this phenomenon are unknown. Recent data suggest that some of the molecular defects underlying type 2 diabetes reside in the CNS. The enzyme carnitine palmitoyltransferase-1 (CPT1) regulates long-chain fatty acid (LCFA) entry into mitochondria, where LCFA undergo beta-oxidation. Hypothalamic inhibition of CPT1 decreases food intake and suppresses endogenous glucose production. Our aim was to investigate the effects of uterine artery ligation, a procedure that mimics uteroplacental insufficiency, on the CNS expression of CPT1 and other key enzymes of LCFA metabolism. Bilateral uterine artery ligation was performed on d 19 of gestation in the pregnant rat; sham-operated pregnant rats served as controls. Hypothalamus, cerebellum, hippocampus, and cortex were dissected and analyzed at birth by real-time PCR. Nonesterified fatty acid (NEFA) serum levels were significantly higher in IUGR pups (p<0.0001). In IUGR rats, the hypothalamic expression of CPT1 isoform C (p=0.005) and acetyl-CoA carboxylase (ACC) isoforms alpha (p<0.05) and beta (p=0.005) were significantly decreased. The data presented here support the hypothesis that an abnormal intrauterine milieu can induce changes in hypothalamic lipid sensing.

Inaccuracy of insulin-like growth factor (IGF) binding protein (IGFBP)-3 assessment in the diagnosis of growth hormone (GH) deficiency from childhood to young adulthood: association to low GH dependency of IGF-II and presence of circulating IGFBP-3 18-kilodalton fragment.

CONTEXT: Poor sensitivity of IGF binding protein (IGFBP)-3 assessment in the work-up of GH deficiency (GHD) has been ascribed to the equal affinity of IGFBP-3 for IGF-I and IGF-II and to IGFBP-3 proteolysis. OBJECTIVE: The objective of this study was to determine the IGF-II GH dependency and IGFBP-3 proteolysis in patients with GHD from childhood to young adulthood. DESIGN: This study was cross-sectional. SETTING: This was a national multicenter study performed in university hospitals. PATIENTS: One hundred thirty-one subjects (chronological age, 1.3-25 yr), 72 patients with GHD and 59 subjects with idiopathic short stature, were studied. INTERVENTIONS: IGF-I, IGF-II, and IGFBP-3 serum concentrations were measured by immunoradiometric assay. IGFBP-3 circulating forms were assessed by Western immunoblot (WIB) analysis. MAIN OUTCOME MEASURES: Main outcome measures were sensitivity and specificity of IGF-I, IGF-II, and IGFBP-3 measurements. RESULTS: Sensitivity and specificity of IGFBP-3 measurement were 27 and 100%, respectively. IGFBP-3 sensitivity was 46% in young adulthood. Sensitivity and specificity of IGF-I were 69 and 81%, respectively. Sensitivity and specificity of IGF-II assessment were 23 and 97%, respectively. IGFBP-3 WIB revealed the presence of the intact form and the major 29-kDa fragment in both GHD and subjects with idiopathic short stature. In patients with GHD, WIB showed the presence of an additional smaller IGFBP-3 fragment migrating at approximately 18 kDa. CONCLUSIONS: Our results suggest that in children and young adults with GHD, the low GH dependency of IGF-II together with IGFBP-3 proteolytic activity yielding the 18-kDa fragment concur to reduce the sensitivity of IGFBP-3 assessment, ultimately making it too inaccurate as a screening test in the work-up of GHD.

Blood glucose concentrations are reduced in children born small for gestational age (SGA), and thyroid-stimulating hormone levels are increased in SGA with blunted postnatal catch-up growth.

Fetal growth restriction is associated with an increased risk of developing insulin resistance and type 2 diabetes in adulthood. In addition, 10-20% of children born small for gestational age (SGA) do not achieve a normal final height. The purpose of this study was to investigate insulin sensitivity and endocrine status in SGA children, compared with that in children born appropriate for gestational age (AGA). Furthermore, within the SGA group, we aimed to relate postnatal growth to anthropometric, biochemical, and endocrine parameters. Eighty-two SGA children (with a mean age of 8.6 +/- 3.5 yr) and 53 short-AGA children (with a mean age of 9.3 +/- 3.3 yr) were studied. A case-control study was carried out in 26 SGA and 26 short-AGA subjects. For each SGA subject, we selected a short-AGA child matched for sex, age (within 1 yr), pubertal status, body mass index (within 0.5 kg/m(2)), and height (within 0.25 z-score). Children's statures were corrected for their midparental height, and SGA children were subdivided into 2 groups: catch-up growth (CG) group (children with corrected height with at least 0 z-score); and non-CG (NCG) group (subjects with corrected height with less than 0 z-score). Comparing SGA with short-AGA subjects, no significant differences in fasting insulin, fasting glucose/insulin ratio, homeostasis assessment model for insulin resistance, and homeostasis assessment model-beta-cell values were observed. SGA children showed significantly reduced levels of glucose (4.4 +/- 0.6 vs. 4.9 +/- 0.6 mM, P < 0.0001), total cholesterol (160.1 +/- 28.8 vs. 171.8 +/- 28.5 mg/dl, P = 0.02), and high-density-lipoprotein cholesterol (53.3 +/- 12.1 vs. 58 +/- 11.4 mg/dl, P = 0.02). The analysis of the subjects selected for the case-control study confirmed that SGA children did not have significant differences in the indices of insulin sensitivity but showed significantly lower glucose levels (4.4 +/- 0.7 vs. 4.9 +/- 0.4 mM, P < 0.005). Subdividing the SGA group into CG (n = 25) and NCG (n = 57) children, we found that NCG children showed significantly higher levels of TSH (2.5 +/- 1.3 vs. 1.9 +/- 0.6 mU/liter, P = 0.002). Our data indicate that SGA children do not have altered insulin sensitivity when compared with auxologically identical AGA subjects but show a significant reduction of glucose concentrations. Whether the lower glucose levels are attributable to an early phase of augmented insulin sensitivity, as previously reported in animal models, has to be established. The finding of higher TSH concentrations in SGA children with blunted CG suggests that intrauterine reprogramming might involve thyroid function, which, in turn, might affect postnatal growth and cholesterol metabolism, eventually increasing the risk of cardiovascular disease.

Growth, IGF system, and cortisol in children with intrauterine growth retardation: is catch-up growth affected by reprogramming of the hypothalamic-pituitary-adrenal axis?

Intrauterine growth retardation (IUGR) is one of the major causes of short stature in childhood. Although postnatal catch-up growth occurs in the majority of IUGR children, approximately 20% of them remain permanently short. The mechanisms that allow catch-up growth or, on the contrary, prevent IUGR children from achieving a normal height are still unknown. Our aim was to investigate whether intrauterine reprogramming of hypothalamic-pituitary-adrenal axis may be involved in postnatal growth retardation of IUGR children through a modulation of the function of the IGF system. Anthropometry, IGF system assessment, cortisol measurement, and lipid profile evaluation were performed in 49 IUGR children. Children were subdivided into two groups according to their actual height corrected for midparental height: CG (catch-up growth) group, 19 children with corrected height >or=0 z-score; and NCG (noncatch-up growth) group, 30 subjects with corrected height <0 z-score. CG children showed significantly higher birth weight (p < 0.005) and body mass index (p < 0.05). No significant differences in IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-3, soluble IGF-II receptor levels (IGF2R), IGF-II/IGF2R ratio, and relative amounts of IGFBP-3 circulating forms were found between CG and NCG children. None of the IGF system-related variables correlated with anthropometric indices. NCG children showed significantly higher concentrations of cortisol (p < 0.005) and cortisol levels resulted inversely to birth weigh (r = -0.34, p < 0.05), birth length (r = -0.36, p < 0.05), and corrected height (r = -0.44, p < 0.01). Whereas total and HDL cholesterol concentrations were not significantly different in the two groups, LDL cholesterol levels were significantly higher in NCG children (p < 0.05), and five of 49 showed LDL cholesterol concentrations >3.4 mM (130 mg/dL). LDL cholesterol was inversely related to birth weight (r = -0.31, p < 0.05), corrected stature (r = -0.32, p < 0.05), and actual height (r = -0.31, p < 0.05) and directly related to the levels of IGF2R (r = 0.44, p < 0.01). Reanalysis of 15 of 30 IUGR newborns in whom we previously reported an inverse relationship between cord blood cortisol levels and first trimester length gain (r = -0.54, p < 0.005) showed that the relative amount of the IGFBP-3 18-kD fragment was related inversely to cortisol (r = -0.67, p < 0.01) and directly to early postnatal growth (r = 0.65, p < 0.05). Our results suggest that catch-up growth in IUGR children might be affected by intrauterine reprogramming of hypothalamic-pituitary-adrenal axis, which may result in a permanent modification of the neuroendocrine response to stress: children with increased cortisol secretion may be at higher risk of growth failure. During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and, therefore, reducing IGF bioavailability.