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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 6 2441-2446
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

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

Johannes D. Veldhuis, Ali Iranmanesh, Kristi Mielke, John M. Miles, Paul C. Carpenter and Cyril Y. Bowers

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TRANSGENIC MODELS IN mice and rare genetic mutations in humans establish that pulsatile (burst-like) GH secretion is regulated by somatostatin, GHRH, and the GH-releasing peptide (GHRP), ghrelin (1, 2, 3, 4, 5, 6, 7). Selective antagonism of somatostatin, GHRH, and ghrelin actions in the experimental animal and of somatostatin and GHRH in the human corroborate key roles for these peptides (8, 9, 10, 11, 12). An emergent concept is that no single peptide acts alone or may be understood to act in isolation (13, 14). For example, pulsatile GH secretion persists, but at greatly reduced amplitude, in patients with inactivating (truncational) mutations of the GHRH receptor gene (7) and unfolds at high amplitude in healthy adults given a constant iv infusion of GHRH, the ghrelin analog GHRP-2, or both agonists together (15, 16, 17). Interactions are illustrated by prominent synergy between GHRH and GHRP/ghrelin (18, 19, 20) and significant inhibition of GHRH and GHRP stimulation by infused somatostatin or octreotide (21, 22, 23, 24, 25).

Inasmuch as hypothalamic somatostatin constitutes the principal inhibitor of pulsatile GH secretion (1), a fundamental question arises of whether somatostatin withdrawal is necessary or sufficient to mediate ghrelin’s stimulation of GH secretion. In particular, if ghrelin acted exclusively by muting somatostatinergic restraint, then experimental reduction of somatostatin outflow should limit additional stimulation by ghrelin, as suggested in one study of six young adults (26). In contrast, if ghrelin additionally acted via nonsomatostatinergic mechanisms, then attenuation of somatostatin outflow should not abrogate and could potentiate ghrelin’s stimulation (14). These postulates were tested by infusion of saline or L-arginine, which putatively restricts hypothalamic somatostatin secretion (27, 28, 29).

A corollary idea is that if ghrelin mutes somatostatin’s central effects, then this secretagogue should also oppose stress-associated inhibition of GH secretion. A prototype of stress peptides is CRH, which stimulates somatostatin release in vitro (30, 31, 32). Human (but not necessarily ovine) CRH enters the central nervous system, inasmuch as iv infusion of this peptide suppresses slow-wave sleep and inhibits sleep-induced GH secretion (33). Human CRH also blocks GHRH stimulation (24). Systematically delivered ghrelin likewise exerts central-neural effects, such as stimulation of deep sleep and appetite (34, 35, 36). Accordingly, a clinical paradigm in which a ghrelin stimulus is combined with L-arginine, CRH, or both should allow testing of the proposition that ghrelin can amplify pulsatile GH secretion in both a high and a low somatostatin milieu even in the face of a strong CRH signal. If verified, this concept has important implications to the design of interventions in stress-adaptive states in which GH secretion is reduced and ACTH outflow is elevated reciprocally.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Human subjects

The study cohort comprised nine healthy estrogen-unreplaced postmenopausal women (age range, 51–68 yr; median, 64 yr) with body mass indices of 21–29 kg/m2 (24). Volunteers were studied in the absence of sex steroid supplementation to obviate confounding by estrogen and androgen, which may influence responses to somatostatin, ghrelin, and CRH (1, 37). Participants provided witnessed, voluntary, informed consent approved by the Mayo institutional review board. After giving a detailed medical history, subjects underwent a physical examination and biochemical screening as outpatients (38). Indices of hepatic, renal, hematological, metabolic, and endocrine function were normal as described in other analogous studies (39). Exclusion criteria were premenopausal status or screening concentrations of FSH less than 30 IU/liter and estradiol greater than 50 pg/ml, sex hormone replacement in the 6 wk before the study, use of antihypertensive or psychoactive drugs that could modify hypothalamo-pituitary function, acute or chronic systemic disease, transmeridian travel within the previous 5 d, weight change exceeding 2 kg in 6 wk, institutionalization, drug or alcohol abuse, hemoglobin less than 11.6 g/dl, body mass index exceeding 30 kg/m2, and unwillingness to provide written, institutional review board-approved informed consent.

Protocol

Each subject participated in eight separate 4-h iv infusion sessions in the morning while fasting, scheduled at least 48 h apart, at the Mayo General Clinical Research Center (GCRC) in a prospectively randomized, double-blind, placebo-controlled fashion. As schematized in Fig. 1Go, the paradigms included 1) continuous iv infusion of saline (20 ml/h) from 0800–1200 h; 2) bolus iv injection of a submaximally stimulatory dose of human ghrelin (0.33 µg/kg) at 0900 h; 3) bolus iv injection of a near-maximal dose of human CRH (1.0 µg/kg at 0830 h), followed immediately by continuous iv infusion of the same dose (1 µg/kg) over 30 min; 4) sequential infusions of CRH (above) and ghrelin (above); 5) constant iv infusion of a maximally effective amount of L-arginine starting at 0815 h (45 g delivered between 0815 and 0900 h); 6) consecutive infusion of L-arginine and ghrelin; 7) tandem infusion of L-arginine and CRH; and 8) combined/sequential infusion of L-arginine, CRH, and ghrelin.


Figure 1
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  		FIG. 1. Schema of eight randomly ordered, double-blind study protocols comprising sequential infusion of saline, L-arginine, and/or human CRH preceding bolus injection of saline or ghrelin. Subjects were studied in the morning at least 48 h apart after a standardized evening meal and an overnight fast (see Subjects and Methods).

 
The dose selected for ghrelin was submaximally effective (40), so as to assess physiological, rather than pharmacological, mechanisms of GH control. The amount of L-arginine infused was maximal by clinical standards of efficacy to enforce putative somatostatin withdrawal (41). The CRH infusion schedule entailed both a bolus loading dose and constant infusion, given an initial plasma half-life of CRH of 5–9 min and a delayed disappearance of 63 min (42).

GCRC schedule

Participants were admitted to the GCRC on the evening before study. To limit nutritional confounds, a vegetarian or nonvegetarian standardized meal (8 kcal/kg; 55% carbohydrate, 15% protein, and 30% fat) was served at 1800 h. Subjects then remained fasting, alcohol abstinent, and caffeine free until 1200 h the next day. A cannula was placed in a forearm vein at or before 0730 h. A second (contralateral) iv catheter was inserted to permit combined blood sampling and peptide infusion. Blood (2.0 ml/sample) was withdrawn every 10 min for 4 h (0800–1200 h) into prechilled EDTA-containing tubes, placed on ice, centrifuged within 10 min, and frozen at –70 C for later assay of GH.

Assays

Plasma concentrations of GH were determined in duplicate in batch (200 samples/subject) via a sensitive, precise, and specific two-site monoclonal chemiluminescence assay (39). To verify CRH action, ACTH and cortisol were measured by immunoradiometric assay in separate 30-min baseline (0800–0830 h) and post-CRH (0900–0930 h) plasma pools (43, 44).

Analytical procedures

Deconvolution analysis was applied to calculate pulsatile GH secretion (summed mass of bursts) over the 3-h poststimulus interval (0900–1200 h), assuming a biexponential model of GH disappearance (45).

Statistical analysis

Analysis of covariance in a 2 x 3 factorial design was used to assess the impact of ghrelin vs. placebo (two factors) on the logarithm of pulsatile GH secretion in response to specific infusions (three factors: CRH, L-arginine, or both). The response to saline was the covariate. Post hoc comparisons were made using the Tukey test at an experiment-wise P < 0.05 (46).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Figure 2Go depicts the cohort mean (±SEM) GH concentration time series monitored every 10 min for 4 h in each of the eight interventions in nine women (72 study sessions in toto). Peak GH concentrations occurred 30 ± 10 min after ghrelin injection (90 ± 10 min after the start of sampling) regardless of whether L-arginine or CRH was infused first. Ghrelin and L-arginine exerted individual stimulatory effects of 7-fold baseline and were synergistic together (34-fold baseline; Fig. 3AGo). Statistical analyses of deconvolution estimates of pulsatile GH secretion revealed the following salient contrasts: 1) L-arginine and ghrelin infusion individually increased pulsatile GH secretion from 2.7 ± 1.0 (saline) to 20 ± 4.5 (L-arginine) and 20 ± 5.0 (ghrelin) µg/liter·3 h (P < 0.01 vs. control for each; not significant for L-arginine vs. ghrelin); and 2) consecutive L-arginine/ghrelin stimulation was synergistic, 93 ± 14 µg/liter·3 h (P = 0.003 vs. L-arginine alone; P = 0.008 vs. ghrelin alone). Concurrent infusion of CRH did not alter GH responses to saline/saline (3.9 ± 1.1 µg/liter·3 h), L-arginine/saline (16 ± 2.7 µg/liter·3 h), saline/ghrelin (19 ± 3.3 µg/liter·3 h), or L-arginine/ghrelin (90 ± 13 µg/liter·3 h; Fig. 3BGo). Statistical calculations predicted a power of greater than 85% in the absence of L-arginine and of greater than 88% in the presence of L-arginine to detect more than 50% suppression by CRH of ghrelin’s stimulation of GH secretion at P < 0.05 assuming paired comparisons.


Figure 2
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  		FIG. 2. Mean (±SEM) 4-h time profiles of GH concentrations (y-axis) sampled every 10 min in nine postmenopausal women undertaking eight infusion protocols each (see Fig. 1Go). L-Arginine and/or CRH infusion began at 40 min and bolus ghrelin/saline injection was given at 70 min (x-axis). The first measurement is designated 10 min.

 

Figure 3
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  		FIG. 3. A, Synergy between ghrelin and L-arginine. Data are individual summed GH secretory-burst mass values (µg/liter·3 h) in nine women. P values are post hoc contrasts using the Tukey test for multiple comparisons. Numbers give the mean ± SEM. B, Human CRH does not inhibit L-arginine and/or ghrelin-stimulated GH secretion. Data are the mean ± SEM. Different alphabetic letters denote significantly different post hoc comparisons (all P < 0.01).

 
Human CRH infusion increased mean ACTH and cortisol concentrations by 3.8- and 1.7-fold baseline, respectively (P < 0.01 each), thus verifying stimulus efficacy.

Ghrelin (uncommonly), CRH (occasionally), and/or L-arginine (occasionally) elicited facial and/or neck flushing. L-Arginine caused a metallic taste in seven volunteers and nausea in two subjects. There was no significant (>10 mm Hg) change in mean blood pressure after peptide infusions.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Salient outcomes of the present clinical study are that, first, ghrelin stimulates pulsatile GH secretion by 7-fold over saline in postmenopausal women, and although L-arginine also does so by 7-fold, the combined agonists amplify GH release by 34-fold, thus documenting true synergy. Second, exposure to human CRH does not alter stimulation by either ghrelin or L-arginine or impair their synergy (33-fold) despite elevating ACTH and cortisol concentrations as expected. Assuming that L-arginine reduces hypothalamic somatostatin outflow (1, 27, 28, 29), then the ability of ghrelin to augment GH secretion significantly after a maximally effective L-arginine stimulus would signify that ghrelin does not act exclusively by antagonizing somatostatinergic inhibition. Conversely, assuming that CRH is able to stimulate central somatostatin outflow (30, 31, 47), the ability of ghrelin to evoke comparable GH secretion after CRH and saline infusions would indicate that ghrelin opposes somatostatinergic repression. These data allow a simple unifying postulate, in which ghrelin can drive GH secretion under normal (saline), low (L-arginine), and high (CRH) somatostatinergic restraint.

Ghrelin and synthetic (GHRP) analogs bind to the cognate type 1a receptor, which is expressed in the hypothalamus, pituitary gland, and various peripheral organs (48). Ghrelin is synthesized in the same locations. Although the relative contributions of local and systemic ghrelin to amplify pulsatile GH secretion are not yet clear, several mechanisms appear to mediate ghrelin’s actions in experimental animals (14, 49). For example, ghrelin stimulates GHRH, CRH, arginine vasopressin, and neuropeptide Y release from hypothalamic explants in vitro (50, 51), and GHRP increases the size or number of GHRH secretory bursts in hypothalamo-pituitary portal blood in sheep in vivo (50, 52). GHRP also opposes certain hypothalamic effects of octreotide and somatostatin in the rat (53). The present clinical study suggests that ghrelin augments pulsatile GH secretion in part independently of opposing central nervous system actions of somatostatin, viz. via an unknown third factor (54), given true synergy between ghrelin and L-arginine. In mechanistic terms, definite synergy denotes that two pathways have distinct regulatory features (55). Although the basis for synergy is not known, potential loci of interaction include hypothalamic neurons expressing GHRH, neuropeptide Y, somatostatin, nitric oxide, and the GH receptor (14, 29, 47, 56). The present and previous inference (54) that ghrelin modulates the action(s) or outflow of a third (unknown) non-somatostatin-ergic factor would also potentially explicate reported synergy between GHRH and a ghrelin analog administered in a putatively low-somatostatin milieu induced by successive infusion and withdrawal of somatostatin systemically (somatostatin rebound paradigm) (57, 58).

In healthy adults, infusion of CRH elicits ACTH secretion, suppresses slow-wave sleep, and blocks both sleep-induced and GHRH-stimulated GH release (17, 19, 33, 36, 42, 45, 59, 60, 61, 62, 63, 64, 65). In the rat, CRH induces neuronal release of somatostatin in vitro and in vivo (31). In contradistinction, the present analyses show that human CRH does not diminish ghrelin-stimulated GH secretion despite elevating ACTH concentrations. Given that human CRH alters sleep and blocks the stimulatory effects of GHRH and deep sleep (but not that of ghrelin) on GH release, a straightforward interpretation of the aggregate data is that ghrelin overcomes CRH-mediated somatostatin-ergic repression. This inference offers a potential mechanism to account for the ability of the ghrelin-like agonist, GHRP, to drive GH secretion in patients with evolving critical illness (66). Nonetheless, the precise role of endogenous ghrelin and the exact site of systemic CRH action are not yet clear (4, 12, 67).

A single previous clinical study of six young men and women found that ghrelin failed to augment stimulation after an infusion of L-arginine (26). Differences from the present design include age, inclusion of men, hormonal milieu, doses of ghrelin and L-arginine used, infusion of L-arginine after ghrelin administration, and a smaller cohort size. Which, if any, of these considerations accounts for the apparent distinction in outcome is not known.

By way of qualification, first, clinical data cannot exclude the possibility that unknown nonsomatostatin-dependent effects of L-arginine also contribute to its stimulation of GH secretion. Second, baseline sampling for 4 h was insufficient to test the separate idea that CRH inhibits endogenously maintained GH pulses. Third, although a lesser total dose of human CRH suppresses both sleep-induced and GHRH-stimulated GH release in young adults (33, 59), precisely analogous data are not available for older individuals.

In summary, ghrelin stimulates GH secretion in presumptively normal and low- and high-somatostatin milieus, including in the presence of a potent CRH stimulus. These data strongly distinguish the actions of ghrelin and GHRH in healthy adults.


   Acknowledgments
 
We thank Sharon Kaufman and Ashley Bryant for excellent support of manuscript preparation, the Mayo Immunochemical Laboratory for assay assistance, and the Mayo research nursing staff for conduct of the protocol.


   Footnotes
 
This work was supported in part by General Clinical Research Center Grant MO1-RR-00585 to the Mayo Clinic and Foundation from the National Center for Research Resources (Rockville, MD), and National Institute on Aging Grants R01-AG-14799 and DK-60717 from the National Institutes of Health (Bethesda, MD).

All authors have nothing to declare.

First Published Online March 14, 2006

Abbreviation: GHRP, GH-releasing peptide.

Received December 15, 2005.

Accepted March 3, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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