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Growth hormone responsiveness in children: results from Swedish multicenter clinical trials of growth hormone treatment
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The general aims of the thesis were to study GH responsiveness by estimation of pharmacokinetics and bioavailability of injected recombinant human GH (rhGH), of growth response as gain in heightSDS during childhood and puberty, and IGF-I response as change in circulating IGF-ISDS and IGFBP3SDS. Methods Short children were recruited during 1988–1999 into two national randomized multicentre clinical trials on growth until adult height. A group of 117 GHD patients who had been treated from prepuberty with a single GH dose of 33μg/kg/day for at least 1 year were randomized at onset of puberty either to remain on this dose regimen or to an increased dose, GH67μg/kg/day, administered once daily or divided into two doses, GH33x2μg/kg/day. Data on IGF-ISDS and IGF binding protein 3 (IGFBP3)SDS were available from 111 patients and analysed as stated below. The 151 short prepubertal non-GHD patients were randomized into three groups: untreated controls, GH33 or GH67μg/kg/day. A subpopulation from both trials, 128 patients examined annually in Gothenburg, formed the study sample on GH uptake. They received sc GH injections to obtain 16–24 hour GH curves and the GH pharmacokinetics and bioavailability was calculated. Results: A dose-dependent effect on Cmax was found with great intra- and inter-individual variability. Of the Cmax variability, 43% was explained by the rhGH dose and proxies for injection depth. Median bioavailability of the injected dose was 71%, with great variation, mainly dependent on injection depth. In the IGHD group a dose-dependent difference in pubertal gain in heightSDS was found, with mean of 0.8 for the GH67 group and 0.4 for GH33, p<0.01. The mean total gain in heightSDS during treatment was 1.9 for GH67 and 1.4 for GH33, p<0.01. A dose-dependent pubertal ΔIGF-ISDS was 0.5 vs −0.1, p=0.007, correlating to pubertal gain in heightSDS, p=0.003; and was the most important variable to explain the variation in pubertal gain in heightSDS. In the non-GHD group the ΔIGF-ISDS from baseline to mean study level was dose-dependent 2.07 vs 1.20, p=0.001; and correlated negatively with baseline values of IGF-ISDS, rho= -0.56 for GH67, p=0.001, vs rho= -0.82 for GH33, p=0.0001, and correlated positively with gain in heightSDS in both GH-treated groups, rho= 0.42, p<0.001. In multivariable regression analyses, ΔIGF-ISDS was always an important explanatory variable for long-term growth response from the prepubertal period until adult height, while the IGF-ISDS study level per se was not. Conclusion: Growth response to GH treatment was dose dependent with great variability between patients. More pubertal growth was attained by an increased rhGH dose, mimicking the physiology of healthy children, in whom GH secretion rate increases during puberty. This resulted in a gain in IGF-ISDS closely correlating to pubertal gain in heightSDS in both IGHD and non-GHD patients. A broad range in GH responsiveness was found for both growth and IGF response in both diagnostic groups, but lower in the non-GHD group. Higher uptake of a given GH dose was observed after a deep injection and a higher GH concentration. These results are clinically applicable for individuals who remain short close to onset of puberty; by identifying and deeply injecting a rhGH dose that accounts for individual responsiveness, we can stimulate an increment in IGF-ISDS that correlates to gain in heightSDS during puberty.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2017. , 106 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1879
Keyword [en]
gain in height, puberty, IGHD, non-GHD, IGF-I, bioavailability
National Category
Pediatrics
Identifiers
URN: urn:nbn:se:umu:diva-134569ISBN: 978-91-7601-662-6 (print)OAI: oai:DiVA.org:umu-134569DiVA: diva2:1094072
Public defence
2017-06-02, Sal D, unod T9, byggnad 1D, plan 9, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2017-05-11 Created: 2017-05-09 Last updated: 2017-05-11Bibliographically approved
List of papers
1. Broad variability in pharmacokinetics and bioavailability of GH following rhGH injecetions in children
Open this publication in new window or tab >>Broad variability in pharmacokinetics and bioavailability of GH following rhGH injecetions in children
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(English)Manuscript (preprint) (Other academic)
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-134568 (URN)
Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2017-05-10
2. Growth Hormone Dose-Dependent Pubertal Growth: A Randomized Trial in Short Children with Low Growth Hormone Secretion
Open this publication in new window or tab >>Growth Hormone Dose-Dependent Pubertal Growth: A Randomized Trial in Short Children with Low Growth Hormone Secretion
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2014 (English)In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 82, no 3, 158-170 p.Article in journal (Refereed) Published
Abstract [en]

Background/Aims: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i. e. idiopathic isolated GH deficiency. Methods: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH(33) mu g/kg/day for >= 1 year. They were randomized to receive 67 mu g/kg/day (GH(67)) given as one (GH(67x1); n = 35) or two daily injections (GH(33x2); n = 36), or to remain on a single 33 mu g/kg/day dose (GH(33x1); n = 40). Growth was assessed as height SDS gain for prepubertal, pubertal and total periods, as well as AH SDS versus the population and the midparental height. Results: Pubertal height SDS gain was greater for patients receiving a high dose (GH(67), 0.73) than a low dose (GH(33x1), 0.41, p < 0.05). AH(SDS) was greater on GH(67) (GH(67x1), -0.84; GH(33x2), -0.83) than GH(33) (-1.25, p < 0.05), and height SDS gain was greater on GH(67) than GH(33) (2.04 and 1.56, respectively; p < 0.01). All groups reached their target height SDS. Conclusion: Pubertal height SDS gain and AH SDS were dose dependent, with greater growth being observed for the GH(67) than the GH(33) randomization group; however, there were no differences between the once-and twice-daily GH(67) regimens. (C) 2014 S. Karger AG, Basel.

Keyword
Gain in height, Prepubertal growth, Growth hormone frequency, Delayed infancy-childhood ansition, Puberty
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-98463 (URN)10.1159/000363106 (DOI)000345448500003 ()2-s2.0-84906588161 (Scopus ID)
Available from: 2015-01-28 Created: 2015-01-22 Last updated: 2017-05-10Bibliographically approved
3. Growth hormone (GH) dose-dependent IGF-I response relates to pubertal height gain
Open this publication in new window or tab >>Growth hormone (GH) dose-dependent IGF-I response relates to pubertal height gain
2015 (English)In: BMC Endocrine Disorders, ISSN 1472-6823, E-ISSN 1472-6823, Vol. 15, 84Article in journal (Refereed) Published
Abstract [en]

Background: Responsiveness to GH treatment can be estimated by both growth and Delta IGF-I. The primary aim of the present study was to investigate if mimicking the physiological increase during puberty in GH secretion, by using a higher GH dose could lead to pubertal IGFs in short children with low GH secretion. The secondary aim was to explore the relationship between IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio and gain in height. Methods: A multicentre, randomized, clinical trial (TRN88-177) in 104 children (90 boys), who had received GH 33 mu g/kg/day during at least 1 prepubertal year. They were followed from GH start to adult height (mean, 7.5 years; range, 4.6-10.7). At onset of puberty, children were randomized into three groups, to receive 67 mu g/kg/day (GH(67)) given once (GH(67x1); n = 30) or divided into two daily injection (GH(33x2); n = 36), or to remain on a single 33 mu g/kg/ day dose (GH(33x1); n = 38). The outcome measures were change and obtained mean on-treatment IGF-I-SDS, IGFBP3(SDS) and IGF-I/IGFBP3 ratio(SDS) during prepuberty and puberty. These variables were assessed in relation to prepubertal, pubertal and total gain in height(SDS). Results: Mean prepubertal increases 1 year after GH start were: 2.1 IGF-I-SDS, 0.6 IGFBP3(SDS) and 1.5 IGF-I/IGFBP3ratio(SDS). A significant positive correlation was found between prepubertal Delta IGFs and both prepubertal and total gain in height(SDS). During puberty changes in IGFs were GH dose-dependent: mean pubertal level of IGF-I-SDS was higher in GH67 vs GH(33) (p = 0.031). First year pubertal Delta IGF-I-SDS was significantly higher in the GH(67) vs GH33 group (0.5 vs -0.1, respectively, p = 0.007), as well as Delta IGF-I-SDS to the pubertal mean level (0.2 vs -0.2, p = 0.028). In multivariate analyses, the prepubertal increase in 'Delta IGF-I-SDS from GH start' and the 'GH dose-dependent pubertal Delta IGF-I-SDS' were the most important variables for explaining variation in prepubertal (21 %), pubertal (26 %) and total (28 %) gain in height(SDS). Conclusion: The dose-dependent change in IGFs was related to a dose-dependent pubertal gain in height(SDS). The attempt to mimic normal physiology by giving a higher GH dose during puberty was associated with both an increase in IGF-I and a dose-dependent gain in height(SDS).

Place, publisher, year, edition, pages
BioMed Central, 2015
Keyword
Gain in height, IGF-I increment, IGF-I level, IGFBP3, Ratio IGF-I/IGFBP3, GH dose-dependent pubertal IGF-I response
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-114618 (URN)10.1186/s12902-015-0080-8 (DOI)000367051700001 ()26682747 (PubMedID)
Available from: 2016-02-05 Created: 2016-01-25 Last updated: 2017-05-10Bibliographically approved
4. IGF-1 and growth response to adult height in a randomized GH treatment trial in short non-GH-deficient children
Open this publication in new window or tab >>IGF-1 and growth response to adult height in a randomized GH treatment trial in short non-GH-deficient children
2014 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 8, 2917-2924 p.Article in journal (Refereed) Published
Abstract [en]

Context: GH treatment significantly increased adult height (AH) in a dose-dependent manner in short non-GH-deficient children in a randomized, controlled, clinical trial; the mean gain in height SD score (height(SDS)) was 1.3 (range 0-3), compared with 0.2 in the untreated group. Objective: The objective of the study was to analyze the relationship between IGF-1(SDS), IGF binding protein-3 SDS (IGFBP3(SDS)), and their ratio(SDS) with a gain in the height(SDS) until AH in non-GH-deficient short children. Design and Setting: This was a randomized, controlled, multicenter clinical trial. Intervention: The intervention included GH treatment: 33 or 67 mu g/kg.d plus untreated controls. Subjects: One hundred fifty-one non-GH-deficient short children were included in the intent-to-treat (ITT) population and 108 in the per-protocol (PP) population; 112 children in the ITT and 68 children in the PP populations had idiopathic short stature (ISS). Main Outcome Measures: Increments from baseline to on-treatment study mean IGF-1(SDS) (Delta IGF-1(SDS)), IGFBP3(SDS), and IGF-1 to IGFBP3 ratio(SDS) were assessed in relationship to the gain in height(SDS). Results: Sixty-two percent of the variance in the gain in height(SDS) in children on GH treatment could be explained by four variables: Delta IGF-1(SDS) (explaining 28%), bone age delay, birth length (the taller the better), and GH dose (the higher the better). The lower IGF-1(SDS) was at baseline, the higher was its increment during treatment. For both the All(PP)- and the ISSPP-treated groups, the attained IGF-1(SDS) study level did not correlate with height gain. Conclusion: In short non-GH-deficient children, the GH dose-related increment in IGF-1(SDS) from baseline to mean study level was the most important explanatory variable for long-term growth response from the peripubertal period until AH, when IGF-1(SDS), IGFBP3(SDS), and their ratio(SDS) were compared concurrently.

Place, publisher, year, edition, pages
Endocrine Society, 2014
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-95293 (URN)10.1210/jc.2014-1101 (DOI)000342341200066 ()24823461 (PubMedID)
Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-05-10Bibliographically approved

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