Long-term Growth Hormone Therapy Research Articles

Growth hormone therapy in Turner Syndrome (TS): A focused review on glucose metabolism outcomes

Introduction: Turner Syndrome (TS) patients inherently possess a higher risk of developing glycemic abnormalities due to their unique genetic makeup, and the administration of growth hormone (GH) therapy, while beneficial for growth, might exacerbate this tendency towards disturbed glucose metabolism. Objective of the Review: To evaluate the existing literature on the effects of GH therapy on glucose metabolism in TS patients, highlighting the balance between therapeutic benefits and potential metabolic risks. Methods: This review scrutinizes studies published from 2000 to 2024, focusing on the outcomes related to glucose metabolism in TS individuals undergoing GH therapy, encompassing aspects like insulin sensitivity, glucose tolerance, and metabolic health. Results: Insulin Sensitivity and Resistance: Initial findings suggest that GH therapy may exacerbate insulin resistance and elevate insulin levels, although these effects appear transient and potentially reversible after the cessation of therapy. Long-term Metabolic Outcomes: Later studies indicate that long-term GH therapy may lead to an improvement in insulin sensitivity and a normalization of carbohydrate metabolism, particularly after the therapy is discontinued. Variable Impacts on Glucose Tolerance: The reviewed literature shows mixed effects on glucose tolerance, with some studies reporting no significant changes, while others highlight a potential risk for worsening glucose metabolism. Body Composition and Metabolic Profile: Positive changes in body composition and lipid profiles were noted, which could confer metabolic benefits, yet the therapy's role in increasing insulin levels warrants careful consideration. Individual Variability and Monitoring Needs: The diverse responses to GH therapy underscore the necessity for individualized treatment plans and diligent metabolic monitoring to mitigate potential risks and optimize therapeutic outcomes. Conclusion: The administration of GH therapy in TS requires a delicate balance, considering its potential to both benefit and pose risks to glucose metabolism. Tailored monitoring and a comprehensive understanding of the individual patient’s metabolic response are essential for maximizing the therapy's efficacy while minimizing associated metabolic complications.

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

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

The Impact of Growth Hormone Therapy on Sleep-Related Health Outcomes in Children with Prader-Willi Syndrome: A Review and Clinical Analysis.

This literature review of growth hormone (GH) therapy and sleep-related health outcomes in children diagnosed with Prader-Willi syndrome (PWS) assembles evidence for the consequences of sleep deprivation and poor sleep quality: difficulty concentrating and learning at school, behavioral problems, diminished quality of life, and growth impairment. Sleep-disordered breathing (SDB) is another factor that impacts a child's well-being. We searched the electronic databases Medline PubMed Advanced Search Builder, Scopus, and Web of Science using MeSH terms and text words to retrieve articles on GH deficiency, recombinant human growth hormone (rhGH) therapy, sleep quality, SDB, and PWS in children. The censor date was April 2023. The initial search yielded 351 articles, 23 of which were analyzed for this review. The study findings suggest that while GH may have a role in regulating sleep, the relationship between GH treatment and sleep in patients with PWS is complex and influenced by GH dosage, patient age, and type and severity of respiratory disorders, among other factors. GH therapy can improve lung function, linear growth, and body composition in children with PWS; however, it can also trigger or worsen obstructive sleep apnea or hypoventilation in some. Long-term GH therapy may contribute to adenotonsillar hypertrophy and exacerbate sleep apnea in children with PWS. Finally, GH therapy can improve sleep quality in some patients but it can also cause or worsen SDB in others, leading to diminished sleep quality and overall quality of life. The current evidence suggests that the initial risk of worsening SDB may improve with long-term therapy. In conclusion, rhGH is the standard for managing patients with PWS. Nonetheless, its impact on respiratory function during sleep needs to be thoroughly evaluated. Polysomnography is advisable to assess the need for adenotonsillectomy before initiating rhGH therapy. Close monitoring of sleep disorders in patients with PWS receiving GH therapy is essential to ensure effective and safe treatment.

Growth Hormone Injection Log Analysis with Electronic Injection Device for Qualifying Adherence to Low-Irritant Formulation and Exploring Influential Factors on Adherence.

Although the treatment success of long-term growth hormone therapy (GHT) is dependent on maintaining patients' adherence to treatment, marked variations in adherence levels among children with GHT (eg, 7-71% nonadherence) have been reported. Barriers to or promoters of GHT adherence have been discussed and investigated, and digital health technologies, such as electronic GH injection devices, may have the potential to assess adherence to GHT more accurately. Thus, we conducted a multicenter, retrospective cohort study using GH injection log analysis of an electronic GH device, GROWJECTOR®L, to qualify adherence and explore the factors influencing adherence. This study enrolled 41 patients (median[range] age, 5.8[3.0 ~ 17.0] years) with short stature from nine Japanese medical institutions. The injection log data (12-48 weeks) were read by smartphones and collected into the data center through a cloud server. Although cumulative adherence rates remained higher than 95% throughout the observation period, five (12.2%) patients had low adherence (<85%). Subsequently, subgroup and logistic regression analyses for exploring factors affecting adherence revealed that self-selection of GH device and irregular injection schedule (ie, frequent injections after midnight) significantly affected adherence rate (p=0.034 and 0.048, respectively). In addition, higher rates of irregular injections significantly affected low adherence (median[range], 11.26[0.79 ~ 30.50]% vs 0.26[0.00 ~ 33.33]%, p = 0.029). Our study indicated that injection log analysis using an electronic GH device could detect irregular injection schedules due to a night owl or disturbance in lifetime rhythm affecting low adherence and had significant potential to encourage collaborative monitoring of adherence with healthcare providers and patients themselves/caregivers, along with growing autonomy and shared decision-making. Our study suggests the significance of narrative and personal approaches to adherence of patients with GHT and the usefulness of digital devices for such an approach and for removing various barriers to patient autonomy, leading to improvement and maintenance of adherence.

Adult Height in Indian Girls with Turner Syndrome Treated with Long-Term Growth Hormone Therapy - A Western India Tertiary Centre Experience.

Owing to paucity of data on adult height in Indian girls with Turner syndrome treated with growth hormone (GH), this study was conducted to assess improvement in height following GH therapy and adult height achieved with long-term GH therapy in Indian girls with Turner syndrome and to assess relationship between achieved and predicted height. Retrospective analysis was performed on 12 girls with karyotype-proven Turner syndrome, who had attained adult height following mean duration of GH therapy of 4.8 years (range: 2.7-7.6). Adult height predictions were performed using index of responsiveness (IOR) and Ranke's prediction model. Mean age at starting GH was 10.2 ± 1.9 years; Pubertal induction was between 11 and 15 years. Mean height gain was 29.3 ± 9.8 cm (range: 14-39.5) from onset of treatment to adult height. Significant improvement in height Z scores (IAP 2015 and Indian Turner reference data) following GH therapy (p = 0.002 and 0.012, respectively) was noted. Using Indian Turner reference data, the height Z score improved from pre-treatment 0.8 ± 0.8 to 2.0 ± 0.9 on stopping GH and adult height Z score of 1.3 ± 0.7. Using Ranke's equation for prediction of near adult height, predicted and achieved adult height showed a strong positive correlation (Spearman correlation coefficient = 0.827, significant at 0.01 level). At a dose in the lower range (40-50 mcg/kg/day) of recommendation and duration of 5 years, Indian girls with Turner syndrome can achieve adult height within the healthy Indian reference range. Dose individualization based on IOR would help in optimizing GH dosage and would turn out to be economically sustainable without compromising on height outcomes.

WeChat-based mobile health management for short-stature children with long-term growth hormone therapy: A nonexperimental study.

To evaluate the role of a WeChat-based mobile platform in growth hormone therapy. Growth hormone therapy and health education information for height growth were embedded in a WeChat-based mobile platform, and the platform was evaluated through medical staff assessments, patient volunteer assessments and quantitative scoring criteria. In the medical staff evaluation, both clinicians and nurses had a positive attitude towards the mobile platform, believing that the design of the mobile platform was clearly visualized and easy to operate. In family volunteers' evaluations, the summary of β-testing results showed that 90-100% of parents had a positive attitude towards the WeChat-based mobile platform. Parents of the patients and doctors and nurses assessed the mobile platform by reviewing quantitative scoring standards developed by professional researchers. All scores were >16 (the average score was 18-19.3). Children treated with growth hormone therapy were included for compliance tracking for one year, and patient adherence was described in this study. The interaction based on the WeChat platform and the health education of the public have greatly increased the interaction between doctors and patients, and improved patient satisfaction and compliance.

Facilitating the adherence journey of children, adolescents, and adults on long-term growth hormone therapy.

Growth hormone deficiency in children and adolescents is treated with recombinant growth hormone injections, with the aim of helping patients reach a final height that falls within their genetically predicted adult height. While this treatment is very successful, overcoming issues of patient adherence is a challenge at each stage of the treatment journey, from early childhood to adulthood. An advisory board of senior endocrine nurses convened to discuss what strategies and tools work well in achieving adherence, and the best practices they identified-including the key strategies of choice, information, teamwork, and support-were presented at the 2016 meeting of The Endocrine Society. The advisers agreed that key steps to improve adherence include: patient/carer-centric endocrine nursing services, good-quality education and support, patient autonomy (where possible), broader treatment choice (in terms of device and self-injection), optimal follow-up from childhood to adulthood, and sharing of best practices.

Update on Diabetes Mellitus and Glucose Metabolism Alterations in Prader-Willi Syndrome.

This review summarizes our current knowledge on type 2 diabetes mellitus (T2DM) and glucose metabolism alterations in Prader-Willi syndrome (PWS), the most common syndromic cause of obesity, and serves as a guide for future research and current best practice. Diabetes occurs in 10-25% of PWS patients, usually in adulthood. Severe obesity is a significant risk factor for developing of T2DM in PWS. Paradoxically, despite severe obesity, a relative hypoinsulinemia, without the expected insulin resistance, is frequently observed in PWS. The majority of PWS subjects with T2DM are asymptomatic and diabetes-related complications are infrequent. Long-term growth hormone therapy does not adversely influence glucose homeostasis in all ages, if weight gain does not occur. Early intervention to prevent obesity and the regular monitoring of glucose levels are recommended in PWS subjects. However, further studies are required to better understand the physiopathological mechanisms of T2DM in these patients.

Benefits and challenges in conducting long-term growth hormone therapy in patients with Prader-Willi syndrome

The purpose of this report is to comment the results from long-term growth hormone (GH) treatment of Bulgarian patients suffering from rare genetic disease-Prader-Willi syndrome (PWS) with reference to the age, body composition, complications and genetic etiology. Statistical analysis was performed by ANOVA with post hoc Kruskal-Wallis test and Dunn's multiple comparison tests. In 90% of the patients maternal uniparental disomy (mUPD) was found to be the cause of the disease. No cases due to imprinting defects are found. The BMI data shows no statistically significant difference between BMI at diagnosis (21.850), at the beginning of the GH therapy (21.852) and current BMI (24.09) - measured under the GH background. Early GH treatment allows to overcome arising obstacles in time and to improve the quality of life for PWS children and their families. During the fourteen years study period only ten patients were diagnosed with the disease. Ninety percent (n=9) of the children were found to be with maternal UPD (mUPD) and only one case was due to deletion in 15q11-13. These results are in agreement with other studies in the field which shows the need for reassessment and new robust statistical analysis of the frequency of genetic mechanisms for PWS.

Evaluation of Efficacy of Long-term Growth Hormone Therapy in Patients with Hypochondroplasia

Hypochondroplasia is a cause of disproportionate short stature and characterized by minor clinical manifestations. The aim of this study was to evaluate the efficacy of long-term growth hormone (GH) therapy in hypochondroplastic cases with inadequate response to GH stimulation tests. In this study, six patients who had a height standard deviation score of -3.43 before the treatment and a mean age of 7.42 years and who had received GH treatment at a dose of 0.2 mg/kg/week for a mean period of 4.45 years were evaluated. A good response was found in the first year of treatment, but this increase was not found to be sufficient for the patients to achieve an adequate final height.

Safety and effectiveness of long-term growth hormone therapy in Japanese patients with adult growth hormone deficiency: a postmarketing, multicenter, observational study.

We aimed to evaluate the long-term safety and effectiveness of growth hormone (GH) therapy in Japanese patients with adult growth hormone deficiency (AGHD). In this observational, multicenter study, Norditropin® (Novo Nordisk A/S, Bagsvaerd, Denmark) was administered as injections of 0.021 mg/kg/week as a starting dose divided into 6-7 doses/week. The dose was increased according to clinical response. Patients' data were obtained from medical records. Measurements (lipids, glucose metabolism, and body composition) taken at baseline; 3, 6, and 12 months; and yearly until the end of the study were collected. Adverse drug reactions (ADRs), serious ADRs, and serious adverse events (SAEs) were evaluated. Of 387 registered patients, 334 were eligible for safety. After GH treatment initiation, a marked decrease in total cholesterol was observed earlier in the child-onset group than in the adult-onset group. LDL-cholesterol also decreased, but no significant differences in changes in LDL-cholesterol between adult-onset and child-onset groups were found. A significant increase in HDL-cholesterol starting 1 year after GH treatment initiation was found in the adult-onset group. There was no effect of GH treatment on glucose metabolism. Because of the small number of dual-energy X-ray absorptiometry data, the overall assessment of changes of body composition was difficult. Fifty-six (16.8%), 12 (3.6%), and 35 (10.5%) patients experienced ADRs, serious ADRs, and SAEs, respectively. This study demonstrated a favorable long-term safety and effectiveness profile of GH therapy in AGHD patients in the real-life Japanese clinical practice setting.

The influence of a long-term growth hormone treatment on lipid and glucose metabolism: a randomized trial in short Japanese children born small for gestational age.

BackgroundLong-term growth hormone (GH) treatments in short children born small for gestational age (SGA) restore lipid metabolism, but also increase insulin resistance. The aim of this study was to evaluate the influence of long-term GH therapy on lipid and glucose metabolism as well as its dose dependency in short Japanese children born SGA.MethodsEighty Japanese children with a short stature who were born SGA participated in this study; 65 were treated with fixed GH doses of 0.033 (low) or 0.067 (high) mg/kg/day for 260 weeks; 15 were untreated controls in the first year and were randomized to one of the two treatment groups at week 52. Serum cholesterol, glucose and insulin levels were regularly measured. An oral glucose tolerance test (OGTT) was conducted annually.ResultsThe mean age at the start of GH therapy was approximately 5.3 years. Serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the high dose group significantly decreased over time during GH therapy. In both dose groups for TC, and in the high dose group for LDL-C, the higher the baseline values, the greater the decrease after 260 weeks. The rate of the decrease observed after 260 weeks in patients with high LDL-C levels was greater in the high dose group. Based on the results of OGTT, no patient was classified as being diabetic; however, annual increases were observed in post-OGTT insulin levels. After 260 weeks, the homeostasis model assessment as an index of insulin resistance (HOMA-IR) increased, suggesting that insulin resistance developed over time with the GH treatment, while 36.6 % of the subjects entered puberty.ConclusionsLong-term continuous GH treatment for children born SGA may have a potentially beneficial effect on several parameters in lipid metabolism and does not adversely affect glucose metabolism.Trial registrationGHLIQUID-1516, GHLIQUID-1517, Japan Pharmaceutical Information Center Clinical trial registration: JapicCTI-050132. Registered 13 September 2005. Retrospectively registered. JapicCTI-050137. Registered 13 September 2005. Retrospectively registered. ClinicalTrials.gov trial registration: NCT00184717. Registered 13 September 2005. Retrospectively registered.

Growth hormone positive effects on craniofacial complex in Turner syndrome

ObjectiveTurner syndrome occurs in phenotypic females with complete or partial absence of X chromosome. The leading symptom is short stature, while numerous but mild stigmata manifest in the craniofacial region. These patients are commonly treated with growth hormone to improve their final height. The aim of this study was to assess the influence of long-term growth hormone therapy on craniofacial morphology in Turner syndrome patients. DesignIn this cross-sectional study cephalometric analysis was performed on 13 lateral cephalograms of patients with 45,X karyotype and the average age of 17.3 years, who have received growth hormone for at least two years. The control group consisted of 13 Turner syndrome patients naive to growth hormone treatment, matched to study group by age and karyotype. Sixteen linear and angular measurements were obtained from standard lateral cephalograms. Standard deviation scores were calculated in order to evaluate influence of growth hormone therapy on craniofacial components. ResultsIn Turner syndrome patients treated with growth hormone most of linear measurements were significantly larger compared to untreated patients. Growth hormone therapy mainly influenced posterior face height, mandibular ramus height, total mandibular length, anterior face height and maxillary length. While the increase in linear measurements was evident, angular measurements and facial height ratio did not show statistically significant difference. Acromegalic features were not found. ConclusionsLong-term growth hormone therapy has positive influence on craniofacial development in Turner syndrome patients, with the greatest impact on posterior facial height and mandibular ramus. However, it could not compensate X chromosome deficiency and normalize craniofacial features.

Response to long-term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: Patterns of growth, puberty and final height data.

RASopathies are developmental disorders caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Reduced growth is a common feature. Several studies generated data on growth, final height (FH), and height velocity (HV) after growth hormone (GH) treatment in patients with these disorders, particularly in Noonan syndrome, the most common RASopathy. These studies, however, refer to heterogeneous cohorts in terms of molecular information, GH status, age at start and length of therapy, and GH dosage. This work reports growth data in 88 patients affected by RASopathies with molecularly confirmed diagnosis, together with statistics on body proportions, pubertal pattern, and FH in 33, including 16 treated with GH therapy for proven GH deficiency. Thirty-three patients showed GH deficiency after pharmacological tests, and were GH-treated for an average period of 6.8 ± 4.8 years. Before starting therapy, HV was -2.6 ± 1.3 SDS, and mean basal IGF1 levels were -2.0 ± 1.1 SDS. Long-term GH therapy, starting early during childhood, resulted in a positive height response compared with untreated patients (1.3 SDS in terms of height-gain), normalizing FH for Ranke standards but not for general population and Target Height. Pubertal timing negatively affected pubertal growth spurt and FH, with IGF1 standardized score increased from -2.43 to -0.27 SDS. During GH treatment, no significant change in bone age velocity, body proportions, or cardiovascular function was observed.

User assessment of Norditropin NordiFlex&amp;reg;,a new prefilled growth hormone pen:a Phase IV multicenter prospective study

Background/aimIn growth disorders, ensuring long-term growth hormone therapy (GHT) remains a challenge that might compromise the clinical outcome. Consequently, strategies aiming at alleviating the burden of daily injection might improve the treatment benefit. The study reported here was performed to assess the ease of use of Norditropin NordiFlex® (Novo Nordisk, Princeton, NJ, USA) compared with that of the devices previously used in children treated with GHT with recombinant somatropin.MethodsThis Phase IV prospective, multicenter, open-label study was conducted in France. All patients received Norditropin NordiFlex for 6 weeks. Oral questionnaires were administered by the physician to the patients and/or the parents at inclusion and at the final visit.ResultsThis study included 103 patients aged between 6 and 17 years. The patients assessed Norditropin NordiFlex as significantly easier to use than their previous device (median value = 7.5, P < 0.001). Almost three-quarters of patients (64.4%) preferred Norditropin NordiFlex to their previous device. Among physicians and nurses, 73% assessed Norditropin NordiFlex training as “very easy” and 26% as “easy.” Norditropin NordiFlex improved patient autonomy, with 41% of patients able to self-inject the treatment.ConclusionThis study has shown that Norditropin NordiFlex is reliable, safe, and easy to use and most study patients preferred it to their previous device. These characteristics may improve the adherence to GHT.

Prader–Willi syndrome—GH therapy and bone

A recent publication in the Journal of Clinical Endocrinology and Metabolism provides new data about the role of growth hormone (GH) in bone in Prader–Willi syndrome. The lack of positive effects of long-term GH therapy on BMD in young adults with Prader–Willi syndrome highlights the need to improve the transition from adolescent to adult health care.

Long-term GH therapy—benefits and unanswered questions

A major limitation in determining the effects of growth hormone (GH) therapy on overall health has been the duration of studies, which have previously ranged from 1 year to 5 years. Elbornsson et al. now report the outcome of 15 years of GH treatment on body composition and lipid profile in patients with GH deficiency, but some questions remain unanswered.

Long-Term Growth Hormone Therapy is Associated With a Dose-Dependent Increase in Height SDS and Insulin-Like Growth Factor-I SDS in Short Japanese Children Born Small for Gestational Age

In children with short stature born small for gestational age (SGA), growth hormone (GH) treatment is associated with an acceleration of growth allowing most to achieve an adult height adequate for their target height. The pathophysiology of growth failure may arise from anomalies in the GH–IGF axis, including deficits in GH/IGF-I concentrations and/or GH/IGF-I sensitivity.

Initiating growth hormone therapy for children and adolescents

It is common for children and adolescents on growth hormone (GH) treatment to miss one or more injections per week, thereby compromising their linear growth outcome. Among factors likely to affect treatment concordance are patient education and support in the selection of the most appropriate GH injection device. The authors discovered inconsistencies in the process of starting patients on GH therapy throughout the UK, and found that there were no clinical recommendations to support health professionals starting patients on treatment. This article describes the issues involved and the development of practical recommendations for use when starting paediatric patients on long-term GH therapy.

Psychosocial health and levels of employment in 851 hypopituitary Swedish patients on long-term GH therapy

The psychosocial health and working capacity in hypopituitary patients receiving long-term growth hormone (GH) therapy are unknown. Psychosocial health and levels of employment were compared between GH deficient (GHD) patients on long-term replacement and the general population. In a Swedish nationwide study, 851 GHD patients [101 childhood onset (CO) and 750 adult onset (AO)] and 2622 population controls answered a questionnaire regarding current living, employment and educational level, alcohol consumption and smoking habits. The median time on GH therapy for both men and women with CO GHD was 9 years and for AO GHD 6 years, respectively. As compared to the controls, the GHD patients were less often working full time, more often on sick leave/disability pension, and to a larger extent alcohol abstainers and never smokers (all; P<0.05). Predominantly CO GHD women and men, but to some extent also AO GHD women and men, lived less frequently with a partner and more often with their parents. Particularly AO GHD craniopharyngioma women used more antidepressants, while AO GHD men with a craniopharyngioma used more analgesics. A working capacity to the level of the general population was not achieved among hypopituitary patients, although receiving long-term GH therapy. Patients were less likely to use alcohol and tobacco. The CO GHD population lived a less independent life.