Short Adult Height After Rapid-tempo Puberty: When is it too Late to Treat?

A rarely reported phenomenon of rapid-tempo puberty in which the physical changes of puberty and testosterone levels increase very rapidly has not been reported outside apart from in two reviews. The resulting rapid advancement of skeletal age causes early completion of growth with shorter adult stature than expected. This appears to be genetic given its occurrence in the present report in two families, one with three brothers, one with two. We also describe potential treatments and found for the youngest that early initiation of standard therapy preserved or reclaimed adult height (AH) potential. The foreshortened AH in this situation involves rapidly advancing puberty resulting from high circulating testosterone levels leading to rapid advance in skeletal age. This was recognized earlier among younger brothers and treatment with gonadotropin-releasing analogues, growth hormone (GH) and/or aromatase inhibitor therapy (AIT) was tried. Two brothers in family A and family B were treated. Case 5 started treatment early enough so his AH was within target height (mid-parental height) range. Cases 2, 3, 4 were tried on GH and/or AIT with outcomes suggesting benefit. The prevalence and mechanism of rapid-tempo puberty requires further study. Furthermore, as illustrated by two of the current cases, this phenomenon may have a heightened prevalence, or at least may occur, in children previously diagnosed with constitutional delay of growth, underscoring the need to be cautious in assurance of a normal AH outcomes in this population, based on data from a single assessment.

Atosiban interacts with growth hormones as adjuvants in frozen-thawed embryo transfer cycles.

Objective: To investigate the interaction between atosiban and growth hormone (GH) as adjuvants in frozen-thawed embryo transfer (FET) cycles. Method: A total of 11627 patients who underwent FET at Xiamen University Affiliated Chenggong Hospital between January 2018 to December 2022 were retrospectively analyzed. Among them, 482 patients received atosiban and 275 patients received GH. The interactions were estimated by comparing the odds ratio (OR) for pregnancy comparing patients with or without atosiban adjuvant in cohorts stratified according to the presence of GH use in either the overall cohort or a propensity score (PS) matched cohort. An interaction term (atosiban × GH) was introduced to a multivariate model to calculate the ratio of OR (ORR) adjusted for confounders. Results: For all patients receiving atosiban administration, no obvious effect on pregnancy was observed in comparison with either matched or unmatched controls. However, when the patients were stratified according to GH administration, atosiban showed a significant association with clinical pregnancy in comparison with either matched or unmatched controls among patients with GH treatment with rate ratios (RR) of 1.32 (95%CI: 1.05,1.67) and 1.35 (95%CI: 1,1.82), respectively. On the other hand, however, the association was absent among patients without GH treatment. The adjusted ORRs in both matched and unmatched cohorts were 2.44 (95%CI: 1.07,5.84) and 1.95 (95%CI: 1.05, 3.49) respectively. Conclusion: The combination use of atosiban and GH in FET cycles is potentially beneficial to the pregnancy. However, indications for the use of atosiban and GH may need further assessment.

Effects of growth hormone therapy on the onset and progression of pubertal development in girls with idiopathic short stature.

OBJECTIVE: The aim of this study was to explore the impact of growth hormone (GH) therapy on the onset and progression of puberty in girls with idiopathic short stature. METHODS: This study included 541 girls aged between 4.5 and 10.6 years who were receiving GH treatment, monitored over a 22-year follow-up period. Of these, 126 girls have been followed up to the onset of menarche. The participants were divided into two groups: a ISS control group (n = 66) and a group receiving daily GH treatment at a dose of 0.15 iu/kg (n = 60). We assessed the pubertal development and GH usage of these girls every three months. RESULTS: (1) There was no significant difference in the onset of puberty between the growth hormone (GH) treatment group and the control group; however, the average duration of puberty was longer in the treatment group compared to the control group. (2) During puberty, there were no significant differences in height growth between the treated and untreated groups. (3) The duration of GH treatment showed a significant negative correlation with the age at onset of gonadal development and the age at menarche in females within the treatment group. CONCLUSION: GH treatment does not seem to accelerate the onset of puberty but may extend its duration, without significantly impacting height growth during puberty. Additionally, longer GH treatment duration is linked to earlier gonadal development and menarche in females.

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Recombinant human growth hormone (rhGH) is an effective therapeutic drug for improving short stature. Currently, rhGH can be used for various causes of short stature, including growth hormone deficiency, and the expansion of its clinical application has raised concerns about its safety. Based on existing evidence, when rhGH is used in a standardized manner for physiological replacement therapy, its safety profile is favorable. In clinical practice, attention should be focused on short-term safety during rhGH treatment, with the combination of literature evidence and clinical experience. There is still no definitive conclusion on the long-term safety due to insufficient duration of rhGH treatment. This paper reviews the possible adverse events that may occur during rhGH treatment and their risk control measures, aiming to help clinical physicians understand the overall safety of rhGH treatment and improve its clinical standardization.

Does growth hormone supplementation of in vitro fertilization/intracytoplasmic sperm injection improve cumulative live birth rates in women with poor embryonic development in the previous cycle?

BACKGROUND: Growth hormone (GH) has been proposed as an adjunct in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles, especially in women with poor ovarian response. However, it is unclear whether GH supplementation is effective in women with poor embryonic development in the previous IVF cycle. The aim of this study was to evaluate the effectiveness of GH supplementation in IVF/ICSI cycles in women with poor embryonic development in the previous cycle. METHODS: This is a retrospective cohort study from a public fertility center in China, in which we performed propensity score-matching (PSM) for female age and AFC in a ratio of 1:1. We compared the cumulative live birth rate per started cycle, as well as a series of secondary outcomes. We included 3,043 women with poor embryonic development in the previous IVF/ICSI cycle, of which 1,326 had GH as adjuvant therapy and 1,717 had not. After PSM, there were 694 women in each group. RESULTS: After PSM, multivariate analyses showed the cumulative live birth rate to be significantly higher in the GH group than the control group [N = 694, 34.7% vs. N = 694, 27.5%, risk ratio (RR): 1.4 (95%CI: 1.1-1.8)]. Endometrial thickness, number of oocytes retrieved, number of embryos available, and number of good-quality embryos were significantly higher in the GH group compared to controls. Pregnancy outcomes in terms of birth weight, gestational age, fetal sex, preterm birth rate, and type of delivery were comparable. When we evaluated the impact of GH on different categories of female age, the observed benefit in the GH group did not appear to be significant. When we assessed the effect of GH in different AFC categories, the effect of GH was strongest in women with an AFC5-6 (32.2% versus 19.5%; RR 2.0; 95% CI 1.2-3.3). CONCLUSIONS: Women with poor embryonic quality in the previous IVF/ICSI cycles have higher rates of cumulative live birth with GH supplementation.

Post hoc subgroup analysis of Asian children with paediatric GHD from the global phase 3 efficacy and safety study of once-weekly somatrogon vs. once-daily somatropin.

OBJECTIVES: Somatrogon is a long-acting recombinant human growth hormone used to treat patients with paediatric growth hormone deficiency (pGHD). This global phase 3 study compared the efficacy and safety of once-weekly somatrogon with once-daily somatropin in children with GHD. METHODS: Prepubertal patients were randomized 1:1 to once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. The primary endpoint was height velocity (HV) at month 12; secondary endpoints included HV at month 6 and change in height standard deviation score (SDS) at months 6 and 12 and insulin-like growth factor 1 (IGF-1) SDS. RESULTS: This post hoc subgroup analysis focused specifically on Asian children (somatrogon: n=24 and mean age=7.76 years; somatropin: n=21 and mean age=8.10 years) across eight countries. Mean HV at month 12 was 10.95 cm/year (somatrogon) and 9.58 cm/year (somatropin); the treatment difference of 1.38 cm/year favoured somatrogon. The lower bound of the two-sided 95 % CI of the treatment difference (somatrogon-somatropin) was -0.20, similar to the overall study population (-0.24). Compared with the somatropin group, the somatrogon group had numerically higher HV at month 6 (8.31 vs. 11.23 cm/year); a similar trend was observed for height SDS and IGF-1 SDS at months 6 and 12. Safety and tolerability were similar between treatment groups; adverse events occurred in 83 % of somatrogon-treated children and 76 % of somatropin-treated children. CONCLUSIONS: This subgroup analysis demonstrated that somatrogon efficacy and safety in Asian children were consistent with the overall study population, where once-weekly somatrogon was non-inferior to once-daily somatropin. Clinicaltrials.gov: NCT02968004.

Diagnosis and treatment of growth hormone deficiency in children on the ketogenic diet: A case series.

The ketogenic diet (KD) can have a negative impact on the linear growth and body composition of children. The aims of this study were to review two centers' experience with children who developed height deceleration on the KD and determine if the height deceleration was secondary to growth hormone deficiency (GHD), and if growth hormone therapy (GHT) would be effective and safe (not altering ketosis or seizure frequency). Retrospective chart reviews were performed on patients with KD referred to Endocrinology between 2013 and 2018. Seventeen children were identified. Data reviewed included: demographics, growth velocity, KD ratio, protein/calorie intake, lab results, GH dosage, Tanner stage, and seizure frequency, and endocrine recommendations. Descriptive statistics were performed. Of the 17 children referred to the Endocrine Division, seven children were growth hormone deficient and began GHT. Data were provided for six patients (2 males, 4 females; age 2-7 years at the start of KD) on the KD for >6 years and on GHT for >4 years. Growth for all patients stabilized or increased. IGF-1 z-scores normalized. GHT did not affect seizure frequency or ketosis. GHT in those with GHD can be an appropriate option allowing better growth while still maintaining ketogenic therapy and seizure control. PLAIN LANGUAGE SUMMARY: The KD can be an effective treatment for difficult-to-control epilepsy and some disorders of carbohydrate metabolism. The KD can adversely affect the linear growth (height) of children. This case series reviewed six patients who had slow linear growth. It was found that all six children had growth hormone deficiency, grew better with growth hormone treatments, and that their seizures and ketone levels were not affected.

Oral SSTR5 Antagonist SCO-240 for Growth Hormone Stimulation: A Phase I Single-Dose Study in Healthy Individuals.

Somatostatin inhibits endocrine and exocrine secretion in various tissues by acting on five somatostatin receptor subtypes (SSTR1-5). The clinical effects of SSTR5 antagonism remain unknown. Herein, we evaluated the effects of SCO-240, an oral SSTR5 antagonist, in healthy individuals. This randomized, single-center, double-blind, placebo-controlled, phase I study included healthy Japanese and White individuals. The effects of ascending single oral doses of SCO-240 were evaluated in healthy individuals. The main outcome measures were safety, tolerability, pharmacokinetics, and pharmacodynamics (gallbladder contractions and levels of serum insulin and plasma glucagon-like peptide-1 (GLP-1)). The levels of pituitary hormones were evaluated in our exploratory analysis. The results indicated that SCO-240 was safe and well-tolerated at all tested doses. Oral SCO-240 was readily absorbed, with its systemic exposure increasing in a dose-dependent manner. The median time to maximum concentration and mean terminal half-life of SCO-240 were 3-4 and 10.2-12.6 hours, respectively, in the ascending dose section. No clinically meaningful changes in SCO-240 pharmacokinetic profiles were observed between fed and fasted or between Japanese and White individuals. No increase in gallbladder contractions or levels of insulin and GLP-1 were detected. SCO-240 induced robust growth hormone (GH) secretion without altering the levels of other pituitary hormones. In conclusion, the study is the first to demonstrate that SSTR5 antagonism stimulates GH secretion in humans. SCO-240 was safe and well-tolerated and exhibited once-daily oral dosing potential. The robust effects of SCO-240 on GH secretion suggest that it may be a treatment option for GH-related disorders.

Experience of switching from a daily to a less frequent administration of injection treatments.

BACKGROUND: Daily injections of recombinant human growth hormone are the standard of care to treat growth failure due to pediatric growth hormone deficiency (GHD). While effective, daily injections are burdensome and can compromise adherence. In recent years, novel injection treatments requiring less frequent administration for growth hormone deficiency (GHD) have been developed. A targeted, pragmatic literature review was conducted to summarize and document the patient experience of moving from daily to less frequent injections, with a specific focus on changing from daily to weekly injection treatments in pediatric GHD (pGHD). OBJECTIVE: Explore and describe the patient experience when switching from a daily to a less frequent injection schedule for GHD. METHODS: Targeted literature searches were conducted to identify literature describing the patient experience of moving from a daily to weekly injection in GHD. Supplementary searches were conducted to identify literature describing the patient experience of moving from daily to less frequent injection regimens in other medical conditions. RESULTS: Across searches, 1,691 abstracts were reviewed and 13 articles were included in the final analysis. These publications reported that patients moving to less frequent injections across a variety of conditions, including GHD, experienced increased convenience and satisfaction, higher adherence rates, fewer adverse events, and improved quality of life. Less frequent injections were also reported to be at least as efficacious as daily treatments. CONCLUSIONS: Less frequent injections in GHD and as other conditions are less burdensome, positively benefit patients, and result in improved adherence that may lead to improved clinical outcomes. Clinicians may consider weekly regimens as an effective alternative for patients, in particular in pGHD, especially when missed injections can negatively impact treatment outcomes. More research is needed to better understand the real-world benefits of injectable therapies that require less frequent administration (e.g., weekly versus daily).

Use of machine learning to identify patients at risk of sub-optimal adherence: study based on real-world data from 10,929 children using a connected auto-injector device.

BACKGROUND: Our aim was to develop a machine learning model, using real-world data captured from a connected auto-injector device and from early indicators from the first 3 months of treatment, to predict sub-optimal adherence to recombinant human growth hormone (r-hGH) in patients with growth disorders. METHODS: Adherence to r-hGH treatment was assessed in children (aged < 18 years) who started using a connected auto-injector device (easypod™), and transmitted injection data for ≥ 12 months. Adherence in the following 3, 6, or 9 months after treatment start was categorized as optimal (≥ 85%) versus sub-optimal (< 85%). Logistic regression and tree-based models were applied. RESULTS: Data from 10,929 children showed that a random forest model with mean and standard deviation of adherence over the first 3 months, infrequent transmission of data, not changing certain comfort settings, and starting treatment at an older age was important in predicting the risk of sub-optimal adherence in the following 3, 6, or 9 months. Sensitivities ranged between 0.72 and 0.77, and specificities between 0.80 and 0.81. CONCLUSIONS: To the authors' knowledge, this is the first attempt to integrate a machine learning model into a digital health ecosystem to help healthcare providers to identify patients at risk of sub-optimal adherence to r-hGH in the following 3, 6, or 9 months. This information, together with patient-specific indicators of sub-optimal adherence, can be used to provide support to at-risk patients and their caregivers to achieve optimal adherence and, subsequently, improve clinical outcomes.

Síndrome de Turner / Turner's Syndrome / Sindrome de Turner

Introducción: el síndrome de Turner es una enfermedad genética caracterizada por la pérdida total o parcial de un cromosoma X, siendo sus características fundamentales la talla baja, la disgenesia gonadal y hallazgos fenotípicos característicos. Tiene una amplia variabilidad en su forma de presentación. Grandes estudios epidemiológicos muestran que la morbilidad aumenta en mujeres con este síndrome, debido a una amplia gama de enfermedades asociadas, sobre todo cardiovasculares, que eleva la mortalidad de manera significativa. Objetivo: realizar una revisión de la literatura, en base a la presentación de un caso clínico, para recabar información sobre las ultimas pautas de manejo y presentar los nuevos objetivos de tratamiento. Conclusiones: el diagnóstico temprano es fundamental, y tiene características propias y criterios de sospecha según la etapa en la que se efectúa, el reto actual en el manejo de estas pacientes consiste en la formación de un equipo médico multidisciplinario, conformado por una amplia gama de especialistas para el adecuado seguimiento, con el fin de disminuir las complicaciones y ayudar a que la paciente alcance sus objetivos para una vida plena. Se presenta el caso de una paciente con síndrome de Turner vista por el equipo médico en el Hospital Pediátrico del Centro Hospitalario Pereira Rossell, Montevideo-Uruguay.

Introduction: Turner's syndrome is a genetic disease characterized by total or partial loss of an X chromosome, its main features being low height, gonadal dysgenesis and characteristic phenotypic findings. It has a wide variability in its form of presentation. Large epidemiological studies show that morbidity increases in women with this syndrome, due to a wide range of associated diseases, especially cardiovascular disease, which significantly raises mortality. Objectives: to carry out a review of the literature, based on a clinical case in order to gather information regarding the latest treatment guidelines and present the new treatment goals. Conclusions: early diagnosis is essential, and has its own characteristics and suspicion criteria according to the stage in which it is carried out. The present challenge regarding the management of these patients consists of the training of a multidisciplinary medical team made up of a wide range of specialists able to carry out proper follow-up, in order to reduce complications and help the patient live a full life. We present a case of a patient with Turner's syndrome assisted at the Pereira Rossell Hospital Center in Montevideo-Uruguay.

Introdução: a síndrome de Turner é uma doença genética caracterizada pela perda total ou parcial de um cromossomo X, sendo suas características fundamentais de baixa estatura, disgenesia gonadal e achados fenotípicos característicos. Tem uma ampla variabilidade em sua forma de apresentação. Consideráveis (grandes, amplos, extensos) estudos epidemiológicos mostram que a morbidade aumenta em mulheres com essa síndrome, devido a uma ampla gama de doenças associadas, especialmente cardiovasculares, o que aumenta significativamente a mortalidade. Objetivos: realizar uma revisão da literatura, a partir da apresentação de um caso clínico, reunir informações sobre as últimas diretrizes de tratamento e apresentar os novos objetivos do tratamento. Conclusões: o diagnóstico precoce é fundamental, e possui características próprias e critérios de suspeita de acordo com a etapa em que é realizado, o desafio atual na gestão desses pacientes consiste na formação de uma equipe médica multidisciplinar, formada por uma ampla gama de especialistas para o acompanhamento adequado, a fim de reduzir complicações e ajudar a paciente a alcançar uma vida plena. Apresentamos o caso de uma paciente com síndrome de Turner atendido pela equipe médica do Hospital Pediátrico do Centro Hospitalar Pereira Rossell, Montevidéu-Uruguai.

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

BACKGROUND: Recombinant 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. RESULTS: We 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. CONCLUSION: Our 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.

Metabolic Impacts of Discontinuation and Resumption of Recombinant Human Growth Hormone Treatment during the Transition Period in Patients with Childhood-Onset Growth Hormone Deficiency.

BACKGROUND: Discontinuing growth hormone (GH) treatment during the transition to adulthood has been associated with adverse health outcomes in patients with childhood-onset growth hormone deficiency (CO-GHD). This study investigated the metabolic changes associated with interrupting GH treatment in adolescents with CO-GHD during the transition period. METHODS: This study included 187 patients with CO-GHD who were confirmed to have adult GHD and were treated at six academic centers in Korea. Data on clinical parameters, including anthropometric measurements, metabolic profiles, and bone mineral density (BMD) at the end of childhood GH treatment, were collected at the time of re-evaluation for GHD and 1 year after treatment resumption. RESULTS: Most patients (n=182, 97.3%) had organic GHD. The median age at treatment discontinuation and re-evaluation was 15.6 and 18.7 years, respectively. The median duration of treatment interruption was 2.8 years. During treatment discontinuation, body mass index Z-scores and total cholesterol, low-density lipoprotein, and non-high-density lipoprotein (HDL) cholesterol levels increased, whereas fasting glucose levels decreased. One year after GH treatment resumption, fasting glucose levels, HDL cholesterol levels, and femoral neck BMD increased significantly. Longer GH interruption (>2 years, 60.4%) resulted in worse lipid profiles at re-evaluation. The duration of interruption was positively correlated with fasting glucose and non-HDL cholesterol levels after adjusting for covariates. CONCLUSION: GH treatment interruption during the transition period resulted in worse metabolic parameters, and a longer interruption period was correlated with poorer outcomes. GH treatment should be resumed early in patients with CO-GHD during the transition period.

Somatropin therapy in italian adults with growth hormone deficiency.

BACKGROUND: In adult population, Growth Hormone Deficiency (GHD) is a complex clinical condition with heterogeneity of causes and duration. Growth Hormone (GH) replacement therapy has beneficial effects entailing a chronic and expensive use. Therefore, entity, appropriateness and standardization of GHD treatment need to be accurately analysed. In Italy, the epidemiological surveillance on somatropin therapy is entrusted to the National Register of Growth Hormone Therapy (Registro Nazionale degli Assuntori dell'Ormone della Crescita-RNAOC) by the Italian Regulation, in accordance of which the RNAOC-database is collecting the notifications of somatropin prescriptions. METHODS: Aim of this study is to analyse data on somatropin-treated adult population communicated to the RNAOC by the specialist centres of 15 Italian regions and 2 autonomous provinces. RESULTS: From 2011 to 2019, the somatropin-treated adults were 970 with 4061 examinations (1.21 ± 0.33 visits/year). The diagnoses were: hypopituitarism (n = 579); hypophysectomy (n = 383); and congenital GHD (n = 3). Five subjects were addressed with diagnoses not included in the regulation. The starting posology of somatropin was 0.320 (± 0.212) mg/day, 0.292 (± 0.167) mg/day in male and 0.360 (± 0.258) in female patients, with 7 administrations/week in 70.31% of the prescriptions. The differences in posology by gender persisted at 10th year of the follow-up. Starting dosage was higher in patients diagnosed with adult GHD before the age of 30 (0.420 ± 0.225 mg/day), with a progressive decrease of the dosage during the follow-up. CONCLUSIONS: This is the first report on adult GH treatment, describing numbers, diagnoses, and pharmaceutical prescriptions associated to somatropin therapy in a large cohort of Italian GHD-adults.

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

BACKGROUND: Non-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. METHODS: This 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. RESULTS: After 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. CONCLUSION: Our 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.

Approach to the Patient: Safety of Growth Hormone Replacement in Children and Adolescents.

The use of recombinant human growth hormone (rhGH) in children and adolescents has expanded since its initial approval to treat patients with severe GH deficiency (GHD) in 1985. rhGH is now approved to treat several conditions associated with poor growth and short stature. Recent studies have raised concerns that treatment during childhood may affect morbidity and mortality in adulthood, with specific controversies over cancer risk and cerebrovascular events. We will review 3 common referrals to a pediatric endocrinology clinic, followed by a summary of short- and long-term effects of rhGH beyond height outcomes. Methods to mitigate risk will be reviewed. Finally, this information will be applied to each clinical case, highlighting differences in counseling and clinical outcomes. rhGH therapy has been used for more than 3 decades. Data are largely reassuring, yet we still have much to learn about pharmaceutical approaches to growth in children and the lifelong effect of treatment.

Application of the Athlete Biological Passport Approach to the Detection of Growth Hormone Doping.

CONTEXT: Because of its anabolic and lipolytic properties, growth hormone (GH) use is prohibited in sport. Two methods based on population-derived decision limits are currently used to detect human GH (hGH) abuse: the hGH Biomarkers Test and the Isoforms Differential Immunoassay. OBJECTIVE: We tested the hypothesis that longitudinal profiling of hGH biomarkers through application of the Athlete Biological Passport (ABP) has the potential to flag hGH abuse. METHODS: Insulin-like growth factor 1 (IGF-1) and procollagen III peptide (P-III-NP) distributions were obtained from 7 years of anti-doping data in elite athletes (n = 11 455) and applied as priors to analyze individual profiles from an hGH administration study in recreational athletes (n = 35). An open-label, randomized, single-site, placebo-controlled administration study was carried out with individuals randomly assigned to 4 arms: placebo, or 3 different doses of recombinant hGH. Serum samples were analyzed for IGF-1, P-III-NP, and hGH isoforms and the performance of a longitudinal, ABP-based approach was evaluated. RESULTS: An ABP-based approach set at a 99% specificity level flagged 20/27 individuals receiving hGH treatment, including 17/27 individuals after cessation of the treatment. ABP sensitivity ranged from 12.5% to 71.4% across the hGH concentrations tested following 7 days of treatment, peaking at 57.1% to 100% after 21 days of treatment, and was maintained between 37.5% and 71.4% for the low and high dose groups 1 week after cessation of treatment. CONCLUSION: These findings demonstrate that longitudinal profiling of hGH biomarkers can provide suitable performance characteristics for use in anti-doping programs.

Reduced Effectiveness and Comparable Safety in Biweekly vs. Weekly PEGylated Recombinant Human Growth Hormone for Children With Growth Hormone Deficiency: A Phase IV Non-Inferiority Threshold Targeted Trial.

Context: Long-acting recombinant human growth hormone (rhGH) has transformed growth hormone deficiency (GHD) treatment. However, the possibility and rationality for flexible time regimen are pending. Objective: We studied the efficacy of biweekly versus weekly PEGylated rhGH (PEG-rhGH) therapy in GHD children. Design Setting and Patients: This multicenter, phase IV trial with a non-inferiority threshold ≥20% enrolled 585 Tanner stage I GHD children. Intervention: Subjects randomly received 0.20 mg/kg once-weekly or biweekly PEG-rhGH, or 0.25 mg/kg.w rhGH once daily for 26 weeks. Main Outcome Measure: The primary outcome was height SD scores for chronological age (HtSDSCA) at week 26 and safety measurements including adverse events (AEs), IGF-2, and IGFBP-2 changes. Results: At week 26, the median HtSDSCA changed from -2.75, -2.82, and -2.78 to -2.31, -2.43, and -2.28 with weekly and biweekly PEG-rhGH, and daily rhGH, respectively. The difference in HtSDSCA was 0.17 ± 0.28 between weekly and biweekly PEG-rhGH, and 0.17 ± 0.27 between daily rhGH and biweekly PEG-rhGH, failing the non-inferiority threshold. Nevertheless, the height velocity of children receiving biweekly PEG-rhGH reached 76.42%-90.34% and 76.08%-90.60% that of children receiving weekly PEG-rhGH and daily rhGH, respectively. The rate of AEs was comparable among the groups. No statistical difference was observed in IGF-2 and IGFBP-2 levels among the groups. IGFBP-2 levels decreased over time in all groups, with no notable difference in IGF-2 and IGFBP-2 changes among the three treatment groups. Conclusions: Although notably promoted height velocity, biweekly PEG-rhGH failed the non-inferiority threshold as compared with either weekly PEG-rhGH or daily rhGH. Compared with short-term rhGH, long-acting PEG-rhGH did not significantly increase tumor-associated IGF-2 and IGFBP-2 expressions. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02976675.

Effect of Weekly Long-Acting Growth Hormone Replacement Therapy Compared to Daily Growth Hormone on Children With Short Stature: A Meta-Analysis.

Background: We performed a meta-analysis to evaluate the efficacy and safety of weekly long-acting growth hormone replacement therapy compared to daily growth hormone in children with short stature. Methods: A systematic literature search up to April 2021 was performed and 11 studies included 1,232 children with short stature treated with growth hormone replacement therapy at the start of the study; 737 of them were using weekly long-acting growth hormone replacement therapy and 495 were using daily growth hormone. They were reporting relationships between the efficacy and safety of long-acting growth hormone replacement therapy and daily growth hormone in children with short stature. We calculated the odds ratio (OR), and mean difference (MD) with 95% confidence intervals (CIs) to assess the efficacy and safety of weekly long-acting growth hormone replacement therapy compared to daily growth hormone in children with short stature using the dichotomous or continuous method with a random or fixed-effect model. Results: Long-acting growth hormone replacement therapy had significantly lower height standard deviation scores chronological age (MD, -0.10; 95% CI, -0.13 to -0.08, p <0.001), and insulin-like growth factor binding protein-3 (MD, -0.69; 95% CI, -1.09 to -0.30, p <0.001) compared to daily growth hormone in children with short stature.However, growth hormone replacement therapy had no significantly difference in height velocity (MD, -0.09; 95% CI, -0.69-0.5, p = 0.76), height standard deviation scores bone age (MD, -0.04; 95% CI, -0.10-0.02, p = 0.16), insulin-like growth factor 1 standard deviation scores (MD, 0.26; 95% CI, -0.26-0.79, p = 0.33), and incidence of adverse events (OR, 1.16; 95% CI, 0.90-1.50, p = 0.25) compared to daily growth hormone in children with short stature. Conclusions: Long-acting growth hormone replacement therapy had significantly lower height standard deviation scores chronological age, and insulin-like growth factor binding protein-3 compared to daily growth hormone in children with short stature. However, growth hormone replacement therapy had no significant difference in height velocity, height standard deviation scores bone age, insulin-like growth factor 1 standard deviation scores, and incidence of adverse events compared to daily growth hormone in children with short stature. Further studies are required to validate these findings.

GH Resistance Is a Component of Idiopathic Short Stature: Implications for rhGH Therapy.

Idiopathic short stature (ISS) is a term used to describe a selection of short children for whom no precise aetiology has been identified. Molecular investigations have made notable discoveries in children with ISS, thus removing them from this category. However, many, if not the majority of children referred with short stature, are designated ISS. Our interest in defects of GH action, i.e. GH resistance, has led to a study of children with mild GH resistance, who we believe can be mis-categorised as ISS leading to potential inappropriate management. Approval of ISS by the FDA for hGH therapy has resulted in many short children receiving this treatment. The results are extremely variable. It is therefore important to correctly assess and investigate all ISS subjects in order to identify those with mild but unequivocal GH resistance, as in cases of PAPP-A2 deficiency. The correct identification of GH resistance defects will direct therapy towards rhIGF-I rather than rhGH. This example illustrates the importance of recognition of GH resistance among the very large number patients referred with short stature who are labelled as 'ISS'.