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Effect of low-normal and high-normal IGF-1 levels on memory and wellbeing during growth hormone replacement therapy: a randomized clinical trial in adult growth hormone deficiency.

ABSTRACT: BACKGROUND:The aim of the present study was to investigate the effect of low-normal and high-normal levels of IGF-1 in growth hormone (GH) deficient adults on cognition and wellbeing during GH treatment. METHODS:A randomized, open-label, clinical trial including 32 subjects receiving GH therapy for at least 1 year. Subjects were randomized to receive either a decrease (IGF-1 target level of -?2 to -?1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) for a period of 24 weeks. Memory was measured by the Cambridge Neuropsychological Test Automated Battery, selecting the Pattern Recognition Memory task and the Spatial Working Memory. Wellbeing was measured as mood by the Profile of Moods States questionnaire, and quality of life by the Nottingham Health Profile and QoL Assessment in GH Deficiency in Adults questionnaires. RESULTS:Data from 30 subjects (65.6% male, mean age 46.6 (9.9 SD) years), who fulfilled the target levels, were analyzed. Females in the low dose treatment arm were found to have a better working memory and a better strategic memory control after 24 weeks as opposed to the females in the high treatment arm. With respect to mood, the decrease in IGF-1 levels in females within the low treatment arm was associated with more fatigue and less vigor. CONCLUSIONS:The adjustment of GH dose in female patients seems to have a narrow window. A dose too high may impair prefrontal cognitive functioning, while a dose too low may result in decreased vigor. TRIAL REGISTRATION:This study is registered with ClinicalTrials.gov , number NCT01877512.

SUBMITTER: van Bunderen CC

PROVIDER: S-EPMC6035403 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Effect of low-normal and high-normal IGF-1 levels on memory and wellbeing during growth hormone replacement therapy: a randomized clinical trial in adult growth hormone deficiency.

van Bunderen Christa C CC Deijen Jan Berend JB Drent Madeleine L ML

Health and quality of life outcomes 20180706 1

<h4>Background</h4>The aim of the present study was to investigate the effect of low-normal and high-normal levels of IGF-1 in growth hormone (GH) deficient adults on cognition and wellbeing during GH treatment.<h4>Methods</h4>A randomized, open-label, clinical trial including 32 subjects receiving GH therapy for at least 1 year. Subjects were randomized to receive either a decrease (IGF-1 target level of - 2 to - 1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) fo ...[more]

PMID: 29980224

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Project description:BackgroundDespite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and GH secretagogues reverse age-related changes in thymus cytoarchitecture and increase thymopoiesis. GH administration also enhances thymic mass and function in HIV-infected patients. Until now, thymic function has not been investigated in adult GH deficiency (AGHD). The objective of this clinical study was to evaluate thymic function in AGHD, as well as the repercussion upon thymopoiesis of GH treatment for restoration of GH/IGF-1 physiological levels.Methodology/principal findingsTwenty-two patients with documented AGHD were enrolled in this study. The following parameters were measured: plasma IGF-1 concentrations, signal-joint T-cell receptor excision circle (sjTREC) frequency, and sj/beta TREC ratio. Analyses were performed at three time points: firstly on GH treatment at maintenance dose, secondly one month after GH withdrawal, and thirdly one month after GH resumption. After 1-month interruption of GH treatment, both plasma IGF-1 concentrations and sjTREC frequency were decreased (p<0.001). Decreases in IGF-1 and sjTREC levels were correlated (r = 0.61, p<0.01). There was also a decrease in intrathymic T cell proliferation as indicated by the reduced sj/beta TREC ratio (p<0.01). One month after reintroduction of GH treatment, IGF-1 concentration and sjTREC frequency regained a level equivalent to the one before GH withdrawal. The sj/beta TREC ratio also increased with GH resumption, but did not return to the level measured before GH withdrawal.ConclusionsIn patients with AGHD under GH treatment, GH withdrawal decreases thymic T cell output, as well as intrathymic T cell proliferation. These parameters of thymus function are completely or partially restored one month after GH resumption. These data indicate that the functional integrity of the somatotrope GH/IGF-1 axis is important for the maintenance of a normal thymus function in human adults.Trial registrationClinicalTrials.gov NTC00601419.

Project description:ObjectiveGH1 gene presents a complex map of single nucleotide polymorphisms (SNPs) in the entire promoter, coding and noncoding regions. The aim of the study was to establish the complete map of GH1 gene SNPs in our control normal population and to analyse its association with adult height.Design, subjects and measurementsA systematic GH1 gene analysis was designed in a control population of 307 adults of both sexes with height normally distributed within normal range for the same population: -2 standard deviation scores (SDS) to +2 SDS. An analysis was performed on individual and combined genotype associations with adult height.ResultsTwenty-five SNPs presented a frequency over 1%: 11 in the promoter (P1 to P11), three in the 5'UTR region (P12 to P14), one in exon 1 (P15), three in intron 1 (P16 to P18), two in intron 2 (P19 and P20), two in exon 4 (P21 and P22) and three in intron 4 (P23 to P25). Twenty-nine additional changes with frequencies under 1% were found in 29 subjects. P8, P19, P20 and P25 had not been previously described. P6, P12, P17 and P25 accounted for 6.2% of the variation in adult height (P = 0.0007) in this population with genotypes A/G at P6, G/G at P6 and A/G at P12 decreasing height SDS (-0.063 +/- 0.031, -0.693 +/- 0.350 and -0.489 +/- 0.265, Mean +/- SE) and genotypes A/T at P17 and T/G at P25 increasing height SDS (+1.094 +/- 0.456 and +1.184 +/- 0.432).ConclusionsThis study established the GH1 gene sequence variation map in a normal adult height control population confirming the high density of SNPs in a relatively small gene. Our study shows that the more frequent SNPs did not significantly contribute to height determination, while only one promoter and two intronic SNPs contributed significantly to it. Studies in larger populations will have to confirm the associations and in vitro functional studies will elucidate the mechanisms involved. Systematic GH1 gene analysis in patients with growth delay and suspected GH deficiency/insufficiency will clarify whether different SNP frequencies and/or the presence of different sequence changes may be associated with phenotypes in them.

Dataset Information

Effect of low-normal and high-normal IGF-1 levels on memory and wellbeing during growth hormone replacement therapy: a randomized clinical trial in adult growth hormone deficiency.

Publications

Effect of low-normal and high-normal IGF-1 levels on memory and wellbeing during growth hormone replacement therapy: a randomized clinical trial in adult growth hormone deficiency.

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