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Ghrelin Potentiates Growth Hormone Secretion Driven by Putative Somatostatin Withdrawal and Resists Inhibition by Human Corticotropin-Releasing Hormone

Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic (J.D.V., K.M., J.M.M., P.C.C.), Rochester, Minnesota 55905; Endocrine Section, Department of Medicine, Salem Veterans Affairs Medical Center (A.I.), Salem, Virginia 24153; and Department of Medicine, Tulane University Health Sciences Center (C.Y.B.), New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Dr. Johannes D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

Context: Ghrelin is a 28-amino acid, Ser³-octanoylated peptide that stimulates GH secretion in vivo and in vitro. Beyond the capability of ghrelin to synergize with GHRH, little is known about multipeptide modulation of ghrelin’s actions in humans.

Objective: The objective of this study was to test the hypothesis that ghrelin can stimulate GH secretion in the absence or presence of somatostatin withdrawal (induced by L-arginine infusion) and stress-like drive by CRH.

Design: This was a randomized, double-blind, placebo-controlled, cross-over interventional study.

Setting: This study was performed at an academic medical center.

Participants: Nine healthy postmenopausal women not receiving sex hormones were studied.

Interventions: Subjects were given an iv infusion of saline and/or L-arginine or human CRH, followed by a bolus iv injection of ghrelin.

Outcome Measures: The outcome measures were pulsatile GH secretion quantified by repetitive blood sampling, immunochemiluminometry, and deconvolution analysis.

Results: Consecutive saline/ghrelin infusion increased pulsatile GH secretion from 2.7 ± 1.0 (saline/saline; mean ± SEM) to 20 ± 5.0 µg/liter·3 h (P < 0.01). The magnitude of the effect of L-arginine/saline was comparable at 20 ± 4.5 µg/liter·3 h (P < 0.01). In contrast, sequential L-arginine/ghrelin evoked true synergy of GH release (93 ± 14 µg/liter·3 h; P = 0.003 vs. L-arginine alone and P = 0.008 vs. ghrelin alone). Human CRH did not affect GH responses to saline/saline (3.9 ± 1.1 µg/liter·3 h), saline/ghrelin (19 ± 3.3 µg/liter·3 h), L-arginine/saline (16 ± 2.7 µg/liter·3 h), or L-arginine/ghrelin (90 ± 13 µg/liter·3 h).

Conclusions: Assuming that L-arginine reduces somatostatin outflow, we infer that ghrelin can activate hypothalamo-pituitary pathways that are both dependent upon and independent of somatostatinergic restraint even in the face of a strong stress-related signal.

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