Years Of Growth Hormone Therapy Research Articles

Near Adult Height and Body Mass Index Changes in Growth Hormone Treated Short Children with Noonan Syndrome: The Belgian Experience

Introduction: A variable near adult height (NAH) outcome after growth hormone (GH) therapy in Noonan syndrome (NS) patients with short stature has been reported. The main objective of this study was to evaluate NAH and body mass index (BMI) evolution in a large Belgian cohort of NS patients treated for short stature. The secondary objectives were to investigate whether sex, genotype, the presence of a thoracic deformity, and/or a heart anomaly might affect NAH and to validate the recently developed NAH prediction model by Ranke et al. Methods: Clinical and auxological data of GH treated short NS patients born before 2001 were extracted from the national Belgrow registry. NAH was available in 54 (35 male) genotyped NS using a gene panel of 9 genes, showing pathogenic variants in PTPN11 in 32 and in SOS1 in 5 patients, while in 17 patients gene panel analysis was inconclusive (no-mutation group). Results: After a median (P10; P90) duration of 5.4 (2.2; 10.3) years of GH therapy with a median dose of 0.05 mg/kg/day NS patients reached a median NAH of −1.7 (−3.1; −0.8) SDS. Median total height gain was 1.1 (0.1; 2.3) SDS. Sex, genotype, and the presence of a thoracic or cardiac malformation did not correlate with NAH or total height gain. Linear regression modelling revealed that height SDS at start (β = 0.90, p β = 0.27; p = 0.005), birth weight SDS (β = 0.15; p = 0.051), age at start (β = 0.07; p = 0.032) were independently associated with NAH SDS. Median BMI SDS increased significantly (p Conclusion: Long-term GH therapy at a dose of 0.05 mg/kg/day in short NS patients is effective in improving adult height and BMI, irrespective of the genotype and presence or absence of cardiac and or thoracic anomalies.

FRI454 The Effect Of Growth Hormone Treatment According To Karyotype Classification In Turner Syndrome Patients

Abstract Disclosure: J. Choi: None. J. Yu: None. H. Kim: None. OBJECTIVES Short stature is the main characteristics for Turner syndrome (TS) patients, and growth hormone (GH) therapy has been used as an essential treatment for developing final adult height. However, there are only a few studies on the difference responsiveness to GH therapy according to the karyotype of Turner syndrome in Korea. The aim of this study was to analyze the effect of different types of TS karyotype abnormality on the response of GH therapy. METHODS The clinical parameters of 194 TS patients registered in the LG Growth Study, who received rhGH therapy (Eutropin inj.,LG Chem Ltd.,Korea) between February 2001 and October 2021, were retrospectively reviewed. Data for four group of subjects were obtained as follow: Monosomy X (n=56); Mosaicism without X structural abnormality (n=41); Mosaicism with X structural abnormality (n=71); X Structural abnormality (n=26). Parameters of biochemical characteristics and growth responses were compared during 3-year GH treatment. RESULTS The baseline height standard deviation score (SDS) was -2.85±0.86 in total TS patients. The growth velocity (cm/year) in the second year was higher in the Mosaicism without X structural abnormality compared to the monosomy X patients. However, the change of Hight SDS over three years was not statistically different between karyotypes. The growth rate was the highest in the first year, and it showed a decreasing trend over time. There was an increase in Height SDS due to growth hormone treatment for three years. The variables affecting the 0-3rd Δ height SDS were not found in the regression analysis CONCLUSIONS Our results indicate that there are no difference in response to three years of growth hormone therapy according to karyotype of TS. It was found that the initial height SDS was the lowest in monosomy compared to the others group. Further studies should be performed on other factors influencing the efficacy of the therapy. Presentation Date: Friday, June 16, 2023

THU178 Predicted Adult Height Outcomes And Relation To Final Adult Height In Children With Isolated Idiopathic Growth Hormone Deficiency Treated With rhGH Therapy

Abstract Disclosure: B. Duong: None. K. Vu: None. A.S. Bhangoo: None. Background: Children with growth hormone deficiency (GHD) are treated with growth hormone therapy for multiple years. Once a year a bone age X ray is done to monitor the development of the epiphysial growth plates and to calculate the predicted adult height (PAH) by using the Bayley-Pinneau tables. There is not much quantitative data on the PAH calculations in relation to Final adult height (FAH) and Mid-parental height (MPH). Methods: We collected data on 42 children with isolated idiopathic GHD (9 females, 33 males). These children had finished GH therapy after multi-year treatment. Data on MPH, FAH and PAH baseline (prior to starting rhGH), 1 yr, 2 yr and 3 yr post treatment was collected, and correlation analysis was performed. Results: The PAH at baseline correlated with FAH (R2 of 0.62), the PAH underestimated the height on average by 2.9 cms with SDS of 5.9 cms. The PAH was >2SDS below the FAH in 42%, >2SDS above in only 8% of children. The PAH after 1 year of rhGH correlated with FAH (R2 of 0.69), the PAH started to slightly overestimate the height on average by 0.6 cms with SDS of 5.9 cms. The PAH after 2 year of rhGH correlated with FAH (R2 of 0.82), the PAH calculated overestimated the height on average by 2.5 cms with SDS of 4.4 cms. The PAH after 3 year of GH therapy correlated with FAH (R2 of 0.94), the PAH also overestimated as compared to FAH on average by 2.6 cms with SDS of 2.3 cms. The PAH was >2SDS above the FAH in only 12% and for 88% within 2SDS of FAH. The PAH at baseline correlated with MPH (R2 of 0.35), the PAH was less than MPH on average by 4.2 cms with SDS of 7.6 cms. The PAH was >2SDS below the MPH in 48% children, >2SDS above the MPH in only 12 %. The PAH after 1 year of rhGH therapy correlated with MPH (R2 of 0.43), the average PAH calculated slightly below the MPH by 0.56 cms with SDS of 7.8 cms. The PAH after 2 years of rhGH therapy correlated with MPH (R2 of 0.57), the PAH was calculated most close to MPH on average by 0.05 cms with SDS of 6.5 cms. The PAH after 3 years of rhGH therapy correlated with MPH (R2 of 0.59), the PAH was now calculated above the MPH on average of 1.08 cms with SDS of 6.1 cms. At 3 years the PAH was >2SDS above the MPH in 28% and >2SDS below in 18% and within range in 64% of children. Conclusion: The PAH correlation with the FAH and MPH grows stronger with successive 3 years of therapy. The PAH correlation was stronger with FAH as compared to MPH. The PAH underestimated the height outcome at the beginning of therapy and overestimated after 3 years of rhGH therapy. The strongest correlation between PAH and FAH was seen after 3 years. The variations in PAH as measured by SDS improved post treatment. These factors should be considered while considering the height trajectory of children receiving rhGH therapy and while counseling parents on child’s height outcome. Presentation: Thursday, June 15, 2023

Components of the metabolic syndrome in girls with Turner syndrome treated with growth hormone in a long term prospective study.

Components of the metabolic syndrome are more common in patients with Turner syndrome (TS) than in the general population. Long-term growth hormone (GH) treatment also affects the parameters of carbohydrate metabolism. Therefore, all these factors should be monitored in girls with TS. To assess the occurrence of metabolic syndrome components in TS girls before GH treatment and to monitor changes in metabolic parameters throughout GH therapy. 89 TS patients were enrolled in the study. Clinical and laboratory data after the 1st (V1), 3rd (V3), 5th (V5) and 10th (V10) year of GH therapy was available respectively in 60, 76, 50 and 22 patients. The patients' biochemical phenotypes were determined by glucose 0', 120', insulin 0', 120', HOMA-IR, Ins/Glu ratio, HDL-cholesterol and triglycerides (TG) concentration. Obesity was found during V0 in 7.9% of patients,V1 - 5%, V3 - 3.9%, V5 - 2%, V10 - 0%. No patient met diagnostic criteria for diabetes. A significant increase in the basal plasma glucose 0' was found in the first five years of therapy (pV0-V1 < 0.001; pV0-V3 = 0.006; pV0-V5 < 0.001). V10 glucose 120' values were significantly lower than at the onset of GH treatment (pV0-V10 = 0.046). The serum insulin 0' and 120' concentrations as well as insulin resistance increased during treatment. No statistically significant differences in serum TG and HDL-cholesterol levels during GH therapy were found. The development of insulin resistance and carbohydrate metabolism impairment have the greatest manifestations during GH therapy in girls with TS. Monitoring the basic parameters of carbohydrate-lipid metabolism in girls with TS seems particularly important.

Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status.

IntroductionMutations in PTPN11 are associated with Noonan syndrome (NS). Although the effectiveness of growth hormone therapy (GHT) in treating short stature due to NS has been previously demonstrated, the effect of PTPN11 mutation status on the long-term outcomes of GHT remains to be elucidated.MethodsThis analysis included pooled data from the observational American Norditropin Studies: Web-Enabled Research Program (NCT01009905) and the randomized, double-blinded GHLIQUID-4020 clinical trial (NCT01927861). Pediatric patients with clinically diagnosed NS and confirmed PTPN11mutation status were eligible for inclusion. The effectiveness analysis included patients who were GHT-naïve and pre-pubertal at GHT start. Growth outcomes and safety were assessed over 4 years of GHT (Norditropin®, Novo Nordisk A/S).ResultsA total of 69 patients were included in the effectiveness analysis (71% PTPN11 positive). The proportion of females was 32.7 and 30.0% in PTPN11-positive and negative patients, respectively, and mean age at GHT start was 6.4 years in both groups. Using general population reference data, after 4 years of GHT, the mean (s.d.) height SD score (HSDS) was −1.9 (1.1) and −1.7 (0.8) for PTPN11-positive and PTPN11-negative patients, respectively, with no statistical difference observed between groups. The mean (s.d.) change in HSDS at 4 years was +1.3 (0.8) in PTPN11-positive patients and +1.5 (0.7) in PTPN11-negative patients (no significant differences between groups). Safety findings were consistent with previous analyses.ConclusionsGHT resulted in improved growth outcomes over 4 years in GHT-naïve, pre-pubertal NS patients, irrespective of PTPN11 mutation status.

Adherence and growth outcomes in children with growth disorders: results from the Easypod™ Connect Observational Study (ECOS) in Indonesia, Singapore, and Taiwan

Background Non-objective assessments indicate poor patient adherence to growth hormone (GH) prescribed for growth failure, with sub-optimal growth response. The easypod™ connect device for GH administration enables real-time, objective assessment of adherence.&#x0D; Objective To examine adherence with pediatric GH therapy in Asia-Pacific countries and relationship with growth outcomes.&#x0D; Methods Subjects were children in Indonesia, Singapore, Taiwan enrolled in the multi-national, open-label Easypod Connect Observational Study (ECOS). Adherence during follow-up was the primary endpoint and a relationship with 1-year growth outcomes was assessed by Spearman’s product-moment correlations.&#x0D; Results Over a 1-year time frame, median overall patient adherence was ≥89%; rates were similar for children with GH deficiency (GHD; n=17) and those born small-for-gestational age (SGA; n=5), except that median adherence dropped between 9 months (94%) and 1 year (83%) for SGA subjects. Median initial GH dose was 42.3µg/kg/day for GHD subjects and 31.4µg/kg/day for SGA subjects. Median age (12 years) and bone age (13 years) indicated that most children had entered puberty at treatment onset. Clinically meaningful improvements in growth were observed at 1 year in the GHD group, but not the SGA group. Statistically significant correlations between adherence and height change (P=0.039) as well as height velocity (P=0.004) were observed.&#x0D; Conclusions Children in Asia-Pacific countries show high adherence over the first year of GH therapy with easypod. The easypod study also shows that adherence is correlated to good growth outcomes.

Brachydactyly Type A3 Is More Commonly Seen in Children With Short Stature But Does Not Affect Their Height Improvement by Growth Hormone Therapy.

IntroductionTo analyze the prevalence of brachydactyly type A3 (BDA3) in children with short stature and the effect on growth hormone (GH) therapy.MethodsWe analyzed the medical records of pediatric patients from July 2009 to July 2021. We included children with short stature defined as their height standard deviation score (HtSDS) < -2 and normal short height as their HtSDS between -2 and -1. We calculated the prevalence of BDA3 in different groups and compared the differences in children’s characteristics and the therapeutic effect of GH therapy between the BDA3 and no BDA3 groups.ResultsA total of 752 cases were included. The overall prevalence of BDA3 was 23.1%; with a female predominance (30.8% vs. 16.1%, P < 0.01). BDA3 was more prevalent in the short stature group (27.2%) than in the normal short stature group (16.7%) and growth hormone deficiency group (16.5%). Birth length, birth weight, HtSDS, and mid-parental height of children with BDA3 were lower than those without BDA3, but there were no significant differences. In patients with Turner syndrome and idiopathic short stature, the HtSDS of the BDA3 group was significantly lower than that of the no BDA3 group (P < 0.01). During four years of GH therapy, the HtSDS improvement per year in the BDA3 group were 0.79 ± 0.29, 0.50 ± 0.31, 0.20 ± 0.30, and 0.10 ± 0.22, which were not significantly different from those in the no BDA3 group. At the end of treatment, there were no significant differences in the duration of treatment and total HtSDS improvement between these two groups.ConclusionsBDA3 is more commonly seen in children with short stature with a female predominance. BDA3 occurrence is independent of the GH pathway and does not affect the therapeutic effect of GH on short stature children.

Cardiac functions in children with growth hormone deficiency: Effects of one year of GH replacement therapy

IntroductionChildren with Growth Hormone deficiency (GHD) are prone to heart dysfunction and, if left untreated, will result in marked cardiac dysfunction in adulthood. The aim was to evaluate the effect of GHD and growth hormone (GH) therapy on cardiac structure in children and adolescents, and to investigate the role of insulin like growth factor-1 (IGF-1) in this. MethodsM-mode, pulse-wave Doppler echocardiography and tissue Doppler imaging (TDI) were performed in 49 children with GHD who were divided into those with a peak GH response < 7 μg/L and 7–10 μg/L after two GH stimulation tests, aged 8–16 years at baseline and at six and 12 months after GH initiation, and 49 healthy peers. IGF-1 concentration was measured. ResultsAlthough the left ventricular end diastolic and systolic diameters in both GH deficient groups were significantly lower than controls (p < 0.01), both diameters increased significantly with one year of treatment and achieved normal values (p > 0.05). Using TDI in both two patients group revealed increased E/A, prolonged isovolumic relaxation time, shortened ejection time, and a significant increase in myocardial performance index compared to controls (p < 0.001). Significant improvement was observed in these parameters from the sixth month of GH treatment (p < 0.001), this improvement does not match parameters measured in healthy peers, even after one year of treatment in both patients group. (p < 0.001). No correlation was found between IGF-1 concentration and any echocardiographic parameter. ConclusionEchocardiographic parameters were similar in children with a GH peak < 7 μg/L and 7–10 μg/L. In TDI, both systolic and diastolic function was impaired in GHD children compared to controls. These parameters improved after one year of GH therapy but did not recover to healthy control levels.

NPR2 Variants are frequent among children with familial short stature and respond well to growth hormone therapy

This study aimed to assess the frequency of natriuretic peptide receptor type B gene (NPR2 ) variants in 87 children with familial short stature (FSS) and evaluate their response to GH therapy. By applying whole-exome or custom-targeted NGS panel sequencing, NPR2 variants were found in 5 children (5.7%) belonging to 4 families. These variants were classified as pathogenic (n =2) or likely pathogenic (n =3) according to the American College of Medical Genetics and Genomics guidelines. Three children were born SGA and 3 were classified as GH deficient (GHD). Two children had disproportionate short stature with short limbs and one had a dysplastic middle phalanx of the fifth finger. All parents with short stature carried the same NPR2 variant as the probands. GH therapy improved growth velocity after the first year of treatment (from 3.6 to 4.2 cm/year) and the gain in height ranged from 0.33 to 0.79 S.D. after 1 year of GH therapy, 0.43 to 1.34 S.D. at 2 years, and 1.2 to 1.8 S.D. after 5 years.

One year of growth hormone therapy in spanish adults with prader-willi syndrome (PWS) improves body composition without changes in bone mineral density

One year of growth hormone therapy in spanish adults with prader-willi syndrome (PWS) improves body composition without changes in bone mineral density

Three years of growth hormone treatment in young adults with Prader-Willi syndrome: sustained positive effects on body composition

BackgroundIn children with Prader-Willi syndrome (PWS), the benefits of growth hormone treatment are well established. Several one-year studies have shown that growth hormone is also beneficial for adults with PWS, improving body composition. However, little is known about the longer-term effects.This study investigated the effects on body composition in adult patients with PWS during 3 years of growth hormone therapy in a dose of 0.33 mg/m2/day.MethodsOpen-label, prospective study in 43 young adults with PWS with a median (IQR) age of 19.0 (17.5 to 20.7) years. Fat mass percentage SDS and lean body mass SDS were measured annually by DXA.ResultsEstimated mean (95% CI) fat mass percentage SDS decreased during the three-year study from 2.1 (1.9 to 2.3) SDS at start to 1.9 (1.8 to 2.1) SDS, p = 0.012, while lean body mass SDS remained stable at − 2.1 (− 2.4 to − 1.8) SDS at start to − 1.9 (− 2.3 to − 1.6) after 3 years, p = 0.15. Fasting glucose and insulin remained similar during the three-year study, glucose being 4.6 (4.4 to 4.8) mmol/l at start and 4.6 (4.5 to 4.7) mmol/l after 3 years of growth hormone, p = 0.93 and insulin being 59.5 (42.2 to 81.5) pmol/l and 55.0 (42.4 to 69.2) pmol/l, resp., p = 0.54. There were no growth hormone-related adverse events during the study.ConclusionsThree years of growth hormone treatment in young adults with PWS maintains the positive effects on body composition attained during childhood. Thus, adults with PWS benefit from longer-term growth hormone treatment.Trial registrationEudraCT, EudraCT number 2011-001313-14. Registered 17 October 2012.

SAT-106 Growth Hormone Treatment Response in Children

OBJECTIVES: Growth hormone (GH) therapy is an effective treatment in addressing growth failure in children with GH deficiency (GHD). It has also been increasingly used in non-GH deficient (nGHD) conditions. We sought to report the growth response of GHD and nGHD patients who received GH therapy at a tertiary care center. METHODS: Data was collected from health records of patients followed in the endocrinology clinic at Alberta Children’s Hospital, Calgary, Canada, from 2005 to 2019, and used to analyze clinical responses based on indication for GH treatment. RESULTS: A total of 167 patient records (87 males and 80 females) were used for analysis. The average age at the start of GH therapy was 7.3 years (range 0.25 to 16.98 yrs). 74 patients were in the GHD group while 93 were nGHD. Of the patients in the nGHD group, the most common diagnosis were: idiopathic short stature (ISS)(n=45), Turner syndrome (TS)(n=26), and Prader Willi Syndrome (PWS)(n=8). The mean height velocity (HV) in year 1 was highest in the GHD group at 11.68 cm/year (n= 62, sd = 5.93), followed by ISS at 9.41cm/year (n = 52, sd = 4.34). The mean first year HV of those who had received chemotherapy (n= 5, mean = 5.48, sd = 1.92) or had Turner syndrome (n= 24, mean = 7.20, sd = 2.15) was significantly lower than both the GHD and ISS groups. GH peak during a GH stimulation test at baseline was not correlated to the first year height velocity while on GH treatment. However there was a negative linear correlation between baseline IGF1 level and first year height velocity (Spearman’s rho = 0.312216, p-value= 0.01516). Age at GH initiation was negatively correlated with height velocity during GH treatment. Height velocity over time decreased sharply from year 1 to year 3, and became stable for the remaining years of GH therapy. For the entire group, HV for years 1-5 was 9.81 (sd=4.83), 7.40 (sd=2.89), 6.29 (sd=2.38), 5.92 (sd=2.56), 5.66 (sd=2.51). There is no significant correlation between GH dose and height velocity response after adjusting for diagnosis. CONCLUSION: In our population, the response to GH therapy was consistent with those reported in the literature. Response to GH therapy was not associated with GH peak on stimulation but rather to baseline IGF-1 level and age at initiation. Although peak GH to stimulation is required to obtain public funding for GH therapy, these findings demonstrate that GH stimulation test results may not indicate which patients may benefit the most from GH therapy. Follow-up until final adult height will allow us to have a better understanding of the efficacy of GH therapy in patients with both GHD and nGHD conditions.

Near Adult Height in Girls with Turner Syndrome Treated with Growth Hormone Following Either Induced or Spontaneous Puberty

To understand whether spontaneous vs induced puberty and the type and route of estrogen influence the height of girls with Turner syndrome on growth hormone (GH). Search of an international database of children treated with GH revealed 772 girls with Turner syndrome followed from GH initiation to near adult height. Data from girls with sustained spontaneous puberty (n=145) were compared with those requiring estrogens for induction or maintenance of puberty (n=627). At GH start, mean age (7.5 vs 7.9years), weight (-1.7 vs -1.7 SDS), and body mass index (0.2 SDS vs 0.1 SDS) were similar for girls with spontaneous puberty and with induced puberty. Although those girls with spontaneous puberty were shorter than those with induced puberty, when midparental height was taken into consideration, starting heights in both groups averaged -2.8 SDS. Both groups received approximately 0.3mg/kg/week of GH. Girls with spontaneous puberty initiated puberty and reached near adult height earlier than girls with induced puberty (12.6±1.8years vs 13.4±1.4years and 16.0±1.3years vs 16.9±1.4years, respectively). Although girls with spontaneous puberty grew more in the first year of GH therapy and between the onset of puberty and near adult height (11.0cm vs 9.3cm), height SDS at near adult height and the length of time in puberty before reaching near adult height were comparable. A 45,X karyotype was detected in 22.1% of girls with spontaneous puberty and in 58.4% of girls with induced puberty. Patients receiving transdermal estrogens did not grow better than those on oral estrogens. Adverse event reporting was comparable between groups. Girls with Turner syndrome with spontaneous puberty tended to grow better in response to GH than girls with induced puberty, but not enough to produce a difference in height SDS at near adult height.

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.

SAT-437 The Patro Adults Study of Omnitrope® for the Treatment of Adult Patients with Growth Hormone Deficiency: Latest Safety Outcomes Including Diabetes Risk

Introduction: PATRO Adults is an international, longitudinal, non-interventional study of the long-term safety and efficacy of Omnitrope® (recombinant human growth hormone, rhGH; Sandoz) in adults treated in routine clinical practice. The study provides data on the long-term safety of rhGH in adult patients with severe GH deficiency (GHD). Methods: The study includes adult patients who are receiving treatment with Omnitrope® and have provided informed consent. Patients treated with another rhGH before starting Omnitrope® therapy are also eligible for inclusion. Here we report the latest safety data, with a focus on the risk of diabetes. Results: As of September 2018, 1298 patients had been enrolled on the study over >10 years; 1084 (83.5%) had adulthood-onset GHD (combined GHD, n=956) and 204 (15.7%) had childhood-onset GHD. Overall, 659 (50.8%) patients had been pre-treated with another rhGH. Mean (standard deviation [SD]) age was 49.3 (15.3) years, and mean (SD) body mass index was 29.5 (6.4) kg/m2. In total, 4009 adverse events (AEs) in 889 patients have been reported, with 643 (353 [27.2%] patients) of these regarded as serious. 154 AEs in 92 (7.1%) patients were suspected to be related to Omnitrope®; these included general disorders/administration site conditions in 23 patients, nervous system disorders in 23 patients and musculoskeletal/connective tissue disorders in 36 patients. A total of 20 serious AEs (SAEs) in 17 (1.3%) patients were suspected to be related to Omnitrope®, leading to treatment discontinuation in 5 patients. Overall, 328 patients (282 with combined GHD) have discontinued the study, 73 (61 with combined GHD) due to AEs (26 were considered related to rhGH treatment). To date, 22 cases of diabetes have been reported (21 in patients with combined GHD; 20 in patients with adult-onset GHD). Nine of these reports were SAEs, 2 of which were considered to be treatment-related. The first case was diabetes mellitus aggravation in a 45 year old male with adulthood-onset combined GHD, following 4-6 months of GH therapy; Omnitrope® was permanently discontinued. The second case was worsening of diabetes mellitus in a male aged 72 years with adulthood-onset combined GHD, following 19 years of GH therapy; Omnitrope® treatment was interrupted. Conclusions: Based on this interim analysis, Omnitrope® treatment in adults with GHD is well tolerated in a real-life clinical practice setting, irrespective of pre-treatment status. The ongoing PATRO Adults study will provide further data on the diabetogenic potential and overall safety of long-term GH treatment in this population.

Evaluation of Changes in Insulin Sensitivity in Prepubertal Small for Gestational Age Children Treated with Growth Hormone.

Background:Although growth hormone (GH) therapy for children born small for gestational age (SGA) has been approved for many years, there are still concerns about increasing their risk for insulin resistance and diabetes mellitus type 2. Monitoring of glucose homeostasis is therefore generally recommended, but there is no consensus on either the methods or consequences.Methods and Aims:The aim of our study was to analyze the oral Glucose Tolerance Tests (oGTTs) which were performed yearly from baseline to 4 years of GH therapy in a collective of 93 SGA children, who were prepubertal during the whole follow-up. We looked for correlations with auxological and laboratory data as well as predictive baseline results for glucose homeostasis during further treatment.Results:While glucose levels remained constant, insulin secretion increased from baseline to the first year of GH therapy. Insulin sensitivity index (ISI) showed no significant change afterwards; HOMA1, HOMA2, and QUICKI stabilized after the second year. For all indices mean values never reached pathological levels and no cases of diabetes mellitus were induced. Higher gestational age, lower birth length, and older age at start of GH therapy were associated with lower insulin sensitivity. No predictive factors for later insulin resistance could be found.Conclusion:As expected, in GH-treated prepubertal SGA children insulin resistance was induced, but not to pathological levels. No special risk factors for disturbed glucose homeostasis could be identified. Based on our opinion, performing oGTTs in GH-treated SGA children at baseline and in puberty should remain mandatory, but the current study recommendations regarding further surveillance of glucose homeostasis are questionable.

Growth hormone therapy in patients with Noonan syndrome.

Noonan syndrome (NS) is an autosomal dominant disorder that involves multiple organ systems, with short stature as the most common presentation (>70%). Possible mechanisms of short stature in NS include growth hormone (GH) deficiency, neurosecretory dysfunction, and GH resistance. Accordingly, GH therapy has been carried out for NS patients over the last three decades, and multiple studies have reported acceleration of growth velocity (GV) and increase of height standard deviation score (SDS) in both prepubertal and pubertal NS patients upon GH therapy. One year of GH therapy resulted in almost doubling of GV compared with baseline; afterwards, the increase in GV gradually decreased in the following years, showing that the effect of GH therapy wanes over time. After four years of GH therapy, ~70% of NS patients reached normal height considering their age and sex. Early initiation, long duration of GH therapy, and higher height SDS at the onset of puberty were associated with improved final height, whereas gender, dosage of GH, and the clinical severity did not show significant association with final height. Studies have reported no significant adverse events of GH therapy regarding progression of hypertrophic cardiomyopathy, alteration of metabolism, and tumor development. Therefore, GH therapy is effective for improving height and GV of NS patients; nevertheless, concerns on possible malignancy remains, which necessitates continuous monitoring of NS patients receiving GH therapy.

Comparison of effectiveness of growth hormone therapy according to disease-causing genes in children with Noonan syndrome.

PurposeTo analyze the growth response to growth hormone (GH) therapy in prepubertal patients with Noonan syndrome (NS) harboring different genetic mutations.MethodsTwenty-three patients with prepubertal NS treated at Pusan National University Children’s Hospital between March 2009 and July 2017 were enrolled. According to the disease-causing genes identified, the patients with NS were divided into 4 groups. Three groups were positive for mutations of the PTPN11, RAF1, and SOS1 genes. The five genes undetected (FGU) group was negative for PTPN11, RAF1, SOS1, KRAS, and BRAF gene mutations. The influence of genotype was retrospectively analyzed by comparing the growth parameters after GH therapy.ResultsThe mean chronological age at the start of GH treatment was 5.85±2.67 years. At the beginning of the GH treatment, the height standard deviation score (SDS), growth velocity (GV), and lower levels of insulin-like growth factor-1 (IGF)-1 levels were not statistically different among the groups. All the 23 NS patients had significantly increased height SDS and serum IGF-1 level during the 3 years of treatment. GV was highest during the first year of treatment. During the 3 years of GH therapy, the PTPN11, RAF1, and SOS1 groups showed less improvement in height SDS, IGF-1 SDS, and GV, and less increase in bone age-to-chronological age ratio than the FGU group.ConclusionThe 3-year GH therapy in the 23 prepubertal patients with NS was effective in improving height SDS, GV, and serum IGF-1 levels. The FGU group showed a better response to recombinant human GH therapy than the PTPN11, RAF1, and SOS1 groups.

Growth hormone therapy in children born small for gestational age: results from the ANSWER program.

Growth hormone (GH) is used to treat short stature and growth failure associated with growth disorders. Birth size and GH status variably modulate response to GH therapy. The aim of this study was to determine the effect of birth size on response to GH therapy, and to determine the impact of GH status in patients born small for gestational age (SGA) on response to GH therapy. Data from the prospective, non-interventional American Norditropin Studies: Web-Enabled Research (ANSWER) Program was analyzed for several growth outcomes in response to GH therapy over 3 years. GH-naïve children from the ANSWER Program were included in this analysis: SGA with peak GH ≥10 ng/mL (20 mIU/L), SGA with peak GH <10 ng/mL (20 mIU/L), isolated growth hormone deficiency (IGHD) born SGA, IGHD not born SGA and idiopathic short stature. For patients with IGHD, those who did not meet criteria for SGA at birth showed greater improvements in height SDS and BMI SDS than patients with IGHD who met criteria for SGA at birth. For patients born SGA, response to GH therapy varied with GH status. Therefore, unlike previous guidelines, we recommend that GH status be established in patients born SGA to optimize GH therapy.

Efficacy and safety of biosimilar growth hormone in Indian children

Objective:To study efficacy and safety of use of biosimilar growth hormone (GH) in Indian children with growth disorders.Materials and Methods:We studied 322 children (May 2012–2017) with growth disorders including growth hormone deficiency (GHD), multiple pituitary hormone deficiency (MPHD, idiopathic short stature (ISS), small for gestational age (SGA), and Turner syndrome (TS). Children were treated either with innovator molecule (Norditropin) or biosimilar GH (Headon) with standard dosage protocol for 1 year. Height and weight was measured using standard protocol. Height and BMI for age Z-scores (HAZ, BMIZ), height velocity (HV), and HV Z-score (HVZ) were computed from available data.Results:Mean age of the studied children (n = 322) was 9.6 ± 4.1 years, 32% children had GHD, 39% had ISS, 11% had MPHD, 12% had SGA, and 6% children had TS. There were no serious adverse events; three patients recorded eight instances of headaches, two had rash at injection site, and one each had hives and facial edema. Reactions were mild and were treated symptomatically. At the end of the 1 year of GH therapy, change in HAZ was similar in children from both the innovator and biosimilar GH groups. Similarly, the HV and HVZ were also similar in children from both groups and all the studied growth disorders.Conclusion:Biosimilar GH was effective and safe for treatment in children with growth disorders where GH use is indicated. However, in the view of scarcity of such data a longitudinal study with large sample size is warranted.