New molecular mechanisms of GH resistance

Rosenfeld, Ron G.; Hwa, Vivian

doi:10.1530/eje.0.151s011

Cited by 36 publications

(25 citation statements)

References 24 publications

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“…First, the majority of 3-M children investigated in our unit have normal/-high peak GH levels and low or normal IGF1 levels: normal GH and low IGF1 could be consistent with a degree of GH resistance, while normal GH and normal IGF1 in a very short child could be consistent with a degree of IGF1 resistance. Both interpretations would be concordant with previous descriptions of GH and IGF1 resistance (Rosenfeld & Hwa 2004, Walenkamp & Wit 2006. Secondly, the growth response to rhGH in 3-M syndrome, treated on the basis that these children are usually born SGA, was relatively poor.…”

Section: Discussionsupporting

confidence: 88%

Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling

Hanson¹,

Murray²,

Coulson³

et al. 2012

Journal of Molecular Endocrinology

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3-M syndrome is a primordial growth disorder caused by mutations in CUL7, OBSL1 or CCDC8. 3-M patients typically have a modest response to GH treatment, but the mechanism is unknown. Our aim was to screen 13 clinically identified 3-M families for mutations, define the status of the GH-IGF axis in 3-M children and using fibroblast cell lines assess signalling responses to GH or IGF1. Eleven CUL7, three OBSL1 and one CCDC8 mutations in nine, three and one families respectively were identified, those with CUL7 mutations being significantly shorter than those with OBSL1 or CCDC8 mutations. The majority of 3-M patients tested had normal peak serum GH and normal/low IGF1. While the generation of IGF binding proteins by 3-M cells was dysregulated, activation of STAT5b and MAPK in response to GH was normal in CUL7

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Section: Discussionsupporting

confidence: 88%

Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling

Hanson¹,

Murray²,

Coulson³

et al. 2012

Journal of Molecular Endocrinology

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“…These patients were distributed in the 4 GH secretory groups (1 in SGHD, 8 in MGHD, 6 in DGHR and 2 in NGHR) and their exclusion did not change the results obtained for the analyzed sample of 318 patients or for any GH secretory group (data not shown). Poor treatment compliance, major genotype anomalies of the GH receptor-IGF-I axis [27,28,29,30,31], or both would contribute to these poor GH therapy responses.…”

Section: Discussionmentioning

confidence: 99%

Growth Hormone Secretory Status Evaluated by Growth Hormone Peak after Two Pharmacological Growth Hormone Release Stimuli Did Not Significantly Influence the Two-Year Catch-Up Growth Induced by Growth Hormone Therapy in 318 Prepubertal Short Children with Idiopathic Growth Retardation

et al. 2010

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Background/Aims: In prepubertal short children with idiopathic growth retardation, growth hormone (GH) peak after GH release stimuli classifies patients as growth hormone- deficient (GHD) or non-GHD. This study compared a 2-year growth response to GH therapy in 318 prepubertal short children. Methods: Patients were classified as: severe GHD (GH peaks <5 ng/ml after 2 stimuli; n = 54), mild GHD (GH peaks <10 ng/ml, but one or two between 5 and 10 ng/ml; n = 140), dissociated GH release (GH peak ≧10 ng/ml after 1 stimulus and <10 ng/ml after the other; n = 89), and normal GH release (GH peaks ≧10 ng/ml after 2 stimuli; n = 35). Results: Two-year height gain did not differ statistically among the 4 groups: 1.39 ± 0.51 SD, 16.4 ± 2.3 cm; 1.23 ± 0.56 SD, 15.8 ± 2.1 cm; 1.18 ± 0.53 SD, 15.3 ± 2.0 cm, and 1.14 ± 0.53 SD, 15.4 ± 2.0 cm, respectively, as was also the case for bone age gain: 2.5 ± 0.6, 2.4 ± 0.7, 2.6 ± 0.7 and 2.3 ± 0.5 years, respectively. Conclusions: Our results suggest that GH release stimuli are of little help for deciding on GH therapy in the clinical management of prepubertal short children with idiopathic growth retardation, while well-defined anthropometric and biochemical criteria may be useful.

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“…To date, no studies have examined the effect of infused, recombinant IL-6 on 1) IGF-I in its free and bound forms; 2) IGFBP-1 and -3; and on 3) GH binding protein (GHBP). In humans, circulating GHBP is the extracellular domain of the GH receptor and, therefore, has been used uniquely as an indicator of GH sensitivity (29).…”

mentioning

confidence: 99%

Effect of rhIL-6 infusion on GH→IGF-I axis mediators in humans

Nemet

Eliakim²,

Zaldivar³

2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Exercise leads to simultaneous increases in mediators signaling apparently antagonistic functional responses such as growth factors and inflammatory mediators. The aim of the present study was to demonstrate the physiological effect of IL-6 on circulating components of the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis. Twelve men (ages 26 ± 2 yr) were divided into two groups ( n = 6 in each group), receiving either albumin or recombinant human (rh) IL-6 infusion. IL-6 was infused via an antecubital vein, and a contralateral antecubital vein was used for blood sampling. The IL-6 dose was chosen to reach plasma levels of IL-6 characteristic of intense exercise (5 μg/h, for 3 h, resulting in plasma levels of 100 pg/ml). Blood samples for GH, GH binding protein, IGF-I, and IGF binding protein (IGFBP)-1 and -3 were collected at baseline, 30 min, and 1, 2, 3, 4, 5, and 8 h after the beginning of the rhIL-6 infusion. IL-6 levels increased only in the rhIL-6-infused group ( P < 0.0005) and returned to baseline after the infusion was stopped. IL-6 infusion led to a significant increase in GH, peaking 1 h after the beginning of infusion ( P < 0.001). A decrease in total IGF-I levels was noted only in the rhIL-6-infused group ( P < 0.027). An initial decrease in IGFBP-1 levels was noted in both groups during infusion ( P < 0.03). Following the initial decrease, there was a significant increase in IGFBP-1 levels only in the IL-6-infused participants, peaking at 2 after the infusion cessation ( P < 0.001). IL-6 infusion had no effect on GH binding protein, IGFBP-3, and acid-labile subunit levels. rhIL-6 levels similar to the levels found after strenuous exercise induced a typical exercise-associated GH→IGF-I axis response (increase GH, decreased IGF-I, and elevated IGFBP-1). The results suggest that IL-6 plays a role in the GH→IGF-I response to intense exercise.

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New molecular mechanisms of GH resistance

Cited by 36 publications

References 24 publications

Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling

Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling

Growth Hormone Secretory Status Evaluated by Growth Hormone Peak after Two Pharmacological Growth Hormone Release Stimuli Did Not Significantly Influence the Two-Year Catch-Up Growth Induced by Growth Hormone Therapy in 318 Prepubertal Short Children with Idiopathic Growth Retardation

Effect of rhIL-6 infusion on GH→IGF-I axis mediators in humans

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