rhGH Administration Research Articles

5162 Oral LUM-201 Restores Pulsatile Growth Hormone Secretion and Growth Response in Moderate Pediatric Growth Hormone Deficiency (PGHD): Key Discoveries from Phase 2 of OraGrowtH212 Trial

Abstract Disclosure: F. Cassorla: Consulting Fee; Self; Lumos Pharma, Inc. Research Investigator; Self; Lumos Pharma, Inc. R. Roman: Research Investigator; Self; Lumos Pharma, Inc. M.L. Johnson: Consulting Fee; Self; Lumos Pharma, Inc. A. Avila: Research Investigator; Self; Lumos Pharma, Inc. G. Iñiguez: Research Investigator; Self; Lumos Pharma, Inc. I. Baier: Research Investigator; Self; Lumos Pharma, Inc. D. Said: Research Investigator; Self; Lumos Pharma, Inc. A. Bruchey: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. C. Smith: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. E. Brincks: Employee; Self; Lumos Pharma. Stock Owner; Self; Lumos Pharma, Inc. J. McKew: Employee; Self; Lumos Pharma. Stock Owner; Self; Lumos Pharma. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Ammonett Pharma LLC. P. Pitukcheewanont: Employee; Self; Lumos Pharma. Stock Owner; Self; Lumos Pharma. Objectives: The primary objective was to examine the pharmacokinetic/pharmacodynamic (PK/PD) aspects of oral LUM-201 at doses of 1.6 and 3.2 mg/kg/d with moderate PGHD, involving frequent GH sampling for 12 hours post-administration. Using deconvolutional analysis, the study compared the GH secretion patterns before & after 6 months (m) daily administration of LUM-201. LUM-201, an investigational agonist of the growth hormone (GH) Secretagogue Receptor 1a (GHSR1a), was employed as part of a predictive enrichment marker (PEM) test to identify moderate PGHD subjects likely to respond, based on baseline insulin-like growth factor-1 (IGF-1) level >30 ng/mL & a peak GH of ≥5 ng/mL post a single 0.8 mg/kg dose of LUM-201. Methods: The OraGrowtH212 Trial, conducted at Santiago, Chile, monitors subjects until they approach their near final height. The current report focuses on data analysis at 6 and 12m, with ongoing subject follow-ups extending to 24m. This trial randomized 22 PEM+ moderate PGHD subjects into two LUM-201 dosage groups: 1.6 or 3.2 mg/kg/d. To assess GH secretion, each child was sampled every 10 min from 0800-2000h at baseline & 6m. Safety was assessed throughout the study and growth evaluated at 6 & 12m intervals. Results: At start of the study, basal GH secretion in the LUM-201 1.6mg/kg/d group (all values expressed as mean ± SD µg/kg body weight) was 0.19 ±0.09, pulsatile GH was 1.17 ± 0.66, and total GH was 1.35 ± 0.66. At 6m, each of these parameters had significantly increased to 0.36 ± 0.21, 1.8 ±0.74 and 2.2 ±0.89 respectively (p values from 0.02-0.04). Similar significant increases were seen for LUM-201 3.2mg/kg/d. Combining the data from both LUM-201 doses demonstrated that GH secretion determined by deconvolution analysis was 3.3-4.0 µg/kg/24hrs compared to 5 µg/kg/24hrs derived from published data on normal children (Zadik et al, Horm Res 1992), indicating restoration of GH secretion by LUM-201. These values are considerably less than 25-34µg/kg/d of recombinant human GH used in the treatment of PGHD. At 6m, the annualized height velocity (AHV) was 7.2cm/yr for the LUM-201 1.6mg/kg/d and 8.1cm/yr for the 3.2 mg/kg/d dose. At 12m, AHV for a subset was 6.9cm/yr for the 1.6 dose and 7.2cm/yr for the 3.2 dose. Baseline IGF-1 SDS (mean ±SD) were -1±0.63 in 1.6mg/kg/d group & -0.85±0.47 in 3.2mg/kg/d group. The change over 12m was +0.9 on 1.6 dose and +1.1 on 3.2 dose, indicating similar efficacy for IGF-1 generation. LUM-201 showed good tolerability in this study, with no observed safety concerns in adverse events (AEs), labs, and ECGs. Conclusions: At 6m LUM-201 was able to restore endogenous GH pulsatile secretion to a similar level to that seen in normal children, while normalizing serum IGF-1 concentrations. These results indicate that by restoring endogenous GH secretion, LUM-201 facilitates growth utilizing a much lower amount of GH than that provided by daily exogenous rhGH administration. Presentation: 6/3/2024

The influence of genotype makeup on the effectiveness of growth hormone therapy in children with Prader-Willi syndrome

BackgroundPrader-Willi syndrome (PWS) is a rare multisystemic hereditary illness. Recombinant human growth hormone (rhGH) therapy is widely recognized as the primary treatment for PWS. This study aimed to examine how different PWS genotypes influence the outcome of rhGH treatment in children with PWS.MethodsA review was conducted on 146 Chinese children with PWS, genetically classified and monitored from 2017 to 2022. Unaltered and modified generalized estimating equations (GEE) were employed to examine the long-term patterns in primary outcomes (growth metrics) and secondary outcomes (glucose metabolism metrics and insulin-like growth factor-1 (IGF-1)) during rhGH therapy. The study also evaluated the prevalence of hypothyroidism, hip dysplasia, and scoliosis before and after rhGH treatment.ResultsChildren with PWS experienced an increase in height/length standard deviation scores (SDS) following rhGH administration. The impact of rhGH therapy on growth measurements was similar in both the deletion and maternal uniparental diploidy (mUPD) cohorts. Nevertheless, the deletion group was more prone to insulin resistance (IR) compared to the mUPD group. No significant variations in growth metrics were noted between the two groups (P > 0.05). At year 2.25, the mUPD group showed a reduction in fasting insulin (FINS) levels of 2.14 uIU/ml (95% CI, -4.26, -0.02; P = 0.048) and a decrease in homeostasis model assessment of insulin resistance (HOMA-IR) of 0.85 (95% CI, -1.52, -0.17; P = 0.014) compared to the deletion group. Furthermore, there was a decrease in the IGF standard deviation scores (SDS) by 2.84 (95% CI, -4.84, -0.84; P = 0.005) in the mUPD group during the second year. The frequency of hip dysplasia was higher in the mUPD group compared to the deletion group (P < 0.05).ConclusionsrhGH treatment effectively increased height/length SDS in children with PWS, with similar effects observed in both deletion and mUPD genotypes. Children with mUPD genetype receiving rhGH treatment may experience enhanced therapeutic effects in managing PWS.

Long-term efficacy and safety of PEGylated recombinant human growth hormone in treating Chinese children with growth hormone deficiency: a 5-year retrospective study.

The study endeavored to evaluate the prolonged efficacy and safety of PEGylated rhGH (PEG-rhGH) administration in Chinese children diagnosed with growth hormone deficiency (GHD) over a 5-year period. A retrospective analysis was conducted on children with GHD, who received a 0.2 mg/kg/week dose of PEG-rhGH between 2016 and 2023 in our department. The height standard deviation score (Ht SDS) exhibited a marked elevation post-PEG-rhGH administration (p<0.001), sustaining this enhancement beyond year 3, with increments recorded at 0.94±0.37, 1.49±0.48, 1.77±0.51, 2.12±0.65, and 2.15±0.58 across 5 years. Similarly, the height velocity (HV), insulin-like growth factor-1 standard deviation score (IGF-1 SDS), and bone age to chronological age ratio (BA/CA ratio) underwent significant augmentations (p<0.01). Remarkably, no signs of rapid bone maturation were detected during the 5-year observation. Among the participants, 31 patients (59.62 %) experienced adverse events, of which eight instances (15.38 %) were classified as treatment-related adverse events, but none were severe or unexpected. Additionally, high-density lipoprotein (HDL) levels rose while low-density lipoprotein (LDL) levels fell, both remaining within the standard range throughout the treatment phase. Administering PEG-rhGH at a dosage of 0.2 mg/kg/week proved both effective and well-tolerated in treating prepubertal children with GHD. This regimen also demonstrated positive impacts on lipid metabolism over an extended treatment period.

Clinical profiles and molecular genetic analyses of 98 Chinese children with short statures.

Short stature is one of the most prevalent endocrine disorders in children, and its genetic basis is a complex and actively researched subject. Currently, there is limited genetic research on exome sequencing for short stature, and more large-scale studies are necessary for further exploration. The retrospective study entailed investigation of 98 Chinese children with short statures (height SDS ≤ -2.5) of unknown etiologies recruited between 2017 and 2021. Whole-exome sequencing (WES) was performed on these patients to identify the potential genetic etiologies. The clinical data were reviewed retrospectively to assess the pathogenicity of the identified mutations. Additionally, 31 patients consented to and received recombinant human growth hormone (rhGH) therapy for 12 months. The short-term effects of rhGH treatment were evaluated across different etiologies of patients with short statures. The WES results were used to identify 31 different variants in 18 genes among 24 (24.5%) patients. Individuals with more severe short statures were more likely to have underlying genetic etiologies. Short stature accompanied by other phenotypes had significantly higher diagnostic yields than simple severe short stature. The rhGH therapy demonstrated efficacy in most children. Nevertheless, the treatment response was suboptimal in a boy diagnosed with 3M syndrome. WES is an important approach for confirming genetic disorders in patients with severe short statures of unknown etiologies, suggesting that it could be used as a primary diagnostic strategy. The administration of rhGH may not be suitable for all children with short statures, and the identification of the genetic cause of short stature by WES has significant guidance value for rhGH treatment.

Evaluating the effect of recombinant human growth hormone treatment on sleep-related breathing disorders in toddlers with Prader–Willi syndrome: a one-year retrospective cohort study

BackgroundRecombinant human growth hormone (rhGH) therapy is beneficial for children with Prader–Willi syndrome (PWS) in improving short stature and metabolism, but the effect of early rhGH treatment on respiratory and sleep parameters for PWS children under three years old remains elusive. Thus, this study aimed to investigate the impact of rhGH treatment on sleep-related breathing disorders (SRBDs) for toddlers with PWS.MethodsA total of 17 age-matched PWS patients receiving rhGH treatment (rhGH group) and 17 control individuals not receiving rhGH treatment (non-rhGH group) were recruited for this study between October 2018 and January 2023. Data related to polysomnography-polygraphy (PSG) and serum levels of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) were collected.ResultsThe mean age in the rhGH group was 20.76 ± 9.22 months, which was comparable to that of the non-rhGH group (25.23 ± 13.81 months). The demographic and anthropometric parameters were similar across the two groups after 52 weeks of treatment. Administration of rhGH to toddlers did not exert adverse effects on the obstructive apnea–hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), mean percutaneous oxygen saturation (SpO2), lowest SpO2, duration when SpO2 is lower than 90%, or proportion of the patients with SpO2 lower than 90%. Furthermore, the increased IGF-1 z-score and IGFBP-3 level did not worsen SRBDs.ConclusionTreatment with rhGH for 52 weeks on young toddlers with PWS showed no deleterious effects on SRBDs. This shed more light on the importance of initiating rhGH therapy early in PWS patients.

A Superlong-Acting Growth Hormone-Polypeptide Fusion for Growth Hormone Deficiency Treatment.

Recombinant human growth hormone (rhGH) is clinically used to treat growth hormone deficiency (GHD). However, daily administration of rhGH is required due to its poor stability and short blood circulation, which causes pains and burdens as well as inconvenience to patients. In this study, a method for genetically fusing rhGH to a thermosensitive polymer of elastin-like polypeptide (ELP) is reported, using which the rhGH-ELP thermosensitive fusion protein can be purified by the thermosensitivity of ELP instead of chromatography. The ELP fusion not only drastically improves the stability of rhGH, but also enables the in situ formation of a sustained-release depot of rhGH-ELP upon subcutaneous (SC)injection, which exhibits gentle release with a platform-to-trough fluctuation in blood and a very long circulatory half-life of 594.6h. In contrast, rhGH exhibits a peak-to-trough fluctuation in blood with a very short circulatory half-life of 0.7h. As a result, a single subcutaneous injection of rhGH-ELP can consecutively promote the linear growth of rats and the development of major tissues and organs over 3weeks without obvious side effects, whereas rhGH is required to be injected daily to achieve similar therapeutic results.

Impact of growth hormone on physical performance

Growth hormone (GH) is an anabolic hormone produced by the pituitary gland. The action of growth hormone is not only to promote growth in children, but it has a significant effect on metabolism and body composition also in adults. Growth hormone deficiency (GHD) leads to physical impairment (worsen muscle strength, aerobic and anaerobic capacity) and altered body composition - with increased fat and reduced lean body mass, particularly reduced skeletal muscle mass. On the other hand, GH excess in patients with acromegaly impairs physical function, especially aerobic capacity and muscle strength irrespective of GH-dependent muscle hypertrophy. There is unclear data about GH impact on physical performance among healthy populations. Some studies showed improvement in anaerobic capacity during recombinant human GH (rh-GH) administration, others showed no significant difference. Muscle strength did not improve after rh-GH administration among healthy adults. However, recombinant GH is abused by professional and recreational athletes to improve their physical performance.

In-depth mass spectrometry analysis of rhGH administration altered energy metabolism and steroidogenesis

Growth hormone, as a proteohormone, is primarily known of its dramatic effect on longitudinal growth. Recombinant DNA technology has provided a safe, abundant and comparatively cheap supply of human GH for growth hormone-deficient individuals. However, many healthy subjects, especially athletics, administrate GH for enhanced athletic performance or strength. A better and more comprehensive understanding of rhGH effect in healthy individuals is urgent and essential. In this study, we recruited 14 healthy young male and injected rhGH once. Untargeted LC-MS metabolomics profiling of serum and urine was performed before and after the rhGH injection. The GH-induced dysregulation of energy related pathways, such as amino acid metabolism, nucleotide metabolism, glycolysis and TCA cycle, was revealed. Moreover, individuals supplemented with micro-doses of rhGH exhibited significantly changed urinary steroidal profiles, suggesting a role of rhGH in both energy metabolism and steroidogenesis. We expect that our results will be helpful to provide new evidence on the effects of rhGH injection and provide potential biomarkers for rhGH administration.

#3571 GROWTH PATTERNS IN PEDIATRIC KIDNEY TRANSPLANT RECIPIENTS: A RETROSPECTIVE SINGLE CENTER STUDY

Abstract Background and Aims Attainment of a normal adult height remains a great challenge in the care of children with end stage kidney disease. Moreover, the incidence of overweight and obesity increases post kidney transplantation (KT). We aimed to describe growth parameters and predictive factors in children post KT. Method We retrospectively reviewed the records of 28 children who underwent KT in our center between 2002-2022. Height (hSDS) and body mass index (BMISDS) z-scores at various time points and possible predictors were assessed. Results Median age at KT was 11.2 years (5.3-14), 20 were male, mean time on dialysis was 5.95 years. KT from a living donor (LRD) was performed in 18 patients. Mean follow-up time was 4.88 (1-10) years. rhGH was administered pre-KT in 15/28 patients and in 3 post KT. Following the first year post KT, steroid free, alternate day and daily steroid regimes were adopted for 9, 11 and 8 patients, respectively. Mean hSDS at the time of KT, one year after and at last visit were -1.76, -1.87, and -1.77 (p&amp;gt;0.05). Mean BMISDS at the respective time points were 0.13, 0.65 and 0.05 respectively (p&amp;gt;0.05). At last visit, 29% and 17% of children showed moderate and severe height deficit. hSDS at last visit was associated with preoperative hSDS, whereas difference between hSDS pre and last visit post KT (ΔhSDS) was associated with the type of KT [mean ΔhSDS for LRD and DDT -1.45 (95%CI -1.87, -1.03) and -2.66 (95%CI -3.4, -1.93) respectively, p = 0.002] and steroid regime [mean ΔhSDS for daily and alternate day steroid treatment -0.39 (95%CI -0.77, -0.003) and 0.55 (95%CI -0.07, 1.17) respectively, p = 0.037]. Τhere was no association between ΔhSDS and rejection episodes or rhGH administration pre-KT. At the time of KT and at last visit 25% and 10.7% were overweight, respectively, whereas only 1 patient was obese preoperatively but none at last visit. The overall incidence of overweight and obesity had reduced at last visit compared to pre-KT (p = 0.01). Conclusion Linear growth post KT remained limited, resulting in short stature in nearly half of children. Strategies to improve height post pediatric KT could include height optimization pre-KT, steroid withdrawal/avoidance protocols, and LRD KT.

Cost-consequence analysis for recombinant human growth hormone treatment administered via different devices in children in Spain

Objetives: To compare height gain and treatment costs of the treatment with recombinant human growth hormone (r-hGH), administered either by Easypod® —an electronic injection allowing adherence monitoring— or other conventional devices licensed in Spain (non-Easypod®) in children and adolescents with growth hormone deficiency. Methods: The analysis was based on a patient-level simulation model including a decision tree and a Markov model; the Markov model represented the different levels of r-hGH use (adherent, non-adherent, and treatment interruption), whereas the decision tree categorized patients according to their r-hGH response. Model characteristics were adapted to Spanish standards and validated through an expert panel. Average costs per cm gained were estimated for each comparator (Easypod® versus non-Easypod®). Different alternative scenarios were performed to analyze the impact of varying individual parameters on the results. Results: For a mean of 10.4 years of treatment, patients receiving r-hGH via Easypod® gained, on average, 19.1 cm (final height: 165.1 cm) compared with 14.8 cm (final height: 160.8 cm) for the comparators (non-Easypod®); resulting in a difference of 4.3 cm. During treatment, patients on Easypod® arm were adherent for a longer time than comparators (52.4% versus 22.2% of the time), involving greater pharmacological costs for Easypod®. Despite greater costs, Easypod® was associated with the lowest cost per cm gained (€3237.0/cm) amongst comparators (non-Easypod®). Costs per cm gained were also lower for Easypod® than for comparators for all the alternative scenarios. Conclusions: The administration of r-hGH with Easypod® improves height gain through better adherence. Easypod® can be the most efficient treatment compared with the other licensed r-hGH treatments in Spain. Keywords: recombinant human growth hormone, device, adherence, cost-consequence analysis.

Preserved Sleep for the Same Level of Respiratory Disturbance in Children with Prader-Willi Syndrome.

Debate remains as to how to balance the use of recombinant human growth hormone (rhGH) as an important treatment in Prader-Willi syndrome (PWS) with its potential role in obstructive sleep apnea. This single-center, retrospective study assessed differences in overnight polysomnography results between children with and without PWS and changes in respiratory parameters before and after the initiation of rhGH treatment in those with PWS. Compared with age-, sex-, and body-mass-index-matched controls (n = 87), children with PWS (n = 29) had longer total sleep time (434 ± 72 vs. 365 ± 116 min; p < 0.01), higher sleep efficiency (86 ± 7 vs. 78 ± 15%; p < 0.05), and lower arousal events (8.1 ± 4.5 vs. 13.0 ± 8.9 events/h; p < 0.05). Mean oxygen saturation was lower in PWS children (94.3 ± 6.0 vs. 96.0 ± 2.0%; p < 0.05), with no other differences in respiratory parameters between groups. Eleven children with PWS (38%) met the criteria for further analyses of the impact of rhGH; polysomnography parameters did not change with treatment. Compared with other children undergoing polysomnography, children with PWS had more favorable markers of sleep continuity and lower oxygen saturation for the same level of respiratory disturbance. rhGH administration was not associated with changes in respiratory parameters in PWS.

Differentially methylated CpGs in response to growth hormone administration in children with idiopathic short stature

BackgroundRecombinant human growth hormone (rhGH) has shown a great growth-promoting potential in children with idiopathic short stature (ISS). However, the response to rhGH differs across individuals, largely due to genetic and epigenetic heterogeneity. Since epigenetic marks on the methylome can be dynamically influenced by GH, we performed a comprehensive pharmacoepigenomics analysis of DNA methylation changes associated with long-term rhGH administration in children with ISS.ResultsWe measured DNA methylation profiles before and after GH treatment (with a duration of ~ 18 months in average) on 47 healthy children using customized methylC-seq capture sequencing. Their changes were compared and associated with changes in plasma IGF1 by adjusting sex, age, treatment duration and estimated blood proportions. We observed a considerable inter-individual heterogeneity of DNA methylation changes responding to GH treatment. We identified 267 response-associated differentially methylated cytosines (DMCs) that were enriched in promoter regions, CpG islands and blood cell-type-specific regulatory elements. Furthermore, the genes associated with these DMCs were enriched in the biology process of “cell development,” “neuron differentiation” and “developmental growth,” and in the TGF-beta signaling pathway, PPAR Alpha pathway, endoderm differentiation pathway, adipocytokine signaling pathway as well as PI3K-Akt signaling pathway, and cAMP signaling pathway.ConclusionOur study provides a first insight in DNA methylation changes associated with rhGH administration, which may help understand mechanisms of epigenetic regulation on GH-responsive genes.

Effect of growth hormone therapy on liver enzyme and other cardiometabolic risk factors in boys with obesity and nonalcoholic fatty liver disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) has become the most common causes of liver disease in children and adolescents. Although several reports have confirmed the significant correlation between NAFLD and growth hormone (GH)-insulin-like growth factor 1(IGF-1) axis, no study further investigates whether or not recombinant human GH (rhGH) treatment can improve NAFLD in obese children.MethodsThis study was a randomized, open-label study comprising 44 boys with obesity and NAFLD (11.76 ± 1.67 year) to evaluate the effects of 6 months of rhGH administration for boys with obesity and NAFLD. The subjects were randomized divided into treatment group (subjects with recombinant human GH (rhGH)) and control group for 6 months.ResultsAfter 6 months, IGF-1 increased significantly during rhGH treatment, in comparison with the control group (582.45 ± 133.00 vs. 359.64 ± 129.00 ng/ml; p < 0.001). A significant reduction in serum alanine aminotransferase(ALT) (15.00 vs. 28.00 U/L; p = 0.001), aspartate aminotransferase(AST) (20.00 vs. 24.50U/L; p = 0.004), gamma glutamyl transferase(GGT) (14.50 vs. 28.50 U/L; p < 0.001) was observed in the GH-treated boys. In addition, the rhGH group showed a significant decrease in C reactive protein (CRP) (1.17 ± 0.76 vs. 2.26 ± 1.43 mg/L) and body mass index standard deviation scores (BMI SDS) (2.28 ± 0.80 vs. 2.71 ± 0.61) than the control group (p = 0.003, p = 0.049 respectively). GH treatment also reduced low density lipoprotein cholesterol (LDL-C) (2.19 ± 0.42 vs. 2.61 ± 0.66 mmol/L; p = 0.016) and increased high density lipoprotein cholesterol (HDL-C) (1.30 vs. 1.15 mmol/L; p = 0.005), and there were no changes in total cholesterol (TC), triglycerides (TG) and uric acid(UA) between the treatment group and the control group.ConclusionOur findings suggest that 6 months treatment with rhGH may be beneficial for liver enzyme and can improve obesity-related other cardiovascular and metabolic complications in boys with obesity and NAFLD.

Yearly Height Gain Is Dependent on the Truly Received Dose of Growth Hormone and the Duration of Periods of Poor Adherence: Practical Lessons From the French Easypod™ Connect Multicenter Observational Study.

ObjectiveTo study the impact of the true mean daily dose and the true mean number of injections per week on the yearly height gain in short children treated with recombinant human growth hormone (rhGH).Design and Methods220 children from the French Easypod™ Connect Observational Study (ECOS) used the Easypod™ electronic device to record rhGH injections. The mean daily rhGH dose (the sum of the doses truly received divided by the number of days) and mean number of injections per week (the number of injections truly performed divided by the number of weeks) were calculated. Linear mixed models were used to study the impact of short (3-month) and long (1-year) variations in rhGH administration on the yearly height change [as a standard deviation score (SDS)], with time on treatment as a covariate. For each patient, several periods of 3 or 12 months were considered and designated as poorly adherence or fully adherence. We studied the impact of each of period on the height change.ResultsAt treatment initiation, the mean ± SD age was 9.8 ± 3.7 years (females: 47%, prepubertal: 86%) and the mean height was -2.28 ± 0.92 SDS. The mean treatment duration was 3.2 ± 1.1 years (685.2 patient years). 122 patients were GH-deficient, 79 were small for gestational age, and 19 had Turner syndrome. When treatment was computed over 12-month periods, receiving a mean daily dose <0.03 mg/kg.d was associated with a 20% lower mean yearly height gain SDS when<3 injections/week were received (vs.>5 injections/week), whereas maintaining a mean daily dose >0.03 mg/kg.d with<3 injections/week was not associated with a lower yearly height gain SDS (vs.>5 injections/week). For 3-month periods, changes in the daily rhGH dose or the number of injections per week over such short period did not influence the yearly height gain SDS.ConclusionThe 12-month treatment model showed that when poor adherence leads to a low true daily GH dose, the yearly height gain is low. The 3-month treatment model showed that poor adherence for short periods (<3 months) had no impact on the height SDS.

Lipoatrophy associated with daily growth hormone injections.

SummaryRecombinant human growth hormone therapy (rhGH) has been available since 1985 for a variety of conditions and has expanded the indications for rhGH therapy and the number of patients receiving therapy. The very nature of the therapy exposes individuals to years of injections. There are a number of well-known adverse events, however, a lesser-known and rarely reported adverse event of rhGH therapy is localized lipoatrophy. We report nine cases of localized lipoatrophy during rhGH therapy accounting for 14.5% of patients taking rhGH presenting to a single centre for routine follow-up over just a 2-month period. The development of localized lipoatrophy does not appear to be age, indication or dose-related but rather related to repeated administration of rhGH into a limited number of sites. The most likely putative mechanism is the local lipolytic action of growth hormone (GH) itself, although the possibility of an excipient-based interaction cannot be excluded. Given the high prevalence of this adverse event and the potential to prevent it with adequate site rotation, we can recommend that patients be informed of the possible development of localized lipoatrophy. Doctors and nurses should closely examine injection sites at each visit, and site rotation should be emphasized during injection technique education.Learning pointsThere are a number of well-known adverse events, however, a lesser-known and rarely reported adverse event of rhGH therapy is localized lipoatrophy.Examination of the injection sites at each visit by the treating healthcare practitioner.To advise the parents/caregivers/patients to change their injection site with each injection.To advise the parents/caregivers/patients to change the needles after every use.For parents, caregivers and patients to self-inspect their injection sites and have a high alert for the development of lipoatrophy and to then immediately report it to their doctor.

Prolonged, Controllable Protein Production of cDNA-Encoded hGH Maintained at Therapeutic Serum Levels Following One Systemic Administration of a Non-Viral, Non-Integrating, DNA-and Liposome-Based in vivo Gene Therapy Platform in Immunocompetent Mice

Abstract Recombinant human growth hormone (rhGH), the mainstay of hGH replacement therapy, is injected daily for years to enable children to achieve normal stature. Daily rhGH injections are required because its serum-T1/2 is &amp;lt;20 minutes. Human trials testing T1/2-extending rhGH proteins are promising, but even weekly rhGH administration poses potential short and long-term toxicity risks, including exacerbation of diabetes or hypertension and potential for oncogenesis. Frequent hGH injections produce non-physiologic IGF-I profiles, (peak serum IGF-I frequently supra-normal, trough IGF-I concentrations at baseline). Therefore, a safe, effective, single administration hGH approach that maintains hGH and IGF-I serum concentrations within their respective therapeutic ranges for approximately one year could offer significant advantages. Accordingly, DNARx tested HEDGESTM, it’s non-viral, non-integrating, DNA-and liposome-based systemic, in vivo gene therapy approach to produce long-term hGH serum levels within the therapeutic range (1 -10 ng/ml) in immunocompetent mice. Previously, one systemic HEDGES-human granulocyte colony stimulating factor (hG-CSF, serum T1/2&amp;lt;3 hours) cDNA administration produced durable therapeutic hG-CSF serum levels (Science advances, 2019, 5, 2019). Importantly, simply by modifying selected aspects of HEDGES’s DNA vector and liposomal components, the duration of serum hG-CSF protein production was controllable over a broad temporal range. Long-term assessment of serum hGH in immunocompetent mice was assessed by injecting either one HEDGES administration or one administration followed by one re-dose of DNA vectors expressing either A) wildtype hGH cDNA (HEDGES-1) or B) wildtype hGH fused to selected serum protein T1/2-extending DNA sequences (HEDGES-2), with these results: 1) One HEDGES-1 administration produced slowly-increasing, but sub-therapeutic hGH serum levels from day 7 to day 99 after injection. From day 99 on, serum hGH levels remained within the therapeutic range for &amp;gt; 230 days; 2) Concurrently, hGH-induced elevation of endogenous mouse serum IGF-I levels remained between 1 to 3 fold above baseline. 3) One HEDGES-1 re-injection was administered 35 days after initial injection, a time when hGH serum levels remained sub-therapeutic. By day 7, one re-injection further elevated cDNA-encoded hGH serum levels into the therapeutic range, maintaining them for &amp;gt;175 days; 4) One HEDGES-2 administration produced therapeutic hGH serum levels by day 7 that were maintained for &amp;gt;250 days. These studies demonstrate the feasibility of achieving very long-term therapeutic levels of hGH and IGF-I following 1-2 injections. DNARx is now focused on selectively modifying its HEDGES hGH cDNA vectors and liposomal components to produce hGH serum levels within the therapeutic range for the equivalent of one human year following administration

Testicular Growth and Pubertal Onset in GH-Deficient Children Treated With Growth Hormone: A Retrospective Study.

The prevalence of idiopathic oligozoospermia has been esteemed as high as 75%. An Italian survey has reported bilateral testicular hypotrophy in 14% of final-year high school students. The search for determinants of testicular growth in childhood is important for the primary prevention of spermatogenic failure. Therefore, this retrospective study aimed to evaluate the testicular growth and pubertal onset in deficient children treated recombinant human growth hormone (rhGH). To accomplish this, the clinical charts of 93 patients with GH deficiency (GHD) were carefully reviewed. Their mean age at the time of diagnosis was 11.2 ± 2.4 years. rhGH was administered for 44.0 ± 22.4 months, and the onset of puberty was recorded after a mean of 25.8 ± 22.4 months from the first rhGH administration. As expected, serum insulin-like growth factor 1 (IGF1) levels increased significantly after treatment. Before rhGH therapy, the Tanner stage was I in 59 out of 70 boys (84.3%), II in 8/70 (11.4%), III in 3/70 (4.3%). No one was on stage IV or V. The mean Tanner stage was 1.19 ± 0.51. At the last visit, the Tanner stage was I in 8/72 boys (11.1%), II in 6/72 (8.3%), III in 6/72 (8.3%), IV in 16/72 (22.2%), and V in 36/72 (50.0%). After a mean of 44.0 ± 22.4 months of rhGH treatment, the mean Tanner stage was 4.05 ± 1.30. Patients treated with rhGH showed a significant testicular volume (TV) growth over time, whereas no growth was observed in age-matched but not yet treated patients, even when the age was compatible with a spontaneous start of puberty. The multivariate regression analysis showed that the duration of treatment and the mean rhGH dose significantly predicted the percentage of TV increase. In contrast, age, serum FSH, and IGF1 levels, and final rhGH dose did not impact TV growth over time. In conclusion, these findings suggest that GH may play a role in testicular growth and pubertal onset, despite the descriptive nature of this study. Further properly designed studies are needed to confirm these findings. This knowledge may be useful to implement the diagnostic-therapeutic algorithm in case of a lack of testicular growth in childhood.

The effect of treatment with recombinant human growth hormone (rhGH) on linear growth and adult height in children with idiopathic short stature (ISS): a systematic review and meta-analysis.

Idiopathic short stature (ISS) is a recognized, albeit a controversial indication for treatment with recombinant human growth hormone (rhGH).The objective of the present study was to conduct a systematic review of the literature and meta-analyses of selected studies about the use of rhGH in children with ISS on linear growth and adult height (AH). A systematic literature search was conducted to identify relevant studies published till February 28, 2017 in the following databases: Medline (PubMed), Scopus and Cochrane Central Registry of Controlled Trials. After exclusion of duplicate studies, 3,609 studies were initially identified. Of those, 3,497 studies were excluded during the process of assessing the title and/or the abstract. The remaining 112 studies were evaluated further by assessing the full text; 21 of them fulfilled all the criteria in order to be included in the current meta-analysis. Children who received rhGH had significantly higher height increment at the end of the first year, an effect that persisted in the second year of treatment and achieved significantly higher AH than the control group. The difference between the two groups was equal to 5.3cm (95% CI: 3.4-7cm) for male and 4.7cm (95% CI: 3.1-6.3cm) for female patients. In children with ISS, treatment with rhGH improves short-term linear growth and increases AH compared with control subjects. However, the final decision should be made on an individual basis, following detailed diagnostic evaluation and careful consideration of both risks and benefits of rhGH administration.

Effect of fermented oyster extract on growth promotion in Sprague–Dawley rats

BackgroundOysters (Crassostrea gigas) are a popular marine product worldwide and have the advantage of nutritional benefits. This study aimed to investigate the effect of fermented oyster extract (FO) on growth promotion, including analysis of body size, bone microarchitecture, hematology and biochemistry in vivo. MethodsThe amount of nutrients and gamma aminobutyric acid (GABA) were determined. Sprague–Dawley rats were randomly divided into four groups: the control group, FO 50 group (FO 50mg/kg), and FO 100 group (FO 100mg/kg) were administered orally once daily and the recombinant human growth hormone (rhGH) group (200μg/kg) was intraperitoneally injected once daily for 14 days. ResultsOral administration of FO 100 significantly increased body length and had no effect on organ damage or hematological profiles. However, administration of rhGH significantly induced hypertrophy of the liver, kidney and spleen along with a marked increase in body length. Tibia length and the growth plate were increased, and bone morphometric parameters were slightly improved by FO and rhGH administration. Serum analysis showed that the levels of GH and insulin like growth factor-1 (IGF-1) were slightly upregulated by FO administration. Nevertheless, the protein expression of hepatic IGF-1 was markedly increased by FO 100 and rhGH administration. ConclusionsFO have high content of GABA, and induced positive effects on body length, tibial length, growth-plate length and hepatic IGF-1 synthesis in SD rats with no toxicity or alterations of hematological profile. Therefore, these results suggest that GABA-enriched FO could be considered a potential alternative treatment for growth stimulation.

Evidence that growth hormone can improve mitochondrial function in oocytes from aged mice.

Decline in successful conception decreases more rapidly after 38 years of age owing to follicular depletion and decreased oocyte quality. However, limited information is available regarding the underlying mechanism and the useful treatment. This study aimed to evaluate the effects of growth hormone supplementation on oocyte maturation in vivo in aged and young mice and to determine its effect on mitochondrial function. The influence of three different doses of recombinant human growth hormone (rhGH) (0.4, 0.8 and 1.6 mg/kg/day) for 8 weeks before ovarian stimulation was analyzed. Superovulated oocytes were released from the oviduct of 12-week-old and 40-week-old female C57BL/6J mice 14–16 h after administration of human chorionic gonadotropin. Ovarian follicle and morphological analysis and oocyte maturation parameters were then evaluated. This study is the first, to our knowledge, to report that medium- and high-dose rhGH significantly increases antral follicles in aged mice but anti-Müllerian hormone (AMH) levels. Furthermore, derived oocytes, MII-stage oocyte rate, ATP levels, mitochondrial membrane potential and frequencies of homogeneous mitochondrial distribution increased. In contrast, in both aged and young mice, the mtDNA copy numbers per oocyte were similar before rhGH administration, and upon saline administration, they did not differ significantly. We conclude that medium-dose rhGH supplementation before standard ovarian stimulation regimens improves oocyte quality in aged mice, probably by enhancing mitochondrial functionality.