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The Growth Hormone Secretagogue Hexarelin Stimulates the Hypothalamo-Pituitary-Adrenal Axis via Arginine Vasopressin

Departments of Endocrinology and Chemical Endocrinology (L.A.P.), St. Bartholomew’s Hospital, London, United Kingdom EC1A 7BE

Address all correspondence and requests for reprints to: Dr. Márta Korbonits, Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London, United Kingdom EC1A 7BE. E-mail: m.korbonits{at}mds.qmw.ac.uk

	Abstract

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GH secretagogues (GHSs) act via specific receptors in the hypothalamus and the pituitary gland to release GH. GHSs also stimulate the hypothalamo-pituitary-adrenal (HPA) axis via central mechanisms probably involving CRH or arginine vasopressin (AVP). We studied the effects of hexarelin, CRH, and desmopressin, an AVP analog, on the stimulation of the HPA axis in 15 healthy young male volunteers. Circulating ACTH, cortisol, GH and PRL concentrations were measured for 2 h after the injection of hexarelin, CRH, or desmopressin alone and the combination of hexarelin plus CRH or hexarelin plus desmopressin. Symptoms during the tests were assessed by visual analog scales. Hexarelin significantly increased ACTH and cortisol release (area under the curve, 3,444 ± 696 ng/L·125 min and 45,844 ± 2,925 nmol/L·125 min, respectively), and this effect was augmented by the addition of CRH in a dose that on its own produces maximal stimulation (6,580 ± 1,572 ng/mL·125 min and 63,170 ± 2,616 nmol/L·125 min; P = 0.01 and 0.001, respectively), but was not influenced by the addition of desmopressin (3,540 ± 852 ng/mL·125 min and 35,319 ± 3,252 nmol/L·125 min; not significant). CRH on its own caused similar or slightly higher ACTH and cortisol release than hexarelin alone. Desmopressin given alone elicited a rapid rise in circulating ACTH and cortisol, but its effects were less than those of any other treatment and were not augmented by hexarelin. Hexarelin also caused significant GH and PRL release, but these effects were not influenced by the coadministration of CRH or desmopressin. Visual analog scales showed an acute small increment in appetite with hexarelin. Our data suggest that the effect of GHSs on the HPA axis involve at least in part the stimulation of AVP release.

In summary, we have shown that in healthy male volunteers, the effect of hexarelin on the HPA axis does not involve CRH, but may occur through the stimulation of AVP release.

	Introduction

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THE GH secretagogues (GHSs) comprise a group of synthetic peptide and nonpeptide analogs that can stimulate GH release through receptors separate from those related to GHRH (1, 2, 3, 4, 5, 6, 7, 8, 9). The identification of a specific receptor in pituitary, hypothalamic, and other areas of the brain suggests that an endogenous ligand exists, although it has yet to be identified (10). The actions of these GHSs are not specific to GH, as they also stimulate PRL, ACTH, and cortisol release in animals and humans (6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19). The site of action for the release of GH is at both the hypothalamic and pituitary levels, but the former is of greater significance in vivo (18). GHSs act as functional antagonists of somatostatin at both the hypothalamus (20) and the pituitary (21). The presence of GHRH activity has been shown to be necessary for the hypothalamic effect of GHSs (22, 23, 24, 25, 26).

The mechanism of action of GHSs on the hypothalamo-pituitary-adrenal (HPA) axis has not been fully clarified. In vitro pituitary tissue does not show ACTH release after the addition of GHRP-6 (27, 28), and it has been postulated that one or both of the two major hypothalamic stimulators of ACTH, CRH or arginine vasopressin (AVP), could be involved. This study was designed to clarify the involvement of CRH and AVP in the mechanism of GHS action in humans. Combined administration of hexarelin, a methyl derivative of GHRP-6, and either CRH or a vasopressin agonist was performed to reveal whether GHSs stimulate the HPA axis through endogenous CRH or vasopressin secretion, or both, or through other independent mechanisms. We used hexarelin at a dose that has been shown to stimulate both GH and the HPA axis (9). Human sequence CRH was used at a dose that is at the top of the dose-response curve (29). AVP exerts its effects via two major classes of G protein-coupled transmembrane receptors, V₁ and V₂. The V₁ receptor is subdivided into V_1a and V_1b (also referred to as the V₃ receptor) on the basis of properties of binding to various agonists. The V_1b receptor is found in large concentrations on pituitary corticotrophs (30). Desmopressin, a long acting synthetic AVP analog, acts principally on the V₂ receptor, but also stimulates V₁ receptors, albeit with lower potency (31). In our study we chose to use desmopressin in preference to AVP, as the latter’s side-effects (vasoconstriction, abdominal cramps, angina, hypertension, and urge to defecate) can induce a potent confusing stress response.

	Subjects and Methods

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Fifteen healthy adult male subjects [aged 20–35 yr; body mass index (body weight/height²), 21.9–25.5 kg/m²] were investigated on five occasions in a double blind, random order with a minimum of 7 days between the studies; the limbs were placebo plus hexarelin, CRH plus hexarelin, desmopressin plus hexarelin, placebo plus CRH, and placebo plus desmopressin. The subjects fasted from 2200 h the evening before until the completion of the study, but water was freely allowed. At 0830 h (-60 min), an iv forearm cannula (Y-Can 19g, Wallace, Colchester, UK) was inserted. At 0925 h (-5 min), an iv bolus of 100 µg CRH, 10 µg desmopressin, or saline as placebo was administered, followed 5 min later (0 min) by an iv bolus of 2 µg/kg hexarelin or placebo. Blood was sampled for serum GH, PRL, and cortisol at -60, -30, -15, -5, 0, 5, 10, and 15 min and then every 15 min until 120 min. Plasma ACTH was also sampled in six subjects. Samples were frozen and stored at -20 C until assay. Visual analog scales were completed by the subjects for the assessment of nausea, arousal, flushing, satiety, and well-being. Subjects were asked to mark a 100-mm line at 30 min before administration of hexarelin and at 15, 60, and 105 min postinjection. Subjects remained recumbent throughout the study. Each subject gave informed consent to participation, which was approved by the research ethics committee of the East London and City Health Authority.

Drugs

Human CRH and desmopressin (DDAVP) were provided by Ferring Pharmaceuticals Ltd. (Malmo, Sweden), and hexarelin was supplied by Pharmacia & Upjohn, Inc. (Stockholm, Sweden).

Assays

GH was measured by a chemiluminescent enzyme immunoassay using murine monoclonal anti-GH antibody coated on a bead (Immulite, Diagnostic Products, Los Angeles, CA). Cortisol and PRL samples were analyzed using the Technicon Immuno 1 (Bayer, Germany) system. This system uses a rabbit polyclonal anticortisol and a mouse monoclonal anti-PRL conjugate. ACTH was analyzed with the Nichols Institute Diagnostics immunoradiometric assay kit (San Juan Capistrano, CA). The intraassay coefficients of variation (CVs) for GH were 4.2% and 2.6%, and the interassay CVs were 4.4% and 2% for low and high controls, respectively. The intraassay CVs for cortisol were 5.2%, 3.1%, and 3.4%, and the interassay CVs were 6.02%, 4.82%, and 4.42% for low, middle, and high controls, respectively. The intraassay CVs for PRL were 2%, 1.7%, and 1.6%, and the interassay CVs were 1.6%, 1.8%, and 1.6% for low, middle, and high controls, respectively. The intraassay CVs for ACTH were 3% and 3.2%, and the interassay CVs were 7.8% and 6.8% for low and high controls, respectively. The minimal reportable concentrations were 0.5 mU/L for GH, 50 nmol/L for cortisol, 2 mU/L for PRL, and 1 ng/L for ACTH. The conversion factor for milliunits per L GH to micrograms per L is 0.39, for nanomoles per L cortisol to micrograms per dL is 0.036, and for milliunits per L PRL to nanograms per mL is 0.05. Samples were assayed singly. All samples taken from an individual subject were analyzed in the same assay.

Statistics

Data are expressed as the mean ± SEM. Two-way ANOVA was used followed by Scheffe’s post-hoc analysis for multiple comparisons. The area under the curve (AUC_{-5 to 120 min}) was calculated by the trapezoidal method. Total and incremental AUC (above baseline) were calculated. Two-tailed tests were applied, and significant differences were accepted with a probability of 5% or less.

	Results

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Cortisol (Fig. 1)

CRH combined with hexarelin resulted in significantly greater serum cortisol levels than any of the other treatments (AUC ANOVA, P < 0.001; individual comparisons, P = 0.001). The effect of hexarelin on its own was similar to that of desmopressin plus hexarelin, greater than that of desmopressin alone (P = 0.01), and less than that of CRH alone (P = 0.039). Similar results were obtained analyzing the peak cortisol responses, except that the peak cortisol levels after CRH and hexarelin given alone were not different from each other (P = 0.28). Frequent sampling during the first 20 min enabled us to demonstrate a significant cortisol rise in normal volunteers after iv desmopressin injection (peak vs. basal cortisol levels, by paired t test, P = 0.01). The incremental AUC (area above baseline) calculations (ANOVA, P < 0.001, followed by multiple comparison) showed that the effect of CRH and hexarelin together is greater than the effect of any of the other treatments, except for CRH on its own, for which no statistical difference was found.

View larger version (30K): [in this window] [in a new window]   Figure 1. The effects of placebo plus hexarelin, CRH plus hexarelin, desmopressin plus hexarelin, CRH plus placebo, and desmopressin plus placebo on serum cortisol levels (mean ± [scap]sem) in 15 normal subjects. The conversion factor for nanomoles per L cortisol to micrograms per dL is 0.036. Hexarelin or placebo was given at 0 min, and the other treatments were given at -5 min.

ACTH (Fig. 2)

CRH combined with hexarelin resulted in significantly greater ACTH release than any of the other treatments (AUC ANOVA, P = 0.014; individual comparisons, all P < 0.05). The effect of placebo plus hexarelin, desmopressin plus hexarelin, CRH plus placebo, and desmopressin plus placebo were not significantly different from each other. Calculations for the peak ACTH values showed similar trends, but did not quite reach formal statistical significance (peak ANOVA, P = 0.057). The incremental AUC (area above baseline) calculations (ANOVA, P = 0.01, followed by multiple comparison) showed that the effect of CRH and hexarelin together is greater than that of CRH or hexarelin alone.

View larger version (29K): [in this window] [in a new window]   Figure 2. The effects of placebo plus hexarelin, CRH plus hexarelin, desmopressin plus hexarelin, CRH plus placebo, and desmopressin plus placebo on plasma ACTH levels (mean ± SEM) in 6 of the 15 normal subjects. Hexarelin or placebo was given at 0 min, and the other treatments were given at -5 min.

GH (Fig. 3)

Hexarelin alone or in combination caused a significant release of GH (AUC ANOVA, P < 0.0001), whereas CRH and desmopressin on their own showed no effect. The administration of CRH or desmopressin 5 min before hexarelin did not cause a significant change in GH release compared to the effect of hexarelin alone. Similar results were obtained when the data for the peak GH responses were analyzed.

View larger version (26K): [in this window] [in a new window]   Figure 3. The effects of placebo plus hexarelin, CRH plus hexarelin, desmopressin plus hexarelin, CRH plus placebo, and desmopressin plus placebo on serum GH levels (mean ± SEM) in 15 normal subjects. The conversion factor for milliunits per L GH to micrograms per L is 0.39. Hexarelin or placebo was given at 0 min, and the other treatments were given at -5 min.

PRL (Fig. 4)

Hexarelin stimulated PRL release; this was independent of either CRH or desmopressin administration (AUC and peak ANOVA, both P < 0.001). CRH and desmopressin caused a small, but significant, PRL release [CRH plus placebo baseline at -5 min, 139.7 ± 15; peak, 176.67 ± 21.45 mU/L (P < 0.001); desmopressin plus placebo baseline at -5 min, 132.4 ± 13.3 mU/L; peak, 150 ± 16 mU/L (P = 0.031)].

View larger version (32K): [in this window] [in a new window]   Figure 4. The effects of placebo plus hexarelin, CRH plus hexarelin, desmopressin plus hexarelin, CRH plus placebo, and desmopressin plus placebo on serum PRL levels (mean ± SEM) in 15 normal subjects. The conversion factor for milliunits per L PRL to nanograms per mL is 0.05. Hexarelin or placebo was given at 0 min, and the other treatments were given at -5 min.

Analysis of the visual analog scales revealed that each treatment caused significant flushing at 15 min compared to that at baseline (-30 min). On the 3 hexarelin treatment days, hunger was significantly increased at 15 min compared to that at baseline (P = 0.035, P = 0.0004, and P = 0.03 for placebo plus hexarelin, CRH plus hexarelin, and desmopressin plus hexarelin, respectively), whereas on the CRH and desmopressin days there was no significant change. Nausea was significantly increased at 15 min on the 2 combination days (CRH plus hexarelin, P = 0.042; desmopressin plus hexarelin, P = 0.034). The well-being score showed a small fall on the 2 treatment days when CRH was administered (CRH plus hexarelin, P = 0.44; CRH plus placebo, P = 0.037).

	Discussion

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As the addition of hexarelin to a maximally effective dose of CRH increased the activity of the HPA axis, our results suggest that the effect of hexarelin on the HPA axis may not involve concomitant CRH stimulation. Furthermore, as the effect of hexarelin did not augment the stimulating effect of exogenous desmopressin, stimulation of the HPA axis may occur at least in part via the release of hypothalamic AVP. Dose-response studies have shown that a 100-µg dose of CRH is the maximal dose in terms of ACTH and cortisol release (29, 32). Nevertheless, the addition of hexarelin augmented the ACTH/cortisol response, suggesting the independence of these two mechanisms. Calculations using incremental AUC showed significant difference between CRH alone and CRH plus hexarelin for ACTH, but not for cortisol. We suggest that changes in ACTH levels are more sensitive to hexarelin administration than are those in cortisol, and similar findings were reported by Arvat et al. previously (33). The dose of desmopressin used was associated with a small significant stimulation of the HPA axis; although maximal activation of the V_1b receptors probably did not occur, there was no augmentation by hexarelin (34, 35). The ACTH- and cortisol-releasing effect of hexarelin seems to be maximal at the 2 µg/kg dose (36). This view, that the effect of hexarelin on ACTH/cortisol release involves enhanced AVP secretion, is supported by previous findings that naloxone, an opiate antagonist, which stimulates the HPA axis via AVP release, also has no additive effect with hexarelin, suggesting that the mechanisms responsible for cortisol and ACTH release after hexarelin and naloxone administration may at least be similar (9, 37).

The mechanism involved in hexarelin stimulation of the HPA axis is mediated through the central hypothalamic control of ACTH release rather than through a direct effect on the pituitary or the adrenal cortex, as after GHS treatment no ACTH release has been observed from pituitary cells in vitro (27, 28), and no change in cortisol levels was observed after hypophysectomy (38) or after pituitary stalk transection in animals (14) or humans (39). CRH and AVP are the two main candidates as the targets of the effects of GHSs. The CRH and AVP neurons involved in the activation of the HPA axis are located mainly in the parvocellular region of the paraventricular nucleus (40). GHS receptors are also present in this area (41, 42), and it is possible that they activate AVP neurons directly. An alternative explanation would be the activation of AVP neurons indirectly through neuropeptide Y secretion (NPY). NPY neurons are located in the arcuate nucleus, a region with a high density of GHS receptors that has been shown to be activated by GH-releasing peptide-6 (43). The interconnection of NPY neurons in the arcuate nucleus with CRH and AVP neurons in the paraventricular nucleus is well characterized; NPY neurons innervate CRH neurons in the paraventricular nucleus, and they stimulate CRH and AVP release from hypothalamic explants (44, 45, 46).

Studies on the involvement of CRH and AVP in the effects of GHSs have produced discrepant results. Our previous in vitro studies in rat hypothalamic explants showed no CRH release after the administration of GHSs, whereas a potent effect in releasing AVP was shown, consistent with the findings of the present study (46, 47). In unanesthetized rats, GHRP-6 administration in combination with CRH did not increase ACTH levels beyond the response to CRH alone, whereas the combination of GHRP-6 and AVP markedly increased ACTH levels compared with the effects of AVP alone, suggesting the involvement of CRH stimulation in the effect of GHRP-6. However, data from the same laboratory showed that iv administration of GHRP-6 in conscious sheep increased both CRH and AVP levels in hypophyseal portal blood (Thomas, G. B., C. Oliver, and I. C. A. F. Robinson, unpublished results), suggesting that both hormones are involved in the effect in this species. Arvat et al. studied seven young women and found no synergistic effect of hexarelin and CRH or of hexarelin and AVP on ACTH and cortisol release, whereas CRH and AVP showed the previously described synergistic phenomenon (31, 33). The effect of CRH plus hexarelin was less than additive and compared to CRH alone was significantly different for ACTH AUC, but not for cortisol. The slight differences between their findings and ours may be explained by their small sample size and the inclusion of female subjects, but could also reflect their use of AVP rather than desmopressin.

Although previously some animal and human studies have suggested a direct effect of CRH to inhibit GH release (19, 48, 49, 50, 51, 52), the results of this study, consistent with those of some others (53, 54), showed no inhibitory effect of CRH on hexarelin-induced GH release. PRL levels were strongly stimulated by hexarelin, with no augmentation by either CRH or desmopressin. There was a small increase in PRL levels after CRH and desmopressin treatment. Similar results were found in some animal studies (40, 55), but not in others (56).

In summary, we have shown that in healthy male volunteers the addition of hexarelin to CRH at a dose that, on its own, is maximally effective augments the ACTH and cortisol responses. This effect is not seen when desmopressin is given with hexarelin. This suggests that hexarelin stimulation of the HPA axis is independent of CRH and is likely to be via increased secretion of endogenous vasopressin. The stimulation of PRL and GH secretion after hexarelin was not altered by CRH or desmopressin.

	Acknowledgments

 
We are most grateful for the excellent assistance of Kathy Maher, Emma Thomson, Clare Gagen, and Louise Conrich.

Received December 17, 1998.

Revised March 12, 1999.

Accepted March 22, 1999.

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