Growth Hormone (GH) Receptor Isoform in Acromegaly: Lower Concentrations of GH but Not Insulin-Like Growth Factor-1 in Patients with a Genomic Deletion of Exon 3 in the GH Receptor Gene

Abstract Background: A genomic deletion of exon 3 (d3-GHR) of the growth hormone (GH) receptor (GHR) has been linked to the effectiveness of GH therapy in children with GH deficiency. Carriers of the d3-GHR genotype had higher GH-induced growth rates than children homozygous for the full-length (fl)-GHR. The aim of this study was to test whether the relationship between GH and insulin-like growth factor-1 (IGF-1) concentrations is influenced by the GHR genotype in patients with acromegaly. Methods: Study participants were 44 adult patients with established diagnosis of acromegaly. The genotype of the GHR was determined in leukocyte DNA from peripheral blood. Clinical and biochemical findings at the time of diagnosis of acromegaly were obtained from the medical records of the patients. Results: fl-GHR homozygosity was found in 22 (50%) of patients, and 22 (50%) of patients had at least 1 d3 allele (d3-GHR). Demographic and clinical characteristics (age, height, weight, estimated duration of disease, and mean tumor size) of the 2 groups were comparable. Median (range) serum IGF-1 concentrations at the time of diagnosis were 670 (447–1443) μg/L in the fl-GHR group and 840 (342–1494) μg/L in the d3-GHR group (P = not significant). Basal GH concentrations were higher in the fl-GHR group [29.7 (3.8–159) μg/L] than in the d3-GHR group [8.4 (2.6–74 μg/L), P = 0.002], and so were mean (30.4 vs 6.1 μg/L, P = 0.005) and nadir (20.5 vs 5.1 μg/L, P = 0.003) GH concentrations during an oral glucose tolerance test. Conclusions: The GHR fl/d3 genotype modulates the relationship between GH and IGF-1 concentrations in patients presenting with acromegaly.

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Growth hormone (GH) stimulates insulin-like growth factor-I (IGF-I) and IGF-I-binding protein-3, but not GH receptor gene expression in livers of juvenile rats.

Endocrinology ◽

10.1210/endo.133.2.7688291 ◽

1993 ◽

Vol 133 (2) ◽

pp. 675-682 ◽

Cited By ~ 19

Author(s):

H Domené ◽

K Krishnamurthi ◽

R Eshet ◽

I Gilad ◽

Z Laron ◽

...

Keyword(s):

Gene Expression ◽

Growth Hormone ◽

Growth Factor ◽

Receptor Gene ◽

Insulin Like Growth Factor ◽

Juvenile Rats ◽

Factor I ◽

Gh Receptor ◽

Igf I ◽

Receptor Gene Expression

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Primary Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor Deficiency Caused by Novel Compound Heterozygous Mutations of the GH Receptor Gene: Genetic and Functional Studies of Simple and Compound Heterozygous States

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-2624 ◽

2007 ◽

Vol 92 (6) ◽

pp. 2223-2231 ◽

Cited By ~ 24

Author(s):

Peng Fang ◽

Stefan Riedl ◽

Serge Amselem ◽

Katherine L. Pratt ◽

Brian M. Little ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Receptor Gene ◽

Compound Heterozygous ◽

Insulin Like Growth Factor ◽

Functional Studies ◽

Gh Receptor ◽

Primary Growth ◽

Factor Deficiency ◽

Compound Heterozygous Mutations

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Revisiting the role of insulin-like growth factor-1 measurement after surgical treatment of acromegaly

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab186 ◽

2021 ◽

Author(s):

In-Ho Jung ◽

Seonah Choi ◽

Cheol Ryong Ku ◽

Sang-Guk Lee ◽

Eun Jig Lee ◽

...

Keyword(s):

Surgical Treatment ◽

Growth Factor ◽

Area Under The Curve ◽

Pituitary Tumors ◽

Tolerance Test ◽

Oral Glucose ◽

Insulin Like Growth Factor ◽

Regression Analyses ◽

Severance Hospital

Abstract Context In the management of growth hormone (GH)-secreting pituitary adenomas, oral glucose tolerance test (OGTT) has been the gold standard not only for diagnoses but also for the determination of biochemical remission. Insulin-like growth factor-1 (IGF-1) is an essential biomarker although it should be adjusted for both age and sex. Objective We evaluated whether IGF-1 levels could serve as a reliable alternative to an OGTT for disease monitoring after the surgical treatment of acromegaly. Design Retrospective study. Setting Severance Hospital. Patients We retrospectively reviewed the medical records of 320 patients who underwent surgical resection of their GH-secreting pituitary tumors. Main Outcome Measures Receiver operator characteristic (ROC) analyses were performed to validate the accuracy of IGF-1 levels for the assessment of remission. In addition, regression analyses were performed to identify factors associated with discrepancy between OGTT and IGF-1 levels. Results Except for 1 week after surgery, ROC analyses showed an area under the curve of greater than 0.8 for IGF-1 at all time points. Of 320 patients, 270 achieved endocrine remission after surgery alone. Among these patients, IGF-1 levels were normalized in 250 patients. The mean duration from surgery to IGF-1 normalization was 4.7 months. Regression analyses demonstrated that risk of failed IGF-1 normalization was increased by 3.1-fold when the tumor invaded the cavernous sinus and increased by 9.0-fold in patients with incomplete tumor removal. Conclusions IGF-1 level is a reliable alternative to OGTT and plays a valuable role in monitoring acromegaly status.

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The Relationship between 24-Hour Growth Hormone Secretion and Insulin-Like Growth Factor I in Patients with Successfully Treated Acromegaly: Impact of Surgery or Radiotherapy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.1.7154 ◽

2001 ◽

Vol 86 (1) ◽

pp. 259-266 ◽

Cited By ~ 33

Author(s):

Steven R. Peacey ◽

Andrew A. Toogood ◽

Johannes D. Veldhuis ◽

Michael O. Thorner ◽

Stephen M. Shalet

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Insulin Like Growth Factor ◽

Factor I ◽

Growth Factor I ◽

The Relationship

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Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

Journal of Endocrinology ◽

10.1677/joe.0.1670295 ◽

2000 ◽

Vol 167 (2) ◽

pp. 295-303 ◽

Cited By ~ 17

Author(s):

JW van Neck ◽

NF Dits ◽

V Cingel ◽

IA Hoppenbrouwers ◽

SL Drop ◽

...

Keyword(s):

Growth Hormone ◽

Growth Factor ◽

Receptor Antagonist ◽

Growth Hormone Receptor ◽

Binding Protein ◽

Mrna Levels ◽

Insulin Like Growth Factor ◽

Gh Receptor ◽

Igf I ◽

Igfbp 3

The effects of growth hormone (GH) in regulating the expression of the hepatic and renal GH and insulin-like growth factor (IGF) system were studied by administering a novel GH receptor antagonist (GHRA) (B2036-PEG) at different doses (0, 1.25, 2.5, 5 and 10 mg/kg/day) to mice for 7 days. No differences were observed in the groups with respect to body weight, food consumption or blood glucose. However, a dose-dependent decrease was observed in circulating IGF-I levels and in hepatic and renal IGF-I levels at the highest doses. In contrast, in the 5 and 10 mg/kg/day GHRA groups, circulating and hepatic transcriptional IGF binding protein-3 (IGFBP-3) levels were not modified, likely resulting in a significantly decreased IGF-I/IGFBP-3 ratio. Hepatic GH receptor (GHR) and GH binding protein (GHBP) mRNA levels increased significantly in all GHRA dosage groups. Endogenous circulatory GH levels increased significantly in the 2.5 and 5 mg/kg/day GHRA groups. Remarkably, increased circulating IGFBP-4 and hepatic IGFBP-4 mRNA levels were observed in all GHRA administration groups. Renal GHR and GHBP mRNA levels were not modified by GHRA administration at the highest doses. Also, renal IGFBP-3 mRNA levels remained unchanged in most GHRA administration groups, whereas IGFBP-1, -4 and -5 mRNA levels were significantly increased in the 5 and 10 mg/kg/day GHRA administration groups. In conclusion, the effects of a specific GHR blockade on circulating, hepatic and renal GH/IGF axis reported here, may prove useful in the future clinical use of GHRAs.

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