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BACKGROUND AND AIMS: Intracranial germ cell tumor (iGCT) survivors have multiple risk factors for growth hormone (GH) deficiency, a commonly reported late effect in childhood cancer survivors. The objective of this study is to examine the prevalence of GH deficiency among childhood iGCT survivors. METHODS: Participants were previously enrolled in the Germ Cell Tumor Epidemiology Study (GaMETES), a case parent triad study conducted using the Children’s Oncology Group registry protocols, including 216 cases with iGCTs. Data on late effects and outcomes are available for 129 iGCT cases who consented for a follow-up study including a self-administered questionnaire and medical record retrieval. GH deficiency was identified via self-report and validated through medical record review. Chi-squared and Fisher’s exact tests were used to examine cases with GH deficiency predating iGCT detection. Logistic regression was used to identify predictors of GH deficiency as a late effect. RESULTS: Of 129 iGCT cases who participated in the late effects study, 45% had GH deficiency; 18% had GH deficiency predating the iGCT and 27% developed GH deficiency within a median of 19 months after diagnosis. Younger age at diagnosis, suprasellar location, and higher radiation doses were associated with GH deficiency as a late effect. CONCLUSIONS: GH deficiency is highly prevalent as an early clinical sign for iGCT and frequently arises as an early late effect after treatment. Additional investigation is needed to address earlier detection and treatment for this highly prevalent late effect in iGCT survivors.

Context Pathologies attributed to perturbations of the growth hormone/insulin like growth factor-I (GH/IGF-I) axis are among the most common referrals received by pediatric endocrinologists. Aim In this article, distinctive cased-based presentations are used to provide a practical and pragmatic approach to the management of pediatric growth hormone deficiency (GHD). Cases We present 4 case vignettes based on actual patients which illustrate: 1) Congenital GHD, 2) Childhood GHD presenting as failure to thrive, 3) Childhood GHD presenting in adolescence as growth deceleration and 4) Childhood onset GHD manifesting as metabolic complications in adolescence. We will review patient presentation, management approach which aims to highlight diagnostic considerations for treatment based on current clinical guidelines, with mention being made of new therapeutic and diagnostic modalities being used in the field. Conclusion Pediatric GHD is diverse in etiology and clinical presentation. Timely management has the potential not only to improve growth, but can also ameliorate or even mitigate adverse metabolic outcomes which can be directly attributed to a growth hormone deficient state.

Lonapegsomatropin, a long-acting GH therapy (LAGH), was approved by the United States Food and Drug Administration in August 2021 for the treatment of pediatric growth hormone deficiency (GHD). Lonapegsomatropin is a prodrug consisting of unmodified GH transiently conjugated to methoxypolyethylene glycol which enables time-release of GH with a half-life of ~25 hours allowing for once-weekly administration. Clinical trials of lonapegsomatropin have demonstrated positive efficacy results in children (phase 2 and 3) and adults (phase 2) with GHD. The phase 3 trial in children with GHD established non-inferiority and statistical superiority of height velocity with lonapegsomatropin (11.2 cm/yr) compared to daily GH (10.3 cm/yr), with no concerning side effects with lonapegsomatropin. Similar growth responses have been reported in other LAGH products in phase 2 (somapacitan) and phase 3 (somatrogon) trials. Lonapegsomatropin is distributed in temperature-stable, prefilled cartridges at 9 different doses that can be prescribed based upon specific weight brackets designed to deliver approximately 0.24 mg/kg/wk. An electronic delivery device is required to combine the powdered medication with the diluent and deliver the medication subcutaneously through a small gauge needle to the recipient. The pharmacodynamic data from the clinical trials of lonapegsomatropin has been used to develop models to estimate an average IGF-1 value drawn at any time during the weekly injection interval. This average IGF-1 value may be used to for safety monitoring and/or to guide dose adjustment. New LAGH products, including lonapegsomatropin, may potentially improve patient adherence, quality of life and clinical outcomes, particularly in patients with poor adherence to daily GH injections in the future. With the availability of new LAGH products, clinicians will need to identify the best candidates for LAGH therapy and understand how to monitor and adjust therapy. Long-term surveillance studies are needed to demonstrate adherence, efficacy, cost-effectiveness and safety of LAGH preparations.

Recombinant human growth hormone (somatropin) is recommended for children with growth hormone deficiency (GHD) to normalize adult height. Prior research has indicated an association between adherence to somatropin and height velocity. Further research is needed using real-world data to quantify this relationship; hence the objective of this study was to investigate the association between adherence to somatropin and change in height among children with GHD.This retrospective cohort study included patients in the IQVIA PharMetrics Plus and Ambulatory Electronic Medical Records databases aged 3 to 15 years, with ≥1 GHD diagnosis code claim and newly initiated on somatropin between January 1, 2007 and November 30, 2019. Adherence was measured over the follow-up using the medication possession ratio (MPR); patients were classified as adherent (MPR ≥ 0.8) or nonadherent (MPR0.8).Among 201 patients initiated on somatropin, 74.6% were male, mean age was 11.4 years, and the mean follow-up was 343.3 days. Approximately 76.6% of patients were adherent to somatropin over the follow-up period. Adjusted growth trajectories were similar between adherent and nonadherent patients pre-treatment initiation (P = .15). Growth trajectories post-initiation were significantly different (P = .001). On average, adherent patients gained an additional 1.8 cm over 1 year compared with nonadherent patients, adjusted for covariates.Greater adherence to somatropin therapy is associated with improved height velocity. As suboptimal adherence to daily somatropin therapy is an issue for children with GHD, novel strategies to improve adherence may improve growth outcomes.

Growth hormone deficiency (GHD) is a clinical syndrome that can manifest either as isolated or associated with additional pituitary hormone deficiencies. Although diminished height velocity and short stature are useful and important clinical markers to consider testing for GHD in children, the signs and symptoms of GHD are not always so apparent in adults. Quality of life and metabolic health are often impacted in patients with GHD; thus, making an accurate diagnosis is important so that appropriate GH replacement therapy can be offered to these patients. Screening and testing for GHD require sound clinical judgment that follows after obtaining a complete medical history of patients with a hypothalamic-pituitary disorder and thorough physical examination with specific features for each period of life, while targeted biochemical testing and imaging are required to confirm the diagnosis. Random measurements of serum GH levels are not recommended to screen for GHD (except in neonates) as endogenous GH secretion is episodic and pulsatile throughout the lifespan. One or more GH stimulation tests may be required, but existing methods of testing might be inaccurate, difficult to perform, and can be imprecise. Furthermore, there are multiple caveats when interpreting test results including individual patient factors, differences in peak GH cut-offs (by age and test), testing time points, and heterogeneity of GH and IGF-I assays. In this article, we provide a global overview of the accuracy and cut-offs for diagnosis of GHD in children and adults, and discuss the caveats in conducting and interpreting these tests.

Context Despite having normal growth hormone (GH) secretion, individuals with Turner syndrome (TS) have short stature. Treatment with recombinant human GH is recommended for TS girls with short stature. Objective This work aimed to evaluate the effectiveness and safety of Norditropin (somatropin, Novo Nordisk) with up to 10 years of follow-up in children with TS. Methods Secondary analysis was conducted of Norditropin data from 2 non-interventional studies: NordiNet® IOS (NCT00960128) and the ANSWER program (NCT01009905). Results A total of 2377 girls with TS were included in the safety analysis set (SAS), with 1513 in the treatment-naive effectiveness analysis set (EAS). At the start of treatment, 1273 (84%) participants were prepubertal (EAS); mean (SD) age was 8.8 (3.9) years. Mean (SD) dose received at the start of GH treatment was 0.045 (0.011) mg/kg/day (EAS). Mean (SD) baseline insulin-like growth factor-1 (IGF-I) SD score (SDS) was −0.86 (1.52), and mean (SD) duration of GH treatment (SAS) was 3.8 (2.8) years. Height SDS (HSDS) increased throughout follow-up, with near-adult HSDS reached by 264 (17%) participants (mean [SD] −1.99 [0.94]; change from baseline +0.90 [0.85]). During the study, 695 (46%) participants (EAS) entered puberty at a mean (SD) age of 12.7 (1.9) years (whether puberty was spontaneous or induced was unknown). Within the SAS, mean IGF-I SDS (SD) at year 10 was 0.91 (1.69); change from baseline +1.48 (1.70). Serious adverse reactions were reported in 10 participants (epiphysiolysis [n = 3]). Conclusion GH-treated participants with TS responded well, without new safety concerns. Our real-world data are in agreement with previous studies.

There are known geographical differences in growth hormone deficiency (GHD) patient populations and treatment practices. Here, we present a comparison of safety and effectiveness data from patients treated with recombinant human growth hormone (rhGH) in the USA versus other countries. PAtients TReated with Omnitrope® (PATRO) Children is an international, non-interventional study with Omnitrope® (somatropin, Sandoz Inc.). All visits and assessments are carried out according to routine clinical practice, and doses of Omnitrope® are given according to country-specific prescribing information. By September 2018, 294 patients had been enrolled in the USA (53% rhGH-naïve) and 6206 patients had been enrolled across 13 other countries (international group; 86% rhGH-naïve). The most common indication in both groups was GHD. Overall, 194 US patients (66%) and 2977 international patients (48%) experienced adverse events (AEs; 886 and 11,716 events, respectively), most of which were of mild or moderate intensity. The AEs were suspected to be treatment-related in five US patients (1.7%) and 452 international patients (7.3%). All reported neoplasms were benign, non-serious, and considered unrelated to rhGH therapy. No cases of diabetes mellitus or hyperglycemia were reported. In rhGH-naïve GHD patients, after 3 years of rhGH therapy, the improvement in mean height SD score from baseline was + 1.25 and + 1.35 in US and international patients, respectively.Conclusion: Omnitrope® treatment appears to be well tolerated and effective in US patients and those from other countries. Across the pediatric indications included, there was no evidence of an increased risk of developing uncommon or unexpected AEs with rhGH.Trial registration: NA. What is Known:• Continued monitoring of patients treated with recombinant human growth hormone (rhGH) is important, particularly in terms of diabetogenic potential and the risk of malignancies.• The PAtients TReated with Omnitrope® (PATRO) Children study is a long-term, post-marketing surveillance program for the rhGH Omnitrope®. What is New:• Omnitrope® is well tolerated and effective in US patients, and those from other countries.• Across all indications included, there were no unexpected adverse events and there was no evidence of an increased risk of developing malignancies or diabetes.

In cross-sectional analyses, early institutional care is associated with shorter stature but not obesity during puberty in children adopted into US families. We examined whether shorter stature and leaner body composition in youth adopted internationally from institutions would continue as puberty progressed. We also examined whether current psychosocial stress would moderate the association between early institutional deprivation and growth during adolescence. Using an accelerated longitudinal design and linear mixed-effects models, we examined the height and body mass index (BMI) of 132 previously institutionalized (PI) and 176 nonadopted (NA) youth. We examined youth aged 7-15 at the beginning of the study three times across 2 years. Nurses assessed anthropometrics and pubertal status. Current psychosocial stress was measured using the Youth Life Stress Interview. Our results indicated that PI youth remained shorter and leaner across three assessments than NA youth. However, age-and-sex-adjusted BMI increased faster in PI youth. Psychosocial stress during puberty predicted greater age-and-sex-adjusted BMI, but this effect did not differ by group. The gap in BMI but not height appears to close between PI and NA youth. Higher psychosocial stress was associated with higher BMI during puberty.

Background Blood flow restriction (BFR) training has been reported to have significant benefits on local skeletal muscle including increasing local muscle mass, strength, and endurance while exercising with lower resistance. As a result, patients unable to perform traditional resistance training may benefit from this technique. However, it is unclear what effects BFR may have on other body systems, such as the cardiovascular and pulmonary systems. It is important to explore the systemic effects of BFR training to ensure it is safe for use in physical therapy. Purpose The purpose of this study was to systematically review the systemic effects of blood flow restriction training when combined with exercise intervention. Study Design Systematic review. Methods Three literature searches were performed: June 2019, September 2019, and January 2020; using MedLine, ScienceDirect, PubMed, Cochrane Reviews and CINAHL Complete. Inclusion criteria included: at least one outcome measure addressing a cardiovascular, endocrinological, systemic or proximal musculoskeletal, or psychosocial outcome, use of clinically available blood flow restriction equipment, use of either resistance or aerobic training in combination with BFR, and use of quantitative measures. Exclusion criteria for articles included only measuring local or distal musculoskeletal changes due to BFR training, examining only passive BFR or ischemic preconditioning, articles not originating from a scholarly peer-reviewed journal, CEBM level of evidence less than two, or PEDro score less than four. Articles included in this review were analyzed with the CEBM levels of evidence hierarchy and PEDro scale. Results Thirty-five articles were included in the review. PEDro scores ranged between 4 and 8, and had CEBM levels of evidence of 1 and 2. Common systems studied included cardiovascular, musculoskeletal, endocrine, and psychosocial. This review found positive or neutral effects of blood flow restriction training on cardiovascular, endocrinological, musculoskeletal, and psychosocial outcomes. Conclusions Although BFR prescription parameters and exercise interventions varied, the majority of included articles reported BFR training to produce favorable or non-detrimental effects to the cardiovascular, endocrine, and musculoskeletal systems. This review also found mixed effects on psychosocial outcomes when using BFR. Additionally, this review found no detrimental outcomes directly attributed to blood flow restriction training on the test subjects or outcomes tested. Thus, BFR training may be an effective intervention for patient populations that are unable to perform traditional exercise training with positive effects other than traditional distal muscle hypertrophy and strength and without significant drawbacks to the individual. Level of Evidence 1b

The growth hormone (GH)–insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI.

Context Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised. Objective This work aims to assess the long-term safety of GH treatment in clinical practice. Methods Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose. Results The combined studies comprised 37 702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130 476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P = .003 and P = .001, respectively) and the non-SGA subgroup (both P = .002), and for SAEs in the intermediate- and high-risk groups (P = .002 and P = .05, respectively). Conclusions We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

Background Somatrogon is a long-acting recombinant human growth hormone (hGH) currently being developed as a once-weekly subcutaneous injectable treatment for pediatric patients with growth hormone deficiency (GHD). A recent global Phase 3 study compared the efficacy and safety of somatrogon administered once weekly with Genotropin administered once daily in pediatric patients with GHD (ClinicalTrials.gov: NCT02968004). Aims To understand and describe physicians’ experiences using once-weekly somatrogon injections compared with once-daily hGH injections during the Phase 3 study. Methods In this quantitative, cross-sectional, observational study, a 14-item multiple choice questionnaire was administered to physicians who were clinical investigators in the Phase 3 study. The questionnaire was designed to assess physicians’ experiences, preferences and satisfaction regarding the use of the once-weekly somatrogon regimen compared with the standard once-daily hGH injection regimen. Survey results were analyzed quantitatively using descriptive statistics. Results A total of 24 physicians who were part of the global Phase 3 study (mean age [SD]: 58.5 [10.1] years; 10 males, 14 females) in 12 different countries completed the on-line survey. Compared with daily injections, most physicians preferred somatrogon (n=18, 75.0%) and reported that somatrogon was more convenient (n=19, 79.2%), less burdensome (n=19, 79.2%) and that they would be more likely to prescribe somatrogon to patients in the future (n=20, 83.3%). In terms of being more likely to support positive long-term growth outcomes, 37.5% (n=9) of physicians selected somatrogon; the remaining physicians (n=15, 62.5%) reported no difference between treatments. The proportion of physicians who were satisfied or very satisfied with somatrogon was 95.8% (n=23), compared with 87.5% (n=21) for daily hGH injections. Most physicians (n=15, 62.5%) reported that daily hGH injections required more effort/much more effort to monitor adherence, compared with somatrogon. Some physicians (n=7, 29.2%) reported that explaining the device instructions to patient/caregivers required more/much more effort for somatrogon compared with daily hGH injections; more than half (n=14, 58.3%) reported no difference in effort required for either regimen. Physicians were divided as to which treatment needed more/much more effort to: (i) explain the injection regimen (n=7 [29.2%] daily injection; n=7 [29.2%] no difference; n=10 [41.7%] somatrogon), (ii) explain what to do if an injection is missed (n=7 [29.2%] daily injection; n=9 [37.5%] no difference; n=8 [33.3%] somatrogon), and (iii) address patient/caregiver questions (n=8 [33.3%] daily injection; n=11 [45.8%] no difference; n=5 [20.8%] somatrogon). Conclusions Overall, physicians from the global Phase 3 study were positive about their experience using somatrogon for the treatment of children with GHD. Physicians generally preferred the once-weekly somatrogon injection regimen, with most physicians reporting somatrogon to be more convenient and less burdensome to patients, indicating that they would be more likely to prescribe somatrogon to their patients in the future. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Background Achondroplasia is associated with disproportionate short stature and significant and potentially severe medical complications. Vosoritide is the first medicine to treat the underlying cause of achondroplasia and data from phase 3 and phase 2 extension studies showed effects on growth and body proportions. However, there are currently no long-term data available on the direct impact on endpoints such as medical complications and health-related quality of life (HRQoL). This study explored the perceived impact of achondroplasia on medical complications, HRQoL, healthcare resource use and mortality, and potential modifying effects of vosoritide, based on published evidence and expert opinion. Structured expert opinion was obtained by an international modified Delphi study among 14 experts in managing achondroplasia performed on a virtual platform and consisting of an explorative phase followed by an anonymous individual rating round. Results Overall, the panelists expect that in individuals starting long-term treatment between 2 years of age and puberty, growth velocity increases observed in the clinical trials will be maintained until final height is reached (92% agreement) and will likely result in clinically meaningful improvements in upper-to-lower body segment ratio (85%). Earlier treatment initiation will likely result in a greater final height (100%) and more likely improve proportionality (92%) than later treatment. Although current data are limited, ≥ 75% of panelists find it conceivable that the earlier long-term treatment is started, the greater the probability of a positive effect on the lifetime incidence of symptomatic spinal stenosis, kyphosis, obstructive sleep apnea, and foramen magnum stenosis. These are among the most clinically important complications of achondroplasia because of their high impact on comorbidity, mortality, and/or HRQoL. A positive effect of vosoritide on the incidence of surgeries through lifetime was considered more likely with earlier long-term treatment (90%). Conclusions This explorative study, based on international expert opinion, provides further insight into the medical and functional impacts of achondroplasia and how these might be modified through long-term use of vosoritide. The results can be used to guide the direction and design of future research to validate the assumptions and to discuss potential treatment outcomes with disease modifying therapies with families and clinicians.

Context Somapacitan, a once-weekly reversible albumin-binding GH derivative, is evaluated in children with GH deficiency (GHD). Objective To demonstrate efficacy and safety of somapacitan vs daily GH. Methods REAL4 is a randomised, multinational, open-labeled, active-controlled parallel group phase 3 trial, comprising a 52-week main trial and 3-year extension (NCT03811535). Setting Eighty-six sites across 20 countries. Patients 200 treatment-naïve patients were randomized and exposed. Interventions Patients were randomized 2:1 to somapacitan (0.16 mg/kg/wk) or daily GH (Norditropin; 0.034 mg/kg/d), administered subcutaneously. Main outcome measures The primary endpoint was annualized height velocity (HV; cm/y) at week 52. Additional assessments included HV SD score (SDS), height SDS, bone age, IGF-I SDS, patient-reported outcomes, and safety measures. Results Estimated mean HV at week 52 was 11.2 and 11.7 cm/y for somapacitan and daily GH, respectively. Noninferiority was confirmed. Changes in HV SDS, height SDS, bone age, and IGF-I SDS from baseline to week 52 were similar between treatment groups. At week 52, mean IGF-I SDS values were similar between treatment groups and within normal range (–2 to +2). Safety of somapacitan was consistent with the well-known daily GH profile. Low proportions of injection-site reactions were reported for somapacitan (5.3%) and daily GH (5.9%). Both treatments similarly reduced disease burden from baseline to week 52, whereas a greater treatment burden reduction was observed for somapacitan. Conclusions Similar efficacy for somapacitan compared to daily GH was demonstrated over 52 weeks of treatment with comparable safety and mean IGF-I SDS levels in treatment-naïve children with GHD.

Objectives Omnitrope® (somatropin, Sandoz Inc.) is one of several recombinant human growth hormones (rhGH) approved in the United States (US) for use in pediatric indications, including growth hormone deficiency (GHD) and idiopathic short stature (ISS). We report data on the effectiveness and safety of Omnitrope® in the US cohort of the PATRO Children (international, longitudinal, non-interventional) study. Methods All visits and assessments are carried out according to routine clinical practice, and doses of Omnitrope® are given according to country-specific prescribing information. Results By September 2018, 294 US patients were recruited; the two largest groups were GHD (n=193) and ISS (n=62). Across all indications, HSDS improvement (ΔHSDS) from baseline at three years was +1.0 (rhGH-naïve, +1.2; pre-treated, +0.7). In pre-pubertal patients, ΔHSDS from baseline at three years was +0.94 (rhGH-naïve, +1.3; pre-treated, +0.7). Following three years of treatment, ΔHSDS from baseline was +1.3 in rhGH-naïve GHD patients and +1.1 in rhGH-naïve ISS patients. In pre-pubertal rhGH-naïve patients, ΔHSDS from baseline was +1.3 and +1.2 in GHD and ISS patients, respectively. Overall, 194 patients (66.0%) experienced adverse events (AEs; n=886 events); most were of mild-moderate intensity. Five patients (1.7%) had AEs that were suspected to be treatment-related (n=5 events). All reported neoplasms were benign, non-serious, and considered unrelated to rhGH therapy. No AEs of diabetes mellitus or hyperglycemia were reported. Conclusions Omnitrope® appears to be well tolerated and effective in the majority of patients, without evidence of an increased risk of developing unexpected AEs, diabetes mellitus, or new malignancies during treatment.