IGF-I in Human Growth: Lessons from Defects in the GH-IGF-I Axis

2013 ◽  
pp. 43-55 ◽  
Author(s):  
Vivian Hwa ◽  
Peng Fang ◽  
Michael A. Derr ◽  
Eva Fiegerlova ◽  
Ron G. Rosenfeld
Keyword(s):  
Human Growth ◽  
Igf I

scholarly journals A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly

2018 ◽  
Vol 179 (2) ◽  
pp. 97-108 ◽  
Author(s):  
Peter J Trainer ◽  
John D C Newell-Price ◽  
John Ayuk ◽  
Simon J B Aylwin ◽  
Aled Rees ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Human Growth ◽  
Phase 2 ◽  
Open Label ◽  
Parallel Group ◽  
Igf I ◽  
Secondary Endpoints ◽  
Efficacy Measures ◽  
Hormone Binding Protein ◽  
Antisense Oligonucleotide Therapy

Objective ATL1103 is a second-generation antisense oligomer targeting the human growth hormone (GH) receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly. Design Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period. Methods The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, acid labile subunit (ALS), GH, growth hormone-binding protein (GHBP)), comparison was between baseline and week 14. Safety was assessed by reported adverse events. Results and conclusions Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups respectively. Compared to baseline, at week 14, twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (P = 0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (P = 0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and remained lower at week 21 than at baseline by a median of 18.7% (P = 0.0005). Compared to baseline, by week 14, IGFBP3 and ALS had declined by a median of 8.9% (P = 0.027) and 16.7% (P = 0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (P = 0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (P = 0.027 and P = 0.005) respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild-to-moderate injection-site reactions. This study provides proof of concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.

Human growth hormone effect on serum IGF-I and muscle function in poliomyelitis survivors

1994 ◽  
Vol 75 (8) ◽  
pp. 889-894 ◽  
Author(s):  
Krishan L. Gupta ◽  
Kaup R. Shetty ◽  
James C. Agre ◽  
Mary C. Cuisinier ◽  
Inge W. Rudman ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Human Growth Hormone ◽  
Muscle Function ◽  
Human Growth ◽  
Hormone Effect ◽  
Igf I

Hemoglobin level is linked to growth hormone-dependent proteins in short children

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 2075-2081 ◽  
Author(s):  
E Vihervuori ◽  
M Virtanen ◽  
H Koistinen ◽  
R Koistinen ◽  
M Seppala ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Skeletal Dysplasia ◽  
Recombinant Human Growth Hormone ◽  
Body Height ◽  
Human Growth ◽  
Gh Treatment ◽  
Blood Hemoglobin ◽  
Igf I ◽  
Igfbp 3

Erythropoiesis was investigated in 32 children wih short stature and in eight children with skeletal dysplasia by studying blood hemoglobin in relation to growth and to serum concentrations of insulin-like growth factor I (IGF-I), IGF binding protein-3 (IGFBP-3), and erythropoietin (EPO) before, during, and after 12 months of recombinant human growth hormone (GH) treatment. Blood hemoglobin concentration was positively correlated with relative body height and with serum IGF-I and IGFBP-3 levels (P = .001 to .02), but not with the concentrations of EPO. The normal age-dependency of hemoglobin was lacking. Hemoglobin levels and their responses to GH treatment were similar in the patients with GH deficiency and those with normal GH secretion. Treatment with GH accelerated growth and elevated the concentrations of hemoglobin, IGF- I, and IGFBP-3. In the eight patients with skeletal dysplasia, body mass increased similarly, but gain in height was less than in the other patients, and the increase in hemoglobin was markedly pronounced. In this group, the correlations between hemoglobin, IGF-I, and IGFBP-3 were extremely close (r = 0.80 to 0.85, P = .031 to .008). These findings are in accord with earlier observations from in vitro and animal studies, and suggest that the GH-IGF axis is involved in the physiologic elevation of hemoglobin levels during childhood.

scholarly journals 20kDa Human Growth Hormone (20K hGH) Stimulates Insulin-Like Growth Factor-I (IGF-I) Gene Expression at Lower Concentrations than 22K hGH in hGH Receptor-Expressing Ba/F3 Cells

2000 ◽  
Vol 47 (SupplMarch) ◽  
pp. S37-S40 ◽  
Author(s):  
HIDEO YOSHIZATO ◽  
MINORU TANAKA ◽  
TAKAHIKO FUJIKAWA ◽  
YOSHIFUMI HIGASHIMOTO ◽  
AYAKO SHIMIZU ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Hormone ◽  
Growth Factor ◽  
Human Growth Hormone ◽  
Human Growth ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
I Gene

Dose-dependent stimulatory effect of human growth hormone on the strength and collagen deposition of colonic anastomoses in the rat

1992 ◽  
Vol 126 (5) ◽  
pp. 438-443 ◽  
Author(s):  
Henrik Christensen ◽  
Allan Flyvbjerg
Keyword(s):  
Growth Hormone ◽  
Human Growth Hormone ◽  
Human Growth ◽  
Dry Weight ◽  
Preoperative Treatment ◽  
Collagen Deposition ◽  
Hydroxyproline Content ◽  
Colonic Anastomoses ◽  
Bursting Strength ◽  
Igf I

The effects of treatment with four different doses of biosynthetic human growth hormone (b-hGH; 0.125mg kg−1 d−1, 0.5mg kg−1 d−1, 2.0 mg kg−1 d−1, 8.0 mg kg−1 d−1) on the bursting strength and collagen deposition of rat colonic anastomoses were studied. Rats receiving 2.0mg and 8.0 mg b-hGH demonstrated increases in the pre- and postoperative body weights, and the bursting strength and hydroxyproline content of the anastomotic segments in these groups were significantly higher than controls on day 4 postoperatively. The serum levels of insulin-like growth factor I (IGF-I) were significantly higher than the controls after four days of preoperative treatment in the groups receiving 2.0 mg and 8.0 mg b-hGH, and postoperatively the IGF-I levels were significantly higher than those of the controls in the groups receiving 0.5 mg, 2.0 mg and 8.0 mg b-hGH per kg. Consequently, positive correlations were found between treatment doses of b-hGH and anastomotic defatted dry weight, hydroxyproline content and bursting strength of colonic anastomoses.

scholarly journals Protein QTL analysis of IGF-I and its binding proteins provides insights into growth biology

2020 ◽  
Author(s):  
Eric Bartell ◽  
Masanobu Fujimoto ◽  
Jane C. Khoury ◽  
Philip R. Khoury ◽  
Sailaja Vedantam ◽  
...  
Keyword(s):  
Birth Weight ◽  
Association Studies ◽  
Genetic Regulation ◽  
Human Growth ◽  
Serum Levels ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Protein Levels ◽  
Igf I ◽  
Igfbp 3

AbstractThe growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGFBP-3, PAPP-A2, IGF-II, and IGFBP-5 in 839 children (3-18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels near IGFBP3 and IGFBP5 genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, the IGFBP3 signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); the IGFBP5 signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated SNPs near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.

scholarly journals Corroboration of Height Velocity Prediction Markers for rhGH with an Oral GH Secretagogue Treatment in Children with GHD

2021 ◽  
Author(s):  
Werner F Blum ◽  
George M Bright ◽  
Minh-Ha T Do ◽  
John C McKew ◽  
Haiying Chen ◽  
...  
Keyword(s):  
Recombinant Human Growth Hormone ◽  
Standard Deviation Score ◽  
Human Growth ◽  
Height Velocity ◽  
First Year ◽  
Growth Responses ◽  
Baseline Serum ◽  
Igf I ◽  
Treatment Data ◽  
Rhgh Treatment

Abstract Context Recombinant human growth hormone (rhGH) is approved for treatment of pediatric GH deficiency (PGHD), with greatest growth responses observed in those with severe GHD. Orally administered GH secretagogues (GHS) may be useful treatment in patients with moderate GHD. Distinguishing children with severe vs. moderate GHD could identify children who would be better treated with rhGH or GHS. Objectives Evaluate baseline insulin-like growth factor-I (IGF-I) and stimulated peak GH response as predictors of 12-month height velocity (HV) in children with GHD. Design Data on children with GHD were analyzed in a legacy data base (GeNeSIS data). Participants 514 naïve to rhGH-treatment, prepubertal children with idiopathic isolated GHD (IGHD) for whom stimulated GH, baseline serum IGF-I and first year HV during rhGH treatment data are available. Outcome Measures Children with severe or moderate GHD were categorized based on GH and IGF-I data and evaluated based on baseline auxologic and hormone profiles and first year growth response to rhGH. Results Cohorts of severe and moderate GHD were 81/514 (15.8%) and 433/514 (84.2%). Cohorts differed significantly with regard to indicators of GHD (e.g., baseline height standard deviation score [SDS], height SDS minus target height SDS, HV, HV SDS, and change in height SDS during rhGH treatment). Multiple regression analysis showed IGF-I and stimulated GH were significant predictors of HV independent of other known variables. Expected first year HV in moderate GHD was 8.3 cm/year. Conclusions The combination of peak GH to GH stimulation testing and baseline IGF-I concentration are predictive enrichment markers for annualized HV responses to rhGH therapy.

Studies on regulation of insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-4 production in human bone cells

1992 ◽  
Vol 127 (6) ◽  
pp. 555-564 ◽  
Author(s):  
Subburaman Mohan ◽  
Donna D Strong ◽  
Uta G Lempert ◽  
Florence Tremollieres ◽  
Jon E Wergedal ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Conditioned Medium ◽  
Cell Cultures ◽  
Bone Cells ◽  
Human Growth ◽  
Bone Cell ◽  
Human Bone ◽  
Human Bone Cell ◽  
Igf I ◽  
Igfbp 3

Previous studies have shown that the actions of IGF-II in bone are determined not only by its concentration, but also by the concentration of IGFBP-4 as well as other IGFBPs. In this study, we sought to determine by Western ligand blotting the effects of growth hormone, IGF-I and IGF-II on the production of IGFBP-3 and IGFBP-4 in TE89 human osteosarcoma cells and in untransformed normal human bone cells derived from rib. Human growth hormone at 10 μg/l decreased the amount of IGFBP-4 but had no effect on the IGFBP-3 level in the conditioned medium of low density cultures of TE89 cells and human bone cells derived from rib. Human growth hormone had no effect on IGFBP-3 or IGFBP-4 levels in the conditioned medium of high density human bone cell cultures. IGF-I and IGF-II, which increased human bone cell proliferation, decreased the level of IGFBP-4 (30% of control at 100 μg/l IGF-I and IGF-II) but increased the level of IGFBP-3 (3–10 fold at 100 μg/l IGF-I and IGF-II) after 48 h of treatment in the conditioned medium of both low and high density TE89 cell cultures. Similar changes in IGFBP-3 and IGFBP-4 levels were also seen in the conditioned medium of human bone cells derived from rib after treatment with IGF-I and IGF-II. Studies to determine the underlying molecular mechanisms by which IGF-II decreased the amount of IGFBP-4 in the conditioned medium revealed that IGF-II decreased the IGFBP-4 mRNA abundance and increased the IGFBP-3 mRNA abundance in human bone cells. Based on the above findings, we conclude that the production of both IGFBP-3 and IGFBP-4 is regulated in bone cells and that local and systemic agents may modulate the responsiveness of bone cells to IGFs by regulated secretion of IGFBP-3 and IGFBP-4.

scholarly journals Enhancement of the peripheral sensitivity to growth hormone in adults with GH deficiency

2001 ◽  
pp. 267-272 ◽  
Author(s):  
G Aimaretti ◽  
G Fanciulli ◽  
S Bellone ◽  
M Maccario ◽  
E Arvat ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Gh Deficiency ◽  
Day Treatment ◽  
Recombinant Human Growth Hormone ◽  
Human Growth ◽  
Normal Subjects ◽  
Short Treatment ◽  
Igf I ◽  
Composition Structure ◽  
Igfbp 3

OBJECTIVE: Adults with severe GH deficiency (GHD) need recombinant human growth hormone (rhGH) replacement to restore body composition, structure functions and metabolic abnormalities. The optimal rhGH dose for replacement has been progressively reduced to avoid side effects. The aim of the present study was to define the minimal rhGH dose able to increase both IGF-I and IGF binding protein (BP)-3 levels in GHD and to verify the possible change in GH sensitivity. DESIGN AND PATIENTS: To this goal, we studied the effect of 4-day treatment with 3 rhGH doses (1.25, 2.5 and 5.0 microg/kg/day) on IGF-I and IGFBP-3 levels in 25 panhypopituitary adults with severe GHD (12 males and 13 females, age: 44.5+/-3.0 years, body mass index (BMI): 27.0+/-0.9 kg/m(2)) and 21 normal young adult volunteers (NV, 12 males and 9 females, age: 30.5+/-2.0 years, BMI: 20.8+/-0.5 kg/m(2)). RESULTS: Basal IGF-I and IGFBP-3 levels in GHD were lower (P<0.001) than in NV. In NV the 1.25 microg/kg dose of rhGH did not modify IGF-I levels. The dose of 2.5 microg/kg rhGH significantly increased IGF-I levels in men (P<0.001) but not in women, while the 5.0 microg/kg dose increased IGF-I levels in both sexes (P<0.001). IGFBP-3 levels were not modified by any of the administered rhGH doses. In GHD patients, all rhGH doses increased IGF-I levels 12 h after both the first (P<0.01) and the fourth rhGH dose (P<0.001). At the end of treatment percentage increases in IGF-I were higher (P<0.001) in GHD patients than in NV. In contrast with NV, in GHD patients the IGF-I response to short-term stimulation with rhGH was independent of gender. Moreover, GHD patients showed increases in IGFBP-3 after the fourth administration of both 2.5 and 5.0 microg/kg rhGH. CONCLUSION: The results of the present study demonstrate that the minimal rhGH dose able to increase IGF-I and IGFBP-3 levels in GHD patients is lower than in normal subjects, at least after a very short treatment. This evidence suggests an enhanced peripheral GH sensitivity in GH deprivation.

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