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Putative Somatostatin Suppression Potentiates Adrenocorticotropin Secretion Driven by Ghrelin and Human Corticotropin-Releasing Hormone

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

Address all correspondence and requests for reprints to: 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, and CRH is a 41-amino-acid peptide, both of which stimulate ACTH secretion. In principle, actions of these agonists could be subject to inhibitory modulation by hypothalamic somatostatin (SS).

Objective: Our objective was to test the hypothesis that endogenous SS restrains ghrelin and CRH-stimulated ACTH secretion, thereby linking all three, ghrelin, CRH, and SS, with ACTH secretion.

Design and Setting: We conducted a randomized, double-blind, placebo-controlled, crossover interventional study at an academic medical center.

Participants: Ten healthy postmenopausal women participated in the study.

Interventions: Interventions included iv injection of saline, ghrelin, human CRH, or both after an infusion of saline vs. L-arginine to putatively inhibit SS outflow (eight visits per subject).

Outcome Measures: ACTH concentrations quantified by repetitive blood sampling and immunochemiluminometry.

Results: Infusion of ghrelin induced peak ACTH concentrations [median (range)] of 21 (17–28) compared with 16 (11–20) ng/liter after saline (P = 0.037). CRH and L-arginine infusion evoked ACTH peaks of 23 (14–48) and 31 (21–286) ng/liter, respectively (P = 0.037 and P = 0.005 vs. saline). L-Arginine enhanced stimulation by ghrelin by 1.43-fold (P = 0.028) and that by CRH by 1.91-fold (P = 0.005). Triple stimulation with ghrelin, CRH, and L-arginine potentiated the effect of combined ghrelin/CRH by 1.45-fold (P = 0.028). Downstream cortisol responses mimicked those of ACTH but were time delayed.

Conclusions: The present outcomes indicate that the peptide ensemble comprising ghrelin, CRH, and SS (inferred by L-arginine infusion) can regulate ACTH and cortisol secretion in healthy adults.