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1.
Biomarkers of GH action in children and adults.
Schilbach, K, Olsson, DS, Boguszewski, MCS, Bidlingmaier, M, Johannsson, G, Jørgensen, JL
Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2018;:1-8
Abstract
Growth hormone (GH) and IGF-I levels in serum are used as biomarkers in the diagnosis and management of GH-related disorders but have not been subject to structured validation. Auxological parameters in children and changes in body composition in adults, as well as metabolic parameters and patient related outcomes are used as clinical and surrogate endpoints. New treatment options, such as long acting GH and GH antagonists, require reevaluation of the currently used biochemical biomarkers. This article will review biomarkers, surrogate endpoints and clinical endpoints related to GH treatment in children and adults as well as in acromegaly.
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2.
Treatment with growth hormone in the prader-willi syndrome.
Moix Gil, E, Giménez-Palop, O, Caixàs, A
Endocrinologia, diabetes y nutricion. 2018;(4):229-236
Abstract
INTRODUCTION The Prader-Willi syndrome (PWS) is a rare genetic disorder caused by absence of expression of the paternal alleles in región 15q11.2-q13. Obesity and hormonal deficiencies, especially of growth hormone (GH), are the most important signs from the therapeutic viewpoint. Recombinant GH (rGH) is effective in children and represents the mainstay in treatment; by contrast, little evidence in available in adult patients. OBJECTIVE To review the reported evidence on the beneficial and adverse effects of treatment with rGH in children and adults. DESIGN A review was made of 62 original articles published between 2000 and 2017 using the PubMed database. RESULTS In pediatric and adult PWS, rGH improves body morphology and composition, physical performance, cognition, psychomotor development, respiratory function, and quality of life with few adverse effects. CONCLUSIONS Treatment with rGH is effective and safe and improves quality of life in both children and adults with PWS.
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Outcomes after multiple courses of granulocyte colony-stimulating factor and growth hormone in decompensated cirrhosis: A randomized trial.
Verma, N, Kaur, A, Sharma, R, Bhalla, A, Sharma, N, De, A, Singh, V
Hepatology (Baltimore, Md.). 2018;(4):1559-1573
Abstract
UNLABELLED Decompensated cirrhosis (DC) carries a high mortality. Liver transplantation (LT) is the treatment of choice; however, the limited availability of donor organs has resulted in high waitlist mortality. The present study investigated the impact of multiple courses of granulocyte-colony stimulating factor (G-CSF) with or without growth hormone (GH) in these patients. Sixty-five patients with DC were randomized to standard medical therapy (SMT) plus G-CSF 3 monthly plus GH daily (group A; n = 23) or SMT plus G-CSF (group B; n = 21) or SMT alone (group C; n = 21). The primary outcome was transplant-free survival (TFS) at 12 months. Secondary outcomes were mobilization of CD34+ cells at day 6 and improvement in clinical scores, liver stiffness, nutrition, episodes of infection, and quality of life (QOL) at 12 months. There was significantly better 12-month TFS in groups A and B than in group C (P = 0.001). At day 6 of therapy, CD34+ cells increased in groups A and B compared to baseline (P < 0.001). There was a significant decrease in clinical scores, improvement in nutrition, better control of ascites, reduction in liver stiffness, lesser infection episodes, and improvement in QOL scores in groups A and B at 12 months as compared to baseline (P < 0.05). The therapies were well tolerated. CONCLUSION Multiple courses of G-CSF improved 12-month TFS, mobilized hematopoietic stem cells, improved disease severity scores, nutrition, fibrosis, QOL scores, ascites control, reduced infections, and the need for LT in patients with DC. However, the use of GH was not found to have any additional benefit. (Hepatology 2017).
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4.
Reduced Growth Hormone Secretion is Associated with Nonalcoholic Fatty Liver Disease in Obese Children.
Liang, S, Yu, Z, Song, X, Wang, Y, Li, M, Xue, J
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2018;(3):250-256
Abstract
The purpose of the study was to evaluate the relationship between arginine-levodopa-induced growth hormone (GH) secretion and nonalcoholic fatty liver disease (NAFLD) in obese children. This study includes a total of 84 obese and 43 normal weight children. The obese subjects are divided into two groups based on the presence or absence of NAFLD. Clinical examination, anthropometric and laboratory examinations, and liver ultrasonography are assessed for all participants. The obese group had significantly lower peak stimulated GH (p<0.001) and lower insulin-like growth factor 1 (IGF-1) (p<0.001) compared with the control group. Children with NAFLD had significantly lower peak stimulated GH (p<0.001) and lower IGF-1 (p=0.022) compared with non-NAFLD group. Results from logistic regression model showed that only peak GH after stimulation test was inversely associated with NAFLD (p=0.015), while body mass index (BMI) was positively associated with NAFLD (p=0.03). Among 84 obese children and adolescents, peak stimulated GH was negatively associated with alanine aminotransferase (r=-0.394, p<0.001), BMI (r=-0.571, p<0.001), systolic blood pressure (r=-0.223, p=0.041), diastolic blood pressure (r=-0.272, p=0.012), homeostasis model assessment of insulin resistance (r=-0.369, p=0.001), insulin (r=-0.382, p<0.001), and positively associated with high density lipoprotein cholesterol (r=0.275, p=0.011). Our study confirms a significant inverse relationship between NAFLD and GH response to standard stimulation testing in obese children without known hypothalamic/pituitary disease.
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Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers.
Sfeir, JG, Kittah, NEN, Tamhane, SU, Jasim, S, Chemaitilly, W, Cohen, LE, Murad, MH
The Journal of clinical endocrinology and metabolism. 2018;(8):2785-2793
Abstract
BACKGROUND Limited guidance exists for selecting a laboratory method for diagnosing GH deficiency (GHD) when it occurs as a late effect of radiotherapy in childhood cancer survivors (CCSs). METHODS We searched Medline, Embase, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus for studies evaluating GHD that used IGF-1 or IGF-binding protein 3 (IGFBP-3) measurements compared with GH dynamic testing. RESULTS We included 15 studies [IGF-1 (8 studies) and IGFBP-3 (7 studies)] enrolling 477 patients. Comparator tests varied widely. Overall, both IGF-1 and IGFBP-3 had suboptimal diagnostic accuracy but were strongly correlated. The use of both tests simultaneously in the same cohort did not improve the diagnostic accuracy. Despite high variability in the testing protocols, dynamic tests remained the most accurate for appropriately identifying patients with GHD. The insulin tolerance test (ITT) appears to be the most accepted reference test when used alone or in combination with arginine; however, standardized testing strategies among practice groups are absent. GHRH and arginine stimulation performed almost similarly to the ITT; however, in one study GHRH with arginine stimulation had 66% sensitivity and 88% specificity compared with the ITT. Insufficient data were available to assess the accuracy of serial GH testing (nocturnal or over 24 hours). CONCLUSION The diagnostic accuracy of various dynamic tests for GHD in CCSs appears to follow the same patterns as those in non-CCSs. Interpreting GHRH stimulation is a challenge given the primarily hypothalamic dysfunction in CCSs. IGF-1 and IGFBP-3 perform poorly in this population.
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Obese adolescents exhibit a constant ratio of GH isoforms after whole body vibration and maximal voluntary contractions.
Rigamonti, AE, Haenelt, M, Bidlingmaier, M, De Col, A, Tamini, S, Tringali, G, De Micheli, R, Abbruzzese, L, Goncalves da Cruz, CR, Bernardo-Filho, M, et al
BMC endocrine disorders. 2018;(1):96
Abstract
BACKGROUND Growth hormone (GH) is a heterogeneous protein composed of several molecular isoforms, the most abundant ones being the 22 kDa- and 20 kDa-GH. Exercise-induced secretion of GH isoforms has been extensively investigated in normal-weight individuals due to antidoping purposes, particularly recombinant human GH (rhGH) abuse. On the other hand, the evaluation of exercise-induced responses in GH isoforms has never been performed in obese subjects. METHODS The acute effects of whole body vibration (WBV) or maximal voluntary contraction (MVC) alone and the combination of MVC with WBV (MVC + WBV) on circulating levels of 22 kDa- and 20 kDa-GH were evaluated in 8 obese male adolescents [mean age ± SD: 17.1 ± 3.3 yrs.; weight: 107.4 ± 17.8 kg; body mass index (BMI): 36.5 ± 6.6 kg/m2; BMI standard deviation score (SDS): 3.1 ± 0.6]. RESULTS MVC (alone or combined with WBV) significantly stimulated 22 kDa- and 20 kDa-GH secretion, while WBV alone was ineffective. In particular, 22 kDa- and 20 kDa-GH peaks were significantly higher after MVC + WBV and MVC than WBV. In addition, 22 kDa-GH (but not 20 kDa-GH) peak was significantly higher after MVC + WBV than MVC. Importantly, the ratio of circulating levels of 22 kDa- to 20 kDa-GH was constant throughout the time window of evaluation after exercise and similar among the three different protocols of exercise. CONCLUSIONS The results of the present study confirm the ability of MVC, alone and in combination with WBV, to stimulate both 22 kDa- and 20 kDa-GH secretion in obese patients, these responses being related to the exercise workload. Since the ratio of 22 kDa- to 20 kDa-GH is constant after exercise and independent from the protocols of exercise as in normal-weight subjects, hyposomatotropism in obesity does not seem to depend on an unbalance of circulating GH isoforms. Since the present study was carried out in a small cohort of obese sedentary adolescents, these preliminary results should be confirmed in further future studies enrolling overweight/obese subjects with a wider age range.
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Clinical assessment of a foam dressing containing growth factor-enhancing hydrated polyurethanes.
Mikosiński, J, Kotala, M, Stücker, M, Twardowska-Saucha, K, Bonnekoh, B, Pańczak, K, Aleksiejew-Kleszczyński, T, Dissemond, J, Eming, SA, Kaspar, D, et al
Journal of wound care. 2018;(9):608-618
Abstract
OBJECTIVE This study assesses a novel dressing concept in venous leg ulcer (VLU) patients. It is based on boosting endogenous growth factor activities synthesised by functional granulation tissue. METHODS Patients received treatment for eight weeks with a hydrated polyurethane-containing foam dressing plus concomitant compression therapy. Wound area reduction (WAR), percentage of wounds achieving a relative WAR of ≥40% and ≥60%, wound pain ratings for the last 24 hours and at dressing changes, EQ-5D Quality of Life questionnaire data, dressing handling and safety parameters were recorded. RESULTS There were 128 patients who received treatment and data for 123 wound treatment courses were documented. Wound area size decreased from 13.3±9.8cm2 to 10.5±12.2cm2 at week eight and median relative WAR was 48.8%. At week eight, a relative WAR ≥40% was reached by 54.5% of the wounds, 41.5% reached a relative WAR of ≥60% and complete healing was observed in 13.5% of wounds. Median wound pain ratings (last 24 hours before dressing change) declined significantly from 30 to 15.5 (100 visual analogue scale [VAS], p=0.0001) and pain at dressing changes from 30 to 12.5 (p≤0.0001). The EQ-5D VAS rating increased from 58.4±19.2mm to 63.1±19.1mm (p=0.0059). CONCLUSION This clinical assessment shows that the concept of boosting endogenous growth factors through hydrated polyurethanes has the potential to accelerate WAR in VLU patients while decreasing pain levels and improving quality of life parameters.
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Variation of bone acquisition during growth hormone treatment in children can be explained by proteomic biomarkers, bone formation markers, body composition and nutritional factors.
Swolin-Eide, D, Andersson, B, Hellgren, G, Magnusson, P, Albertsson-Wikland, K
Bone. 2018;:144-153
Abstract
OBJECTIVE Growth hormone (GH) regulates both longitudinal growth and bone acquisition in children, and has profound metabolic effects. The aim was to investigate the association between proteomic biomarkers, body fat, nutrition and bone formation markers, and longitudinal growth in response to GH during the first year of treatment. The degree to which changes in these factors could explain variations in GH-dependent longitudinal growth and bone mineralization was also assessed. METHODS The individualized GH dose trial included 128 short prepubertal children with either normal (non-GH-deficient) or reduced levels of GH secretion (GH-deficient) (mean age ± SD, 8.6 ± 2.6 years; 90 boys), i.e., with a broad range of GH-secretion and GH-responsiveness, receiving GH treatment (mean 43 μg/kg/day). Blood samples were taken and dual-energy X-ray absorptiometry (DXA) measured at baseline and 1 year of treatment. Step-wise multiple regression models were constructed including three steps with different independent variables added at each step to explain the variance in outcome variables (heightSDS, bone mineral content (BMC) and bone mineral density (BMD). Independent variables included in Step I were previously identified proteomic markers related to GH treatment response, bone formation markers (intact PINP, bone-specific alkaline phosphatase and osteocalcin), variables at treatment start (GH dose mU/kg/day, GH maximum secretion, and difference between child's current and mid-parental heightSDS). Step II explored the added influence of body composition data (body mass index or DXA). Step III explored the added influence of serum nutritional markers and hormones. RESULTS Step I variables explained 71% of the variation in first year heightSDS gain, median (minimum-maximum) 0.8 (0.24-1.67); and the proportion explained rose to 73% following inclusion of step II variables and 75% following step III. Corresponding values for total body BMC were 58%, 78%, and 80%, respectively. Proportions fell by approximately 20% when BMC was adjusted for height; 33%, 57%, and 57% for steps I, II, and III, respectively. Corresponding values for total body BMD were 29%, 39%, and 45%, respectively. CONCLUSION For total BMC, as much as 80% of the variation during the first year of GH treatment could be explained by proteomic biomarkers, body fat, nutrition and bone formation markers, whereas for height-adjusted BMC 57% could be explained. The inclusion of information about either body composition (fat/lean mass) or nutritional markers contributed with approximately 20%. The variation in heightSDS gain could be explained to 75%. Hence, information of fat or nutrition markers was needed for explaining the variation in bone acquisition to the same magnitude as explaining the variation in height response.
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9.
Recombinant growth hormone therapy for cystic fibrosis in children and young adults.
Thaker, V, Carter, B, Putman, M
The Cochrane database of systematic reviews. 2018;(12):CD008901
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Abstract
BACKGROUND Cystic fibrosis (CF) is an inherited condition causing disease most noticeably in the lungs, digestive tract and pancreas. People with CF often have malnutrition and growth delay. Adequate nutritional supplementation does not improve growth optimally and hence an anabolic agent, recombinant human growth hormone (rhGH), has been proposed as a potential intervention. This is an update of a previously published review. OBJECTIVES To evaluate the effectiveness and safety of rhGH therapy in improving lung function, quality of life and clinical status of children and young adults with CF. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 22 October 2018.We also searched ongoing trials registers in clinicaltrials.gov from the United States and WHO International Clinical Trials Registry Platform (ICTRP). Date of latest search: 05 March 2018.We conducted a search of relevant endocrine journals and proceedings of the Endocrinology Society meetings using Web of Science, Scopus and Proceedings First. Date of latest search: 04 March 2018. SELECTION CRITERIA Randomised and quasi-randomised controlled trials of all preparations of rhGH compared to either no treatment, or placebo, or each other at any dose (high-dose and low-dose) or route and for any duration, in children or young adults (aged up to 25 years) diagnosed with CF (by sweat test or genetic testing). DATA COLLECTION AND ANALYSIS Two authors independently screened papers, extracted trial details and assessed their risk of bias. We assessed the quality of the evidence using the GRADE system. MAIN RESULTS We included eight trials (291 participants, aged between five and 23 years) in this revision of the review. Seven trials compared standard-dose rhGH (approximately 0.3 mg/kg/week) to no treatment and one three-arm trial (63 participants) compared placebo, standard-dose rhGH (0.3 mg/kg/week) and high-dose rhGH (0.5 mg/kg/week). Six trials lasted for one year and two trials for six months. We found that rhGH treatment may improve some of the pulmonary function outcomes but there was no difference between standard and high-dose levels (low-quality evidence, limited by inconsistency across the trials, small number of participants and short duration of therapy). The trials show evidence of improvement in the anthropometric parameters (height, weight and lean body mass) with rhGH therapy, again no differences between dose levels. We found improvement in height for all comparisons (very low- to low quality evidence), but improvements in weight and lean body mass were only reported for standard-dose rhGH versus no treatment (very low-quality evidence). There is some evidence indicating a change in the level of fasting blood glucose with rhGH therapy, however, it did not cross the clinical threshold for diagnosis of diabetes in the trials of short duration (low-quality evidence). There is low- to very low-quality evidence for improvement of pulmonary exacerbations with no further significant adverse effects, but this is limited by the short duration of trials and the small number of participants. One small trial provided inconsistent evidence on improvement in quality of life (very low-quality evidence). There is limited evidence from three trials in improvements in exercise capacity (low-quality evidence). None of the trials have systematically compared the expense of therapy on overall healthcare costs. AUTHORS' CONCLUSIONS When compared with no treatment, rhGH therapy is effective in improving the intermediate outcomes in height, weight and lean body mass. Some measures of pulmonary function showed moderate improvement, but no consistent benefit was seen across all trials. The significant change in blood glucose levels, although not causing diabetes, emphasizes the need for careful monitoring of this adverse effect with therapy in a population predisposed to CF-related diabetes. No significant changes in quality of life, clinical status or side-effects were observed in this review due to the small number of participants. Long-term, well-designed randomised controlled trials of rhGH in individuals with CF are required prior to routine clinical use of rhGH in CF.
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Short-term, supra-physiological rhGH administration induces transient DNA damage in peripheral lymphocytes of healthy women.
Fantini, C, Sgrò, P, Pittaluga, M, de Perini, A, Dimauro, I, Sartorio, A, Caporossi, D, Di Luigi, L
Journal of endocrinological investigation. 2017;(6):645-652
Abstract
PURPOSE While a good safety for recombinant human growth hormone (rhGH) therapy at replacement doses is recognized, a possible link between high concentration of the GH-IGF-I axis hormones and side negative effect has been reported. The aim of this pilot study was to assess whether a short-term exposure to supra-physiological doses of rhGH may affect DNA integrity in human lymphocytes (PBL). METHODS Eighteen healthy Caucasian female (24.2 ± 3.5 years) were randomly included in a Control (n = 9) and rhGH administration group (n = 9, 3-week treatment). DNA damage (comet assay), chromosomal breaks, and mitotic index in phytohemagglutinin-stimulated PBL were evaluated before (PRE), immediately (POST), and 30 days (POST30) after the last rhGH administration (0.029 mg kg- 1 BW; 6 days/week), together with serum IGF-1 and IGFBP-3 concentrations. RESULTS rhGH administration increased IGF-I, without evidence of persisting IGF-I and IGFBP-3 changes 30 days after withdrawal. Total DNA breakage (% DNA in tails) was not significantly different in subjects treated with rhGH in comparison with controls, although the rhGH-treated subjects showed an higher percentage of heavily damaged nuclei immediately after the treatment (POST30 vs. PRE: p = 0.003), with a lower mitogenic potential of lymphocytes, detectable up to the POST30 (PRE vs. POST p = 0.02; PRE vs. POST30: p = 0.007). CONCLUSIONS This pilot study showed that 3 weeks of short-term supra-physiological rhGH administration in healthy women induce a transient DNA damage and mitogenic impairment in PBL. The analysis of DNA damage should be explored as useful tool in monitoring the mid to long-term effects of high rhGH treatment or abuse.