Growth Hormone (GH) Treatment Up-Regulates GH Receptor mRNA Levels in Adipocytes from Patients with GH Deficiency and Prader-Willi Syndrome

ABSTRACT In the rat, many actions of GH depend upon the sexually dimorphic pattern of exposure to GH. Hepatic human GH (hGH) receptor binding differs between the sexes and is sensitive to GH deficiency, but this has mostly been studied in acutely hypophysectomized rats, which lack all pituitary hormones. We have used a strain of GH-deficient dwarf (Dw) rats to determine whether chronic GH deficiency alters the normal developmental pattern and sexually dimorphic expression of hepatic GH receptors. Adult female Dw rats had lower levels of 125I-labelled hGH binding (reflecting predominantly lactogenic receptors) than their normal counterparts whereas there was no difference between adult Dw and normal males; binding capacity increased from 25 days of age, becoming sexually dimorphic from 40 days to adulthood in both strains (% specific binding/mg protein: normal males 1·6 ± 0·3, normal females 13·2 ± 1·1, Dw males 2·1 ±0·4, Dw females 10·0 ± 0·6). In contrast, hepatic 125I-labelled bovine GH (bGH) binding (somatogenic receptors) was much lower, and similar in both Dw and normal animals. A sex difference in 125I-labelled bGH binding was only seen in adult animals, and was considerably less marked in Dw rats compared with normal animals (normal males 1·3 ±0·1, normal females 2·5 ± 0·2, Dw males 1·9 ± 0·2, Dw females 2·4 ± 0·2%/mg protein). Continuous hGH infusion stimulated growth in female Dw rats, and raised somatogenic and lactogenic GH binding (3·2 ± 0·4 and 19·6 ± 2·5%/mg protein) compared with sham-infused controls (2·4 ± 0·2 and 7·9 ± 0·6%/mg protein). Dw rats had significantly smaller amounts of hepatic GH receptor mRNA than normal rats, but there was no significant sex difference in GH receptor mRNA levels in the dwarfs. The pituitary GH deficiency in Dw rats was present at birth and the relative deficit remained constant despite large increases in pituitary GH that occurred from birth to maturity. Thus whilst hepatic GH receptor expression can be altered by GH in Dw rats, their chronic GH deficiency causing severe dwarfism is accompanied by only small differences in hepatic GH receptor expression. Journal of Endocrinology (1993) 138, 267–274

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Regulation of porcine insulin-like growth factor I and growth hormone receptor mRNA expression by energy status

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1994.266.5.e776 ◽

1994 ◽

Vol 266 (5) ◽

pp. E776-E785 ◽

Cited By ~ 5

Author(s):

P. A. Weller ◽

M. J. Dauncey ◽

P. C. Bates ◽

J. M. Brameld ◽

P. J. Buttery ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Growth Rates ◽

Mrna Levels ◽

Energy Status ◽

Factor I ◽

Receptor Mrna ◽

Gh Receptor ◽

Igf I ◽

Class 1

Regulation of insulin-like growth factor I (IGF-I) and growth hormone (GH) receptor mRNA in liver and muscle by energy status was assessed in 2-mo-old pigs by altering thermoregulatory demand and energy intake over a 5-wk period to produce a range of plasma IGF-I concentrations from 3.5 +/- 0.7 to 28.9 +/- 6.2 nmol/l. These values were related directly to growth rates (0.06 +/- 0.02 to 0.44 +/- 0.01 kg/day) and total hepatic IGF-I mRNA levels. Increased growth rates were accompanied by an increase in hepatic class 1 and class 2 IGF-I mRNA levels and an increase in the ratio of class 2 to class 1 IGF-I mRNA in liver, suggesting a distinct role for class 2 expression in the endocrine growth response. High levels of class 1 transcripts and a virtual absence of class 2 transcripts characterized all muscle tissues examined, and there was no correlation with plasma IGF-I levels. This suggests that growth promotion in response to increased energy status is regulated via endocrine hepatic IGF-I rather than via a paracrine response. The levels of GH receptor mRNA were positively correlated with overall growth rate (P < 0.005) in liver and negatively correlated (P < 0.05) in muscle, indicating distinct tissue-specific effects of energy status.

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Cortisol increases growth hormone-receptor expression in human osteoblast-like cells

Journal of Endocrinology ◽

10.1677/joe.0.1560099 ◽

1998 ◽

Vol 156 (1) ◽

pp. 99-105 ◽

Cited By ~ 10

Author(s):

D Swolin-Eide ◽

A Nilsson ◽

C Ohlsson

Keyword(s):

Growth Hormone ◽

Control Culture ◽

Receptor Expression ◽

Serum Starvation ◽

Maximal Effect ◽

Mrna Levels ◽

Dependent Manner ◽

Human Osteoblast ◽

Receptor Mrna ◽

Gh Receptor

It is well known that high levels of glucocorticoids cause osteoporosis and that physiologic levels of growth hormone (GH) are required for normal bone remodeling. It has been suggested that glucocorticoids regulate GH-responses via the regulation of GH-receptor expression. The aim of the present study was to investigate whether cortisol plays a role in the regulation of GH-receptor expression in cultured human osteoblasts. The effect of serum starvation and cortisol on GH-receptor expression was tested in human osteoblast (hOB)-like cells. Serum starvation for 24 h resulted in an increase in GH-receptor mRNA levels (90 +/- 1% over control culture). Cortisol increased GH-receptor mRNA levels in a dose-dependent manner with a maximal effect at 10(-6)M. The stimulating effect of cortisol on GH-receptor mRNA levels was time-dependent, reaching a peak 12 h after the addition of cortisol (126 +/- 29% over control culture) and remaining up to 12 h later. The increase in GH-receptor mRNA levels was accompanied by an increase in 125I-GH binding which reached a maximum at 24 h (196 +/- 87% over control culture). In conclusion, glucocorticoids increase GH-receptor expression in hOB-like cells. Further studies are needed to clarify whether glucocorticoid-induced regulation of the GH-receptor is important in human bone physiology.

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Proinflammatory cytokines interleukin 1β and tumor necrosis factor α inhibit growth hormone stimulation of insulin-like growth factor I synthesis and growth hormone receptor mRNA levels in cultured rat liver cells

Acta Endocrinologica ◽

10.1530/eje.0.1350729 ◽

1996 ◽

Vol 135 (6) ◽

pp. 729-737 ◽

Cited By ~ 83

Author(s):

Matthias Wolf ◽

Sebastian Böhm ◽

Marcus Brand ◽

Georg Kreymann

Keyword(s):

Growth Hormone ◽

Tumor Necrosis Factor ◽

Proinflammatory Cytokines ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Mrna Levels ◽

Receptor Mrna ◽

Gh Receptor ◽

Tnf Α ◽

Igf I

Wolf M, Böhm S, Brand M, Kreymann G. Proinflammatory cytokines interleukin 1β and tumor necrosis factor α inhibit growth hormone stimulation of insulin-like growth factor I synthesis and growth hormone receptor mRNA levels in cultured rat liver cells. Eur J Endocrinol 1996;135:729–37. ISSN 0804–4643 Low levels of insulin-like growth factor I (IGF-I) in critical illness are observed despite increased or normal levels of growth hormone (GH). The mechanisms for this apparent GH resistance have not been elucidated. As many of the acute inflammatory responses in critical illness are mediated by the proinflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), the present studies evaluated IL-1β and TNF-α effects on steady-state and GH-stimulated IGF-I synthesis and GH receptor mRNA levels. In rat hepatocytes in primary culture, IGF-I released into culture medium was determined by radioimmunoassay, and quantitative competitive polymerase chain reaction was used to measure IGF-I mRNA and GH receptor mRNA concentrations. Growth hormone increased GH receptor mRNA, IGF-I mRNA and IGF-I protein secreted into the culture medium. In cells not stimulated with GH, modest inhibitory effects of IL-1β on GH receptor mRNA, IGF-I mRNA and IGF-I protein levels were seen. However, the stimulatory effects of GH were inhibited in a dose-dependent manner both by IL-1β and TNF-α, and at higher cytokine concentrations no stimulatory effects of GH were observed. Both IL-1β and TNF-α in submaximal dose had additive inhibitory effects on IGF-I protein concentrations but these effects did not result in irreversible damage to cells, as indicated by restoration of IGF-I and GH receptor mRNA levels to normal after withdrawal of cytokines. In conclusion, we demonstrated that in rat hepatocytes in primary culture IL-1β and TNF-α inhibited GH-stimulated IGF-I synthesis. Diminished GH receptor mRNA concentrations in response to IL-1β and TNF-α indicate that low IGF-I levels during severe illness, despite high circulating GH levels, may at least partially be a consequence of suppression of hepatic GH receptor synthesis by IL-1β and TNF-α. Matthias Wolf, Medizinische Kern- und Poliklinik, Universitäts-Krankenhaus Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany

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Outcomes in children treated with growth hormone for Prader-Willi syndrome: data from the ANSWER Program® and NordiNet® International Outcome Study

International Journal of Pediatric Endocrinology ◽

10.1186/s13633-020-00090-6 ◽

2020 ◽

Vol 2020 (1) ◽

Author(s):

Moris Angulo ◽

M. Jennifer Abuzzahab ◽

Alberto Pietropoli ◽

Vlady Ostrow ◽

Nicky Kelepouris ◽

...

Keyword(s):

Growth Hormone ◽

Standard Deviation ◽

Pediatric Patients ◽

Treatment Time ◽

Gh Deficiency ◽

Prader Willi Syndrome ◽

Outcome Study ◽

Gh Treatment ◽

Over Time ◽

Adult Stature

Abstract Background Growth hormone (GH) deficiency is common in patients with Prader-Willi syndrome (PWS) and leads to short adult stature. The current study assessed clinical outcomes based on real-world observational data in pediatric patients with PWS who were treated with GH. Methods Data from patients previously naïve to treatment with GH who began therapy with somatropin were collected from 2006 to 2016 in the observational American Norditropin® Studies: Web-Enabled Research (ANSWER) Program® and NordiNet® International Outcome Study. Variables affecting change from baseline in height standard deviation scores (HSDS; n = 129) and body mass index standard deviation scores (BMI SDS; n = 98) were determined. Results Patients included in both HSDS and BMI SDS analyses were treated with a mean GH dose of 0.03 mg/kg/d (SD, 0.01 mg/kg/d). Results from the HSDS analysis revealed that baseline age and years on treatment had a significant impact on the change in HSDS. In the BMI SDS analysis, longer GH treatment time led to a greater change in BMI SDS from baseline, and patients with a higher BMI at the start of treatment had a greater decrease in BMI over time. Conclusions GH is effective in the management of children with PWS. Earlier treatment resulted in a greater gain in height, and a longer treatment period resulted in better outcomes for both height and BMI. Trial registration This study was registered with ClinicalTrials.gov (NCT01009905) on November 9, 2009.

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Elevated Insulin-Like Growth Factor-I Values in Children with Prader-Willi Syndrome Compared with Growth Hormone (GH) Deficiency Children over Two Years of GH Treatment

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-1831 ◽

2010 ◽

Vol 95 (10) ◽

pp. 4600-4608 ◽

Cited By ~ 18

Author(s):

Eva Feigerlová ◽

Gwenaëlle Diene ◽

Isabelle Oliver ◽

Isabelle Gennero ◽

Jean-Pierre Salles ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Gh Deficiency ◽

Prader Willi Syndrome ◽

Insulin Like Growth Factor ◽

Gh Treatment ◽

Factor I ◽

Growth Factor I

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Time for a general approval of growth hormone treatment in adults with Prader–Willi syndrome

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01651-x ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Charlotte Höybye ◽

◽

Anthony J. Holland ◽

Daniel J. Driscoll

Keyword(s):

Growth Hormone ◽

Body Composition ◽

Transition Period ◽

Neurodevelopmental Disorder ◽

Hormone Treatment ◽

Psychomotor Development ◽

Prader Willi Syndrome ◽

Gh Treatment ◽

Beneficial Effects ◽

Positive Effects

AbstractPrader-Willi syndrome (PWS) is a complex, multi-system, neurodevelopmental disorder characterised by neonatal muscular hypotonia, short stature, high risk of obesity, hypogonadism, intellectual disabilities, distinct behavioural/psychiatric problems and abnormal body composition with increased body fat and a deficit of lean body mass. Growth hormone (GH) deficiency and other hormone deficiencies are common due to hypothalamic dysfunction. In children with PWS GH treatment has been widely demonstrated to improve body composition, normalise height and improve psychomotor development. In adults with PWS, GH’s main effects are to maintain normal body structure and metabolism. The positive effects of GH treatment on body composition, physical fitness and beneficial effects on cardiovascular risk markers, behaviour and quality of life in adults with PWS are also well established from several studies. GH treatment is approved for treatment of children with PWS in many countries, but until recently not as a treatment in young adults in the transition period or for adults in general. In this commentary we want to draw attention to the uneven global use of GH treatment, specifically in adults with PWS, and advocate for GH treatment to be approved internationally, not just for children, but also for adults with PWS and based only on the diagnosis of genetically confirmed PWS.

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