Reduced Pericellular Sensitivity to IGF-I in Fibroblasts From Girls With Turner Syndrome: A Mechanism to Impair Clinical Responses to GH

Westwood, Melissa; Tajbakhsh, Shahin; Siddals, Kirk; Whatmore, Andrew; Clayton, Peter E.

doi:10.1203/pdr.0b013e31821b570b

Cited by 9 publications

(3 citation statements)

References 32 publications

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“…134 Patients with Turner syndrome require high doses of growth hormone to achieve optimal develop ment because they are resistant to its metabolic effects. 7,135 Growth hormone therapy aids the decrease of adiposity and abdominal fat, and increases lean mass and circulating IGF1 levels, 7 whereas HRT is necessary for female sexual development, normalization of BMD and improvement of neurocognitive functions. 118 Furthermore, estrogen therapy has important beneficial effects on the metabolic derangements associated with Turner syndrome, resulting from decreasing visceral adipose tissue, 7 increasing HDL levels 121 and maintaining normal liver metabolism.…”

Section: Impaired Muscle and Bone Physiologymentioning

confidence: 99%

Energy metabolism and fertility—a balance preserved for female health

et al. 2013

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In female animals, energy metabolism and fertility are tightly connected, and reciprocally regulated. However, the relative contributions of metabolic and reproductive pathways have changed over the course of evolution. In oviparous animals, metabolic factors take precedence over fertility, enabling egg production to be inhibited in a nutritionally poor environment. By contrast, in placental mammals, the opposite occurs: the need to feed a developing embryo and neonate forces metabolic pathways to adapt to these reproductive needs. This physiological necessity explains why in female mammals alterations of gonadal activity, including age-dependent cessation of ovarian functions, are associated with a disruption of metabolic homeostasis and consequent inflammatory reactions that trigger the onset of metabolic, cardiovascular, skeletal and neural pathologies. This Review discusses how metabolic homeostasis and reproductive functions interact to optimize female fertility and explains the pathogenic mechanisms underlying the disordered energy metabolism associated with human ovarian dysfunction owing to menopause, polycystic ovary syndrome and Turner syndrome. Finally, this article highlights how hormone replacement therapy might aid the restoration of metabolic homeostasis in women with ovarian dysfunction.

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Section: Impaired Muscle and Bone Physiologymentioning

confidence: 99%

Energy metabolism and fertility—a balance preserved for female health

et al. 2013

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“…These doses were based on previous GH and IGF1 stimulation assays using human skin fibroblast cells (Freeth et al 1997, Westwood et al 2011.…”

Section: Signal Transduction Assaysmentioning

confidence: 99%

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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“…In contrast, IGFBP3 has been identified as a negative factor in prediction models for response to r-hGH in children who are small for gestational age (23). In addition, in an ex vivo fibroblast model of growth factor action, TS cells produced more IGFBP3 than control cells in the basal state, but generated less IGFBP3 in response to IGF1 stimulation, implying that higher IGFBP3 levels in the media around these cells were inhibiting IGF1 action (29). Therefore, the influence of IGFBP3 appears to be disease dependent, and this is reflected in the divergent growth responses associated with the same IGFBP3 SNP in GHD and TS.…”

Section: Discussionmentioning

confidence: 99%

A pharmacogenomic approach to the treatment of children with GH deficiency or Turner syndrome

Clayton

Chatelain

Tatò

et al. 2013

European Journal of Endocrinology

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ObjectiveIndividual sensitivity to recombinant human GH (r-hGH) is variable. Identification of genetic factors contributing to this variability has potential use for individualization of treatment. The objective of this study was to identify genetic markers and gene expression profiles associated with growth response on r-hGH therapy in treatment-naïve, prepubertal children with GH deficiency (GHD) or Turner syndrome (TS).DesignA prospective, multicenter, international, open-label pharmacogenomic study.MethodsThe associations of genotypes in 103 growth- and metabolism-related genes and baseline gene expression profiles with growth response to r-hGH (cm/year) over the first year were evaluated. Genotype associations were assessed with growth response as a continuous variable and as a categorical variable divided into quartiles.ResultsEleven genes in GHD and ten in TS, with two overlapping between conditions, were significantly associated with growth response either as a continuous variable (seven in GHD, two in TS) or as a categorical variable (four more in GHD, eight more in TS). For example, in GHD, GRB10 was associated with high response (≥Q3; P=0.0012), while SOS2 was associated with low response (≤Q1; P=0.006), while in TS, LHX4 was associated with high response (P=0.0003) and PTPN1 with low response (P=0.0037). Differences in expression were identified for one of the growth response-associated genes in GHD (AKT1) and for two in TS (KRAS and MYOD1).ConclusionsCarriage of specific growth-related genetic markers is associated with growth response in GHD and TS. These findings indicate that pharmacogenomics could have a role in individualized management of childhood growth disorders.

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Reduced Pericellular Sensitivity to IGF-I in Fibroblasts From Girls With Turner Syndrome: A Mechanism to Impair Clinical Responses to GH

Cited by 9 publications

References 32 publications

Energy metabolism and fertility—a balance preserved for female health

Energy metabolism and fertility—a balance preserved for female health

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

A pharmacogenomic approach to the treatment of children with GH deficiency or Turner syndrome

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