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Published on: May 10, 2018
Insulin Sensitivity and β-Cell Function in SGA Children Treated With GH and GnRHa: Results of a Long-Term Trial
Manouk van der Steen1, Annemieke J Lem1, Daniëlle C M van der Kaay1
1Dutch Growth Research Foundation (M.v.d.S., A.J.L., D.C.M.v.d.K., A.C.S.H.-K.), 3001 KB Rotterdam, The Netherlands; and Erasmus University Medical Center/Sophia Children's Hospital ((M.v.d.S., A.C.S.H.-K.), 3000 CA Rotterdam, The Netherlands.
Insights
Growth hormone (GH) and gonadotropin-releasing hormone analog (GnRHa) combination therapy does not negatively impact long-term insulin sensitivity in children. Higher GH doses (2 mg/m(2)/d) show similar insulin sensitivity to lower doses (1 mg/m(2)/d) when initiated in early puberty.
Area of Science:
- Pediatric Endocrinology
- Metabolic Research
- Growth Hormone Therapy
Background:
- Children born small for gestational age (SGA) with poor adult height (AH) prospects may benefit from growth hormone (GH) and gonadotropin-releasing hormone analog (GnRHa) treatment.
- Concerns exist regarding the potential negative impact of combined GH and GnRHa on insulin sensitivity.
- Long-term effects of GH dosage on insulin sensitivity in children receiving combined therapy remain unclear.
Purpose of the Study:
- To investigate the long-term effects of GH treatment, with or without GnRHa, on insulin sensitivity and beta-cell function.
- To compare insulin sensitivity at AH between GH doses of 1 mg/m(2)/d and 2 mg/m(2)/d when combined with GnRHa.
Main Methods:
- A randomized, dose-response GH trial involving 110 short SGA children.
- Sixty-seven children received additional 2-year GnRHa treatment.
- Insulin sensitivity (Si), acute insulin response (AIR), and disposition index (DI) were calculated using frequently sampled intravenous glucose tolerance tests and MINMOD.
Main Results:
- After 5.9 years, insulin sensitivity, AIR, and DI were similar in children treated with combined GH/GnRHa versus GH alone.
- In a subgroup treated from early puberty with GH (1 or 2 mg/m(2)/d) and GnRHa, no significant differences in Si, AIR, or DI were observed between GH dose groups.
Conclusions:
- Combined GH/GnRHa therapy does not lead to long-term negative effects on insulin sensitivity or beta-cell function compared to GH monotherapy.
- Initiating GH treatment at 2 mg/m(2)/d in early puberty, alongside GnRHa, results in comparable adult height insulin sensitivity to a 1 mg/m(2)/d GH dose.
Context:
Pubertal children born small for gestational age with a poor adult height (AH) expectation can benefit from treatment with GH 1 mg/m(2)/d (∼0.033 mg/kg/d) in combination with 2 years of GnRH analog (GnRHa) and even more so with GH 2 mg/m(2)/d. Because both GH and GnRHa can negatively influence insulin sensitivity, combining these treatments has raised concerns. The long-term GH dose effects on insulin sensitivity in children treated with combined GH/GnRHa are unknown.
Objective:
The purpose of this study was to investigate insulin sensitivity and β-cell function by a very precise method during long-term GH treatment, either with or without 2 years of additional GnRHa and to study differences in insulin sensitivity during treatment until AH between GH at 1 or 2 mg/m(2)/d.
Methods:
This was a randomized, dose-response GH trial involving 110 short small for gestational age children (59 girls) treated with GH until AH (GH randomized to 1 or 2 mg/m(2)/d). Sixty-seven children received additional GnRHa treatment. Frequently sampled intravenous glucose tolerance tests were performed and insulin sensitivity (Si), acute insulin response (AIR), and disposition index (DI) were calculated using Bergman's MINMOD. The GH dose effect was evaluated in a subgroup of 48 children who started GH treatment in early puberty (randomized to 1 or 2 mg/m(2)/d) combined with 2 years of GnRHa.
Results:
At AH, after 5.9 years of GH treatment, Si, AIR, and DI were similar between children treated with combined GH/GnRHa and those treated with GH only. In the subgroup of children who started GH treatment in early puberty (randomized to 1 or 2 mg/m(2)/d) together with 2 years of GnRHa treatment, there were no significant differences in Si, AIR, or DI between the GH dose groups during the treatment.
Conclusions:
Combined GH/GnRHa treatment has no long-term negative effects on insulin sensitivity and β-cell function compared with GH only. Started in early puberty, a GH dose of 2 mg/m(2)/d results in a similar insulin sensitivity at AH as a GH dose of 1 mg/m(2)/d.
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