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Modulation of IGF-I receptors by exogenous hGH treatment in constitutionally short children
R Eshet1, B Klinger, A Silbergeld
1Institute of Pediatric and Adolescent Endocrinology, Children's Medical Center of Israel, Petah Tikva.
Insights
Human growth hormone (hGH) treatment in short children increases insulin-like growth factor I (IGF-I) levels and decreases IGF-I receptors on red blood cells (RBC). This suggests IGF-I regulates its own receptors in vivo.
Area of Science:
- Endocrinology
- Molecular Biology
- Pediatrics
Background:
- Growth hormone (GH) therapy is increasingly used for children with short stature, including those with constitutional growth delay.
- Understanding the in-vivo regulation of insulin-like growth factor I (IGF-I) by GH is crucial for optimizing treatment outcomes.
- Erythrocytes (RBC) possess IGF-I binding sites that may reflect systemic IGF-I receptor status.
Purpose of the Study:
- To investigate the effect of human growth hormone (hGH) administration on IGF-I binding sites on erythrocytes in children with constitutional short stature.
- To assess the in-vivo regulation of IGF-I receptors in response to hGH therapy.
Main Methods:
- Eleven children with constitutional short stature received daily subcutaneous injections of recombinant hGH (rhGH).
- IGF-I levels and IGF-I binding sites on erythrocytes were measured before and 1-2 months after initiating hGH treatment.
- Erythrocytes were isolated using Ficoll-Hypaque density gradient centrifugation for binding site analysis.
Main Results:
- Serum IGF-I levels significantly increased from a mean of 14.93 +/- 1.50 nmol/l to 30.29 +/- 2.32 nmol/l (P = 0.00001).
- The number of IGF-I binding sites per erythrocyte significantly decreased from 5.77 +/- 0.81 to 2.10 +/- 0.36 (P = 0.0003).
- IGF-I receptor affinity increased, indicated by a decreased dissociation constant (Kd) from 0.47 +/- 0.16 nM to 0.10 +/- 0.02 nM (P = 0.02).
Conclusions:
- hGH treatment effectively increases circulating IGF-I levels in constitutionally short children.
- IGF-I administration leads to down-regulation of IGF-I receptors on erythrocytes, demonstrating in-vivo receptor regulation.
- Measurement of IGF-I binding sites on RBC may serve as a diagnostic tool for subtle IGF-I resistance states.
Objective:
To study the in-vivo regulation of IGF-I binding sites on erythrocytes (RBC) following administration of growth hormone (hGH) to constitutionally short children. Recently, owing to biosynthetic techniques, treatment with hGH has been administered not only to children with GH deficiency but also to children with constitutional growth delay and with familial short stature.
Patients And Design:
Growth hormone (rhGH-Norditropin, Novo/Nordisk) was administered at a dose of 0.1 U/kg/day s.c. to 11 children with constitutional short stature. Before and at 1-2 months after initiation of treatment IGF-I binding sites and serum IGF-I were determined. Erythrocytes were separated from whole blood by centrifugation over Ficoll Hypaque and used to assess IGF-I binding sites.
Results:
Serum IGF-I levels increased from 14.93 +/- 1.50 nmol/l (mean +/- SEM) to 30.29 +/- 2.32 nmol/l, with a mean difference of 15.36 +/- 2.21 (P = 0.00001). Concomitantly, the number of binding sites per cell decreased from 5.77 +/- 0.81 sites per cell (m +/- SEM) to 2.10 +/- 0.36, with a mean difference of -3.67 +/- 0.76 (P = 0.0003). The dissociation constant (Kd) also decreased from 0.47 +/- 0.16 nM (m +/- SEM) to 0.10 +/- 0.02 with a mean difference of -0.37 +/- 0.16 (P = 0.02), indicating an increase in the affinity of the receptors.
Conclusion:
Treatment of children with constitutional short stature with hGH raises the circulating IGF-I levels and down-regulates the IGF-I receptors. This study shows that IGF-I is capable of regulating its homologous receptor concentrations in vivo and it is suggested that the measurement of IGF-I binding sites on RBC may be used for the diagnosis of subtle states of resistance to IGF-I.