Telomere length is not altered in girls with idiopathic central precocious puberty treated with a GnRH analog - leuprolide acetate.

BACKGROUND: Idiopathic central precocious puberty (iCPP) presents a disproportionate advancement of bone age and maturation, as well as metabolic and endocrinological changes that may be related to effects on telomere biology. OBJECTIVE: To investigate the telomere length in iCPP girls treated with GnRHa. STUDY DESIGN: Observational case-control study with 85 girls, including 45 iCPP treated with GnRHa and 40 controls. It was analyzed age, height, weight and body mass index (BMI), insulin, triglycerides, testosterone, insulin resistance by HOMA, and telomere length by real-time PCR. Statistical analyses were determined by Wilcoxon test and Spearman correlation was carried out. RESULTS: Weight, BMI, insulin level and HOMA index were higher in the iCPP than in the control group (p < .01); without difference between mean ages. The telomere length did not differ between iCPP and control group. However, a negative correlation was observed between the telomere length and age in iCPP (p = .0009) and control group (p = .014), and weight in the iCPP (p = .017). CONCLUSIONS: We did not observe any difference in the telomere length in the iCPP and control group. Even though, some characteristics of the disease, such as increased weight and body fat, negatively influence the telomere biology.

Spindle assembly checkpoint gene expression in childhood adrenocortical tumors (ACT): Overexpression of Aurora kinases A and B is associated with a poor prognosis.

BACKGROUND: Pediatric adrenocortical tumors (ACT) are rare malignancies and treatment has a small impact on survival in advanced disease and the discovery of potential target genes could be important in new therapeutic approaches. METHODS: The mRNA expression levels of spindle checkpoint genes AURKA, AURKB, BUB, and BUBR1 were analyzed in 60 children with ACT by quantitative real time PCR. The anticancer effect of ZM447439, an experimental AURK inhibitor, was analyzed in a primary childhood ACT culture carrying the TP53 p.R337H mutation. RESULTS: A significant association was observed between malignancy as defined by Weiss score ≥3 and higher AURKA (2.0-fold, P = 0.01), AURKB (7.0-fold, P = 0.007), and BUBR1 (5.8-fold, P = 0.007) gene expression, and between unfavorable event (death or relapse) and higher expression of AURKA (6.0-fold, P = 0.034) and AURKB (17-fold, P = 0.013). Overexpression of AURKA and AURKB was associated with lower event-free survival in uni- (P < 0.001 and P = 0.006, respectively) and multivariate (P = 0.002 and P = 0.03, respectively) analysis. Significant lower Event free survival (EFS) was also observed in patients with moderate/strong immunostaining to AURKA (P = 0.012) and AURKB (P = 0.045). ZM447439 was able to induce inhibition of proliferation and colony formation in a primary childhood ACT culture carrying the TP53 p.R337H mutation. CONCLUSION: Our results suggest that AURKA and AURKB overexpression in pediatric ACT may be related to more aggressive disease and the inhibition of these proteins could be an interesting approach for the treatment of these tumors.

Vitamin A deficiency and association between serum retinol and IGF-1 concentrations in Brazilian children with Down syndrome.

OBJECTIVE: To determine the prevalence of vitamin A deficiency (VAD) and serum concentrations of retinol, correlating them with IGF-1 concentrations in preschoolers with DS. METHODS: Cross-sectional study was conducted on 47 children with DS aged 24 to 72 months, in Ribeirão Preto, Brazil. VAD was determined by the relative dose-response (RDR) test. Retinol serum concentration ≤ 0.70 µmol/L and IGF-1 serum concentration below the 3rd percentile for sex and age were considered to represent deficiency. C-reactive protein (CRP) was determined at the beginning of the study. Weight, height, and information about fever and/or diarrhea were obtained at the beginning of the study. RESULTS: VAD prevalence was 25.5% (12/47), and 74.5% (35/47) of the children had deficient retinol before the intervention. CRP was not associated with VAD. Mean IGF-1 were 103.5 ng/mL (SD = 913) for the group with VAD and 116.3 ng/mL (SD = 54.9) for the group with no VAD (p-value = 0.85); 8.5% (4/47) of the children showed deficient IGF-1, but without VAD. No association was observed between VAD and IGF-1 deficiency. A moderate positive correlation was observed between pre-intervention retinol and IGF-1 (ρ = 0.37; p-value = 0.01). CONCLUSION: a high prevalence of VAD and deficient retinol was observed and there was a positive correlation between serum retinol and IGF-1.

Serum IGF-I concentrations are low in female bodybuilders in the pre-contest phase.

Bodybuilding involves athletes performing a series of poses/postures on the stage so that they can be classified according to their best esthetic and physical appearance during the competition. In the weeks prior to the target competition, the athletes subject themselves to restrictive diets and different physical training methods, as well as using dietary supplementation and, in some cases, anabolic steroids, to reduce body fat to low levels and maintain or increase muscle mass. On the other hand, it is known that physical training is a potent stimulator for releasing the components of the GH/IGF-I axis that are directly linked to the anabolic process. Based on these assumptions, this study aimed to verify the kinetics of IGF-I and of its binding protein IGFBP-3 in female bodybuilders. Serum IGF-I and IGFBP-3 concentrations were recorded before and after standardized training sessions at two different times: in the initial phase (phase 1) and in the final phase of the pre-contest (phase 2) of a 12-week training season. It was possible to conclude that there was a significant reduction in serum IGF-I values at the end of the pre-contest phase that preceded the athletes' participation in a competition. With relation to the serum IGF-I and IGFBP-3 values measured before and after the standardized training session, it was only possible to verify significant changes in the IGF-I values in the initial phase of the pre-contest. It seems reasonable to suggest that the caloric restriction used by bodybuilders may be related to the decrease in IGF-I values verified at the end of the pre-contest phase.

IGF-1R mRNA expression is increased in obese children.

OBJECTIVES: Obese children are often taller than age-matched subjects. Reports on GH and IGF-I levels in obese individuals are controversial, with normal and reduced GH-IGF-I levels having been reported in this group of patients. Thus, the aim of this study was to analyse insulin-like growth factor type 1 receptor (IGF-IR) mRNA expression in obese children. METHODS: Forty-seven pre-pubertal children were included in this study: 29 were obese and taller than their target height, and 18 were normal eutrophic controls. Fasting blood samples were collected for IGF-IR mRNA expression in isolated lymphocytes and serum IGF-I, ALS, IGFBP-3, and IGFBP-1 concentration analysis. RESULTS: Relative IGF-IR gene expression (2-ΔΔCT) was significantly (P=0.025) higher in obese children (median 1.87) than in controls (1.15). Fourteen of the 29 obese subjects showed 2-ΔΔCT values greater than or equal to 2, while only 2 individuals in the control group showed values above 2 (P=0.01). Obese children showed significantly (P=0.01) higher IGF-I concentrations than the control group (237ng/ml and 144ng/ml, respectively). Among obese patients, 65.5% had IGF-I values above the 75 percentile of the control group (P=0.02). ALS concentration was significantly (P=0.04) higher in the obese group, while IGFBP-3 levels were similar in obese and control children. IGFBP-1 concentration was lower in obese children, while insulin levels and HOMA-IR index were higher than in controls. CONCLUSIONS: The higher IGF-IR mRNA expression observed in obese children, associated with the higher IGF-I and ALS and the lower IGFBP-1 levels, suggest that the higher stature observed in these children may be due to increased IGF-I bioactivity.

IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis.

Deregulation of the IGF system observed in human tumors indicates a role in malignant cell transformation and in tumor cell proliferation. Although overexpression of the IGF2 and IGF1R genes was described in adrenocortical tumors (ACTs), few studies reported their profiles in pediatric ACTs. In this study, the IGF2 and IGF1R expression was evaluated by RT-qPCR according to the patient's clinical/pathological features in 60 pediatric ACT samples, and IGF1R protein was investigated in 45 samples by immunohistochemistry (IHC). Whole transcriptome and functional assays were conducted after IGF1R inhibition with OSI-906 in NCI-H295A cell line. Significant IGF2 overexpression was found in tumor samples when compared with non-neoplastic samples (P<0.001), significantly higher levels of IGF1R in patients with relapse/metastasis (P=0.031) and moderate/strong IGF1R immunostaining in 62.2% of ACTs, but no other relationship with patient survival and clinical/pathological features was observed. OSI-906 treatment downregulated genes associated with MAPK activity, induced limited reduction of cell viability and increased the apoptosis rate. After 24h, the treatment also decreased the expression of genes related to the steroid biosynthetic process, the protein levels of the steroidogenic acute regulatory protein (STAR), and androgen secretion in cell medium, supporting the role of IGF1R in steroidogenesis of adrenocortical carcinoma cells. Our data showed that the IGF1R overexpression could be indicative of aggressive ACTs in children. However, in vitro treatments with high concentrations of OSI-906 (>1µM) showed limited reduction of cell viability, suggesting that OSI-906 alone could not be a suitable therapy to abolish carcinoma cell growth.

Clinical and molecular data from 61 Brazilian cases of Congenital Hyperinsulinemic Hypoglycemia.

OBJECTIVE: To study the clinical and molecular characteristics of a sample of Brazilian patients with Congenital Hyperinsulinemic Hypoglycemia (CHH). METHODS: Electronic message was sent to members from Endocrinology Department- Brazilian Society of Pediatrics requesting clinical data for all cases of CHH. A whole blood sample from living patients was requested for DNA extraction followed by a search for mutations of the genes ABCC8, KCNJ11, GCK, GLUD1, HADH, SLC16A1 and HNF4A. RESULTS: Of the 61 patients evaluated, 36 (59%) were boys, and only 16 (26%) were born by normal delivery. Gestational age ranged from 32 to 41 weeks (mean = 37 weeks and 6 days). Birth weight ranged from 1590 to 5250 g (mean = 3430 g). Macrossomia occurred in 14 cases (28%). Age at diagnosis ranged from 1 to 1080 days (mean = 75 days). DNA for molecular analysis was obtained from 53 of the 61 patients. Molecular changes in the ABCC8 gene were detected in 15 (28%) of these 53 cases, and mutations in the KCNJ11 gene were detected in 6 (11%). Mutations in the GLUD1 gene were detected in 9 cases (17%) of the total series. Mutations of the GCK gene in heterozygosis were detected in 3 cases. No mutations were detected in the sequencing of genes HADH, SLC16A1 and HNF4A. CONCLUSION: The present study conducted in Brazil permitted the collaborative compilation of an important number of CHH cases and showed that the present clinical and molecular data are similar to those of published global series.

Triglyceride-induced diabetes mellitus in congenital generalized lipodystrophy.

High levels of triglycerides and free fatty acids have been implicated in the pathogenesis of type 2 diabetes mellitus (DM). Congenital generalized lipodystrophy (CGL) is an autosomal recessive syndrome characterized by intense whole body reduction of subcutaneous fat. Its clinical manifestations appear during the first years of life. However, DM is usually a late event. We report a patient with CGL, diagnosed at 4 months of age, who has severe hypertriglyceridemia (serum triglyceride 12.34 mmol/l and cholesterol 3.90 mmol/l), muscular hypertrophy, hepatomegaly and DM (fasting glycemia 25.9 mmol/l). Hepatic biopsy revealed steatosis and fibrosis. A modified normolipidic (composed of medium chain triglycerides) normocaloric normoproteic milky diet and insulin therapy were instituted. After 1 month treatment a reduction of serum glucose and triglyceride levels (4.13 mmol/I and 7.7 mmol/l, respectively) was noted, with later normalization, which led to the discontinuation of insulin therapy. The patient has been maintaining good control with diet alone, presenting normal serum lipid levels (triglycerides 1.07 mmol/l, total cholesterol 2.71 mmol/l) and the following glycemic profile at OGTT: 0' 4.4 mmol/l; 30' 7.0 mmol/l; 60' 3.8 mmol/l; 90' 5.3 mmol/l, and 120' 5.2 mmol/l. The disappearance of hepatic steatosis was evidenced by a biopsy obtained 1 year after the beginning of treatment. In conolusion, this report suggests that the DM occurring in CGL can be precipitated by high triglyceride levels.

Comparison between the growth response to growth hormone (GH) therapy in children with partial GH insensitivity or mild GH deficiency.

OBJECTIVES: GH therapy is still controversial, except in severe GH deficiency (SGHD). The objective of this study was to compare the response to growth hormone (GH) therapy in children with partial GH insensitivity (PGHIS) and mild GH deficiency (MGHD) with those with SGHD. SUBJECTS AND METHODS: Fifteen PGHIS, 11 MGHD, and 19 SGHD subjects, followed up for more than one year in the Brazilian public care service, were evaluated regarding anthropometric and laboratory data at the beginning of treatment, after one year (1st year) on treatment, and at the last assessment (up to ten years in SGHD, up to four years in MGHD, and up to eight years in PGHIS). RESULTS: Initial height standard deviation score (SDS) in SGHD was lower than in MGHD and PGHIS. Although the increase in 1 st year height SDS in comparison to initial height SDS was not different among the groups, height-SDS after the first year of treatment remained lower in SGHD than in MGHD. There was no difference in height-SDS at the last assessment of the children among the three groups. GH therapy, in the entire period of observation, caused a trend towards lower increase in height SDS in PGHIS than SGHD but similar increases were observed in MGHD and SGHD. CONCLUSION: GH therapy increases height in PGHIS and produces similar height effects in MGHD and SGHD.

Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3.

CONTEXT: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. OBJECTIVES: The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. SETTING AND PARTICIPANTS: We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. MAIN OUTCOME MEASURES: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. RESULTS: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3 mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. CONCLUSIONS: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis.

Measurement of salivary cortisol as a marker of stress in newborns in a neonatal intensive care unit.

AIMS: The study was designed to evaluate the newborn (NB) stress response during the inpatient time in the neonatal intensive care unit. METHODS: A quantitative, prospective, observational study was conducted with two NB groups. The first group consisted of 12 NB patients in the neonatal intensive care unit as the experimental group (EG), and the second included 43 NBs who were sent to their own homes and were considered the control group (CG). The EG's salivary cortisol concentration was measured on the 2nd day (D2) and 9th day (D9) of life. The CG's salivary cortisol concentration was measured on the 14th day of life at the child's own home. RESULTS: The salivary cortisol concentration levels for the EG on D2 and D9 and for the CG were 4.3151 ± 2.6492, 1.826 ± 1.2252, and 1.0166 ± 0.8300 ng/dl, respectively. These findings indicated the presence of an adrenal response to stress during the first inpatient days. CONCLUSIONS: The salivary cortisol concentration is an accurate method to indicate neonatal stress. The glucocorticoids frequently used in the prenatal period suppress the adrenal glands and interfere with the stress response.

A rational, non-radioactive strategy for the molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

CONTEXT: Molecular diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) has not been straightforward. OBJECTIVE: To conduct a comprehensive genetic analysis by Multiplex Ligation dependent Probe Amplification (MLPA) and evaluate its reliability for the molecular CAH-21OHD diagnosis. PATIENTS AND METHODS: We studied 99 patients from 90 families with salt-wasting (SW; n=32), simple-virilizing (SV; n=29), and non-classical (NC; n=29) CAH-21OHD. Molecular analysis was sequentially performed by detecting the most frequent point mutations by allele-specific oligonucleotide polymerase chain reaction (ASO-PCR), large rearrangements by MLPA, and rare mutations by direct sequencing. Parental segregation was evaluated. RESULTS: ASO-PCR detected microconversions in 164 alleles (91.1%). MLPA identified CYP21A1P large conversions to CYP21A2 in 7 of the remaining 16 (43.7%), 30-kb deletions including the 3'-end of CYP21A1P, C4B, and the 5'-end of CYP21A2 in 3 of the 16 (18.7%), and a complete CYP21A2 deletion in one (6.3%). Five alleles (2.7%) required direct sequencing; three mutations located in the CYP21A2 gene and two derived from CYP21A1P were found. No parental segregation was observed in patients with the c.329_336del and/or the CL6 cluster mutations. These cases were not diagnosed by ASO-PCR, but MLPA detected deletions in the promoter region of the CYP21A2 gene, explaining the genotype/phenotype dissociation. CONCLUSION: Using the proposed algorithm, all alleles were elucidated. False-positive results in MLPA occurred when mutations or polymorphisms were located close to the probe-binding regions. These difficulties were overcome by the association of MLPA with ASO-PCR and paternal segregation. Using these approaches, we can successfully use MLPA in a cost-effective laboratory routine for the molecular diagnosis of CAH-21OHD.

Impact of hypoxia on IGF-I, IGF-II, IGFBP-3, ALS and IGFBP-1 regulation and on IGF1R gene expression in children.

UNLABELLED: Hypoxia is one of many factors involved in the regulation of the IGF system. However, no information is available regarding the regulation of the IGF system by acute hypoxia in humans. OBJECTIVE: The aim of this study was to evaluate the effect of acute hypoxia on the IGF system of children. DESIGN: Twenty-seven previously health children (14 boys and 13 girls) aged 15 days to 9.5 years were studied in two different situations: during a hypoxemic state (HS) due to acute respiratory distress and after full recovery to a normoxemic state (NS). In these two situations oxygen saturation was assessed with a pulse-oximeter and blood samples were collected for serum IGF-I, IGF-II, IGFBP-1, IGFBP-3, ALS and insulin determination by ELISA; fluoroimmunometric assay determination for GH and also for IGF1R gene expression analysis in peripheral lymphocytes by quantitative real-time PCR. Data were paired and analyzed by the Wilcoxon non-parametric test. RESULTS: Oxygen saturation was significantly lower during HS than in NS (P<0.0001). IGF-I and IGF-II levels were lower during HS than in NS (P<0.0001 and P=0.0004, respectively). IGFBP-3 levels were also lower in HS than in NS (P=0.0002) while ALS and basal GH levels were higher during HS (P=0.0015 and P=0.014, respectively). Moreover, IGFBP-1 levels were higher during HS than in NS (P=0.004). No difference was found regarding insulin levels. The expression of IGF1R mRNA as 2(-ΔΔCT) was higher during HS than in NS (P=0.03). CONCLUSION: The above results confirm a role of hypoxia in the regulation of the IGF system also in humans. This effect could be direct on the liver and/or mediated by GH and it is not restricted to the hepatocytes but involves other cell lines. During acute hypoxia a combination of alterations usually associated with reduced IGF action was observed. The higher expression of IGF1R mRNA may reflect an up-regulation of the transcriptional process.

Expression profile of apoptosis-related genes in childhood adrenocortical tumors: low level of expression of BCL2 and TNF genes suggests a poor prognosis.

BACKGROUND: Impaired apoptosis has been implicated in the development of childhood adrenocortical tumors (ACT), although the expression of apoptosis-related gene expression in such tumors has not been reported. METHODS: The mRNA expression levels of the genes CASP3, CASP8, CASP9, FAS, TNF, NFKB, and BCL2 were analyzed by quantitative real-time PCR in consecutive tumor samples obtained at diagnosis from 60 children with a diagnosis of ACT and in 11 non-neoplastic adrenal samples. BCL2 and TNF protein expression was analyzed by immunohistochemistry. RESULTS: A significant association was observed between tumor size ≥100 g and lower expression levels of the BCL2 (P=0.03) and TNF (P=0.05) genes; between stage IV and lower expression levels of CASP3 (P=0.008), CASP9 (P=0.02), BCL2 (P=0.002), TNF (P=0.05), and NFKB (P=0.03); Weiss score ≥3 and lower expression of TNF (P=0.01); unfavorable event and higher expression values of CASP9 (P=0.01) and lower values of TNF (P=0.02); and death and lower expression of BCL2 (P=0.04). Underexpression of TNF was associated with lower event-free survival in uni- and multivariate analyses (P<0.01). Similar results were observed when patients with Weiss score <3 were excluded. CONCLUSION: This study supports the participation of apoptosis-related genes in the biology and prognosis of childhood ACT and suggests the complex role of these genes in the pathogenesis of this tumor.

Surgical management of pediatric Cushing's disease: an analysis of 15 consecutive cases at a specialized neurosurgical center.

OBJECTIVE: The aim of this study was to review the results of surgery for pediatric patients with Cushing's disease who were less than 18 years old and underwent transsphenoidal surgery in a specialized center during a 25-year period. SUBJECTS AND METHODS: Retrospective study, in which the medical records, histology and pituitary imaging of 15 consecutive pediatric patients with Cushing's disease (mean age: 13 years) were evaluated by the same team of endocrinologists and a neurosurgeon from 1982 to 2006. Patients were considered cured when there was clinical adrenal insufficiency and serum cortisol levels were below 1. 8 microg/dL or 50 nmol/L after one, two, three, or seven days following surgery; they therefore required cortisone replacement therapy. Follow-up was for a median time of 11.5 years (range: 2 to 25 years). RESULTS: Clinical and biochemical cure was achieved in 9/15 patients (60%) exclusively after transsphenoidal surgery. Hypopituitarism was observed in four patients; growth hormone deficiency, in two; permanent diabetes insipidus, in one case. CONCLUSIONS: Cushing's disease is rare in children and adolescents. Transsphenoidal surgery is an effective and safe treatment in most of these patients. Plasma cortisol level < 1. 8 microg/dL following surgery is the treatment goal and is a good predictive factor for long-term cure of Cushing's disease.

[hrGH treatment of glucocorticoid-induced short stature in children]. / Tratamento com hrGH da baixa estatura induzida pelo uso crônico de glicocorticóide em crianças.

The treatment of systemic diseases with glucocorticoids is often associated with decreased height velocity (HV), and can result in shorter final height. Interactions between adrenal and GH-IGF axis have been described and can occur at hypothalamic-pituitary level or at the regulation of IGF system, including the IGF1R signaling. The clinical state of these patients may be considered as an absolute and/or functional IGF-1 deficiency. Interventions aiming to restore the normal function of GH-IGF axis might reduce the glucocorticoids-induced growth suppression in these children. It has been shown that recombinant human GH (hrGH) induces an increase in HV and a decrease in protein loss in patients with juvenile idiopathic arthritis treated with glucocorticoids. Significant increment in HV was also described after hrGH treatment in children under glucocorticoid therapy due to inflammatory bowel disease or renal transplantation. There is a positive correlation between HV and the dose of hrGH. The results support that the IGF-1 deficiency in these children may be counteract by hrGH therapy. The effect of hrGH is observed only during the treatment period and depends on the replacement strategy, nutritional status and disease control.

[Physiology of the GH-IGF axis]. / Fisiologia do eixo GH-sistema IGF.

Growth, the main characteristic of childhood and adolescence, has a similar pattern in the majority of the individuals. Genetic background and GH-IGF axis are the factors that directly influence this process. Pituitary GH acts on growth mainly through the regulation of IGF system. The IGFs (IGF-1 and IGF-2) are growth factors produced in the majority of the organs and body tissues. They have autocrine, paracrine and endocrine actions on metabolism and cell proliferation, growth and differentiation. The IGFs bind with high specificity and affinity to a family of 6 binding proteins, called IGFBPs (1 to 6) that modulate their bioactivity. Most of the known IGF actions are mediated via IGF type 1 receptor (IGF1R). In this article we are going to review the composition and regulation of the GH-IGF axis and the role of each component in the regulation of the growth process.

Final height in patients with idiopathic short stature and high growth hormone responses to stimulation tests.

UNLABELLED: Children with idiopathic short stature (ISS) may have normal or increased growth hormone (GH) responses to provocation tests and achieve a final height (FH) below -2.0 standard deviation score (SDS) if untreated. FH of subjects with high stimulated GH levels has not been studied in detail. AIM: It was the aim of this study to analyse FH in ISS patients with high GH peak responses to the provocation test. PATIENTS AND METHODS: We studied 16 patients (9 pre-pubertal) with ISS and a GH peak >or=40 mU/l to insulin-induced hypoglycaemia. The patients were recalled at age 19.7 +/- 2.5 years for measurement of FH when blood samples were obtained for serum insulin-like growth factor (IGF)-I, IGF binding protein 3, acid-labile subunit and GH binding protein measurements. GH bioactivity was determined using the Nb2 bioassay. RESULTS: FH was -3.1 +/- 1.0 SDS, being significantly lower than target height (TH). At FH, IGF-I levels were within -1.5 and +1.5 SDS for age and sex in 10 patients and higher than +1.5 SDS in 6 patients. IGF binding protein 3, acid-labile subunit, GH binding protein levels and GH bioactivity values were normal. SUMMARY: These data suggest that patients with ISS and high GH levels during a GH stimulation test may have a more compromised FH. The association of severe ISS with a peak GH >40 mU/l might suggest a degree of insensitivity for the GH-IGF-I axis.

Different states of clinical control are associated with changes in IGF-I and IGFBPs in children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is characterized by high androgen levels, ambiguous genitalia or premature pubarche, increased height velocity and skeletal maturation. Considering the possibility of changes in the IGF system components depending on the state of clinical control, the objective of the present study was to analyse serum IGF-I, IGF-II and IGFBP levels in children with 21-OHD under two states of clinical control. PATIENTS AND DESIGN: We studied 12 prepubertal children with 21-OHD CAH aged 4.0 +/- 0.7 years. They were classified as good (GC) or poor control (PC) based on growth rate, signs of adrenal insufficiency or Cushing syndrome, progression of sexual characteristics and serum androgens levels. Blood samples were obtained from each patient in two different states of clinical control (GC and PC) for biochemical measurements. MEASUREMENTS: IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 were determined by immunoassays. IGFBPs were also analysed by Western ligand blotting (WLB). RESULTS: Levels of IGF-I (P = 0.03) and IGFBP-3 (P = 0.01) were higher in GC than in PC while IGFBP-1 (P = 0.004) concentrations were lower in GC patients. A trend towards higher levels of IGF-II (P = 0.08) and lower levels of IGFBP-2 (P = 0.08) was observed in GC children. Increased IGFBP-4 band intensity was observed in GC children (P = 0.03). CONCLUSION: Higher levels of IGF-I, IGFBP-3 and IGFBP-4, but lower levels of IGFBP-1, were associated with better control in children with 21-OHD CAH. These findings are different from those observed in children with other causes of increasing androgens levels and are likely to be related to the insufficient glucocorticoid status.