Ghrelin potentiates growth hormone secretion driven by putative somatostatin withdrawal and resists inhibition by human corticotropin-releasing hormone.
BACKGROUND
Ghrelin is a 28-amino acid, Ser(3)-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.


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


METHODS
This study was performed at an academic medical center.


METHODS
Nine healthy postmenopausal women not receiving sex hormones were studied.


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


METHODS
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 microg/liter.3 h (P < 0.01). The magnitude of the effect of l-arginine/saline was comparable at 20 +/- 4.5 microg/liter.3 h (P < 0.01). In contrast, sequential l-arginine/ghrelin evoked true synergy of GH release (93 +/- 14 microg/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 microg/liter.3 h), saline/ghrelin (19 +/- 3.3 microg/liter.3 h), l-arginine/saline (16 +/- 2.7 microg/liter.3 h), or l-arginine/ghrelin (90 +/- 13 microg/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.
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, USA. veldhuis.johannes@mayo.edu
Johannes D
JD
Veldhuis
Ali
A
Iranmanesh
Kristi
K
Mielke
John M
JM
Miles
Paul C
PC
Carpenter
Cyril Y
CY
Bowers
D000368:Aged; D001120:Arginine / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D004311:Double-Blind Method; D004357:Drug Synergism; D005260:Female; D054439:Ghrelin; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D036361:Peptide Hormones / Q000494:pharmacology*; D013004:Somatostatin / Q000502:physiology*
D054439:Ghrelin; D036361:Peptide Hormones; D019382:Human Growth Hormone; D013004:Somatostatin; D003346:Corticotropin-Releasing Hormone; D001120:Arginine