Long-term Growth Hormone Treatment Research Articles

Discontinuation of long-term growth hormone treatment in adults with growth hormone deficiency: a survey of UK practice.

We conducted a survey of UK endocrine clinicians between June 2022 and August 2022 to understand current practices regarding GH treatment discontinuation in adults with growth hormone deficiency. Using Survey Monkey®, a web-based multiple-choice questionnaire was disseminated to the UK Society for Endocrinology membership. It consisted of 15 questions on demographics, number of patients receiving GH and current practice on GH treatment discontinuation. In total, 102 endocrine clinicians completed the survey. Of these, 65 respondents (33 endocrinologists and 32 specialist nurses) indicated active involvement in managing patients with growth hormone deficiency. In total, 27.7% of clinicians were routinely offering a trial of GH discontinuation to adults receiving long-term GH therapy. Only 6% had a clinical guideline to direct such practice. In total, 29.2% stated that GH discontinuation should be routinely offered as an option to patients on long-term treatment, whilst 60% were not clearly in favour or against this approach but stated that it should probably be considered, and 9.2% were against. During the GH withdrawal period, most clinicians monitor signs and symptoms (75.4%), measure IGF-1 (84.6%), and complete a quality-of-life assessment (89.2%). The practice of offering a trial of GH discontinuation in growth hormone deficiency adults on long-term GH therapy is highly variable, reflecting the lack of high-quality evidence. Around a quarter of clinicians offer GH withdrawal for a number of reasons, but only a few have a local clinical guidance. A further 60% of clinicians stated they would probably consider such an approach. Methodologically sound studies underpinning the development of safe and cost-effective guidance are needed. In this UK survey of endocrine clinicians managing adults with growth hormone deficiency on long-term GH therapy, we explored for the first-time current practice and views on offering GH treatment discontinuation. In total, 27.7% of clinicians were routinely offering this option for a variety of reasons. Only 6% have local clinical guideline available to direct their practice on this. The majority of clinicians (60%), were not clearly in favour or against this approach but indicated it should probably be considered. In the absence of robust evidence on consequences of GH withdrawal, clinicians proposed monitoring of various clinical, biochemical and quality-of-life parameters during the period of discontinuation. Methodologically sound studies that will underpin the development of a safe, cost-effective guidance are needed.

Measured Resting Energy Expenditure by Indirect Calorimetry and Energy Intake in Long-Term Growth Hormone-Treated Children with PWS

Introduction: Severe obesity can develop in children with PWS when food intake is not controlled. Maintenance of body weight requires an energy balance, of which energy intake and energy expenditure are important components. Previous studies described a decreased resting energy expenditure (REE) in growth hormone (GH)-untreated children with PWS. In short-term studies, no difference in REE was found between GH-treated and untreated children with PWS. However, there are limited data on REE in children with PWS who were GH-treated for a long period. Methods: This study describes measured REE (mREE), energy intake, and body composition during long-term GH treatment in children with PWS. Patients were treated with 1.0 mg GH/m2/day (∼0.035 mg/kg/day). REE was determined by indirect calorimetry; dietary energy intake was calculated using a 3-day dietary record. Body composition by dual-energy X-ray absorptiometry (DXA) scans. Results: We included 52 GH-treated children with PWS with a mean (SD) age of 8.53 (4.35) years and a median (IQR) GH-treatment duration of 7 (4–11) years. mREE increased with age, but was not associated with GH-treatment duration. A higher LBM was associated with higher mREE. Mean energy intake was significantly lower compared to daily energy requirements (DER) for age- and sex-matched healthy children (p Conclusion: In children with PWS, mREE increases with age. GH-treatment duration is not associated, whereas LBM is an important determinant of mREE. Children with PWS have a low to very low energy intake compared to DER for age- and sex-matched children, with a declining intake when becoming older.

Auxological and metabolic effects of long-term treatment with recombinant growth hormone in children born small for gestational age: a retrospective study.

Children born small for gestational age (SGA) not showing catch-up during the first two years of life reportedly show an impaired growth rate and adult height, as well as a worse metabolic outcome, mainly in terms of glycemic and lipid profile, compared to general population. In SGA children with short stature, treatment with recombinant growth hormone (GH) is currently recommended until adolescence; therefore, it may last long-term. The aim of the current study was to evaluate the auxological and metabolic effects and the safety of long-term recombinant GH treatment in SGA children. The study included 15 SGA children (5 F, 10 M; mean age: 6.78 yrs) treated with GH for at least 48 months. Growth and metabolic parameters, including glycemic and lipid profile, transaminases, and urycemia, were collected every six months. Compared to baseline, SGA children showed a significant improvement in height, weight, and growth rate after four yaers of treatment with GH (p ≤ 0.002), being already evident after six months of treatment (p < 0.001). Noteworthy, patients showed a constant, significant improvement in height throughout the treatment, as it was significantly higher at each follow-up compared to the previous one, until 42 months of treatment, except at 30 months of treatment (p < 0.001 T6VST12; p < 0.01 T12VST18, T18VST24; p < 0.05 T30VST36, T36VST42). Considering metabolic parameters, compared to baseline, a recurring increase in glycemia (p ≤ 0.028 vs T30, T36, and T48) and decrease in AST (p ≤ 0.035 vs T36, T42, and T48) and an occasional decrease in LDL cholesterol (p ≤ 0.04 vs T24 and T42) and triglycerides (p = 0.008 vs T18) and increase in urycemia (p = 0.034 vs T42). Considering safety profile, treatment was well tolerated, as the most frequently reported adverse event was poor compliance (20%); no hyperglycemia, hypercholesterolemia or hyperstransaminasemia occurred throughout the treatment, CONCLUSIONS: Long-term GH treatment showed to be effective in improving height and growth rate in SGA children, with a positive impact of metabolic profile and a safety profile, although glycemia should be carefully monitored over time.

3M syndrome: Evaluating the clinical and laboratory features and the response of the growth hormone treatment: Single center experience

Introduction & objective3 M Syndrome is a rarely encountered autosomal recessive syndrome characterized by low birth weight, severe postnatal growth deficiency, and minor dysmorphic abnormalities. 3 M-related short stature has been attributed to the resistance to growth hormone (GH) to a certain extent rather than to GH deficiency. The resistance to GH, on the other hand, has been associated with impaired protein scaffolding, transport, and p53-mediated apoptosis at the IGF-1 post-receptor pathway. In this context, the objective of this study is to evaluate the clinical, laboratory, and genetic characteristics of the patients with 3 M syndrome, detect the mutations frequently observed in these patients, and assess their response to GH treatment. Material&methodsThe sample of this single-center study consisted of patients diagnosed with 3 M syndrome based on genetic tests between 2007 and 2021. Patients’ clinic, laboratory, and genetic characteristics pertaining to the time of admission and follow-up were recorded. All patients except one underwent a growth hormone stimulation test (GHST) (Levo-dopa or insulin tolerance test). Insulin-like growth factor (IGF) generation test was performed on those with sufficient GHST results (0.1 mg/kg/day for four days). ResultsThe median age of the patients, five females and three males, was 2.8 (0.25–8.12) years at admission. All but one patient were small for gestational age (SGA). The patient with normal birth weight was the baby of a diabetic mother. Obscurin-like 1 (OBSL1) variant was detected in all cases. The median height standard deviation score (SDS) at admission was −4.94 ((-5.63)- (−3.27)) SDS, and the median midparenteral height SDS was −1.27 SDS ((-3.1)- (0.34)). All patients were prepubertal at admission. The GHST response was sufficient in five cases. IGF generation test was performed in three cases. Seven patients received GH therapy (35–57 μg/kg/day). Five of these patients discontinued GH therapy since their growth velocity (GV) fell below normal during treatment. In addition, one case discontinued GH therapy because her IGF-1 value was>2 SDS, and another case received gonadotropin-releasing hormone (GnRH) analogs together with GH therapy. The median age and height SDS of the patients were 10.1 (1.79–18) years and −5.09 SDS ((-7.11)- (2.45)), respectively, as of the last follow-up visit. The height SDS values of the two cases that reached the final height were −7.11 SDS and −3.39 SDS. There were no side effects of GH treatment. ConclusionThe study findings indicated a good GV during the early stages of the long-term GH treatment administered to patients with 3 M syndrome. However, response to GH therapy decreased in the following years, and the desired improvement in height SDS could not be achieved in patients who reached their final heights. Taken together with the literature data, it has been concluded that initiating GH therapy in the prepubertal period provided better outcomes than after puberty.

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.

Discontinuation of long-term growth hormone treatment in adults with severe growth hormone deficiency: A United Kingdom web-based survey of endocrine practice

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

An Augmented Reality Mobile App (Easypod AR) as a Complementary Tool in the Nurse-Led Integrated Support of Patients Receiving Recombinant Human Growth Hormone: Usability and Validation Study

Children with growth hormone deficiency face the prospect of long-term recombinant human growth hormone (r-hGH) treatment requiring daily injections. Adherence to treatment is important, especially at treatment initiation, to achieve positive health outcomes. Historically, telenursing services embedded in patient support programs (PSPs) have been a valid approach to support r-hGH treatment initiation and patient education and facilitate adherence by identifying and optimizing appropriate injection techniques. The development of mobile phones with augmented reality (AR) capabilities offers nurses new tools to support patient education. To investigate experiences among nurses of a new mobile phone app developed to support patient training with a phone-based PSP for r-hGH treatment. In 2020, the Easypod AR mobile app was launched to support nurse-driven telehealth education for patients initiating r-hGH therapy with the Easypod electromechanical auto-injector device. Nurses who were part of PSPs in countries where the Easypod AR app had been launched or where training was provided as part of an anticipated future launch of the app were invited to participate in an online survey based on the Mobile App Rating Scale to capture their feedback after using the app. In total, 23 nurses completed the online questionnaire. They positively rated the quality of the app across multiple dimensions. The highest mean scores were 4.0 for engagement (ie, adaptation to the target group; SD 0.74), 4.1 (SD 0.79) for functionality (navigation) and 4.1 (SD 0.67) for aesthetics (graphics). Responses indicated the potential positive impact of such a tool on enhancing patient education, patient support, and communication between patients and PSP nurses. Some participants also suggested enhancements to the app, including gamification techniques that they felt have the potential to support the formation of positive treatment behaviors and habits. This study highlights the potential for new digital health solutions to reinforce PSP nurse services, including patient education. Future studies could explore possible correlations between any behavioral and clinical benefits that patients may derive from the use of such apps and how they may contribute to support improved patient experiences and treatment outcomes.

The Effects of Long-term Growth Hormone Treatment on Ocular Findings.

This study aimed to examine the long-term changes in anterior chamber depth (ACD), central corneal thickness (CCT), axial length (AxL), peripapillary retinal nerve fibre layer thickness (RNFLT), peripapillary ganglion cell layer - inner plexiform layer (GCL-IPL) thickness, and peripapillary choroidal thickness (ChT) after rhGH replacement treatment in paediatric patients with IGHD, compared to healthy controls. Twenty-two children with IGHD including 12 girls and 10 boys were enrolled in the study group, and 30 (16 girls, 14 boys) healthy children composed the control group. A detailed ophthalmological examination was performed for each participant. ACD, CCT, AxL, peripapillary RNFLT, GCL-IPL thickness and ChT measurements were performed before the rhGH replacement treatment and in the 12th month of the post-treatment period, as well as the corresponding visits in the control group. AxL ultrasound pachymetry (CCT), peripapillary RNFL thickness, peripapillary RNFLT, GCL-IPL thickness, and peripapillary ChT parameters were measured by spectral-domain optical coherence tomography. The mean age of the groups were similar (p = 0.143). 12-month CCT, ACD, and AxL measurements of the study group showed significantly higher results than the pre-treatment measurements (p = 0.005, p = 0.024, and p = 0.002, respectively). Similarly, the mean RNFLT and ChT measurements of the study group obtained from all sectors were significantly higher in the 12th-month visit (p < 0.001 for both) other than the RNFLT, and GCL-IPL thickness measurements (p > 0.05 for all). However, all these parameters were similar at pre- and post-treatment visits in the control group (p > 0.05 for all). The mean pre-treatment values of all these parameters were significantly lower in the study group compared to the control group (p < 0.05 for all), other than the RNFLT, GCL-IPL thickness measurements (p > 0.05 for all), while the mean post-treatment values of all these parameters in both groups were similar at month 12 (p > 0.05 for all). GH replacement treatment in childhood may play an important role in the development of the neural retina and can be effective on the anterior segment, RNFLT and ChT measurements.

Short-Term Growth Hormone Administration Mediates Hepatic Fatty Acid Uptake and De Novo Lipogenesis Gene Expression in Obese Rats

Obesity has been linked to metabolic syndrome, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). Obesity causes a decrease in growth hormone (GH) levels and an increase in insulin levels. Long-term GH treatment increased lipolytic activity as opposed to decreasing insulin sensitivity. Nonetheless, it is possible that short-term GH administration had no impact on insulin sensitivity. In this study, the effect of short-term GH administration on liver lipid metabolism and the effector molecules of GH and insulin receptors were investigated in diet-induced obesity (DIO) rats. Recombinant human GH (1 mg/kg) was then administered for 3 days. Livers were collected to determine the hepatic mRNA expression and protein levels involved in lipid metabolism. The expression of GH and insulin receptor effector proteins was investigated. In DIO rats, short-term GH administration significantly reduced hepatic fatty acid synthase (FASN) and cluster of differentiation 36 (CD36) mRNA expression while increasing carnitine palmitoyltransferase 1A (CPT1A) mRNA expression. Short-term GH administration reduced hepatic FAS protein levels and downregulated gene transcription of hepatic fatty acid uptake and lipogenesis, while increasing fatty acid oxidation in DIO rats. DIO rats had lower hepatic JAK2 protein levels but higher IRS-1 levels than control rats due to hyperinsulinemia. Our findings suggest that short-term GH supplementation improves liver lipid metabolism and may slow the progression of NAFLD, where GH acts as the transcriptional regulator of related genes.

Reduced CV risk with long-term GH replacement in AGHD: data from two large observational studies.

Adult growth hormone deficiency (AGHD) is associated with an increased risk of cardiovascular (CV) disease. Long-term growth hormone (GH) treatment could improve CV outcomes. The objective of this study was to evaluate CV disease risk in patients with AGHD who received GH replacement therapy for up to 10 years as part of NordiNet® IOS (NCT00960128) and the ANSWER Program (NCT01009905). The studies were observational, non-interventional and multicentre, monitoring long-term effectiveness and safety of GH treatment. NordiNet® IOS involved 23 countries (469 sites) across Europe and the Middle East. The ANSWER Program was conducted in the USA (207 sites). This analysis included patients aged 18-75 years who were GH naïve at study entry, who had ≤10 years of GH treatment data and who could be assessed for CV risk for at least 1 follow-up year. The main outcome measure was risk of CV disease by age 75 years, as calculated with the Multinational Cardiovascular Risk Consortium model (Brunner score) using non-high-density lipoprotein cholesterol adjusted for age, sex and CV risk factors. The results of this analysis showed that CV risk decreased gradually over the 10-year period for GH-treated patients. The risk was lower for patients treated for 2 and 7 years vs age- and sex-matched control groups (not yet started treatment) (14.51% vs 16.15%; P = 0.0105 and 13.53% vs 16.81%; P = 0.0001, respectively). This suggests that GH treatment in people with AGHD may reduce the risk of CV disease by age 75 years compared with matched controls.

Molecular Genetics and Pathogenesis of the Floating Harbor Syndrome: Case Report of Long-Term Growth Hormone Treatment and a Literature Review.

Introduction: Floating Harbor syndrome (FHS) is an extremely rare disorder, with slightly more than a hundred cases reported worldwide. FHS is caused by heterozygous mutations in the SRCAP gene; however, little is known about the pathogenesis of FHS or the effectiveness of its treatment. Methods: Whole-exome sequencing (WES) was performed for the definitive molecular diagnosis of the disease. Identified variants were validated using Sanger sequencing. In addition, systematic literature and public data on genetic variation in SRCAP and the effects of growth hormone (GH) treatment was conducted. Results: We herein report the first case of FHS in the Russian Federation. The male proband presented with most of the typical phenotypic features of FHS, including short stature, skeletal and facial features, delayed growth and bone age, high pitched voice, and intellectual impairment. The proband also had partial growth hormone deficiency. We report the history of treatment of the proband with GH, which resulted in modest improvement in growth prior to puberty. WES revealed a pathogenic c.7466C>G (p.Ser2489*) mutation in the last exon of the FHS-linked SRCAP gene. A systematic literature review and analysis of available genetic variation datasets highlighted an unusual distribution of pathogenic variants in SRCAP and confirmed the lack of pathogenicity for variants outside of exons 33 and 34. Finally, we suggested a new model of FHS pathogenesis which provides possible basis for the dominant negative nature of FHS-causing mutations and explains limited effects of GH treatment in FHS. Conclusion: Our findings expand the number of reported FHS cases and provide new insights into disease genetics and the efficiency of GH therapy for FHS patients.

Long-Term Growth Hormone Treatment of Children with PWS: The Earlier the Start, the Better the Outcomes?

Long-term effects of growth hormone (GH) treatment in young children with Prader-Willi syndrome (PWS) have never been compared with untreated age-matched controls with PWS, and it is unclear if starting GH in the first year of life is safe and more effective than starting GH in early childhood. We investigated the effects of long-term GH on body composition, anthropometrics and cognition in young children with PWS compared to untreated controls and assessed whether starting GH in the first year of life is optimal and safe. An open-label, prospective study was performed, comparing GH-treated children with untreated controls, and comparing children who started GH in the first year of life (subgroup A) with children who started between 2–5 years (subgroup C). A total of 82 GH-treated children with PWS and 22 age-matched controls with PWS were included. The main outcome measures were body composition, anthropometrics, IQ, and safety parameters. After 8 years, GH-treated children had significantly better body composition and were taller than age-matched controls. Subgroup A had a lower FM% trajectory during treatment than subgroup C and showed a greater and longer-term increase in the LBM index. After 8 years, subgroup A had a lower trunk/peripheral fat ratio (p = 0.043) and higher IQ (p = 0.043). No adverse effects of starting GH in the first year were found. Children with PWS who received long-term GH had a better body composition and growth than untreated age-matched controls and starting GH in the first year of life was optimal and safe.

Growth hormone treatment does not to lead to insulin resistance nor excessive rise in IGF-1 levels, while improving height in patients small for gestational age A long-term observational study.

ObjectiveIn children born small for gestational age (SGA), the relationship between growth hormone (GH) treatment and insulin resistance (IR) has only been investigated for a short period, necessitating a longer observation period. This study aimed to evaluate the long‐term (10 years) effect of GH to SGA‐children on IR and safety during treatment.DesignThis was a multicenter observational study. Patients: SGA‐children who received GH treatment in Spain (stratified by Tanner‐stage and age at GH onset [two groups: ≤6 years old or >6 years old]). Measurements: The analysed variables (yearly measures) included auxologic, metabolic (insulin‐like growth factor‐1 (IGF‐1), height velocity [HV], weight and homeostatic model assessment‐IR [HOMA‐IR]) and safety data. Data were collected prospectively (since the study approval: 2007) and retrospectively (since the initiation of GH treatment: 2005–2007).ResultsA total of 389 SGA children (369 Tanner‐I) were recruited from 27 centres. The mean age (standard deviation) of the children at GH treatment onset was 7.2 (2.8) years old. IGF‐1 (standard deviation score [SDS]) and HOMA‐IR values tended to increase until the sixth year of GH‐treatment, with significant differences being observed only during the first year, while these remained stable in the later years (within normal ranges). Height (SDS) increased significantly (basal: −3.0; tenth year: −1.13), and the maximum HV (SDS) occurred during the first year (2.75 ± 2.39).ConclusionsHOMA‐IR values increased significantly in SGA‐children during the first year of GH‐treatment, remained stable and were within normal ranges in all cases. Our 10‐year data suggests that long‐term GH treatment does not promote IR and is well‐tolerated, safe and effective.

Growth hormone treatment and bone mineral density in pediatric patients with Prader-Willi syndrome.

Previous reports indicate that growth hormone (GH) treatment for Prader-Willi syndrome (PWS) improves bone mineral density (BMD) only when initiated at a young age and not when initiated in adulthood. However, there are no data on BMD during long-term GH treatment of Japanese children and adolescents with PWS. Thus, this study aimed to investigate BMD changes among patients with PWS, who were undergoing GH treatment from childhood to adolescence. Sixty-seven pediatric patients with PWS who had GH treatment initiated during childhood between January 2003 and June 2020 were evaluated. To avoid underestimation, we used total body BMD, which was evaluated using dual-X-ray absorptiometry adjusted for the BMD z-score using patient height, sex, and age. In both sexes, age was negatively correlated with the BMD-standard deviation score (SDS) (male: r=-0.156 [p=0.042]; female: r=-0.197 [p=0.043]), which started to decrease in childhood. The BMD-SDS of patients with PWS decreases gradually despite GH treatment. As there are no clear recommendations about monitoring of bone health in patients with PWS, further studies are needed to improve the guidelines for screening of BMD and treatment of patients with PWS.

Twenty Years of GH Treatment in Adults with Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder. In adults, the syndrome is characterised by muscular hypotonia, a different body composition with more body fat than muscle mass, hyperphagia, behavioural problems, and cognitive dysfunction. Endocrine deficiencies are common, including growth hormone (GH) deficiency. Here, we present data from a cross-sectional study in adults with PWS with a focus on the long-term safety of GH treatment. A total of 22 patients (14 men) were treated with GH for a median of 20 years. Data on body composition, hormones, and metabolic parameters were retrieved from the patients’ medical records. The median age was 27 years. The median GH dose was 0.5 mg/day. Insulin-like growth factor 1 (IGF-I) and blood lipids were normal, while fasting glucose and HbA1c were slightly elevated in three men with diabetes. Fat mass was less than fat free mass in all, though this was less pronounced in women. GH treatment did not negatively affect the metabolic profile, and none developed cardiovascular diseases or cancer. All adults on long-term GH treatment had a normal body composition and our results indicate that treatment was safe. However, PWS is a complex, multisystemic disease and continuous, individual considerations are required during GH treatment, especially in patients with risk factors for adverse effects.

Prevention of Growth Failure in Turner Syndrome: Long-Term Results of Early Growth Hormone Treatment in the “Toddler Turner” Cohort

Introduction: In the randomized “Toddler Turner” study, girls who received growth hormone (GH) starting at ages 9 months to 4 years (early-treated [ET] group) had marked catch-up growth and were 1.6 ± 0.6 SD taller than untreated (early-untreated [EUT]) control girls after 2 years. However, whether the early catch-up growth would result in greater near-adult height (NAH) was unknown. Therefore, this extension study examined the long-term effects of toddler-age GH treatment on height, pubertal development, and safety parameters. Methods: Toddler Turner study participants were invited to enroll in a 10-year observational extension study for annual assessments of growth, pubertal status, and safety during long-term GH treatment to NAH for both ET and EUT groups. Results: The ET group was taller than the EUT group at all time points from preschool to maturity and was significantly taller at the onset of puberty (p = 0.016), however, the difference was not significant at NAH. For the full cohort (ET + EUT combined, n = 50) mean (± SD) NAH was 151.2 ± 7.1 cm at age 15.0 ± 1.3 years. NAH standard deviation score (SDS) was within the normal range (>−2.0) for 76% of ET and 60% of EUT subjects (68% overall) and correlated strongly with height SDS at GH start (r = 0.78; p < 0.01), which in turn had a modest inverse correlation with age at GH start (i.e., height SDS declined with increasing age in untreated girls [r = −0.30; p = 0.016]). No new safety concerns arose. Conclusion: Although the ET group was taller throughout, height SDS at NAH was not significantly different between groups due to catch-down growth of ET girls during lapses in GH treatment after the Toddler study and similar long-term GH exposure overall. Early initiation of GH by age 6 years, followed by uninterrupted treatment during childhood, can prevent ongoing growth failure and enable attainment of height within the normal range during childhood, adolescence, and adulthood.

Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome

Introduction: Few data exist on long-term growth hormone (GH) treatment in patients with Noonan syndrome (NS). Objective: To evaluate the effectiveness and safety of GH treatment in NS in clinical practice. Methods: Height gain, near-adult height (NAH), and safety were assessed in 2 complementary non-interventional studies: NordiNet® IOS and ANSWER. The safety analysis included 412 patients, and the effectiveness analysis included 84 GH-treated patients (male, n = 67) with ≥4 years’ height standard deviation score (HSDS) data. HSDS was determined using national reference (NR) and NS-specific (NSS) data. Results: The mean (SD) baseline age was 8.38 (3.57) years; HSDS, −2.76 (1.03); GH dose, 41.6 (11.1) µg/kg/day. The mean (SD) HSDS increase from baseline (ΔHSDS) was 0.49 (0.37) (first year), 0.79 (0.58) (second year), and 1.01 (0.60) (third year) (NR). The mean (SD) HSDS at year 3 was −1.66 (1.00) (NR; 1.06 [1.12] [NSS]). Twenty-four patients achieved NAH. The mean (SD) NAH SDS (NR) was −1.51 (0.60) (154.90 [3.21] cm) in females and −1.79 (1.09) (165.61 [7.19] cm) in males; 70.8% (17/24) had NAH SDS ≥ −2. Adverse drug reactions and GH-unrelated serious adverse events (n = 34) were reported in 22/412 (5.3%) patients. Four neoplasms and 3 cases of scoliosis were reported; no cardiovascular adverse events occurred. Conclusions: GH-treated children with NS achieved substantial height gain during the first 3 years of follow-up. Overall, 24 patients achieved NAH, with 70.8% having NAH SDS ≥ –2. There was no evidence to support a higher prevalence of neoplasm, or cardiac or other comorbidities.

Influence of growth hormone therapy on the occurrence of a second neoplasm in survivors of childhood cancer.

Growth hormone (GH) deficiency is a common late effect of cranial irradiation. However, concerns have been raised that GH treatment might lead to an increased risk of a second neoplasm (SN). To study the impact of GH treatment on the risk of SN in a French cohort of survivors of childhood cancer (CCS) treated before 1986. Cohort study and nested case-control study. Of the 2852 survivors, with a median follow-up of 26 years, 196 had received GH therapy (median delay from cancer diagnosis: 5.5 years). Occurrence of SN. In total, 374 survivors developed a SN, including 40 who had received GH therapy. In a multivariate analysis, GH treatment did not increase the risk of secondary non-meningioma brain tumors (RR: 0.6, 95% CI: 0.2-1.5, P = 0.3), secondary non-brain cancer (RR: 0.7, 95% CI: 0.4-1.2, P = 0.2), or meningioma (RR: 1.9, 95% CI: 0.9-4, P = 0.09). Nevertheless, we observed a slight non-significant increase in the risk of meningioma with GH duration: 1.6-fold (95% CI: 1.2-3.0) after an exposure of less than 4 years vs 2.3-fold (95% CI: 0.9-5.6) after a longer exposure (P for trend = 0.07) confirmed by the results of a case-control study. This study confirms the overall safety of GH use in survivors of childhood cancer, which does not increase the risk of a SN. The slight excess in the risk of meningioma in patients with long-term GH treatment is non-significant and could be due to difficulties in adjustment on cranial radiation volume/dose and/or undiagnosed meningioma predisposing conditions.

Analysis of real-world data on growth hormone therapy adherence using a connected injection device

BackgroundPoor adherence to long-term recombinant human growth hormone (r-hGH) treatment can lead to suboptimal clinical outcomes; consequently, supporting and monitoring adherence is a crucial part of patient management. We assessed adherence to r-hGH treatment in children with growth disorders over 48 months using a connected monitoring device (easypod™), which automatically transmits adherence data via an online portal (easypod™ connect); both sit within an adherence decision support system (ADSS). We also investigated the effect of age and sex on adherence.MethodsData from children transmitting over 10 injections between January 2007 and February 2019 were analyzed. Adherence (mg injected/mg prescribed) was categorized as high (≥85%), intermediate (> 56–84%) or low (≤56%) and assessed at seven time points from the start of treatment up to 48 months. Adherence was investigated over time and stratified by puberty status and sex. Mean transmission rate in each adherence category (total number of transmissions/total number of children) at each time point was calculated as a proxy measure of engagement in disease and treatment management. Descriptive analyses were performed.ResultsLongitudinal records were available for 13,553 children. Overall, 71% (n = 9578) had high adherence, 22% (n = 2989) intermediate and 7% (n = 986) low. The proportion of children with high adherence decreased over time from 87% (n = 12,964) to 65% (n = 957) and was higher in pre-pubertal than pubertal children (girls: 80% [n = 1270] vs 70% [n = 4496]; boys 79% [n = 2573] vs 65% [n = 5214]). Children with high adherence had a higher mean number of transmissions (12.5 [SD 24.9]) than children with intermediate (7.2 [SD 15.3]) or low (3.5 [SD 5.7]) adherence.ConclusionsHigh adherence was seen in patients administering r-hGH using the connected device. Children with high adherence were most likely to regularly transmit data. Pubertal children showed lower adherence. We show the potential to develop an ADSS to analyze trends in real-world adherence data. This may prove useful to direct interventions to improve adherence while the ability to readily share data with healthcare professionals may itself improve adherence.

Growth and metabolic effects of long-term recombinant human growth hormone (rhGH) treatment in short children born small for gestational age: GH-RAST study.

Objectives To study the efficacy and influence on metabolism of recombinant human growth hormone (rhGH) treatment in short children born small for gestational age (SGA). Methods Retrospective, observational, multicenter study in 305 short children born SGA, treated with rhGH during a mean±SD of 5.03±1.73yearsat a mean±SD dose of 37±8μg/kg/day. Auxological and metabolic assessment including glucose and lipids profile were collected. Results Mean±SD age at the start of treatment was 7.11±2.78 years. Height and weight improved significantly until the end of treatment from mean-2.72 (CI95%:-2.81 to -2.63) standard deviation score (SDS) to-1.16 (CI95%:-1.44 to -0.88) SDS and from-1.62 (CI95%:-1.69 to -1.55) SDS to-0.94 (CI95%:-1.14 to -0.74) SDS respectively. Mean height gain was 1.27 (CI95%: 0.99-1.54) SDS. Prepubertal patients showed higher height gain than pubertal children (mean [CI95%]=1.44 [CI95%: 1.14-1.74] vs. 0.73 [CI95%: 0.22-1.24], p=0.02). Height gain SDS during treatment negatively correlated with chronological age (CA) and bone age (BA) delay and positively correlated with duration of treatment, height gain during first year of treatment, years on prepubertal treatment and height SDS from target height (TH). Glucose, insulin, and triglycerides increased significantly but remained within the normal range. Total and LDL-cholesterol decreased significantly, and HDL-cholesterol remained unchanged. Conclusions rhGH treatment in short SGA children effectively normalized height in most of the patients and showed a safe metabolic profile. Children who benefit the most are those with greater height SDS distance from TH, BA delay, longer duration of treatment and prepubertal treatment initiation.