Organic Growth Hormone Deficiency Research Articles

THU172 Accuracy Of The Glucagon Testing In The Diagnosis Of Growth Hormone Deficiency During Transition

Abstract Disclosure: N. Di Iorgi: None. D. Guglielmi: None. N. Flavia: None. A. Allegri: None. D. Fava: None. E. Casalini: None. G. Patti: None. M. Maghnie: None. Objectives: To evaluate the accuracy of the Glucagon test (GST) compared with the Insulin Tolerance test (ITT) as the gold standard in the diagnosis of Growth Hormone deficiency (GHD) in young adults with childhood-onset GHD (COGHD). Methods: Eighty-six subjects with COGHD (33F, 55M) were evaluated by ITT and GST stimulation tests and IGF-1 SDS at adult height achievement (median age of 17.5; IQR 13.9-18.4 years). Subjects were recruited from a single Center and based on the AACE 2019 Guidelines [1] classified as 1. idiopathic isolated GHD (I-GHD n=40 with normal brain MRI); 2. organic moderate GHD (omGHD with less than 3 pituitary deficiencies-PD and IGF-1<0 SDS, total n=40; n=12 midline defects, n=2 ALL, n=26 CNS tumors); 3. congenital/genetic defects/organic severe GHD (osGHD ≥3 PD and IGF-1 <-2 SDS, total n=6; n=1 midline defect, n=5 CNS tumors). ROC analyses were performed in order to analyze the Sensitivity (Se) and Specificity (Sp) of the GH peak after GST and of IGF-1 SDS compared to ITT. A peak GH value <6μg/L after ITT was suggestive of permanent GHD [2]. Results: Median GH peak to ITT (0.2; IQR 0.01-0.7 μg/L) and GST (0.1; IQR 0.01-1.4μg/L) were lower in osGHD compared to I-GHD subjects (15.0; IQR 8.6-21.9 to ITT and 12.6; IQR 10.5-18.8 μg/L to GST, P’s <0.0001); similarly, GH peak to ITT (2.1; IQR 1.1-6.8 μg/L) and GL (2.7; IQR 1.2-5.8) were lower in omGHD compared to I-GHD subjects (P’s <0.0001). Mean IGF-1 were also lower in osGHD (-3.2 SDS; IQR -7.4- -2.9, P<0.0001) and in omGHD (-2.0 SDS; IQR -2.8 - -0.7; P<0.0001) compared to I-GHD subjects (0,1; IQR -0.6-1.1SDS). A GH peak value to GST of 7.59 mcg/L (Se 92.3%, Sp of 87.2%; AUC=0.94; 95% CI, 0.89-0.99) correctly classified 89.5% of the entire cohort while an IGF-1 cut-off of -1.45 SDS (Se 73%; Sp 93.5%; AUC=0.84; 95% CI, 0.75 - 0.94) correctly classified 83,1%. A GH peak value to GST of 5.81 mcg/L (Se 96.6%, Sp of 81.8%; AUC=0.95; 95% CI, 0.88-1.02) correctly classified 92.5% of omGHD patients while an IGF-1 cut-off of -1.64 SDS (Se 72.3%, Sp of 90.9%; AUC=0.94; 95% CI, 0.89-0.99) correctly classified 77.5% omGHD patients. Median BMI SDS was higher in patients with osGHD (1.8; IQR 1,6- 2.2, P<0.001) and omGHD (0.6; IQR 0.1- 1.8, P<0.001) compared to I-GHD (0.2; IQR -0.7- 1.1). GH peak to GST correlated with BMI SDS only in the total cohort (r -0.313, P=0.0031). Conclusions: Our results suggest that a peak value <6 μg/L after GST is accurate in detecting permanent GHD during transition in a cohort of patients with organic GHD with less than 3 pituitary defects and IGF-1 values <0 SDS; the GH response to GST could be affected by BMI SDS, but further studies are needed. [1] Yuen KCJ et al. Endocr Pract 2019; 25 (11):1191-1232. [2] Maghnie M et al, EJE 2005; 152:589-596. Presentation: Thursday, June 15, 2023

Safety and Efficacy of Pediatric Growth Hormone Therapy: Results From the Full KIGS Cohort.

The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort. Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (≥ 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth. The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls. Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions.

Metabolic Impacts of Discontinuation and Resumption of Recombinant Human Growth Hormone Treatment during the Transition Period in Patients with Childhood-Onset Growth Hormone Deficiency.

Background Discontinuing growth hormone (GH) treatment during the transition to adulthood has been associated with adverse health outcomes in patients with childhood-onset growth hormone deficiency (CO-GHD). This study investigated the metabolic changes associated with interrupting GH treatment in adolescents with CO-GHD during the transition period.Methods This study included 187 patients with CO-GHD who were confirmed to have adult GHD and were treated at six academic centers in Korea. Data on clinical parameters, including anthropometric measurements, metabolic profiles, and bone mineral density (BMD) at the end of childhood GH treatment, were collected at the time of re-evaluation for GHD and 1 year after treatment resumption.Results Most patients (n=182, 97.3%) had organic GHD. The median age at treatment discontinuation and re-evaluation was 15.6 and 18.7 years, respectively. The median duration of treatment interruption was 2.8 years. During treatment discontinuation, body mass index Z-scores and total cholesterol, low-density lipoprotein, and non-high-density lipoprotein (HDL) cholesterol levels increased, whereas fasting glucose levels decreased. One year after GH treatment resumption, fasting glucose levels, HDL cholesterol levels, and femoral neck BMD increased significantly. Longer GH interruption (>2 years, 60.4%) resulted in worse lipid profiles at re-evaluation. The duration of interruption was positively correlated with fasting glucose and non-HDL cholesterol levels after adjusting for covariates.Conclusion GH treatment interruption during the transition period resulted in worse metabolic parameters, and a longer interruption period was correlated with poorer outcomes. GH treatment should be resumed early in patients with CO-GHD during the transition period.

Factors affecting IGF-I level and correlation with growth response during growth hormone treatment in LG Growth Study.

Growth hormone treatment strategies to achieve the goal include the titration of GH doses according to serum insulin-like growth factor I (IGF-I) concentrations. However, IGF-I levels do not always correlate well with the growth response. This study aims to identify the factors affecting the IGF-I concentration and identify the relationship between IGF-I and the treatment response. The data of prepubertal children treated with recombinant human GH for more than one year were obtained from the LG Growth Study (LGS) Database. This study includes patients with idiopathic growth hormone deficiency (IGHD), organic growth hormone deficiency (OGHD), or Turner syndrome (TS) or small for gestational age (SGA). Among 2,021 participants registered in LGS, 366 subjects were selected, 252 had IGHD, 16 had OGHD, 31 had TS, and 67 were SGA. In the IGHD and SGA groups, IGF-I levels had a positive correlation with weight SDS. There was no significant relationship between the pre-treatment IGF-I level and growth response. However, in the IGHD group, the growth response was significantly higher when the change in the IGF-I SDS value was 1 or more (p = 0.0013). Therefore, IGF-I concentrations should be used as an indicator to monitor the treatment compliance rather than for efficacy determination in Korean children of short stature with GH treatment.

Effectiveness and Overall Safety of NutropinAq® for Growth Hormone Deficiency and Other Paediatric Growth Hormone Disorders: Completion of the International Cooperative Growth Study, NutropinAq® European Registry (iNCGS).

ObjectiveThe International Cooperative Growth Study, NutropinAq® European Registry (iNCGS) (NCT00455728) monitored long-term safety and effectiveness of recombinant human growth hormone (rhGH; NutropinAq® [somatropin]) in paediatric growth disorders.MethodsOpen-label, non-interventional, post-marketing surveillance study recruiting children with growth disorders. Endpoints included gain in height standard deviation score (SDS), adult height, and occurrence of adverse events (AEs).Results2792 patients were enrolled. 2082 patients (74.6%) had growth hormone deficiency (GHD), which was isolated idiopathic in 1825 patients (87.7%). Non-GHD diagnoses included Turner syndrome (TS) (n=199), chronic renal insufficiency (CRI) (n=10), other non-GHD (n=498), and missing data for three participants. Improvements from baseline height SDS occurred at all time points to Month 132, and in all subgroups by disease aetiology. At Month 12, mean (95% CI) change in height SDS by aetiology was: idiopathic GHD 0.63 (0.61;0.66), organic GHD 0.71 (0.62;0.80), TS 0.59 (0.53; 0.65), CRI 0.54 (-0.49;1.56), and other non-GHD 0.64 (0.59;0.69). Mean height ( ± SD) at the last visit among the 235 patients with adult or near-adult height recorded was 154.0 cm ( ± 8.0) for girls and 166.7 cm ( ± 8.0) for boys. The most frequent biological and clinical non-serious drug-related AEs were increased insulin-like growth factor concentrations (314 events) and injection site haematoma (99 events). Serious AEs related to rhGH according to investigators were reported (n=30); the most frequent were scoliosis (4 events), epiphysiolysis (3 events), and strabismus (2 events).ConclusionsThere was an improvement in mean height SDS in all aetiology subgroups after rhGH treatment. No new safety concerns were identified.

Adolescent boys with constitutional delay of growth and puberty grow faster than patients with organic growth hormone deficiency.

Constitutional delay of growth and puberty (CDGP) is a tempo variant with a good prognosis. Healthy late-maturing adolescents grow slower than postulated by age-related references, and therefore, CDGP is frequently confused with growth hormone deficiency (GHD). For differential diagnosis, height velocity references for CDGP are needed. Here, we provide height velocity data for late-maturing boys based on mixed longitudinal and cross-sectional observations in a group of 38 German adolescents with proven CDGP and compare them with cross-sectional observations in a group of 164 adolescents with organic GHD from the National Cooperative Growth Study registry. In the critical age interval from 13.4 to 14.9years, the growth of prepubertal adolescents with CDGP was faster (mean/median height velocity, 5.2/5.4cm/years; quartiles, 4.4-6.2cm/years) than that of prepubertal adolescents with organic GHD (3.5/3.2cm/years; quartiles, 2.0-4.4cm/years) in the cross-sectional analysis (p<.0001). Based on our mixed longitudinal and cross-sectional analysis, the height velocity of adolescent boys with CDGP exceeded previous model calculations on average by 1.0cm. In conclusion, prepubertal adolescents with CDGP grow faster than patients with organic GHD. Previous model estimates underestimated height velocity of boys with CDGP.

SAT-090 Factors Affecting IGF-1 Level and Correlation with Growth Response During Growth Hormone Treatment in LGS Patients

Background: Primary goal of growth hormone (GH) treatment for short children is to achieve an adult height in the normal range. Different GH treatment strategies to achieve this goal include titration of GH dose according to serum insulin-like growth factor I (IGF-I) concentrations. However, IGF-I levels do not always correlate well with the growth response. The purpose of this study is to identify the factors affecting IGF-I concentration in each disease and to correct the related factors and then to identify the relationship between IGF-1 and treatment response. Methods: In this study, data of pre-pubertal children with idiopathic growth hormone deficiency (IGHD), organic GHD (OGHD), Turner syndrome (TS), small for gestational age (SGA) who were treated with recombinant human GH more than one year were obtained from the LGS Database. The LGS has been progressing since 2012 and is an open-label, multicenter, prospective, and retrospective observational study. Results: Among 2,021 registered in LGS, the subjects were 366 except for the violation of selection criteria. Among them, IGHD was 252, 16 OGHD, 31 TS, and 67 SGA. The mean age of IGHD was 6.02, and the mean bone age was 4.49 years. OGHD was 7.38, 5.74, TS was 7.13, 6.52, and SGA was 5.61, 4.96 years. The height SDS according to chronologic age was -2.76 in IGHD group, OGHD -2.33, TS -2.9, SGA -2.57. In the IGHD and SGA group, IGF-I level has a positive correlation with weight and BMI (weight; r=0.0071 in IGHD, r=0.0009 in SGA, BMI; r=0.0411 in IGHD, r=0.003 in SGA). IGF-I showed a negative correlation with chronological age in the IGHD group (r=0.0411) and mid-parental height in the SGA group (r=0.0069). There was no significant relationship between pretreatment IGF-I level and growth response. However, in the IGHD group, the growth response was significantly higher when the change in IGF-I SDS value was 1 or more (P=0.0013). Conclusion: This study is the first study using LGS data to identify factors affecting IGF-I levels in Korean children with short stature and the relationship with treatment response. IGF-I levels were positively correlated with body weight in IGHD and SGA groups. There was no significant relationship between pre-treatment IGF-I levels and post-treatment growth response. In conclusion, IGF-I concentrations should be used as a tool for treatment compliance rather than for efficacy determination.

Impact of BMI on peak growth hormone responses to provocative tests and therapeutic outcome in children with growth hormone deficiency

This study investigated the relationship between peak stimulated growth hormone (GH) and body mass index (BMI), as well as the impact of BMI on therapeutic response in patients with GH deficiency (GHD). A total of 460 patients were enrolled in the study. The patients were divided into four groups as per the etiology and peak GH values: idiopathic (n = 439), organic (n = 21), complete (n = 114), and partial (n = 325) GHD groups. Subsequently, they were classified as normal, overweight, or obese based on their BMI. There was no difference in BMI between complete and partial GHD. A significant negative relationship between peak GH and BMI were found. Moreover, obese GHD children had a considerably better therapeutic response in height increase and BMI decrease during 2 years of GH treatment compared to non-obese children with GHD. There was no difference between peak GH and type of GH stimulation test (GHST), except the clonidine test, which showed a much lower peak GH in obese GHD children. In conclusion, BMI had a negative impact on peak GH response, and therapeutic outcome was more favorable in the obese group. Despite no difference in GH response by type of GHST, the degree of obesity differentially affected the results.

Long-term safety and effectiveness of growth hormone therapy in Korean children with growth disorders: 5-year results of LG Growth Study.

PurposeThe aim of this registry study was to analyze the long-term safety and effectiveness of recombinant human growth hormone (rhGH) in South Korean pediatric patients (≥2 years of age) with growth hormone deficiency GHD) of idiopathic or organic etiology, idiopathic short stature, Turner syndrome, small for gestational age and chronic renal failure.MethodsThe study patients were followed-up till two years after the epiphyseal closure, with visits scheduled every six months. The outcome measures included the incidence of adverse events (AEs, in particular, neoplasia, glucose intolerance and hypothyroidism), as well as height standard deviation score (Ht SDS) and annual height velocity. The results of the interim analysis of a 5-year accumulated data for 2,024 patients (7,342 patient-years, PY) are presented.ResultsA total of 14 neoplasms were diagnosed (191/100,000 PY); 7 out of 9 malignancies were recurrent craniopharyngioma found in patients with organic GHD. Seven cases of glucose intolerance (95/100,000 PY) and 22 cases of hypothyroidism (300/100,000 PY) were detected; about half of the cases (4 and 10 cases each) were considered to be related with rhGH treatment. Most of the growth-retarded patients showed continuous improvement in Ht SDS, with the most prominent effect observed within a year of treatment initiation. The beneficial effect of rhGH on Ht SDS gain was maintained for 2–4 years.ConclusionsThe incidence of AEs of interest in rhGH-treated patients was low, and most of the neoplasms were benign and/or non-related to rhGH. Most patients benefited from the therapy in terms of height increment.

MON-248 Impact of Body Mass Index on Peak Growth Hormone Response to Provocative Testing and Therapeutic Outcome in Children with Growth Hormone Deficiency

Introduction: The growth hormone (GH) stimulation test can be influenced by various factors, including type of GH stimuli, age, body mass index (BMI), and pubertal state. It is known that GH secretion is inversely related to BMI, but there is no available BMI - specific cut off value in children with growth hormone deficiency (GHD). The purpose of the study was to evaluate the therapeutic response according to obesity and relationship between GH secretion and BMI in children with GHD Methods: Among the GHD patients met the inclusion criteria, 460 patients conducted insulin stimulation test in common were enrolled for this study. Of these, the group were divided into idiopathic GHD (n=439), organic GHD (n=21), complete GHD (n=114), and partial GHD (n=325). We compared the variables including age, peak GH level, bone age, height standard deviation score (SDS), BMI SDS, and insulin-like growth factor-1 (IGF-1) SDS of each group. Results: Of the 439 patients with idiopathic GHD, 385 patients were normal (88%), 28 patients were overweight (6%), and 26 patients were obese (6%). The peak GH for the insulin stimulation test was 4.7 in obese group and 5.1 in non-obese group. The peak GH in organic GHD was 1.6 for obesity and 3.1 for non-obese group. According to the multiple regression analysis, the peak GH was significantly reduced by 1.06 as BMI SDS was increased by 1 in patients with complete GHD (p=0.03). The cutoff value of complete GHD in obese children was lower than that of non-obese group [response to insulin: obese group ≤ 4.7 (area under the curve AUC= 0.87, 95% CI 0.7-1.0), non-obese group ≤ 4.92 (AUC= 0.83, 95% CI 0.80-0.87); response to L-dopa: obese group ≤ 4.3 (AUC= 0.90, 95% CI 0.76-1.0), non-obese group ≤ 4.9 (AUC= 0.83, 95% CI 0.79-0.87)]. IGF-1 SDS and height SD at initiation of GH therapy of obese group were higher than those of non-obese group, but the height gain during GH therapy between two groups was similar. Regardless of obesity, therapeutic response of the first year of GH therapy was better than the second year of treatment. Conclusion: The BMI and GH peak of obese children with GHD shows inverse correlation, with a relatively low cutoff value. Further comparative research to better understand of the relationship between BMI and GH secretion with simple obese children is needed to expand clinical application.

SUN-256 Limited Usefulness of Single IGF-I Measurement as a Screening Test for Growth Hormone Deficiency in Children and Adolescents

Introduction: IGF-I measurement has been proposed as a screening tool for the diagnosis of Growth Hormone Deficiency (GHD). However, few studies evaluated the accuracy of IGF-I measurement as a screening test and the results have been controversial. Objective: To evaluate the value of a single IGF-I measurement as screening test in the diagnosis of GHD in short children and adolescents. Patients and Methods: 439 short children (median-IQR age 10.5 (7.1-12.8) y, 273 boys), were included in this retrospective analysis. The patient group consisted of 102 subjects (54 boys) with GHD (peak GH <7.0 μg/L after two provocative tests with Arginine, Insuline Tolerance Test, and Clonidine), 60 of whom had GHD of organic or genetic origin (OGHD) and 42 were idiopathic (IGHD). The 337 subjects with a GH peak ≥7 μg/L and no other recognizable cause for their shortness were considered as controls. All provocative tests were performed between 8.00 and 9.00 am after fasting overnight, without steroid priming. GH and IGF-I were measured by the same chemiluminescence assay in all samples (Immulite, Siemens). Receiver operating characteristic (ROC) analysis was used to evaluate the optimal IGF-I cut-offs and the diagnostic accuracy of IGF-I. The analysis was repeated including only 67 patients with severe GHD (SGHD, peak GH <5.0 μg/L after two provocative tests): 54 organic/genetic (SOGHD) and 18 idiopathic (SIGHD). Results: IGF-I SDS was significantly lower in patients than in controls (-2 (-2.9 - -1.7), -1 (-1.8 - -0.1), respectively, p<0.0001). IGF-I SDS ≥ -2 was found in 42% and 69% of OGHD and IGHD patients, respectively. The Area Under the Curve (AUC, measure of discriminative ability of the test) of IGF-I SDS was 0.73. The IGF-I SDS cut-off of -2 had 50% sensitivity (Se), 80% specificity (Sp), 2.4 likelihood ratio for positive test results (LR+), and 74% diagnostic efficiency (Ef). The best pair of values for Se and Sp was found at IGF-I SDS cut-off of -1.8 (B cut-off, Se 60%, Sp 75%, LR+ 2.3, Ef 71%). For OGHD, AUC was 0.82. For cut-off -2 SDS: Se 60%, Sp 80%, LR+ 3, Ef 80%. B cut-off was -1.9 SDS (Se 68%, Sp 78%, LR+ 3.1, EF 77%). For IGHD, AUC was 0.61. For cut-off -2 SDS: Se 36%, Sp 79%, LR+ 1.7, Ef 77%. B cut-off was -1.4 SDS (Se 52%, Sp 65%, LR+ 1.5, Ef 64%). The results were similar when only patients with SGHD were analysed. Among them, 42% had IGF-I SDS ≥ -2. IGF-I SDS ≥ -2 was found in 41% of SOGHD and in 67% of SIGHD. Conclusions: In our large cohort of short children, IGF-I measurement has shown suboptimal accuracy in discriminating GHD from non-GHD patients. The accuracy is better for patients with organic or genetic GHD. IGF-I values should be interpreted in combination with other clinical and biochemical parameters, and cannot be used alone as a screening tool.

Safety Outcomes During Pediatric GH Therapy: Final Results From the Prospective GeNeSIS Observational Program.

ContextSafety concerns have been raised regarding premature mortality, diabetes, neoplasia, and cerebrovascular disease in association with GH therapy.ObjectiveTo assess incidence of key safety outcomes.DesignProspective, multinational, observational study (1999 to 2015).SettingA total of 22,311 GH-treated children from 827 investigative sites in 30 countries.PatientsChildren with growth disorders.InterventionsGH treatment.Main outcome measuresStandardized mortality ratio (SMR) and standardized incidence ratio (SIR) with 95% CIs for mortality, diabetes, and primary cancer using general population registries.ResultsPredominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean ± SD follow-up of 4.2 ± 3.2 years (∼92,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with an SMR (95% CI) of 0.61 (0.44, 0.82); the SMR was elevated for patients with cancer-related organic GH deficiency [5.87 (3.21, 9.85)]. Based on 18 cases, type 2 diabetes mellitus (T2DM) risk was elevated [SIR: 3.77 (2.24, 5.96)], but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed [SIR: 0.71 (0.39, 1.20)]. Second neoplasms occurred in 31 of 622 cancer survivors [5.0%; 10.7 (7.5, 15.2) cases/1000 PY] and intracranial tumor recurrences in 67 of 823 tumor survivors [8.1%; 16.9 (13.3, 21.5) cases/1000 PY]. All three hemorrhagic stroke cases had risk factors.ConclusionsGeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study) data support the favorable safety profile of pediatric GH treatment. Overall risk of death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared with the general population, but most cases had diabetes risk factors.

Growth hormone treatment of Canadian children: results from the GeNeSIS phase IV prospective observational study.

Country-specific data on outcomes of treatment with recombinant human growth hormone are lacking. We present such data for children treated with growth hormone in Canada. We describe characteristics and outcomes of 850 children (mean age at baseline 8.5 yr) treated with growth hormone constituting the Canadian cohort of the multinational phase IV prospective observational Genetics and Neuroendocrinology of Short-stature International Study (GeNeSIS). The diagnosis associated with short stature was as determined by the investigator. Auxological data were evaluated yearly until near-adult height. Adverse events were assessed in all growth-hormone-treated patients. The diagnosis ascribed as the cause of short stature was growth hormone deficiency in 526 children (61.9%), predominantly organic rather than idiopathic, particularly congenital pituitary abnormalities and intracranial tumours. All diagnostic groups with sufficient patients for analysis had increased height velocity standard deviation score (SDS) and height SDS during growth hormone treatment. For patients who reached near-adult height (n = 293), the mean height SDS was within the normal range for about 80% of patients with organic growth hormone deficiency (n = 131) or idiopathic growth hormone deficiency (n = 50), 50% of patients with idiopathic short stature (n = 10) and 46% of patients with Turner syndrome (n = 79). Eleven deaths were reported, 7 in patients with organic growth hormone deficiency. Serious adverse events considered related to growth hormone treatment (n = 19) were isolated except for medulloblastoma recurrence (n = 2) and adenoidal hypertrophy (n = 2). Growth hormone treatment was effective and had a good safety profile in Canadian children. Growth hormone dosages were lower than in the US and global GeNeSIS cohorts, and a greater proportion of treated Canadian children had organic growth hormone deficiency. ClinicalTrials.gov, no. NCT01088412.

Cut-off limits of the peak GH response to stimulation tests for the diagnosis of GH deficiency in children and adolescents: study in patients with organic GHD.

The diagnosis of GH deficiency (GHD) in children and adolescents is established when GH concentrations fail to reach an arbitrary cut-off level after at least two provocative tests. The objective of the study was to define the optimal GH cut-offs to provocative tests in children and adolescents. Retrospective study in 372 subjects who underwent evaluation of GH secretion. GH and IGF-I were measured by chemiluminescence assay in all samples. Receiver operating characteristic (ROC) analysis was used to evaluate the optimal GH cut-offs and the diagnostic accuracy of provocative tests. Seventy four patients with organic GHD (GH peak <10μg/L after two provocative tests) and 298 control subjects (GH response >10μg/L to at least one test) were included in the study. The provocative tests used were arginine, insulin tolerance test (ITT) and clonidine. Diagnostic criteria based on cut-offs identified by ROC analysis (best pair of values for sensitivity and specificity) were evaluated for each test individually and for each test combined with IGF-I SDS. The optimal GH cut-off for arginine resulted 6.5μg/L, 5.1μg/L for ITT and 6.8μg/L for clonidine. IGF-I SDS has low accuracy in diagnosing GHD (AUC=0.85). The combination of the results of provocative tests with IGF-I concentrations increased the specificity. The results of the ROC analysis showed that the cut-off limits which discriminate between normal and GHD are lower than those commonly employed. IGF-I is characterized by low diagnostic accuracy.

Efficacy and safety of growth hormone treatment in children with short stature: the Italian cohort of the GeNeSIS clinical study.

PurposeWe examined auxological changes in growth hormone (GH)-treated children in Italy using data from the Italian cohort of the multinational observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) of pediatric patients requiring GH treatment.MethodsWe studied 711 children (median baseline age 9.6 years). Diagnosis associated with short stature was as determined by the investigator. Height standard deviation score (SDS) was evaluated yearly until final or near-final height (n = 78). Adverse events were assessed in all GH-treated patients.ResultsThe diagnosis resulting in GH treatment was GH deficiency (GHD) in 85.5 % of patients, followed by Turner syndrome (TS 6.6 %). Median starting GH dose was higher in patients with TS (0.30 mg/kg/week) than patients with GHD (0.23 mg/kg/week). Median (interquartile range) GH treatment duration was 2.6 (0.6–3.7) years. Mean (95 % confidence interval) final height SDS gain was 2.00 (1.27–2.73) for patients with organic GHD (n = 18) and 1.19 (0.97–1.40) for patients with idiopathic GHD (n = 41), but lower for patients with TS, 0.37 (−0.03 to 0.77, n = 13). Final height SDS was >−2 for 94 % of organic GHD, 88 % of idiopathic GHD and 62 % of TS patients. Mean age at GH start was lower for organic GHD patients, and treatment duration was longer than for other groups, resulting in greater mean final height gain. GH-related adverse events occurred mainly in patients diagnosed with idiopathic GHD.ConclusionsData from the Italian cohort of GeNeSIS showed auxological changes and safety of GH therapy consistent with results from international surveillance databases.

Association between Decreased Klotho Blood Levels and Organic Growth Hormone Deficiency in Children with Growth Impairment

ObjectiveKlotho is an aging-modulating protein expressed mainly in the kidneys and choroid plexus, which can also be shed, released into the circulation and act as a hormone. Klotho deficient mice are smaller compared to their wild-type counterparts and their somatotropes show marked atrophy and reduced number of secretory granules. Recent data also indicated an association between klotho levels and growth hormone (GH) levels in acromegaly. We aimed to study the association between klotho levels and GH deficiency (GHD) in children with growth impairment.DesignProspective study comprising 99 children and adolescents (aged 9.0±3.7 years, 49 male) undergoing GH stimulation tests for short stature (height-SDS = −2.1±0.6). Klotho serum levels were measured using an α-klotho ELISA kit.ResultsKlotho levels were significantly lower (p<0.001) among children with organic GHD (n = 11, 727±273 pg/ml) compared to both GH sufficient participants (n = 59, 1497±754 pg/ml) and those with idiopathic GHD (n = 29, 1645±778 pg/ml). The difference between GHS children and children with idiopathic GHD was not significant. Klotho levels positively correlated with IGF-1- standard deviation scores (SDS) (R = 0.45, p<0.001), but were not associated with gender, pubertal status, age or anthropometric measurements.ConclusionsWe have shown, for the first time, an association between low serum klotho levels and organic GHD. If validated by additional studies, serum klotho may serve as novel biomarker of organic GHD.

Ocena wyników leczenia hormonem wzrostu polskich pacjentów z idiopatycznym niedoborem hormonu wzrostu (IGHD) i niedoborem hormonu wzrostu z współistniejącymi zmianami organicznymi (OG HD) w wieku przedpokwitaniowym – na podstawie bazy danych KIGS

Ocena wyników leczenia hormonem wzrostu polskich pacjentów z idiopatycznym niedoborem hormonu wzrostu (IGHD) i niedoborem hormonu wzrostu z współistniejącymi zmianami organicznymi (OG HD) w wieku przedpokwitaniowym – na podstawie bazy danych KIGS

Changes in BMI and Management of Patients with Childhood Onset Growth Hormone Deficiency in the Transition Phase

We aimed at evaluating BMI changes during GH therapy pause, to assess the transfer pattern between children and adult medical services in our clinic and to confirm the previous growth hormone deficiency (GHD) diagnosis. Retrospective cohort study. We identified 75 transition patients (age at first visit <25 years) with pituitary deficiency (ICD-10:E.23) and GHD referred to our clinic between 2000-2009. Out of 75 patients with GHD (45 males, 30 females), 20 subjects suffered from an idiopathic GHD (iGHD) and 55 from an organic GHD (oGHD). During the GH therapy pause (26.4±34.8 months), we observed a significant BMI increase (23.6±4.4 to 27.1±7.2, p=0.02). Most males with iGHD discontinued endocrinologic control and GH substitution completely (5 patients out of 20) or after the first contact (3 patients out of 20). Most females with GHD continued medical control after transferral (22 patients). We retested 34/75 patients with GHD (45.3%). The preferred test was the growth hormone-releasing hormone-arginine (GHRH-arginine) (20/34 patients, 58.9%), followed by the insulin hypoglycemia test (IHT) alone (9 patients). 4 patients received both, the GHRH-arginine and the IHT. Seven retested patients with iGHD (63.6%) and all oGHD retested patients were still deficient. Our results provide information on negative effects of the discontinuation of GH treatment during the transition phase and should help to improve the compliance with treatment in this group of patients. Paediatric and adult endocrinologists participating together in a transition programme should emphasize on the positive effect of GH substitution in adulthood. Efforts should be made to particularly improve the transferral of male adolescents with iGHD, since they seem to escape medical care.

Response to growth hormone therapy in Indian patients

To analyse response to growth hormone therapy on Indian patients with short stature. Data were collected on 71 patients of short stature on GHT. All patients underwent clinical and hormonal evaluation. GHD was diagnosed in the presence of short stature (height SDS < 2) and peak GH levels < 10 ng/ml. Bone age was estimated using Tanner Whitehouse 3 method (TW3). Primary GHD (73%) was the commonest diagnosis among patients on GHT, followed by organic GHD (12.6%), genetic syndromes (8.4%) and systemic diseases (5.4%). Mean chronological age at presentation was 10.07+/-3.26 years (median-11 years, range 3-15 years), mean height age was 6.98+/-2.82 years (median 7.5 years, range 1-13 years) and mean bone age (available for 55 patients) was 7.19+/-3.1 years (median 8.2 years, range 1.3-13 years). Patients with systemic diseases (6.75+/-3.5 years) presented earlier, compared to patients with GHD (10.27+/-3.16 years) and genetic syndromes (10.18+/-3.20 years) (p=0.349). Most of the patients on GHT were in the age group 9-15 years (60.6%). Mean height gain with GHT was 8.7+/-2.7 cm (median 8.3 cm, range 3.0-13 cm) during 1st year then decreased to 6.9+/-2.4 cm (median 7.0 cm, range 3.0-12.5 cm) in the second year, and was maintained through the third year (mean 7.1+/-3.0 cm, median 7.0, range 3.0-13 cm). Among patients with GHD, those with primary deficiency had significantly better response to GHT in 1st year than secondary deficiency (9.0+/-2.65 vs 6.8+/-3.03 cm, p = 0.026). Response to GHT was negatively correlated with CA (r-0.27, p = 0.05), HA (r-0.47, p = 0.027) and BA (r-0.31, p=0.022) at presentation. Four patients (5.6%) developed hypothyroidism and one patient each developed disseminated tuberculosis and rickets. One patient of Turner's syndrome died of adrenal carcinoma. Short follow up and absence of measurement of IGF-1 and IGFBP3 were major limitations of this study. Response to GHT in Indian patients is comparable to western counterparts. Maximum height gain on GHT is during the first year than decreases in second year, but is maintained through third year. Patients with primary GHD had better response than secondary GHD. Response to GHT is negatively correlated with chronological, height and bone age at presentation.

Long-Term Safety of Recombinant Human Growth Hormone in Children

Between 1985 and 2006, the National Cooperative Growth Study (NCGS) monitored the safety and efficacy of recombinant human growth hormone (rhGH) in 54,996 children. Enrolled patients were followed until rhGH discontinuation. Investigators submitted adverse event reports for targeted events or those potentially rhGH-related. Early concerns about de novo leukemia in patients without risk factors have not been substantiated--three observed vs. 5.6 expected in age-matched general population based on years at risk [standard incidence ratio (SIR), 0.54; 95% confidence interval (CI), 0.11-1.58]. De novo malignancies (intracranial and extracranial) were not significantly increased in patients without risk factors (29 confirmed vs. 26 expected; SIR, 1.12; 95% CI, 0.75-1.61). Second neoplasms occurred in 49 patients, of whom 37 had irradiation for their initial tumors (including five of 16 retinoblastoma patients, three of whom had bilateral retinoblastoma) consistent with an increased risk with rhGH. Thirty-three patients developed type 1 diabetes mellitus (DM) (37 expected; SIR, 0.90; 95% CI, 0.62-1.26). Type 2 DM and nonspecified DM were reported in 20 and eight patients, respectively. Two deaths were reported in patients with Prader-Willi syndrome and five deaths from aortic dissection in patients with Turner syndrome. In patients with organic GH deficiency and idiopathic panhypopituitarism, 11 events of acute adrenal insufficiency occurred, including four deaths, consistent with a reported increased risk for adrenal insufficiency in hypopituitary patients with or without rhGH treatment. After more than 20 yr, leukemia, a major safety issue initially believed associated with GH, has not been confirmed, but other signals, including risk of second malignancies in patients previously treated with irradiation, have been detected or confirmed through the NCGS. These data further clarify the events associated with rhGH and, although confirming a favorable overall safety profile, they also highlight specific populations at potential risk.