Sex steroids, GHRH, somatostatin, IGF-I, and IGFBP-1 modulate Ghrelin's dose-dependent drive of pulsatile GH secretion in healthy older men

Johannes D Veldhuis, Catalina Norman, John M. Miles, Cyril Y. Bowers

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Context: Ghrelin is a potent endogenous stimulator of GH secretion. However, clinical factors that regulate ghrelin dose-responsiveness are incompletely defined. Objective: The aim of the study was to test the multipathway hypothesis that testosterone (T) and estradiol, GHRH, and somatostatin (SS) jointly modulate ghrelin's action. Design/Participants/ Setting: Healthy older men (n = 21) participated in a double-blind, prospectively randomized, placebo (Pl)-controlled study in a Clinical Translational Research Center. Interventions: To create a range of sex-steroid milieus, men received leuprolide + Pl (n = 10) or leuprolide + T addback (n = 11). Sixteen to 21 d later, subjects received three separate randomly ordered overnight constant iv infusions of saline, GHRH, and SS. Interactions between the peptide clamp and ghrelin were tested by superimposed injections of four randomly ordered bolus iv doses of ghrelin (0.03, 0.135, 0.60, and 2.7 μg/kg). GH was measured every 10 min, and GH responses were assessed by nonlinear dose-response analysis. Linear associations were assessed by stepwise regression. Outcome Measures/Results: The descending numerical order of ghrelin efficacy (maximal GH secretory-burst mass; micrograms/liter) was 107 (GHRH + Pl), 104 (GHRH + T), 73 (saline + T), 73 (SS + T), 60 (saline + Pl), and 52 (SS + Pl) [means], wherein SS + T exceeded SS + Pl. GHRH and IGF binding protein-1 augmented, whereas IGF-I attenuated ghrelin potency. Age and IGF-I decreased ghrelin/GHRH synergy. Ghrelin sensitivity was independent of interventions. Conclusions: These studies introduce composite regulatory effects of sex hormones, GHRH, SS, IGF binding protein-1, and IGF-Ionghrelin dose-responsiveness, suggesting multipathway modulation of GH-secretagogue action.

Original languageEnglish (US)
Pages (from-to)4753-4760
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume97
Issue number12
DOIs
StatePublished - Dec 2012

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Insulin-Like Growth Factor Binding Protein 1
Ghrelin
Somatostatin
Insulin-Like Growth Factor I
Steroids
Placebos
Leuprolide
somatostatin-22
Translational Medical Research
Clamping devices
Gonadal Steroid Hormones
Testosterone
Estradiol
Healthy Volunteers
Modulation
Outcome Assessment (Health Care)
Peptides
Injections

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Sex steroids, GHRH, somatostatin, IGF-I, and IGFBP-1 modulate Ghrelin's dose-dependent drive of pulsatile GH secretion in healthy older men. / Veldhuis, Johannes D; Norman, Catalina; Miles, John M.; Bowers, Cyril Y.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 97, No. 12, 12.2012, p. 4753-4760.

Research output: Contribution to journalArticle

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abstract = "Context: Ghrelin is a potent endogenous stimulator of GH secretion. However, clinical factors that regulate ghrelin dose-responsiveness are incompletely defined. Objective: The aim of the study was to test the multipathway hypothesis that testosterone (T) and estradiol, GHRH, and somatostatin (SS) jointly modulate ghrelin's action. Design/Participants/ Setting: Healthy older men (n = 21) participated in a double-blind, prospectively randomized, placebo (Pl)-controlled study in a Clinical Translational Research Center. Interventions: To create a range of sex-steroid milieus, men received leuprolide + Pl (n = 10) or leuprolide + T addback (n = 11). Sixteen to 21 d later, subjects received three separate randomly ordered overnight constant iv infusions of saline, GHRH, and SS. Interactions between the peptide clamp and ghrelin were tested by superimposed injections of four randomly ordered bolus iv doses of ghrelin (0.03, 0.135, 0.60, and 2.7 μg/kg). GH was measured every 10 min, and GH responses were assessed by nonlinear dose-response analysis. Linear associations were assessed by stepwise regression. Outcome Measures/Results: The descending numerical order of ghrelin efficacy (maximal GH secretory-burst mass; micrograms/liter) was 107 (GHRH + Pl), 104 (GHRH + T), 73 (saline + T), 73 (SS + T), 60 (saline + Pl), and 52 (SS + Pl) [means], wherein SS + T exceeded SS + Pl. GHRH and IGF binding protein-1 augmented, whereas IGF-I attenuated ghrelin potency. Age and IGF-I decreased ghrelin/GHRH synergy. Ghrelin sensitivity was independent of interventions. Conclusions: These studies introduce composite regulatory effects of sex hormones, GHRH, SS, IGF binding protein-1, and IGF-Ionghrelin dose-responsiveness, suggesting multipathway modulation of GH-secretagogue action.",
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AU - Bowers, Cyril Y.

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N2 - Context: Ghrelin is a potent endogenous stimulator of GH secretion. However, clinical factors that regulate ghrelin dose-responsiveness are incompletely defined. Objective: The aim of the study was to test the multipathway hypothesis that testosterone (T) and estradiol, GHRH, and somatostatin (SS) jointly modulate ghrelin's action. Design/Participants/ Setting: Healthy older men (n = 21) participated in a double-blind, prospectively randomized, placebo (Pl)-controlled study in a Clinical Translational Research Center. Interventions: To create a range of sex-steroid milieus, men received leuprolide + Pl (n = 10) or leuprolide + T addback (n = 11). Sixteen to 21 d later, subjects received three separate randomly ordered overnight constant iv infusions of saline, GHRH, and SS. Interactions between the peptide clamp and ghrelin were tested by superimposed injections of four randomly ordered bolus iv doses of ghrelin (0.03, 0.135, 0.60, and 2.7 μg/kg). GH was measured every 10 min, and GH responses were assessed by nonlinear dose-response analysis. Linear associations were assessed by stepwise regression. Outcome Measures/Results: The descending numerical order of ghrelin efficacy (maximal GH secretory-burst mass; micrograms/liter) was 107 (GHRH + Pl), 104 (GHRH + T), 73 (saline + T), 73 (SS + T), 60 (saline + Pl), and 52 (SS + Pl) [means], wherein SS + T exceeded SS + Pl. GHRH and IGF binding protein-1 augmented, whereas IGF-I attenuated ghrelin potency. Age and IGF-I decreased ghrelin/GHRH synergy. Ghrelin sensitivity was independent of interventions. Conclusions: These studies introduce composite regulatory effects of sex hormones, GHRH, SS, IGF binding protein-1, and IGF-Ionghrelin dose-responsiveness, suggesting multipathway modulation of GH-secretagogue action.

AB - Context: Ghrelin is a potent endogenous stimulator of GH secretion. However, clinical factors that regulate ghrelin dose-responsiveness are incompletely defined. Objective: The aim of the study was to test the multipathway hypothesis that testosterone (T) and estradiol, GHRH, and somatostatin (SS) jointly modulate ghrelin's action. Design/Participants/ Setting: Healthy older men (n = 21) participated in a double-blind, prospectively randomized, placebo (Pl)-controlled study in a Clinical Translational Research Center. Interventions: To create a range of sex-steroid milieus, men received leuprolide + Pl (n = 10) or leuprolide + T addback (n = 11). Sixteen to 21 d later, subjects received three separate randomly ordered overnight constant iv infusions of saline, GHRH, and SS. Interactions between the peptide clamp and ghrelin were tested by superimposed injections of four randomly ordered bolus iv doses of ghrelin (0.03, 0.135, 0.60, and 2.7 μg/kg). GH was measured every 10 min, and GH responses were assessed by nonlinear dose-response analysis. Linear associations were assessed by stepwise regression. Outcome Measures/Results: The descending numerical order of ghrelin efficacy (maximal GH secretory-burst mass; micrograms/liter) was 107 (GHRH + Pl), 104 (GHRH + T), 73 (saline + T), 73 (SS + T), 60 (saline + Pl), and 52 (SS + Pl) [means], wherein SS + T exceeded SS + Pl. GHRH and IGF binding protein-1 augmented, whereas IGF-I attenuated ghrelin potency. Age and IGF-I decreased ghrelin/GHRH synergy. Ghrelin sensitivity was independent of interventions. Conclusions: These studies introduce composite regulatory effects of sex hormones, GHRH, SS, IGF binding protein-1, and IGF-Ionghrelin dose-responsiveness, suggesting multipathway modulation of GH-secretagogue action.

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