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Objective We assessed the efficacy and safety of a weekly pegylated human growth hormone (PEG-rhGH) (Jintrolong) vs daily rhGH for children with growth hormone deficiency (GHD). Design Phase II and III, multicenter, open-label, randomized controlled trials. Methods 108 and 343 children with treatment-naive GHD from 6 hospitals in China were enrolled in the phase II and III studies respectively. Patients in the phase II study were randomized 1:1:1 to weekly Jintrolong (0.1 mg/kg/week PEG-rhGH complex), weekly Jintrolong (0.2 mg/kg/week PEG-rhGH complex) or daily rhGH (0.25 mg/kg/week) for 25 weeks. Patients in the phase III study were randomized in a 2:1 ratio to weekly Jintrolong (0.2 mg/kg/week) or daily rhGH (0.25 mg/kg/week) for 25 weeks. The primary endpoint for both studies was height velocity (HV) increase at the end of treatment. Other growth-related parameters, safety and compliance were also monitored. Results The phase II study established the preliminary efficacy, safety and recommended dose of Jintrolong PEG-rhGH. In the phase III study, we demonstrated significantly greater HV increases in patients receiving Jintrolong treatment (from 2.26 ± 0.87 cm/year to 13.41 ± 3.72 cm/year) vs daily rhGH (from 2.25 ± 0.82 cm/year to 12.55 ± 2.99 cm/year) at the end of treatment (P P Conclusion Jintrolong PEG-rhGH at a dose of 0.2 mg/kg/week for 25 weeks is effective and safe for GHD treatment and is non-inferior to daily rhGH.

SummaryObjective Turner syndrome (TS), which is characterized by short stature and gonadal dysfunction, is managed by pharmacotherapy. This study aimed to investigate the therapeutic effects of recombinant human growth hormone (rhGH) combined with low-dose stanozolol on the growth and final adult height (FAH) of girls with Turner syndrome (TS). Design Prospective study. Patients A total of 44 girls with TS were treated with rhGH (47·6–52·4 μg/kg/day) and low-dose stanozolol (20–35 μg/kg/day), starting at a mean age of 12·65 ± 1·99 year. The control group consisted of 22 girls with TS, who did not receive treatment. Measurements Subjects’ growth velocity (GV) was investigated. Height standard deviation score (HtSDS) was calculated relative to healthy Chinese girls (HtSDSNor) as well as untreated Chinese girls with TS (HtSDSTS). Post-treatment follow-up was performed until the subjects achieved FAH or near FAH. Results FAH was significantly higher in subjects receiving treatment compared to the untreated controls (151·42 vs 137·75 cm, P

The objective of this study was to identify variables that might interfere with reaching the near final height (NFH) in Congenital adrenal hyperplasia (CAH) due to classic 21-hydroxylase deficiency (21-OHD).A cross-sectional study of 82 (24 males and 58 females) classic (23 salt-wasting form [SW] and 59 simple-virilizing form [SV]) CAH 21-OHD patients seen in our institution between 1989 and 2015 with 10.6 (0.5~25.5) years of follow-up who reached their NFH was conducted. The variables related to NFH were explored.NFH (153.35±8.31) cm, (–1.9±1.1) SD was significantly lower than the normal population (pPatients with classic 21-OHD have blunted final height, as compared with their target height and the population norm, not-treated even worse. Careful treatment adjustments have a favorable influence on growth. Alternative treatments, such as the use of puberty inhibitors GnRHa in addition to anti-estrogen therapy letrozole can somewhat improve NFH in children with 21-OHD complicated by CPP.

Background/Aim: This study was designed to evaluate the effects of a high-protein (HP) diet on insulin resistance and body fat in catch-up growth (CUG) rats born small for gestational age (SGA). Methods: SGA rats were randomly divided into standard diet and HP diet groups. Perirenal fat weight and blood glucose, serum insulin and insulin-like growth factor-1 levels were measured at 4 and/or 8 weeks. Insulin resistance and β-cell function were evaluated by homeostatic model assessment for insulin resistance (HOMA-IR) and HOMA%. Results: The values of HOMA-IR in both CUG-SGA groups were significantly higher than those in the appropriate for gestational age (AGA) group (p < 0.01), whereas they were significantly lower in the HP diet CUG-SGA group than in the standard diet CUG-SGA group at week 8 (p < 0.01). At week 8, perirenal fat weight and adipocyte diameters were higher in both CUG-SGA groups than in the AGA group (p < 0.05), but these values were significantly lower in the HP diet CUG-SGA group than in the standard diet CUG-SGA group (p < 0.05). Conclusion: The HP diet had positive effects on the prevention of insulin resistance, which may have been caused by the reduction of body fat.

1. Growth hormone (GH) has been demonstrated to overcome the inappropriate deceleration of growth rate in children with central precocious puberty treated with gonadotropin-releasing hormone analogue (GnRHa). However, the underlying mechanisms remain largely unclear. In the present study, we investigated the potential involvement of the epidermal growth factor receptor (EGFR) pathway in the growth promotion by GH using in vitro cultured growth plate chondrocytes isolated from adolescent rats treated with GnRHa. 2. Chondrocytes were stimulated with GH in the presence or absence of the Janus tyrosine kinase (JAK) 2 inhibitor AG490 (1, 10 and 100 nmol/L), the EGFR kinase inhibitor AG1478 (0.1, 1 and 10 nmol/L), U0126 (an inhibitor of extracellular signal-regulated kinase (Erk) activation; 10 μmol/L) or a neutralizing antibody against epidermal growth factor (EGF Ab; 0.1, 1 and 10 μg/mL). The proliferation of chondrocytes was assessed by the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay and immunostaining for proliferating cell nuclear antigen (PCNA). Phosphorylation of Erk1/2 and EGFR was detected by western-blotting. Intracellular mRNA and extracellular protein levels of EGF were detected using reverse transcription-polymerase chain reaction and ELISA, respectively. 3. Growth hormone promoted the proliferation of chondrocytes, which was correlated with increased phosphorylation of Erk1/2 and EGFR and enhanced expression of EGF. Pretreatment with AG490, AG1478, U0126 or EGF Ab completely or partially inhibited the proliferation of chondrocytes and activation of Erk1/2 and EGFR. Pretreatment with AG490, AG1478, or U0126 partially inhibited the expression of EGF. 4. The findings indicate that GH promotes chondrocyte proliferation by activating EGFR signalling.

We describe current pubertal development in healthy urban Chinese boys. A cross-sectional study of the pubertal development of 18,807 urban Chinese boys aged from 3.50 to 18.49years was conducted between 2003 and 2005. Testicular volume was evaluated with a Prader orchidometer. Pubic hair development was assessed according to the Tanner method. Data on spermarche were collected using the status quo method. Probit analysis was used to calculate the median age and 95% CI at different stages of testicular development, pubic hair development and spermarche. By age 9, 12.99% of the boys had a testicular volume of 4mL or greater. The median age of onset of puberty defined as the age at attainment of testicular volume of 4mL or greater was 10.55 (95% CI 10.27-10.79) years. The median age for onset of pubic hair development (PH(2) ) and spermarche was 12.78 (95%CI 12.67-12.89) years and 14.05 (95%CI 13.80-14.32) years, respectively. Pubertal onset in urban Chinese boys is earlier than currently used clinical norms but their pubic hair development occurs relatively late in comparison with the reported data from numerous other countries. There is also evidence of a secular trend towards an earlier age of spermarche since 1979 in Chinese urban boys.

This study was performed to test whether children born small for gestational age (SGA) with catch-up growth (CUG) could be associated with the early development of insulin resistance and the β-cell dysfunction and to explore the impacts of height CUG and weight CUG on the insulin resistance in a Chinese population. A total of 30 children born SGA with CUG, 37 non-CUG (NCUG), and 42 born appropriate for gestational age (AGA) with normal height were recruited. Their fasting serum insulin, fasting glucose, insulin-like growth factor-1 (IGF-1) concentrations, and the homeostasis assessment model for insulin resistance (HOMA-IR) and β-cell function (HOMA%) were evaluated. The values of HOMA-IR in CUG SGA were significantly higher than that in NCUG SGA (P = 0.002) and AGA children (P = 0.036), respectively. Correlation analysis revealed that the concentrations of fasting serum insulin were positively correlated with IGF-1 (r = 0.443, P = 0.001) and Δheight standard deviation score (SDS; r = 0.500, P = 0.002) in ≤6-year-old SGA children, but only with Δweight SDS (r = 0.496, P = 0.030) in >6-year-old children. In conclusion, SGA children with CUG in height and a higher body mass index are prone to the development of insulin resistance. Higher levels of insulin were closely correlated with the postnatal height CUG in young SGA children and with the weight CUG in old children.

Recombinant human growth hormone (rhGH) has been widely used in the clinical treatment of growth hormone deficiency. To simplify the injection process and increase drug compliance, application of the GH injection has become a new treatment plan in recent years. The purpose of the current study was to evaluate the efficacy and safety of rhGH injection for the treatment of growth hormone deficiency (GHD) in children in China. In a nationwide, noncomparative, prospective, randomized, open trial, 31 children with confirmed complete GHD received subcutaneous injection of rhGH at 0.25 mg/kg·wk (0.107 IU/kg·d). The injection was given daily and the total weekly amount was separated into 6–7 injections. The patients were followed up at 3-month intervals and the treatment duration was 12 months. The height (HT), annual growth velocity (GV), mean height standard deviation score (HT SDS), blood serum insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and bone maturity before and after treatment were compared, and the safety of the treatment was analyzed. The mean HT, GV, and HT SDS were increased from 109.0±14 cm, 2.7±0.9 cm/yr, and −4.62 ±1.46 at baseline to 121.8±13.4 cm, 12.9±3.3 cm/yr, and −2.47±1.86 after 12 months of treatment, respectively (P

Background/Aims: Children born small for gestational age (SGA) are at increased risk for short stature and type 2 diabetes mellitus as a result of growth hormone (GH) resistance and insulin resistance. The mechanisms of multiple hormone resistance remain unclear. This study was designed to investigate the relationship between GH resistance and insulin resistance in non-catch-up growth (NCU-SGA) rats, and how their signaling pathways are related based on their crosstalk on the insulin receptor substrate-1 phosphatidylinositol 3′-kinase (IRS-1-PI3K) pathway. Methods: NCU-SGA rat model was developed by restricting prenatal food intake in pregnant dams. Activated levels of IRS-1 and Akt in liver protein extracts were compared between NCU-SGA and age- and sex-matched controls born appropriate for gestational age rats at baseline, after insulin stimulation, and after pretreatment with AG490 (GH-JAK2 pathway inhibitor) followed by insulin stimulation. Results: GH secretion was positively related to markedly increased insulin levels in NCU-SGA rats. There was no difference of IRS-1 phosphorylation in response to insulin between two groups, however, insulin-stimulated Akt phosphorylation was attenuated in NCU-SGA rats compared to appropriate for gestational age rats. Pretreatment with AG490 restored the Akt response to insulin demonstrated by significantly increased Akt phosphorylation. Conclusion: GH plays a role in inducing insulin resistance via signaling crosstalk with insulin at the level of PI3K/Akt in NCU-SGA rats.

SummaryBackground Being born as small for gestational age (SGA) has an increased risk of developing metabolic/cardiovascular disturbances in later life. The role of adiponectin in the metabolic disturbance in SGA children remained undefined. Objective The aim of this study was to investigate the association between serum levels of adiponectin and insulin sensitivity as well as lipid profile in short children born SGA at prepubertal ages. Patients and methods Serum levels of adiponectin, fasting glucose, insulin, IGF-I, IGFBP-1, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein A-I (ApoA-I) and Apo B were measured in 30 prepubertal short children born SGA. Insulin resistance (IR) and β-cell function were assessed using the method of homeostatic model (HOMA). Data were compared to those of 30 short appropriate for gestational age (AGA) children matched for age, gender, height and body mass index, and correlation analysis was performed. Results Short SGA children had significantly higher levels of fasting insulin, HOMA-IR and HOMA-β but lower levels of adiponectin than short AGA controls. No significant differences in the level of IGFBP-1 and IGF-I were found between the two groups. Serum levels of TC, TG, Apo B and Apo B/ApoA-I ratio were significantly higher in SGA, with 33% of hypercholesteraemia and 23% of hyperglyceridaemia. Stepwise multiple regression analysis revealed that serum adiponectin level was negatively correlated with HOMA-IR and TG and was positively correlated with birthweight SDS in SGA children. Conclusions These findings suggest that low serum adiponectin levels are associated with reduced insulin sensitivity and unfavourable lipid profiles in short children born SGA at prepubertal ages.

Recombinant human growth hormone (r-hGH) is indicated for pediatric patients with a variety of growth disorders. Until recently, analysis of adherence to treatment has been limited by recall bias and reliance on self-reporting. Accurate recorded data on r-hGH use can now be collected using the easypod™ auto-injector. The multinational easypod™ connect observational study (ECOS) was launched in 2010 to collect and analyze r-hGH dosing, clinical and auxological data from patients prescribed r-hGH via easypod™. Twelve countries are currently recruiting patients. The primary objective is to assess adherence in patients receiving r-hGH via easypod™. Secondary objectives include describing the impact of adherence on clinical outcomes and identifying adherence patterns. Data will be obtained from patients’ medical notes and uploaded from auto-injectors. Auxological parameters are collected, and prescribed dosing data recorded at clinic visits as per routine clinical practice. Annual adherence will be calculated (number of days the patient administered injections divided by the expected number of injection days over 1 year, as a percentage). Dose intensity (total amount of dose received divided by planned amount of dose over 1 year, as a percentage) will be analyzed. Adherence data will be correlated with clinical outcomes. An adherence pattern will also be developed based on patients’ age, sex, indication, self-injection, and time on treatment. The study will run until 2015, with yearly analyses, and will be overseen by a multinational scientific steering committee. With data from ECOS, it will be possible to accurately assess r-hGH treatment adherence in various growth disorders and explore its potential impact on growth. Ultimately, drivers of and barriers to treatment adherence will be identified, allowing appropriate support programs to be developed.

The mechanism of linear growth reduction during GnRHa treatment in central precocious puberty has not been elucidated.

Objectives: To compare the response between Chinese children with growth hormone deficiency (GHD) born either small for gestational age (SGA) or appropriate for gestational age (AGA) after 4 weeks of recombinant human growth hormone (r-hGH) therapy. Methods: This was a phase IV, open-label, multicenter, interventional study (NCT01187550). Prepubertal children with GHD received open-label treatment with daily r-hGH (0.033 mg/kg) for 4 weeks. Serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor-binding protein 3 (IGFBP3), and metabolic markers (including fasting glucose, insulin, total cholesterol, and homeostasis model assessment of insulin resistance) were assessed at baseline and after 4 weeks of treatment, and were analyzed according to patient subgroup (SGA or AGA). Results: A total of 205 children with GHD (mean age 10.4 years; 175 AGA, 30 SGA) were included in the analysis. Mean baseline serum IGF-I and IGFBP3 standard deviation scores (SDS) across the whole patient population were lower than the population norms (mean values: -2.1 SDS for IGF-I and -1.2 SDS for IGFBP3), with no significant differences between the two patient subgroups. After 4 weeks, IGF-I and IGFBP3 levels increased by 1.0 SDS ( p < 0.001) and 0.34 SDS ( p < 0.001), respectively, but no significant differences were found between the two patient subgroups for growth-related or metabolic markers. Conclusions: For children with GHD born SGA, IGF-I and IGFBP3 are short-term biomarkers of responsiveness to treatment with growth hormone, as for children with GHD born AGA.

s Background and objective The study was performed to determine whether catch-up growth is associated with the development of insulin resistance and to explore serum endocrine markers associated with the metabolism of adipose tissue in a Chinese population born small for gestational age(SGA) Subjects and methods We recruited 56 children born SGA with catch-up growth and 55 born without catch-up growth, who were further grouped into groups I (with BMI catch-up) and II (without BMI catch-up) respectively, as well as 52 children born appropriate for gestational age (AGA) with normal height. Their serum fasting insulin, fasting glucose, insulin-like growth factor-1, adiponectin, IGFBP-1, triglyceride concentrations, and the homeostasis assessment model for insulin resistance (HOMA-IR) were evaluated. Results (1) The HOMA-IR values in SGA-I with catch-up growth group were significantly higher than those in SGA-II with catch-up growth, SGA-I without catch-up growth and AGA children respectively. (2) The serum adiponectin levels of individuals in the SGA-I without catch-up growth and SGA-II with catch-up growth groups were significantly lower than those from the SGA-II without catch-up growth group. There was no difference in triglyceride or IGFBP-1 levels among the groups. (3) The degree of HOMA-IR was positively correlated with age, current BMI and △height SDS in SGA children. Conclusion The development of insulin resistance and lower levels of adiponectin were closely correlated with higher BMI and the postnatal height catch-up growth in SGA children.

Prader-Willi Syndrome (PWS) is a genetic disorder that is difficult to detect, particularly at an early age. PWS is caused by disruption of normal, epigenetically controlled gene function in the chromosome 15q11-q13 region. Clinical symptoms are difficult to diagnose in infants and only become clearer at later ages as the patients develop hyperphagia and morbid obesity. Molecular genetic tests are able to definitively diagnose PWS and allow early diagnosis of the syndrome. High resolution cytogenetic testing, methylation-specific PCR (MS-PCR), and linkage analysis are routinely used to diagnose PWS. To establish a linkage analysis method for Chinese patients, this study identified a useful set of STR markers in the typical PWS deletion and adjacent area, for linkage analysis in two Chinese families with PWS offspring. Using this method, the authors confirmed that one patient had a paternal deletion in chromosome 15q11-q13 and the other patient had maternal uniparental heterodisomy of chromosome 15. MS-PCR and high resolution chromosome G-banding also confirmed this diagnosis. This linkage analysis method can detect both deletion and uniparental disomy, thus providing valuable information for genetic counseling and the opportunity to analyze the relationship between the genotype and phenotype of PWS.

Objective To investigate possible correlations between apelin-12 levels and obesity in children in China and associations between apelin-12 and obesity-related markers, including lipids, insulin sensitivity and insulin resistance index (HOMA-IR). Methods Forty-eight obese and forty non-obese age- and gender-matched Chinese children were enrolled between June 2008 and June 2009. Mean age was 10.42±2.03 and 10.86±2.23 years in obesity and control groups, respectively. Main outcome measures were apelin-12, BMI, lipids, glucose and insulin. HOMA-IR was calculated for all subjects. Results All obesity group subjects had significantly higher total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), insulin levels and HOMA-IR (all P