| 1. |
- Dauber, A., et al.
(författare)
-
A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness
- 2020
-
Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 105:10
-
Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness. OBJECTIVE: To identify genetic variants associated with GH responsiveness. DESIGN: Genome-wide association study (GWAS). SETTING: Cohorts from multiple academic centers and a clinical trial. PATIENTS: A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age. INTERVENTION: Association of more than 2 million variants was tested. MAIN OUTCOME MEASURES: Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness. RESULTS: No common variant associations reached genome-wide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score. CONCLUSIONS: We performed the largest GWAS of GH responsiveness to date. We identified 2 loci with a suggestive effect on GH responsiveness in our primary analysis and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to GH responsiveness, likely distinct from the genetic regulators of adult height. © Endocrine Society 2020.
|
|
| 2. |
- Maghnie, M., et al.
(författare)
-
Safety and Efficacy of Pediatric Growth Hormone Therapy: Results From the Full KIGS Cohort
- 2022
-
Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 107:12, s. 3287-3301
-
Tidskriftsartikel (refereegranskat)abstract
- Context The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. Objective This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort. Methods Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (>= 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth. Results The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls. Conclusion Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions.
|
|
| 3. |
- Savendahl, L., et al.
(författare)
-
Long-term mortality after childhood growth hormone treatment: the SAGhE cohort study
- 2020
-
Ingår i: Lancet Diabetes & Endocrinology. - : Elsevier BV. - 2213-8587. ; 8:8, s. 683-692
-
Tidskriftsartikel (refereegranskat)abstract
- Background Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis. Methods This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs). Findings The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1.1, 95% CI 0.9-1.3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1.5, CI 1.1-1.9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3.8, 3.3-4.4; and 17.1, 15.6-18.7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups. Interpretation In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance. Copyright (C) 2020 Elsevier Ltd. All rights reserved.
|
|
| 4. |
- Wit, J M., et al.
(författare)
-
Personalized Approach to Growth Hormone Treatment: Clinical Use of Growth Prediction Models
- 2013
-
Ingår i: Hormone Research in Paediatrics. - : Karger. - 1663-2818 .- 1663-2826. ; 79:5, s. 257-270
-
Forskningsöversikt (refereegranskat)abstract
- The goal of growth hormone (GH) treatment in a short child is to attain a fast catch-up growth toward the target height (TH) standard deviation score (SDS), followed by a maintenance phase, a proper pubertal height gain, and an adult height close to TH. The short-term response variable of GH treatment, first-year height velocity (HV) (cm/year or change in height SDS), can either be compared with GH response charts for diagnosis, age and gender, or with predicted HV based on prediction models. Three types of prediction models have been described: the Kabi International Growth Hormone Study models, the Gothenburg models and the Cologne model. With these models, 50-80% of the variance could be explained. When used prospectively, individualized dosing reduces the variation in growth response in comparison with a fixed dose per body weight. Insulin-like growth factor-I-based dose titration also led to a decrease in the variation. It is uncertain whether adding biochemical, genetic or proteomic markers may improve the accuracy of the prediction. Prediction models may lead to a more evidence-based approach to determine the GH dose regimen and may reduce the drug costs for GH treatment. There is a need for user-friendly software programs to make prediction models easily available in the clinic.
|
|
| 5. |
- Mancini, M. C., et al.
(författare)
-
Effect of gastric bypass on spontaneous growth hormone and ghrelin release profiles
- 2006
-
Ingår i: Obesity (Silver Spring). ; 14:3, s. 383-7
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The purpose of this study was to analyze growth hormone (GH) concentrations in obese women before and after Roux-en-Y gastric bypass (RYGBP) and how resulting changes in weight, fat mass, ghrelin levels, and insulin sensitivity affect GH secretion. RESEARCH METHODS AND PROCEDURES: Blood was sampled at 20-minute intervals for 24 hours in 10 non-diabetic premenopausal severely obese women before and 6 months after RYGBP. GH concentrations were measured in all samples, and serum ghrelin was collected at five time-points. RESULTS: After a 27% BMI drop (55.9 +/- 6.2 to 40.7 +/- 5.8 kg/m(2)), blunted GH profiles underwent partial recovery. Basal, postprandial, and mean ghrelin concentrations were not changed. A negative correlation was found between mean GH levels and insulin and homeostasis model assessment (p < 0.01). BMI accounted for 54% of GH variation. DISCUSSION: Partial recovery of GH secretion after RYGBP-induced weight loss suggests that a blunted secretion is not a causal factor of obesity but a consequence of the obese state and does not seem to be ghrelin-level dependent.
|
|
| 6. |
- Ranke, M. B., et al.
(författare)
-
Major determinants of height development in Turner syndrome (TS) patients treated with GH: analysis of 987 patients from KIGS
- 2007
-
Ingår i: Pediatr Res. - : Springer Science and Business Media LLC. - 0031-3998. ; 61:1, s. 105-10
-
Tidskriftsartikel (refereegranskat)abstract
- Little is known about factors determining height outcome during GH treatment in Turner syndrome (TS). We investigated 987 TS children within the Kabi International Growth Study (KIGS) who had reached near adult height (NAH) after >4 y GH treatment (including >1 y before puberty). Through multiple regression analysis we developed a model for NAH and total gain. Our results were as follows (median): 1) At start, age 9.7 yrs, height (HT) 118.0 cm (0.0 TS SDS), projected adult height 146.1 cm, GH dose 0.27 mg/kg wk; 2) NAH HT 151.0 cm (1.5 TS SDS); 3) Prepubertal gain 21.2 cm (1.6 TS SDS); 4) Pubertal gain 9.4 cm (0.0 TS SDS). NAH correlated (r = 0.67) with (ranked) HT at GH start (+), 1 year responsiveness to GH (+), MPH (+), age at puberty onset (+), age at GH start (-), and dose (+). The same factors explained (R = 0.90) the total HT gain. However, HT at GH start correlated negatively. Karyotype had no influence on outcome. Evidently, height at GH start (the taller, the better), age at GH start (the younger, the better), the responsiveness to GH (the higher, the better) and age at puberty (the later, the better) determine NAH.
|
|
| 7. |
- Hochberg, Z., et al.
(författare)
-
Child health, developmental plasticity, and epigenetic programming
- 2011
-
Ingår i: Endocrine reviews. - : The Endocrine Society. - 0163-769X .- 1945-7189. ; 32:2, s. 159-224
-
Forskningsöversikt (refereegranskat)abstract
- Plasticity in developmental programming has evolved in order to provide the best chances of survival and reproductive success to the organism under changing environments. Environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental, and behavioral strategies in response to local ecological and/or social conditions. The window of developmental plasticity extends from preconception to early childhood and involves epigenetic responses to environmental changes, which exert their effects during life-history phase transitions. These epigenetic responses influence development, cell- and tissue-specific gene expression, and sexual dimorphism, and, in exceptional cases, could be transmitted transgenerationally. Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research. Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs.
|
|
| 8. |
|
|
| 9. |
- Ranke, M. B., et al.
(författare)
-
Age at Growth Hormone Therapy Start and First-Year Responsiveness to Growth Hormone Are Major Determinants of Height Outcome in Idiopathic Short Stature
- 2007
-
Ingår i: Horm Res. - : S. Karger AG. - 0301-0163. ; 68:2, s. 53-62
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: To develop methods to identify factors associated with a favorable outcome in GH-treated children with idiopathic short stature (ISS). Methods: From 4,685 children listed as having ISS within KIGS (Pfizer International Growth Database), we studied (a) the prediction model group (n = 657) to develop the first-year prediction model, and (b) the near adult height group (NAH; n = 256) which received GH for >4 years to develop descriptive models for adult height and overall height gain. Results: NAH group at GH start: age was 10.0 years, height -2.5 SD score (SDS), weight -2.3 SDS, height minus mid-parental height (MPH) -1.5 SDS; GH dose 0.19 mg/kg/week. Height gain was 1.1 SDS at a median age of 17.2 years. Growth response correlated positively with GH dose and weight at the start of GH treatment, and negatively with age and height SDS minus MPH SDS. The model explains 39% (error SD 1.2 cm) of the variability. Adult height correlated (R(2) = 0.64) positively with height at GH start, MPH and the first-year responsiveness to GH, and negatively with age. Conclusions: Prepubertal children with ISS who show an appropriate first-year response to GH are likely to benefit from long-term treatment, even on low GH dosages. Copyright (c) 2007 S. Karger AG, Basel.
|
|
| 10. |
- Ranke, M. B., et al.
(författare)
-
Increased response, but lower responsiveness, to growth hormone (GH) in very young children (aged 0-3 years) with idiopathic GH Deficiency: analysis of data from KIGS
- 2005
-
Ingår i: J Clin Endocrinol Metab. ; 90:4, s. 1966-71
-
Tidskriftsartikel (refereegranskat)abstract
- In children, GH secretion and sensitivity to GH are influenced by developmental changes. It is not clear whether the response to GH in very young children with GH deficiency (GHD) is the same as that in older, prepubertal children. A cohort of 265 children (180 males and 85 females) with idiopathic GHD from KIGS (Pfizer International Growth Database), with treatment started at less than 3 yr of age (mean age, 1.9 yr; group I) was compared with a cohort of 509 children (331 males and 178 females; group II) with treatment started at 7-8 yr of age (mean age, 7.5 yr). The following differences (P < 0.01) were found (given in mean values) between groups I and II at the start of GH treatment: 9% vs. 5% breech delivery, 38% vs. 14% multiple pituitary hormone deficiency, 4.2 vs. 5.9 ng/ml maximum GH in response to tests, -0.1 vs. -0.8 midparental height (MPH) sd score (SDS), -3.1 vs. -2.5 height SDS, 0.83 vs. 0.66 IU/kg.wk GH dose. After the first year of GH, the results were: 13.3 vs. 8.6 cm/yr height velocity, and 1.7 vs. 0.6 maximum change in height SDS. Using the previously developed growth prediction models for prepubertal children with idiopathic GHD more than 2 yr of age, our analysis revealed differences in the indexes of responsiveness in prediction models (Studentized residuals SDS, 0.7 vs.-0.3) and strikingly higher responsiveness to treatment among the young cohort, but with large scatter. Thus, new prediction models of height velocity (centimeters per year) were derived by means of multiple regression analysis for the young cohort, either involving (model A) or excluding (model B) the GH peak in tests. Model A explained 54% of the total variability with an error sd of 2.1 cm. Height velocity correlated with (parameters in order of importance) age (-), maximum GH (-), GH dose (+), weight SDS (+), height SDS minus MPH SDS (-), and birth weight SDS (+). Model B explained 45% of the total variability with an error sd of 2.3 cm. Height velocity correlated with (parameters in order of importance) age (-), GH dose (+), birth weight SDS (+), height SDS minus MPH SDS (-), and weight SDS (+). The predictors were qualitatively the same as those in the total prepubertal model involving all children more than 2 yr of age, but their quantitative impact in terms of partial contribution and the order of their importance were different for the young cohort. In particular, the partial contribution of the GH dose was higher, suggesting a greater gain in height per GH dose unit in the very young than in the older children. However, the rank order of the GH dose in the new models was lower, which suggests a slightly low sensitivity to GH in toddlers after the phase of severe GH insensitivity during early infancy. The early detection and GH treatment of congenital GHD is advantageous as a cost-effective strategy for achieving greater improvement of absolute height and growth velocity.
|
|
