IGF-I Standard Deviation Score Research Articles

THU073 Somapacitan Administered Subcutaneously At 5 mg/1.5 mL Or 10 mg/1.5 mL Strengths Yields Clinically Similar PK And IGF-I Profiles In Healthy Participants

Abstract Disclosure: M. Højby Rasmussen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. R.J. Kildemoes: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. C. Sværke: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. Background: Somapacitan is a once-weekly long-acting GH for treatment of AGHD. Objectives: To confirm bioequivalence of sc somapacitan 5 mg/1.5 mL and 10 mg/1.5 mL strengths in equimolar doses of 0.04 mg/kg body weight and investigate pharmacokinetic/pharmacodynamic (PK/PD) properties of the two strengths. Methods: A randomized, double-blind, single-dose, three-period crossover trial. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) bioequivalence guidelines require area under the curve (AUC0-t) and maximum serum concentration (Cmax) to be identical within predefined limits. The 10 mg/1.5 mL strength (reference treatment) was administered in two separate treatment periods. Healthy participants (full analysis set n=32; 5 females; 31 White, 1 Black; mean age 35.1 years; mean BMI 22.8 kg/m2) were randomized to receive treatment in one of three sequences. Each participant attended three in-house 5-day dosing and PK/PD sampling visits, each followed by daily PK/PD sampling visits for 3 days after each dosing visit and again 1 week later, and finally an end-of-trial visit. Dosing visits were separated by 3 weeks’ washout. Results: For AUC0-t, treatment ratio (5 mg/1.5 mL vs 10 mg/1.5 mL) was 0.95 [90% CI 0.89;1.01]. Point estimate and 90% CIs were within the acceptance range [0.80;1.25]; bioequivalence criterion for AUC was met. For Cmax, treatment ratio was 0.77 [0.68;0.89]. Point estimate was outside [0.80;1.25] and the 90% CI was outside the widened acceptance range [0.70;1.43], defined in line with the EMA guideline on bioequivalence due to within-subject variability of Cmax; EMA and FDA bioequivalence criteria for Cmax were not met. Treatment ratios of AUC0-168 h and AUC0-∞ were 0.93 [0.84;1.02] and 0.95 [0.89;1.01], respectively. Geometric mean value of t½ was comparable for somapacitan 5 mg/1.5 mL (52.7 hours) and reference treatment periods (53.9 and 50.5 hours). Median tmax values were 10 hours (5 mg/1.5 mL) and 8 hours (both reference treatment periods). Mean IGF-I and IGF-I standard deviation score (SDS) concentration-time curves for the two strengths were almost identical. Treatment ratio of AUCIGF-I, 0-168 h was 1.00 [90% CI 0.98;1.02]. Median tmax, IGF-I values for the two strengths were identical. Geometric mean value of Cmax, IGF-I for 5 mg/1.5 mL was similar to that for somapacitan 10 mg/1.5 mL. The two somapacitan strengths showed similar safety profiles, with no new safety issues identified. Conclusion: Bioequivalence criterion for somapacitan 5 mg/1.5 mL and 10 mg/1.5 mL was met for AUC0-t but not for Cmax. Treatment ratios of AUC0-168 h and AUC0-∞ were similar to those of AUC0-t. Concentration-time curves of IGF-I and IGF-I SDS for the two strengths were almost identical. Observed difference in Cmax was not considered clinically significant; 5 mg/1.5 mL and 10 mg/1.5 mL were equivalent from a clinical perspective, and have been approved by authorities. Presentation: Thursday, June 15, 2023

THU170 Clinical And Immunological Response To Somatrogon In Two Siblings With A Homozygous Whole Gene Deletion Of The Growth Hormone 1 Gene

Abstract Disclosure: R. Gupta: None. R. Khadgawat: None. R.G. Rosenfeld: Advisory Board Member; Self; Lumos, DNARx, BioMarin. Consulting Fee; Self; OPKO Health. M.T. Dattani: Advisory Board Member; Self; Ferring Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sandoz. Consulting Fee; Self; Ipsen, Novo Nordisk, Pfizer, Inc. Speaker; Self; Pfizer, Inc., Novo Nordisk, Sandoz, Ipsen. L. Dyer: Employee; Self; GeneDx. B. Friedman: Employee; Self; GeneDx. J. Korth-Bradley: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. M. Nijher: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C.L. Roland: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C.T. Taylor: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J.F. Cara: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J. Hsiao: Employee; Self; OPKO Health. Stock Owner; Self; OPKO Health. M.P. Wajnrajch: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. Introduction: Somatrogon, a long-acting recombinant human growth hormone (LAGH), is approved in multiple countries as a once-weekly treatment for pediatric growth hormone deficiency (GHD). A global Phase 3 study in pediatric subjects with GHD compared the efficacy and safety of once-weekly somatrogon (0.66 mg/kg/wk) vs once-daily Genotropin® (0.24 mg/kg/wk) in a 12-mo main study, followed by an open-label extension (OLE) where all subjects received somatrogon (0.66 mg/kg/wk). Results: Subjects #1 (male; 6 y) and #2 (female; 9 y) are siblings from India randomized in the main study to somatrogon and Genotropin, respectively. Both had severe growth and weight attenuation at baseline, with peak GH levels (GH stimulation test) of 0.1 ng/ml; their IGF-1 standard deviation scores (SDS) were -3.96 and -3.94, respectively. At main study Mo 12, subject #1 had an annual height velocity (HV) of 11.77 cm/year (height SDS improved from -7.48 to -6.4) and IGF-I SDS increased to -1.84. After a 116-day drug holiday (started at the end of main study Mo 12), he continued into the OLE; at OLE Mo 9, his HV decreased to 3.08 cm/y, there was no additional improvement in height SDS (-6.76) and his IGF-1 SDS was -2.31. A test for anti-drug antibodies (ADAs) to somatrogon was positive at main study Mo 6; tests for ADAs, and neutralizing antibodies (NAbs) were positive at Mo 12. At OLE ∼Mo 1 and 3, tests were ADA+ and NAb-; at OLE Mo 6 and 9, tests were ADA-. At main study Mo 12, subject #2 had an annual HV of 11.87 cm/year (height SDS improved from -9.93 to -7.36); IGF-I SDS increased to -2.97. After a 123-day drug holiday, she switched to somatrogon during the OLE (per protocol) and had an HV of 10.01 cm/y and IGF-1 SDS of -1.83 at OLE Mo 9. Low titer ADAs to human GH were detected during the drug holidays. In the OLE, anti-GH ADAs were still detected, but at very low titers and tests were NAb−. Whole exome sequencing revealed a homozygous whole gene deletion of the GH1 gene in both siblings. Both completed the main study and OLE without any serious adverse events or dose reductions. Conclusions: Both siblings have classic congenital isolated GHD due to a homozygous GH1 deletion. Development of anti-GH ADAs and growth attenuation during GH therapy are likely due to lack of exposure to GH during fetal life followed by exposure to exogenous GH. The variability in antibody production and heterogeneity in clinical responsiveness to GH replacement has been well described, even in siblings,1 and if encountered in clinical practice, should prompt clinicians to consider the possibility of a GH1 deletion. To our knowledge, this is the first description of GH1 deletions in LAGH-treated subjects and the study findings are wholly consistent with those for daily GH products. Clinicaltrials.gov: NCT02968004 Reference: Ghosh et al. J Clin Res Pediatr Endocrinol 2021;13:456-60. Acknowledgements: The authors wish to thank all the investigators involved in this study. Presentation: Thursday, June 15, 2023

Long-term Effectiveness and Safety of GH Replacement Therapy in Adults ≥60 Years: Data From NordiNet® IOS and ANSWER.

Effectiveness and safety data on GH replacement therapy (GHRT) in older adults with adult GH deficiency (AGHD) are limited. To compare GHRT safety and clinical outcomes in older (≥60 years and, for some outcomes, ≥75 years) and middle-aged (35-<60 years) patients with AGHD. Ten-year follow-up, real-world data from 2 large noninterventional studies-NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program-were analyzed. GH-naïve and non-naïve patients with AGHD. Norditropin® (somatropin). Outcomes included GH exposure, IGF-I standard deviation scores (SDS), body mass index (BMI), glycated hemoglobin (HbA1c), serious and nonserious adverse reactions (SARs and NSARs, respectively), and serious adverse events (SAEs). Adverse reactions were events with possible/probable causal relationship to GHRT. The effectiveness analysis set comprised 545 middle-aged and 214 older patients (19 aged ≥75 years) from NordiNet® IOS. The full analysis set comprised 1696 middle-aged and 652 older patients (59 aged ≥75 years) from both studies. Mean GH doses were higher in middle-aged vs older patients. For both age groups and sexes, mean IGF-I SDS increased following GHRT, while BMI and HbA1c changes were similar and small.Incidence rate ratios (IRRs) did not differ statistically between older and middle-aged patients for NSARs [IRR (mean, 95% confidence interval) 1.05 (.60; 1.83)] or SARs [.40 (.12; 1.32)]. SAEs were more frequent in older than middle-aged patients [IRR 1.84 (1.29; 2.62)]. Clinical outcomes of GHRT in AGHD were similar in middle-aged and older patients, with no significantly increased risk of GHRT-related adverse reactions in older patients.

Reference values for IGF-I serum concentration in an adult population: use of the VARIETE cohort for two new immunoassays.

ObjectiveMeasurement of IGF-I is important in the management of patients with growth hormone disorders. Here we aim to establish normative data for two new IGF-I assay kits based on a large random sample of the French general adult population.Subjects and methodsWe measured IGF-I in 911 healthy adults (18–90 years) with two immunoassays (ROCHE Elecsys® and IMMULITE-2000 calibrated against the new IS 02/2547). We compared the data with those of the six immunoassays (iSYS, LIAISON XL, IMMULITE-2000 calibrated against the first IS 87/518, IGF-I RIACT, Mediagnost ELISA, and Mediagnost RIA) that we reported previously. The pairwise concordance among the eight assays was assessed with Bland–Altman plots for both the IGF-1 raw data and the standard deviation scores (SDS), as well as with the percentage of observed agreement and the weighted Kappa coefficient for categorizing IGF-I SDS (ClinicalTrials.gov Identifier: NCT01831648).ResultsThe normative data included the range of values (2.5–97.5 percentiles) given by the two new IGF-I assays according to age group and sex. A formula for the SDS calculation is provided. As for the previous six assays, the lower limits of the reference intervals of the two new assays were similar, but the upper limits varied markedly. The pairwise concordances were only moderate (kappa 0.57).ConclusionsData obtained for these two new IGF-I immunoassays confirm that despite being obtained in the same large healthy population, the reference intervals of the eight commercial IGF-1 assay kits showed noteworthy differences. The agreement among the various methods was moderate to good.

High Prevalence of Nonalcoholic Fatty Liver Disease Among Adolescents and Young Adults With Hypopituitarism due to Growth Hormone Deficiency

ObjectiveTo investigate the prevalence of nonalcoholic fatty liver disease (NAFLD) in adolescents and young adults with hypopituitarism and to examine the associations of growth hormone (GH) deficiency with the occurrence of NAFLD. MethodsA cross-sectional study for the determination of NAFLD prevalence included 76 patients with childhood-onset hypopituitarism and 74 controls matched by age and body mass index (BMI). We investigated the prevalence of NAFLD in adolescent and young adult patients with hypopituitarism as well as the age- and BMI-matched controls. Among patients with hypopituitarism, anthropometric, clinical, and biochemical assessments using transient elastography and magnetic resonance imaging were performed. Logistic regression was used to identify the factors associated with NAFLD. ResultsThe adolescents and young adults with hypopituitarism exhibited higher prevalence of NAFLD than the age- and BMI-matched controls. Among patients with hypopituitarism, obesity and obesity-related metabolic derangements were significantly associated with liver steatosis and fibrosis, whereas lower insulin-like growth factor (IGF)-I standard deviation score (SDS) and IGF-I/IGF-binding protein 3 molar ratios were associated with steatosis. In regression analyses adjusted for BMI SDS, steatosis was found to be associated with a lower IGF-I SDS and IGF-I/IGF-binding protein 3 molar ratios, whereas liver fibrosis was found to be associated with a lower IGF-I SDS. ConclusionOur results suggest that GH deficiency contributes to the occurrence of NAFLD, along with obesity and obesity-related metabolic changes. Because NAFLD occurs early in patients with hypopituitarism, the surveillance, weight control, and timely replacement of deficit hormones, including GH, are essential.

Ten years with biosimilar rhGH in clinical practice in Sweden \u2013 experience from the prospective PATRO children and adult studies

BackgroundIn 2007, Omnitrope® was the first biosimilar recombinant human growth hormone (rhGH) to be approved in Sweden for treatment in adults and children. Over 10 years’ safety and effectiveness data for biosimilar rhGH can now be presented.MethodsPATRO Children and PATRO Adults are multicenter, longitudinal, observational, post-marketing surveillance studies. Eligible patients include children 0–18 years and adults receiving biosimilar rhGH treatment. Adverse events (AEs) are monitored for safety evaluation. Growth variables in children and metabolic data in adults are recorded for effectiveness evaluation.ResultsAs of January 2019, data from 136 children (48% male) were reported from Swedish centers. Mean age in rhGH treatment-naïve patients at study entry (n = 114) was 7.5 years, with mean 3.6 years treatment duration. No severe AEs of diabetes, impaired glucose tolerance, or malignancy were reported. The most frequently reported AE was nasopharyngitis (n = 16 patients). No clinically relevant anti-hGH or neutralizing antibodies were observed. The mean change from baseline in height standard deviation score (SDS) in naïve prepubertal GH deficiency patients was + 0.79 at 1 year, + 1.27 at 2 years, and + 1.55 at 3 years. Data from 293 adults (44% rhGH-naïve, 51% male) were included. Fatigue was the most frequently reported AE (n = 26 patients). The incidence of new neoplasms or existing neoplasm progression was 23.8 patients per 1000 patient-years. Type 2 diabetes mellitus was reported in four patients. At baseline in rhGH-naïve adults, mean (SD) body mass index (BMI) was 29.1 (5.6) kg/m2 and mean (SD) insulin-like growth factor (IGF)-I SDS was − 3.0 (1.4). Mean daily dose increased from 0.1 mg at baseline to 0.3 mg after 4 years. IGF-I SDS normalized during the first year of treatment. Mean BMI and glucose were unchanged over 4 years, while low−/high-density lipoprotein cholesterol ratio decreased.ConclusionsFor the first time, Swedish data from the PATRO Children and Adults studies are presented. The 10-year data suggest that biosimilar rhGH is well tolerated across pediatric and adult indications. Safety and effectiveness were similar to previous reports for other rhGH preparations. These results need to be confirmed in larger cohorts, highlighting the importance of long-term post-marketing studies.

SUN-247 Once-Weekly Somapacitan in Childhood Growth Hormone Deficiency: Efficacy and Safety Results of a Randomized, Open-Label, Controlled Phase 2 Trial (REAL 3)

Background: Growth hormone deficiency (GHD) requires long-term daily injections with GH replacement therapy and is associated with considerable treatment burden. Somapacitan is a long-acting GH derivative being developed for once-weekly dosing in adults and children with GHD. A well-established protraction method, successfully used to extend the half-life of insulin and glucagon-like peptide (GLP)-1, has been applied in developing somapacitan: an albumin-binding moiety (1.3 kDa) is attached to a single amino acid substitution in the GH molecule (22 kDa). Objective: To evaluate the efficacy, safety, and tolerability of three once-weekly somapacitan doses, compared with Norditropin®, a daily GH. Methods: This multicenter, open-label, randomized, controlled phase 2 study (ClinicalTrials.gov: NCT02616562) was double-blind with regard to dose levels of somapacitan, and height assessors were blinded to treatment. GH-treatment-naïve prepubertal children with GHD were randomized to somapacitan (N=45) or Norditropin® (N=14). Patients received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/wk (n=14) subcutaneous (sc) somapacitan once weekly, or sc Norditropin® 0.034 mg/kg/day (0.24 mg/kg/wk; n=14). Patients completed 6 months of treatment as follows: somapacitan 0.04 (n=14), 0.08 (n=15) and 0.16 (n=14) mg/kg/wk, and Norditropin® 0.034 mg/kg/day (n=13). Results: At 6 months, mean (SD) annualized height velocity (HV, cm/year) for the three somapacitan doses was 8.0 (2.0), 10.9 (1.9) and 12.9 (3.5), respectively. HV for the 0.08 and 0.16 mg/kg/wk doses did not differ significantly from HV with Norditropin® (11.4 [3.3]). Insulin-like growth factor (IGF)-I increased dose-dependently: change from baseline in IGF-I standard deviation score (SDS) was 1.08, 2.15 and 3.21 for the somapacitan groups, respectively, when measured at peak of the IGF-I profile over the dosing interval, and 2.03 for Norditropin®. Modeling yielded IGF-I SDS average over the dosing interval for the somapacitan 0.16 mg/kg/wk group that was similar to observed values for Norditropin®. Adverse events were mild-to-moderate and most were evaluated as unrelated to treatment by the investigator. One patient had persistent anti-hGH antibodies of low titer and three patients had a single positive measurement of anti-somapacitan antibodies of low titer. All antibody positive samples were negative for in vitro neutralizing antibodies. There were no clinically relevant changes from baseline to Week 26 in any treatment group in mean HbA1c, fasting glucose or insulin. Tolerability was consistent with known properties of GH. Conclusion: In children with GHD, the efficacy, safety and tolerability of once-weekly somapacitan was similar to that of daily Norditropin®. Results from this phase 2 trial provide support for the initiation of a phase 3 trial of somapacitan in children with GHD.

Sequential measurements of IGF-I serum concentrations in adolescents with Laron syndrome treated with recombinant human IGF-I (rhIGF-I).

Background Recombinant human insulin-like growth factor 1 (rhIGF-I) has been approved as an orphan drug for the treatment of growth failure in children and adolescents with severe primary IGF-I deficiency (SPIGFD) with little pharmacokinetic data available. Therefore, sequential measurements of serum IGF-I, glucose, potassium, insulin and cortisol were performed in patients treated with rhIGF-I to evaluate their significance in safety and efficacy. Methods Repetitive blood samples were taken after meals before and 30, 60, 120, 180 and 360 min after rhIGF-I injections in two male patients with Laron syndrome at times of dose adjustments. Results Maximal IGF-I concentrations were observed 2 h after injections (495 ng/mL) and concentrations were still higher 6 h after injections than at baseline (303 ng/mL vs. 137 ng/mL). Thirteen percent of all and 33% of maximum IGF-I concentrations were greater than +2 standard deviation score (SDS) calculated for bone age (BA) (IGF-I SDS BA) rather than chronological age (CA) as BA was significantly delayed to CA by 3.2 years (p=0.0007). Height velocities correlated with individual maximum IGF-I SDS BA (ρ=0.735; p<0.0001). Serum insulin, cortisol and glucose did not correlate with IGF-I concentrations, but serum potassium showed a negative correlation (ρ=-0.364; p<0.0001) with IGF-I concentrations. Conclusions Sequential measurements of serum IGF-I, glucose and potassium in patients with Laron syndrome may aid in optimizing and individualizing rhIGF-I treatment. IGF-I concentrations should be referenced according to BA which better reflects the biological age. The inverse correlation of IGF-I and serum potassium concentrations after injections of rhIGF-I has not been reported before and warrants further consideration.

Factors correlated with serum insulin-like growth factor-I levels in health check-up subjects

BackgroundMost of circulating IGF-I is derived from the liver and circulating IGF-I levels are decreased in several pathological conditions, such as liver cirrhosis, uncontrolled diabetes, renal failure, and malnutrition. However, it has not fully been elucidated which factors modify IGF-I level in a physiological condition. ObjectiveTo identify the factors which are associated with circulating IGF-I levels. DesignCross-sectional study. MethodsThis study included 428 subjects who undertook health check-up. Subjects diagnosed with non-alcoholic fatty liver disease (NAFLD) by ultrasonography were analyzed separately. Univariate and multivariate regression analyses were conducted to identify the factors associated with circulating IGF-I levels. ResultsRegression analyses revealed that serum albumin levels, total-bilirubin levels, calcium levels, and HOMA-IR were positively correlated with IGF-I levels. Serum transaminase levels and habitual drinking (ethanol intake >20 g/day) were negatively correlated with serum IGF-I levels. Although serum IGF-I standard deviation scores (SDS) in subjects with and without NAFLD were comparable, after adjusting confounding factors clarified by multivariate regression analysis, IGF-I SDS negatively correlated with the presence of NAFLD. ConclusionIn this study, we demonstrated that serum bilirubin and calcium levels are correlated with serum IGF-I levels. Although further study is necessary, these data suggest a presence of interaction between GH-IGF-I axis and bilirubin and calcium metabolism.

Circulating IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 Molar Ratio Concentration and Height Outcome in Prepubertal Short Children on rhGH Treatment over Two Years of Therapy

Objective: To investigate the occurrence of abnormally elevated values of biomarkers of growth hormone (GH) action in short children on recombinant human GH (rhGH) therapy. Methods: Sixty-three prepubertal short children were examined: 31 with GH deficiency (GHD), 25 small for gestational age (SGA), and 9 with Turner syndrome (TS). The main outcomes were the following: standard deviation score (SDS) values of IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio before, at the 1st and at the 2nd year on rhGH and Δheight (Ht)-SDS to evaluate GH treatment efficacy (adequate 1st-year ΔHt SDS: >0.4 SDS for GHD and >0.3 SDS for non-GHD). Results: Seventy-eight percent of GHD, 78% of SGA and 55% of TS children had adequate 1st-year ΔHt SDS. In GHD, 88% of IGF-I SDS and IGFBP-3 SDS that were ≤–2.0 SDS at baseline normalized on treatment. Abnormal IGF-I values >+2.0 SDS were observed in 52% of SGA and in 55% of TS patients on rhGH. Within each group, the IGF-I/IGFBP-3 molar ratio increased significantly from pretreatment and throughout therapy, remaining within normal range for most patients. ΔIGF-I/IGFBP-3 molar ratio SDS were significantly higher in children with an adequate response (p < 0.01). Conclusion: Non-GHD groups presented markedly elevated concentrations of GH biomarkers on rhGH and normal IGF-I/IGFBP-3 molar ratio in most patients. Since there is a lack of consensus regarding the molar ratio usefulness, we think that interventions towards a more physiological IGF-I serum profile should be implemented.

Growth Hormone Therapy in Children with Kabuki Syndrome: 1-year Treatment Results

Background/Aims: Kabuki syndrome (KS) is a rare genetic malformation syndrome, resulting in characteristic features such as short stature. We investigate whether growth hormone (GH) treatment increases linear height and influences body proportions in KS children. Methods: In this prospective study, 18 genetically confirmed prepubertal KS children (9 females and 9 males) aged from 3.8 to 10.1 years (mean 6.8 ± 2.1 years) were treated with recombinant human GH (rhGH) for 1 year. Calculations for height, height velocity, BMI, sitting height, and subischial leg length were made. Bone age, insulin-like growth factor (IGF-I), and IGF binding protein 3 (IGFBP-3) were also measured. Results: This study showed an increase in height standard deviation score (SDS) for the whole group from –2.40 to –1.69 (p < 0.05) after 1 year of rhGH treatment. The change in height SDS within 1 year was >0.7 SDS for 10 subjects and >0.5 SDS for 3 subjects. The mean IGF-I SDS at the start of the study was –0.70 (±1.07), which increased after 12 months to 1.41 (±0.91) (p < 0.05). KS children who received rhGH at a younger age displayed significantly greater increases in height than those who started when they were older. The same was true for both gene mutation KMT2D versus KDM6A and for GH deficiency versus non-GH deficiency KS children (p < 0.05). Throughout the course of rhGH treatment, the subjects’ body proportions remained normal. Conclusions: All participants experienced catch-up growth during the year of rhGH treatment, but without an influence on body proportions.

Classification of Patients With GH Disorders May Vary According to the IGF-I Assay.

Insulinlike growth factor I (IGF-I) measurement is essential for the diagnosis and management of growth hormone (GH) disorders. However, patient classification may vary substantially according to the assay technique. We compared individual patient data and classifications obtained with six different IGF-I assay kits in a group of patients with various GH disorders. In this cross-sectional study, we measured IGF-I with six immunoassays in 102 patients with active or treated acromegaly or GH deficiency. IGF-I normative data previously established for the same six assay kits were used to classify the patients (high, low, or normal IGF-I levels), using both raw data and standard deviation scores (SDSs). Pairwise concordance between assays was assessed with Bland-Altman plots and with the percentage of observed agreement and the weighted κ coefficient for categorized IGF-I SDS. We observed marked variability both across each individual's IGF-I raw data and across IGF-I SDS values obtained with each of the six immunoassays. Pairwise concordance between assay values, as assessed with the weighted κ coefficient, ranged from 0.50 (moderate) to 0.81 (excellent). Even when using normative data obtained in the same large population of healthy subjects and when using calculated IGF-I SDSs, agreement among IGF-I assay methods is only moderate to good. Differences in assay performance must be taken into account when evaluating and monitoring patients with GH disorders. This argues for the use of the same IGF-I assay for a given patient throughout follow-up.

Is GH dosing optimal in female patients with adult-onset GH deficiency? An analysis from the NordiNet® International Outcome Study.

To evaluate gender differences in GH dosing, IGF-I and cardiovascular risk markers in adults with GH deficiency (GHD). NordiNet® International Outcome Study (NCT00960128), a noninterventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (Novo Nordisk A/S) in the real-life clinical setting. Nondiabetic patients (n = 252; 41·7% female) with adult-onset GHD (age ≥20 years at GH start), ≥4 years' GH therapy and glycosylated haemoglobin (HbA1c ) data at baseline and 4 years. Effects of gender (adjusted for baseline age and body mass index [BMI], average GH dose, treatment duration and concomitant medication) on change from baseline to 4 years (∆) in HbA1c , fasting plasma glucose (FPG), IGF-I, lipids and waist circumference were evaluated. GH dose (mean [SE]; mg/day) was similar between females (0·22 [0·02]) and males (0·21 [0·01]) at baseline, but higher in females from year 1 (year 4, females, 0·45 [0·03]; males, 0·32 [0·02]). Mean IGF-I standard deviation score [SDS] was lower in females vs males at each treatment year; more than one-third of females still had an IGF-I SDS below 0 at year 4, compared with only 21·8% of men. An adverse lipid profile at baseline remained poor in more females than males at 4 years. Improvement in total cholesterol was significantly associated with gender (P < 0·0001), improving less in females than in males. These data highlight that, even after 4 years, GH dose is suboptimal in many female patients, which may impact clinical outcomes; therefore, GH titration for women requires further improvement.

Comparison of Body Surface Area versus Weight-Based Growth Hormone Dosing for Girls with Turner Syndrome

Background/Aims: Growth Hormone (GH) dosage in childhood is adjusted for body size, but there is no consensus whether body weight (BW) or body surface area (BSA) should be used. We aimed at comparing the biological effect and cost-effectiveness of GH treatment dosed per m² BSA in comparison with dosing per kg BW in girls with Turner syndrome (TS). Methods: Serum IGF-I, GH dose, and adult height gain (AHG) from girls participating in two Dutch and five Swedish studies on the efficacy of GH were analyzed, and the cumulative GH dose and costs were calculated for both dose adjustment methods. Additional medication included estrogens (if no spontaneous puberty occurred) and oxandrolone in some studies. Results: At each GH dose, the serum IGF-I standard deviation score remained stable over time after an initial increase after the start of treatment. On a high dose (at 1 m² equivalent to 0.056-0.067 mg/kg/day), AHG was at least equal on GH dosed per m² BSA compared with dosing per kg BW. The cumulative dose and cost were significantly lower if the GH dose was adjusted for m² BSA. Conclusion: Dosing GH per m² BSA is at least as efficacious as dosing per kg BW, and is more cost-effective.

Relationship between serum insulin-like growth factor-1, IGF binding protein-3 levels and body height before and after gonadotropin-releasing hormone agonist therapy.

PurposeThe gonadotropin-releasing hormone agonist (GnRHa) is widely used to treat patients with precocious puberty. However, its effect on growth is often difficult to predict because of the diverse nature of its causes and presentation. This study aims to show the impact of GnRHa treatment on insulin-like growth factor-1 (IGF-I) and IGF binding protein-3 (IGFBP-3) secretion, growth, and on other parameters that may help estimate the height velocity.MethodsData from 60 girls (mean age, 8.8±0.7 years) treated with GnRHa were analyzed. Their height, bone age (BA), serum IGF-I, and IGFBP-3 concentrations were measured at the start and after a year of GnRHa treatment. To eliminate the confounding effect of chronological age (CA), the standard deviation scores (SDSs) of their height, IGF-I, and IGFBP-3 concentrations according to their CA at the start and after a year of GnRHa treatment were calculated. We looked for possible correlations between these variables and compared the subgroups based on their height velocities and midparental heights.ResultsDuring their one-year GnRHa therapy, height SDS for CA significantly decreased to 0.81±0.83 (P<0.001), but height SDS for BA increased to -0.28±0.68 (P<0.001). There was no significant change in serum IGF-I SDS, IGFBP-3 SDS, and IGF-I/IGFBP-3 ratio. The advanced BA was the factor most strongly correlated to the height velocity (R=0.265, P=0.041).ConclusionThese findings suggest that GnRHa treatment may affect the height velocity due to mechanisms other than suppression of the IGF-I and IGFBP-3 secretory axis.

Baseline IGF-I Levels Determine Insulin Secretion and Insulin Sensitivity during the First Year on Growth Hormone Therapy in Children Born Small for Gestational Age. Results from a North European Multicentre Study (NESGAS)

Objective: Developmental programming alters growth and metabolic outcome in children born small for gestational age (SGA). We explored insulin and glucose metabolism in SGA children treated with a fixed GH dose over 1 year. Methods: In the North European Small for Gestational Age Study (NESGAS), 110 short SGA children received GH at 67 µg/kg/day for 1 year. Insulin secretion was assessed by acute insulin response (AIR), insulin sensitivity (IS) by HOMA and disposition index (DI) by insulin secretion adjusted for IS. Results: First-year GH therapy led to increases in height and IGF-I standard deviation score (SDS), and reductions in IS (p < 0.0001). Compensatory increases in AIR (p < 0.0001) were insufficient and resulted in reduced DI (p = 0.032). Children in the highest IGF-I SDS tertile at baseline were the least insulin sensitive at baseline (p = 0.024) and 1 year (p = 0.006). IGF-I responses after 1 year were positively related to AIR (r = 0.30, p = 0.007) and DI (r = 0.29, p = 0.005). Conclusion: In SGA children treated with a high GH dose for 1 year, baseline IGF-I levels were related to IS whilst gains in height and IGF-I responses were associated with insulin secretion. Defining heterogeneity in IGF-I in SGA children may be useful in predicting growth and metabolic response.

Effects of growth hormone withdrawal in obese premenopausal women

We previously reported improved body composition and cardiovascular risk markers plus a small decrease in glucose tolerance with GH administration vs placebo for 6 months to abdominally obese premenopausal women. The objective of this study was to determine whether the effects of GH treatment on cardiovascular risk markers, body composition and glucose tolerance in obese women persist 6 months after GH withdrawal. Fifty abdominally obese premenopausal women completed a trial of rhGH vs placebo for 6 months; thirty-nine women completed a subsequent 6-month withdrawal observation period. IGF-I, body composition by CT, (1) H-MRS and DXA, serum cardiovascular risk markers, oral glucose tolerance test (OGTT). IGF-I standard deviation scores (SDS) within the GH group were -1.7 ± 0.1 (pretreatment),-0.1 ± 0.3 (after 6 months of GH) and -1.7 ± 0.1 (6 months post-GH withdrawal). Six months after GH withdrawal, total abdominal and subcutaneous adipose tissue, total fat, trunk fat, trunk/extremity fat, hsCRP, apoB, LDL, and tPA were higher than at the 6-month (GH discontinuation) timepoint (P ≤ 0.05). All body composition and cardiovascular risk markers that had improved with GH returned to baseline levels by 6 months after GH discontinuation, as did fasting and 2-h OGTT glucose levels. The effects of GH administration to abdominally obese premenopausal women have a short time-course. The beneficial effects on body composition and cardiovascular risk markers, and the side effect of altered glucose tolerance returned to pretreatment levels after GH withdrawal. There was no suppression of endogenous IGF-I levels, which returned to baseline after GH withdrawal.

Efficacy of IGF‐based growth hormone (GH) dosing in nonGH‐deficient (nonGHD) short stature children with low IGF‐I is not related to basal IGF‐I levels

Weight-based GH dosing is the standard for treating children with short stature. The current study validates the usefulness of IGF-based GH dosing for GH therapy in nonGH-deficient (nonGHD) children and its relationship with pretreatment serum IGF-I concentration. In this twelve-month, open-label, randomized controlled study, 151 nonGHD (based on GH-stimulation tests), prepubertal children with short stature and IGF-I levels ≤ 33rd percentile [-0.44 standard deviation score (SDS)] were randomly assigned to receive GH (dose based on IGF-I titration algorithm; n = 114) or to observation (n = 37). GH dose (initially 40 μg/kg/d) was adjusted every 3 months to achieve an IGF-I SDS in the upper normal range (66-99 th percentile). In treated children, mean height SDS (HSDS) increased from -2.5 at baseline to -1.7 at 12 months and mean IGF-I SDS increased from -1.7 to 0.1. These parameters remained unchanged in untreated children. There was no relationship between change in HSDS (ΔHSDS) and degree of IGF-I deficiency at baseline. No safety problems were observed. Both groups had a similar advance in bone age. At the end of study, ΔHSDS in treated children showed a positive correlation with IGF-I SDS, but not with GH dose [mean 59 μg/kg/d (range 29-92)], basal IGF-I SDS or 1-month IGF parameters. In nonGHD subjects with short stature and serum IGF-I concentrations within and below the lower third of normal, adjusting GH dose to achieve an IGF-I level in the upper normal range resulted in a significant increase in HSDS, regardless of basal IGF-I levels.

Variation of the baseline characteristics and treatment parameters over time: an analysis of 15 years of growth hormone replacement in adults in the German KIMS database

The purpose of this study is to examine potential implications of changes in the approach to adult growth hormone (GH) replacement (GHR) over the last 15 years. Therefore, we analysed the German KIMS database as one of the largest single country pharmacoepidemiological databases on adult GH deficiency (GHD). Based on the date of their first GH application patients were assigned to three intervals (1995-1999, 2000-2004, 2005-2009). A multivariate analysis of variance with interval and sex as independent variables was conducted. Differences were analysed with respect to IGF-I standard deviation score (SDS), quality of life, latency between GHD diagnosis and first GH dose, body mass index, waist-hip ratio, lipid profile, and GH dose. All analyses were conducted at baseline, 1 year, and 3 years of GHR. We detected significant associations between time interval and patient characteristics at baseline and with treatment effects. Recently, patients with less severe GHD (mean IGF-I SDS: -2.1, -1.6, -1.0 in the 1st, 2nd and 3rd interval; p = 0.000) are treated with lower GH starting doses (mean 0.30, 0.19, 0.21 mg/day in the 1st, 2nd and 3rd interval; p = 0.000). In the first time interval, IGF-I SDS was not normalized in females after 3 years of GHR. The results of our analysis demonstrate prominent changes in patient characteristics and handling of GHR. They highlight that approach to therapy and patient inclusion criteria change over time and may represent an important confounder for any analysis in epidemiological surveillance surveys.

Characterisation and growth outcomes of children with Insulin-like Growth Factor-1 deficiency in idiopathic short stature

Background/aimsChildren with idiopathic short stature (ISS) constitute a heterogenous group. Recombinant IGF-I (rhIGF-I) have been licensed for the treatment of severe short stature (height <−3 standard deviation scores (SDS)) in...