| 1. |
- Albertsson-Wikland, Kerstin, 1947, et al.
(författare)
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Mortality is not increased in rhGH-treated patients when adjusting for birth characteristics.
- 2016
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 101:5, s. 2149-2159
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Tidskriftsartikel (refereegranskat)abstract
- Objective: This study aimed to investigate whether reported high mortality in childhood recombinant human GH (rhGH)-treated patients was related to birth-characteristics and/or rhGH treatment. Design and Setting: We sought to develop a mortality model of the Swedish general population born between 1973 and 2010, using continuous-hazard functions adjusting for birth characteristics, sex, age intervals, and calendar year to estimate standardized mortality ratio (SMR) and to apply this model to assess expected deaths in Swedish rhGH-treated patients with idiopathic isolated GH deficiency (IGHD), idiopathic short stature (155) or born small for gestational age (SGA). Participants:The general population: Swedish Medical Birth Register (1973-2010: 1 880 668 males; 1 781 131 females) and Cause of Death Register (1985-2010). Intervention Population: Three thousand eight hundred forty-seven patients starting rhGH treatment between 1985 and 2010 and followed in the National GH Register and/or in rhGH trials diagnosed with IGHD (n = 1890), ISS (n = 975), or SGA (n=982). Main Outcome Measures: Death. Results: Using conventional models adjusting for age, sex, and calendar-year, the SMR was 1.43 (95% confidence interval, 0.89-2.19), P = .14, observed/expected deaths 21/14.68. The rhGH population differed (P < .001) from the general population regarding birth weight, birth length, and congenital malformations. Application of an Advanced Model: When applying the developed mortality model of the general population, the ratio of observed/expected deaths in rhGH-treated patients was 21/21.99; SMR = 0.955 (0.591-1.456)P = .95. Model Comparison: Expected number of deaths were 14.68 (14.35-14.96) using the conventional model, and 21.99 (21.24-22.81) using the advanced model, P < .001, which had at all ages a higher gradient of risk per SD of the model, 24% (range, 18-42%; P < .001). Conclusions: Compared with the general Swedish population, the ratio of observed/expected deaths (21/21.99) was not increased in childhood rhGH-treated IGHD, ISS, and SGA patients when applying an advanced sex-specific mortality model adjusting for birth characteristics.
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| 2. |
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| 3. |
- Andersson, Björn, 1977, et al.
(författare)
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Decrease in adiponectin levels correlates to growth response in growth hormone-treated children.
- 2009
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Ingår i: Hormone research. - : S. Karger AG. - 1423-0046 .- 0301-0163. ; 71:4, s. 213-8
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Tidskriftsartikel (refereegranskat)abstract
- Adiponectin is secreted by adipose tissue and circulates in human plasma at high levels. Decreased adiponectin levels are associated with insulin resistance and obesity. The aim of this study was to investigate whether changes in serum adiponectin levels are related to the growth response, insulin levels and insulin resistance during growth hormone (GH) treatment.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Decker, Ralph, 1968, et al.
(författare)
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Different thresholds of metabolic GH effects in prepubertal children
- 2009
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Ingår i: Hormone Research.
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Konferensbidrag (refereegranskat)abstract
- Context: In addition to growth hormone (GH) effects to promote linear growth in children, GH also has substantial effects on insulin sensitivity, lipolysis, lipids, and body composition. A dissociation between anabolic and lipolytic GH effects has been suggested. Objective: The objective of the present study was to further investigate dissociated GH effects by calculating the GH doses to attain half of a given metabolic effect, the effective dose 50% (ED50%). Hypothesis: The hypothesis was that there are dose-dependent thresholds in different variables reflecting metabolism. Design: A randomized, prospective, multicentre trial was performed for a 2 years period, with two treatment regimens in short prepubertal GHD and ISS children a) individualized GH dose with six different dose groups ranging 17-100 g/kg/day (n=87) and b) fixed GH dose of 43 g/kg/day (n=41). Results: Contrary to changes in fat mass, leptin, lipids and skinfold measurements, there was evidence for different thresholds in metabolic variables for a given GH dose when performing ANOVA, p<0.001. was calculated as the difference between 2 years and start of GH treatment. Besides height (SDS), growth related variables like weight SDS and BMI (kg/m ); measures of body composition such as fat-free mass (FFM) (kg), FFM index (FFMI) (kg/m ), waist (cm), hip (cm); as well as biochemical markers like IGF-1 (SDS), IGFBP-3 (SDS); insulin (mU/L) showed dose-dependency with different ED50% levels. Conclusions: Differences of the ED50% on metabolic variables were seen in-between different GH dose spans. Thus we propose that there are different thresholds in GH effects on variables reflecting different metabolic aspects, suggesting muscle tissue being more sensitive than linear growth, GH induced insulin resistance, the rise in IGF-1 and the increase in hip circumference as a measure of 3-dimensional body growth.
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| 8. |
- Decker, Ralph, 1968, et al.
(författare)
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Early increase of the bone formation marker PINP is in a higher degree related to growth response compared to bone mineralization in GH treated prepubertal children
- 2015
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Ingår i: Horme Research in Paediatrics. - : S. Karger AG. - 1663-2818 .- 1663-2826. ; 84:Suppl 1
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: It has been reported that short-term increases of the bone formation markers intact amino-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BALP) and osteocalcin display different temporal patterns. In adults, the biphasic model of GH action in bone remodelling shows that GH treatment results initially in an increased bone resorption with a concomitant bone loss, which later on is followed by increased bone formation. In children, little is known how bone remodelling takes place. Objective and hypotheses: Bone formation markers reflect different events during osteogenesis, and respond with different time courses during anabolic GH treatment. Method: The study population comprised 128 short prepubertal children (age range 3−11 years; 90 boys, 38 girls) who participated in a longitudinal, prospective, multicenter study in individual GH dosing1, TRN 98-0198-003. The investigated children had either normal or reduced levels of GH secretion. Data from the first 2 years of GH treatment were analyzed. The bone markers were measured using the IDS-iSYS automatic system (Immunodiagnostic Systems)2. The DXA derived variable bone mineral density (BMD) was measured by Lunar DPX-L or Lunar Prodigy. Results: The bone markers PINP, BALP, osteocalcin and 25-hydroxyvitamin D (25(OH)D) at start and deltaPINP at 3 months of GH treatment explained 63% of the growth response at 2 years (p<0.0001), while only 26% of the variation in BMD response after 2 years of treatment was explained (p<0.0001). Conclusion: Bone markers at start of GH treatment, and the 3 months increase of PINP were associated with both growth response and bone mineralization after 2 years of treatment, but with different magnitude of impact on these anabolic GH effects.
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| 9. |
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| 10. |
- Decker, Ralph, 1968, et al.
(författare)
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Hyperbolic function shows close correlation between growth hormone (GH) sensitivity and GH secretion
- 2013
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Ingår i: Hormone Research in Paediatrics. 9th Joint Meeting of Paediatric Endocrinology. - 1663-2818 .- 1663-2826. - 9783318025040 ; 80:suppl 1, s. 301-302
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Konferensbidrag (refereegranskat)abstract
- Background Impressive similarities exist between the insulin resistance-associated metabolic syndrome and untreated growth hormone (GH) deficiency in both children and adults. Central findings are visceral obesity and cardiovascular morbidity. Children with lower GH sensitivity but normal GH secretion like in idiopathic short stature (ISS) belong to a continuous spectrum of imbalanced GH secretion in relation to GH sensitivity. Hypothesis The relationship between secretion and sensitivity is similar for GH and insulin. Materials & methods 153 short prepubertal children with a broad range of secretion and sensitivity were included. From the 24-hour GH profile (72 x 20 min), the 24h GH secretion rate was estimated with a deconvolution method. The secretion rates above the basal level was calculated by PULSAR (GHb). The prediction model estimated the growth response, predicted delta height SDS, a measure of GH sensitivity/ responsiveness. Discussion GH treatment is neither individualized like insulin treatment with adaption to individual sensitivity nor applied in children with ISS. In order to fill gaps in knowledge, we have previously shown that individualized GH treatment is beneficial in reducing the range of growth response and metabolic responses in both GHD and ISS prepubertal children(2, 5, 6). Thus, despite administering higher doses to children being less sensitive to GH, individualized GH treatment is safe in metabolic terms. As insulin dosing is individualized in type-2 diabetes mellitus, it can be recommended to individualize GH dosing in ISS children. The metabolic impact of untreated versus treated ISS in the long term is an issue of further studies. Conclusion Our data confirms similarities between insulin and GH regarding the hyperbolic function between secretion and sensitivity.
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| 11. |
- Decker, Ralph, 1968, et al.
(författare)
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Individualized GH treatment gives improved growth but not higher insulin nor IGF1 compared to standard GH dose after 2 years of catch-up growth
- 2007
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Ingår i: Hormone Research. - 3805583273 ; 68:Supplement Issue 1
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Konferensbidrag (refereegranskat)abstract
- Weight-based approaches for ‘standard’ GH dosing result in dramatic variability in height outcome and IGF-1 levels. In a recent study we showed that growth response variability can be reduced by individualized GH dosing guided by the individual responsiveness estimated by our prediction model. The hypothesis was that despite many individuals needed higher GH doses, the individualized GH regimen would not give higher levels of metabolic variables compared to the group of children receiving standard treatment. We performed an open, prospective, randomized, multicentre trial in 128 prepubertal short children diagnosed as GHD or ISS, for a 2 yr catch-up growth period, with two treatment regimens providing the same mean GH dose a) individualized GH dose, ranging 17-100 µg/kg/day (n=87) and b) standard GH dose: 43 µg/kg/day (n=41). The set goal for treatment effect was to reach midparental height (MPH) SDS after 2 yrs of GH treatment. This goal was reached for a higher proportion of children treated with the individualized dose (p<0.01). Despite this there were no differences between the individual and the standard dose group concerning the mean and variances of Δinsulin, Δleptin, ΔIGF1(SDS), ΔIGF-BP3(SDS) and ΔIGF1/IGF-BP3(SDS). Δ is calculated as the difference between the value at 2 yrs and at the start of treatment. Moreover there were no differences between the groups regarding the mean or the range of these variables at 2 yrs of treatment. It can be concluded that despite a much broader range in GH dose, which comprised a maximum dose of more than 200% of the standard dose, the variability of the metabolic parameters during treatment within the groups and the absolute levels reached at 2 yrs were the same in the two groups. In fact a better growth response in relation to MPH(SDS) was achieved without a difference in metabolic variables between the groups. Individual dosing is preferable in GH treatment.
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| 12. |
- Decker, Ralph, 1968, et al.
(författare)
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Individualized GH treatment reduces the variation in insulin levels and in body composition during the maintenance growth phase in prepubertal children
- 2011
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Ingår i: Horm Res Paediatr. - 9783805598354 ; 2011:76 (suppl)
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Konferensbidrag (refereegranskat)abstract
- Background: Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in prepubertal short children during different growth phases. We have studied individualized GH treatment in the catch-up growth phase and found a reduction in variation of fasting insulin levels by 34% compared to unchanged standard dose. Thereafter, GH-treated children appear to need lower GH doses to maintain SDscore channel-parallel growth. The individualized approach using prediction models for estimation of GH responsiveness has the advantage of narrowing the range of growth response around mid-parental heights, avoiding too low or high GH doses. Methods: Short prepubertal children with either isolated GHD or ISS participated in a 2-year randomized trial of either individualized GH treatment (range, 17–100 μg/kg/day) or a unchanged (USD) standard dose. After achieving near mid-parental height, children with individualized dosage were randomized to either reduced individualized dose (RID, n=28) (i.e. 50% decreased dose) or unchanged individualized dose (UID, n=37) for 2 more years. The 33 children randomized to the USD (43 μg/kg/day) at start of treatment remained unchanged. Objective and hypotheses: To evaluate if bisection of the reduced individualized GH dose (RID) diminishes the variation in the metabolic parameters measured during maintenance growth compared to reduced individualized GH dose. Hypothesis: Reduction of GH dosage reduces the range of metabolic outcomes without decreasing growth velocity during the maintenance growth phase. Results: : We observed a narrower variation in fasting insulin levels (-50%) and in insulin sensitivity as assessed by homoeostasis model assessment, HOMA (-55.1%), lean soft tissue, LST (-27.8%) and bone mineral content, BMC (-31.3%), in RID compared to UID (p<0.05).
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| 13. |
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| 14. |
- Decker, Ralph, 1968, et al.
(författare)
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Lipolytic and anabolic effects of GH are dissociated during individualized GH treatment
- 2008
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Ingår i: European Society for Paediatric Endocrinology. - 9783805586207 ; 70:Supplement Issue 1
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Konferensbidrag (refereegranskat)abstract
- Context: There is a broad variation in longitudinal growth response during GH treatment among prepubertal children. Yet, growth is but one of the several effects of GH. Our working hypothesis was a dissociation of anabolic and lipolytic effects of GH. Objective: To investigate whether diverse metabolic functions respond analogical to growth. Design: A randomized, prospective, multicentre trial was performed, for a 2 years period, with two treatment regimens providing the same mean GH dose a) individualized GH dose, six different dose groups ranging 17-100 µg/kg/day (n=87) and b) standard GH dose: 43 µg/kg/day (n=41). Patients: 128 prepubertal short children, 75% of them diagnosed as GH deficient and 25% as idiopathic short stature. Main Outcome Measures: Changes in metabolic variables (delta 2 years - start). Results: Changes in IGF-1 correlated to height gain (r=0.54, p<0.0001). Stepwise regression showed that 71% of the variation in IGF-1 was explained by height gain (49%), chnages in insulin (9%), free fat mass (FFM) (5%), and biceps skinfold (4%), as well as GH dose (4%). Changes in IGF-1 solely accounted for all changes in FFM (31%). In contrast to total fat mass, changes in FFM were significantly higher after 2 years of GH doses above 40 µg/kg/day (p<0.001 Mann-Whitney test). In principle component analysis it can be demonstrated that the anabolic variables IGF-1, IGFBP-3, FFM, and insulin target in the same direction as height gain. All variables in this vector bundle show high reciprocal partial regressions. The anabolic component is dose-dependent. Variables derived from adipose tissue (total fat mass, leptin, skin fold measurements, triglycerides) and lipid metabolism (cholesterol, HDL, LDL, triglycerides, lipoprotein(a), apolipoprotein A-II) form up a lipolytic bundle. This is unrelated to the anabolic component and dose-independent. Conclusions: This study suggests that lipolytic and anabolic effects of GH are dissociated. The threshold of GH's lipolytic effects is much lower than its anabolic and growth effects.
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| 15. |
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| 16. |
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| 17. |
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| 18. |
- Kriström, Berit, 1949, et al.
(författare)
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GH dosing guided by individual responsiveness decreases variability in growth response and insulin in GHD and ISS children
- 2010
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Ingår i: New Inroads to Child Health (NICHe).
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- GH responsiveness on growth can be estimated before treatment by use of prediction models in GHD and ISS children, and may be used for individualizing the GH dose to reach a set goal for catch-up growth, i.e. Midparental Height (MPH) SDS. Conclusions: The prospective randomized study shows that by using the GH responsiveness estimated by our prediction model for individualizing the GH dose during 2 years of catch-up growth, too low and too high growth response can be avoided, and the variance in fasting insulin and HOMA was reduced.
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| 19. |
- Schmiegelow, Kjeld, et al.
(författare)
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Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study.
- 2009
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 113:24, s. 6077-84
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Tidskriftsartikel (refereegranskat)abstract
- Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyltransferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL.
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| 20. |
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| 21. |
- Wikland, Kerstin Albertsson, et al.
(författare)
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Validated multivariate models predicting the growth response to GH treatment in individual short children with a broad range in GH secretion capacities.
- 2000
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Ingår i: Pediatric Research. - : International Pediatrics Research Foundation, Inc. - 0031-3998 .- 1530-0447. ; 48:4, s. 475-484
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to develop and validate models that could predict the growth responses to GH therapy of individual children. Models for prediction of the initial one and 2-y growth response were constructed from a cohort of 269 prepubertal children (Model group) with isolated GH deficiency or idiopathic short stature, using a nonlinear multivariate data fitting technique. Five sets of clinical information were used. The "Basic model" was created using auxological data from the year before the start of GH treatment and parental heights. In addition to Basic model data, the other four models included growth data from the first 2 y of life, or IGF-I, or GH secretion estimated during a provocation test (AITT) or a spontaneous GH secretion profile. The performance of the models was validated by calculating the differences between predicted and observed growth responses in 149 new GH treated children (Validation group) who fulfilled the inclusion criteria used in the original cohort. The SD of these differences (SD(res)) in the validation group was compared with the SD(res) for the model group. For the 1st y, the SD(res) for the Basic model was 0.28 SDscores. The lowest SD(res) (0.19 SDscores), giving the most narrow prediction interval, was achieved adding the 24h GH profile and data on growth from the first 2 y of life to the Basic model. The models presented permit estimation of GH responsiveness in children over a broad range in GH secretion, and with an accuracy of the models substantially better than when using maximal GH response during an provocation test. The predicted individual growth response, calculated using a computer program, can serve as a guide for evidence-based decisions when selecting children to GH treatment.
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