help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ghigo, E.
Right arrow Articles by Camanni, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ghigo, E.
Right arrow Articles by Camanni, F.
The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 8 2439-2444
Copyright © 1997 by The Endocrine Society

Clinical Studies

Adrenocorticotropin- and Cortisol-Releasing Effect of Hexarelin, a Synthetic Growth Hormone-Releasing Peptide, in Normal Subjects and Patients with Cushing’s Syndrome1

E. Ghigo, E. Arvat, J. Ramunni, A. Colao, L. Gianotti, R. Deghenghi, G. Lombardi and F. Camanni

Division of Endocrinology, Department of Internal Medicine, University of Turin, Turin; and the Division of Endocrinology, University of Naples (A.C., G.L.), Naples, Italy; and Europeptides (R.D.), Argenteuil, France

Address all correspondence and requests for reprints to: F. Camanni, M.D., Divisione di Endocrinologia, Ospedale Molinette, C. so Dogliotti 14, 10126 Torino, Italy.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
GH-releasing peptides (GHRPs) are synthetic, nonnatural molecules that strongly stimulate GH secretion, but also slightly increase PRL, ACTH, and cortisol levels in man. To investigate the mechanism underlying the ACTH- and cortisol-releasing activity of GHRPs in man, we compared the ACTH- and cortisol-releasing activity of Hexarelin (HEX; 2.0 µg/kg, iv), a hexapeptide belonging to the GHRP family, with that of human CRH (hCRH; 2.0 µg/kg, iv) in normal subjects (6 men and 6 women, 24–68 yr old) and patients with Cushing’s syndrome (2 men and 15 women, 16–68 yr old). The GH response to HEX administration was also studied. In normal subjects, HEX administration significantly increased ACTH (peak vs. baseline, mean ± SD, 32.4 ± 17.7 vs. 16.3 ± 7.2 pg/mL; P < 0.005) and cortisol levels (135.9 ± 51.0 vs. 110.0 ± 31.6 µg/L; P < 0.01). The ACTH and cortisol responses to hCRH [35.7 ± 13.2 vs. 17.1 ± 7.7 pg/mL (P < 0.01) and 162.8 ± 50.1 vs. 102.8 ± 28.1 µg/L (P < 0.01), respectively] were similar to the responses to HEX. The stimulatory effect of HEX, but not that of hCRH, on both ACTH and cortisol secretion in Cushing’s disease was clearly higher (P < 0.01) than that observed in normal subjects. In fact, in Cushing’s disease both HEX and hCRH elicited a clear increase in ACTH levels [381.1 ± 350.0 vs. 52.4 ± 25.0 (P < 0.005) and 100.0 ± 86.2 vs. 53.3 ± 29.7 pg/mL (P < 0.01), respectively], but the ACTH increase induced by HEX was about 7-fold greater (P < 0.02) than that induced by hCRH. Similarly, both HEX and hCRH elicited a significant increase in cortisol levels [366.9 ± 189.5 vs. 189.7 ± 86.3 µg/L (P < 0.005) and 209.9 ± 125.4 vs. 167.2 ± 96.3 µg/L (P < 0.02), respectively], but the cortisol increase induced by HEX was about 4-fold greater (P < 0.05) than that induced by hCRH. In patients with Cushing’s syndrome due to adrenal adenoma or ectopic ACTH, no change in ACTH and cortisol levels was observed after either HEX or hCRH administration. The peak GH response to HEX in normal subjects was clearly higher (P < 0.03) than that in hypercortisolemic patients (45.8 ± 20.5 vs. 22.4 ± 21.1 µg/L). In conclusion, the ACTH- and cortisol-releasing activity of HEX is similar to that of hCRH in normal subjects, whereas it is dramatically enhanced in patients with Cushing’s disease. This evidence indicates the importance of the ACTH-releasing activity of GHRPs and suggests that it could be at least partially independent of CRH-mediated mechanisms. As the stimulatory effect of HEX on ACTH and cortisol secretion is lost in patients with Cushing’s syndrome due to adrenal adenoma or ectopic ACTH, these findings suggest the usefulness of GHRPs to investigate the activity of the hypothalamo-pituitary-adrenal axis in pathophysiological conditions and possibly to differentiate pituitary from ectopic ACTH-dependent Cushing’s syndrome.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GH-RELEASING peptides (GHRPs) are a family of synthetic nonnatural peptides that, like other nonpeptidyl GHRP mimetics, posses a strong stimulatory effect on GH secretion (1, 2, 3, 4, 5, 6). However, the activity of both GHRPs and nonpeptidyl GHRP mimetics is not fully specific; in fact, they are also able to increase PRL, ACTH, and cortisol levels (6, 7, 8, 9, 10, 11, 12, 13, 14, 15).

GHRPs have specific receptors at the pituitary and the hypothalamic levels as well as in other central nervous system (CNS) areas (16, 17, 18). Notably, the GHRP receptor has recently been cloned and shows no similarity to any other G protein-coupled receptor (19), pointing to the existence of a natural GHRP-like ligand, as yet unknown.

The mechanisms underlying the GH-releasing activity of GHRPs include concomitant actions at both pituitary and hypothalamic levels (1, 2, 4). On the other hand, the mechanism underlying the ACTH-releasing activity of these substances is even less clear, although there are data suggesting that it takes place at the CNS level (20, 21).

The aim of our present study was to compare the ACTH- and cortisol-releasing activity of Hexarelin (HEX), a hexapeptide belonging to the GHRP family (3), with that of human CRH (hCRH), the specific hypophysiotropic stimulatory neurohormone, in normal subjects and patients with Cushing’s syndrome. The GH response to HEX was also studied in both normal and hypercortisolemic subjects.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Peptides and drugs

Vials containing 100 µg lyophilized HEX were provided by Europeptides (Argenteuil, France). Vials containing 100 µg hCRH were purchased from Ferring (Kiel, Germany).

Study design

Twelve normal subjects (6 men and 6 women, 24–68 yr old; body mass index, 22.1 ± 1.2 kg/m2) and 17 patients with Cushing’s syndrome (2 men and 15 women, 16–68 yr old; body mass index, 28.1 ± 2.5 kg/m2) were studied. Clinical details of the patients are reported in Table 1Go. Based on classical hormonal and radiological findings, patients with Cushing’s syndrome were divided into 3 groups: 1) Cushing’s disease (n = 10), 2) adrenal adenoma (n = 5), and 3) ectopic ACTH (1 bronchial carcinoid tumor and 1 microcytoma). The study was approved by our ethical committee, and informed consent was obtained from all subjects.


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical details of the patients with Cushing’s syndrome

 
All subjects received the following treatments in different sessions at least 3 days apart: 1) HEX (2.0 µg/kg, iv, at 0 min), and 2) hCRH (2 µg/kg, iv, at 0 min). In normal subjects a placebo test (saline) was also performed. The tests started between 0830–0900 h after an overnight fast and 30 min after venous cannulation, which was kept patent by a slow infusion of isotonic saline. Blood samples were taken under basal conditions (-15 and 0 min) and then every 15 min up to 120 min after drug administration. All samples from an individual subject were analyzed together for ACTH, cortisol, and GH determinations.

Plasma ACTH levels were measured in duplicate by immunoradiometric assay (Allegro HS-ACTH, Nichols Institute Diagnostic, San Juan Capistrano, CA). The sensitivity of the assay was 1.0 pg/mL. The inter- and intraassay coefficients of variation ranged from 6.9–8.9% and from 1.1–3.0%, respectively. Serum cortisol levels were measured in duplicate by RIA (CORT-CTK 125, IRMA, Sorin, Saluggia, Italy). The sensitivity of the assay was 4.0 µg/L. The inter- and intraassay coefficients of variation ranged from 6.6–7.5% and from 3.8–6.6%, respectively. Serum GH levels were measured in duplicate by immunoradiometric assay (hGH-CTK IRMA, Sorin). The sensitivity of the assay was 0.15 µg/L. The inter- and intraassay coefficients of variation were 2.9–4.5% and 2.4–4.0%, respectively. Serum insulin-like growth factor I (IGF-I) levels were measured in duplicate by RIA (Nichols Institute Diagnostics). All samples were treated with acid-ethanol to avoid interference by binding proteins. The sensitivity of the assay was 0.1 µg/L. The inter- and intraassay coefficients of variation were 10.1–15.7% and 7.6–15.5%, respectively.

The hormonal responses are expressed as the absolute peak increment above baseline levels or as areas under the curves (from 0–120 min) calculated by trapezoidal integration. Statistical analysis was carried out using a nonparametric ANOVA (Kruskal-Wallis) and then Mann-Whitney and Wilcoxon tests where appropriate. Results are expressed as the mean ± SD.


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

Mean basal ACTH and cortisol levels were 16.7 ± 7.4 pg/mL and 106.4 ± 29.0 µg/L, respectively. Mean basal GH and IGF-I levels were 1.7 ± 0.8 and 159.7 ± 61.5 µg/L, respectively.

hCRH administration induced a significant increase in both ACTH (peak vs. baseline, 35.7 ± 13.2 vs. 17.1 ± 7.7 pg/mL; P < 0.01) and cortisol (162.8 ± 50.1 vs. 102.8 ± 28.1 µg/L; P < 0.01) levels.

Similarly, HEX administration induced a significant increase in both ACTH (32.4 ± 17.7 vs. 16.3 ± 7.2 pg/mL; P < 0.005) and cortisol (135.9 ± 51.0 vs. 110.0 ± 31.6 µg/L; P < 0.01) levels.

The ACTH and cortisol responses to hCRH overlapped those to HEX when evaluated as peaks, whereas they were not significantly higher than those to HEX when evaluated as the area under the curve (1658.9 ± 548.6 vs. 1223.3 ± 515.4 pg/min·mL and 8731.0 ± 2371.7 vs. 6639.6 ± 3802.5 µg/min·L, respectively). No significant change in ACTH and cortisol levels occurred after saline administration (Fig. 1Go).



View larger version (14K):
[in this window]
[in a new window]
  		Figure 1. Mean (±SEM) ACTH (left panel) and cortisol (right panel) levels after HEX, hCRH, or saline administration in normal subjects.

 
As expected, HEX administration induced a marked increase in GH secretion (45.8 ± 20.5 vs. 1.8 ± 0.6 µg/L; P < 0.001; Fig. 5Go).



View larger version (17K):
[in this window]
[in a new window]
  		Figure 5. Mean (±SEM) GH levels after HEX administration in normal and hypercortisolemic subjects (entire group).

 
Cushing’s syndrome

Mean basal cortisol levels in patients with Cushing’s disease and Cushing’s syndrome due to adrenal adenoma were 179.1 ± 91.2 and 197.1 ± 80.4 µg/L, respectively; they were higher (P < 0.001) than those in normal subjects. Basal cortisol levels in the two patients with ectopic ACTH were 232.2 and 417.3 µg/L.

Mean basal ACTH levels in patients with Cushing’s disease and Cushing’s syndrome due to adrenal adenoma were 52.9 ± 27.1 and 6.8 ± 5.0 pg/mL, respectively; the ACTH levels in patients with Cushing’s disease were higher (P < 0.01) and those in patients with Cushing’s syndrome were lower (P < 0.01) than those in normal subjects. Basal ACTH levels in the two patients with ectopic ACTH were 102.1 and 163.2 pg/mL.

Basal GH and IGF-I levels in the entire group of patients with Cushing’s syndrome were similar to those in normal subjects (1.1 ± 0.4 and 241.5 ± 33.5 µg/L, respectively).

The ACTH- and cortisol-releasing effect of HEX, but not that of hCRH, in Cushing’s disease was clearly greater (P < 0.01) than that in normal subjects.

In Cushing’s disease, both hCRH and HEX elicited a significant increase in ACTH levels [100.0 ± 86.2 vs. 53.3 ± 29.7 pg/mL (P < 0.01) and 381.1 ± 350.0 vs. 52.4 ± 25.0 pg/mL (P < 0.005), respectively], but the ACTH increase induced by HEX was about 7-fold greater than that induced by hCRH (Fig. 2Go).



View larger version (15K):
[in this window]
[in a new window]
  		Figure 2. Mean (±SEM) ACTH levels after hCRH (left panel) or HEX (right panel) administration in patients with Cushing’s disease or adrenal adenoma.

 
Similarly, both hCRH and HEX elicited a significant increase in cortisol levels [209.9 ± 125.4 vs. 167.2 ± 96.3 µg/L (P < 0.02) and 366.9 ± 189.5 vs. 189.7 ± 86.3 µg/L (P < 0.005), respectively], but the cortisol increase induced by HEX was about 4-fold greater than that induced by hCRH (Fig. 3Go).



View larger version (14K):
[in this window]
[in a new window]
  		Figure 3. Mean (±SEM) cortisol levels after hCRH (left panel) or HEX (right panel) administration in patients with Cushing’s disease or adrenal adenoma.

 
In patients with Cushing’s syndrome due to adrenal adenoma or ectopic ACTH, no change in ACTH and cortisol levels was observed after either hCRH or HEX administration ( Figs. 2–4GoGoGo and Table 2Go).



View larger version (7K):
[in this window]
[in a new window]
  		Figure 4. Individual maximum ({Delta}) ACTH and cortisol peaks (logarithmic scale) after HEX administration in patients with Cushing’s syndrome. •, Cushing’s disease; {diamondsuit}, adrenal adenoma; {blacksquare}, ectopic ACTH.

 

View this table:
[in this window]
[in a new window]
  		Table 2. ACTH (picograms per mL) and cortisol (micrograms per L) levels after HEX or hCRH treatment in the two patients with ectopic ACTH

 
In Cushing’s syndrome (entire group), HEX induced a significant increase in GH secretion (22.4 ± 21.1 vs. 1.1 ± 1.6 µg/L; P < 0.01), but this was clearly lower (P < 0.03) than that in normal subjects (Fig. 5Go).

Side-effects

Transient facial flushing was observed after both HEX and hCRH administration in 21 and 13 subjects, respectively. Mild sleepiness was recorded in 12 subjects after HEX administration.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present results demonstrate that in normal subjects, the ACTH and cortisol responses to HEX are not significantly different from those to hCRH, the specific hypophysiotropic stimulatory neurohormone. On the other hand, in patients with Cushing’s disease, the ACTH and cortisol responses to HEX are markedly higher than those to hCRH, whereas both HEX and hCRH are unable to modify ACTH and cortisol levels in patients with Cushing’s syndrome due to adrenal adenoma or ectopic ACTH-secreting tumor.

In the presence of hypothalamo-pituitary disconnection, previous studies showed that the ACTH- and cortisol-releasing activity of GHRPs is completely abolished, whereas their GH-releasing activity is strongly reduced but still present (20, 21). Thus, although the GH-releasing activity of GHRPs is the result of concomitant actions at both the pituitary and the hypothalamic level (1, 2, 4), their stimulatory effect on ACTH and cortisol secretion seems fully dependent on CNS-mediated mechanisms. In agreement with this assumption, GHRPs have been reported to stimulate GH, but not ACTH, secretion from rat pituitary (22, 23).

In man, HEX and naloxone, a CRH-mediated stimulus (24), have a similar stimulatory effect on ACTH and cortisol secretion, whereas their coadministration has an effect less than additive (14), suggesting that GHRPs also act via a CRH-mediated mechanism (14). Interestingly, the ACTH- and cortisol-releasing activity of GHRPs is independent of mediation by serotonin and histamine (25), two neurotransmitters that play an important role in neural control of the hypothalamo-pituitary-adrenal axis (24).

The evidence that HEX and hCRH have similar ACTH- and cortisol-releasing activity in normal subjects fits well with the similar activity reported for HEX and naloxone (14) and clearly indicates that the stimulatory effect of GHRPs on the activity of the pituitary-adrenal axis cannot be considered negligible, although it is probably acute. In fact, 24-h cortisol secretion in man is not enhanced after prolonged treatment with nonpeptidyl GHRP in humans (15, 26).

The fact that the ACTH and cortisol responses to HEX as well as those to hCRH are abolished in patients bearing cortisol-secreting adrenal adenoma or ectopic ACTH-secreting tumor suggests that the ACTH-releasing effect of GHRPs is sensitive to a glucocorticoid negative feedback mechanism. On the other hand, it is noteworthy that in patients with Cushing’s disease the ACTH and cortisol responses to HEX are strikingly higher than those to hCRH, suggesting that in this condition the ACTH-releasing effect of GHRPs overrides the cortisol negative feedback and takes place via a mechanism other than endogenous CRH.

A direct effect of GHRPs on pituitary ACTH-secreting adenoma may be hypothesized. However, going against this hypothesis is evidence that GHRPs do not stimulate ACTH release from rat pituitary (22, 23). On the other hand, our findings showing that in Cushing’s disease the ACTH-releasing effect of HEX is markedly higher than that of CRH suggest that this activity of HEX is independent of CRH-mediated mechanisms. An arginine vasopressin-mediated action for GHRPs cannot be ruled out, or alternatively, one could speculate that an endogenous GHRP-like ligand plays a major role in neural control of the pituitary-adrenal axis.

The evidence that ACTH and cortisol responses to HEX in patients with Cushing’s disease are strongly different from those in patients with Cushing’s syndrome due to cortisol-secreting adrenal adenoma or to ectopic ACTH-secreting tumor suggests that HEX, more than hCRH, could have diagnostic usefulness to differentiate pituitary from ectopic ACTH-dependent Cushing’s syndrome. This point will be clarified in ongoing studies.

Concerning the GH-releasing activity of GHRPs, our present data confirm that it is markedly reduced in patients with Cushing’s syndrome (27), in whom the GH response to all known secretagogues is strongly impaired (27, 28, 29, 30). In this condition, the GH-releasing activity of GHRPs could be reduced by glucocorticoid-induced somatostatinergic hyperactivity, although there is evidence that GHRPs counteract somatostatin activity at both the pituitary and hypothalamic levels (31, 32). On the other hand, high free fatty acid levels could play a major role in reducing the GH response to GHRPs in Cushing’s syndrome as well as in obesity (33, 34). In agreement with this hypothesis, the reduced GH response to HEX in Cushing’s syndrome overlaps with that recorded in normal subjects during lipid-heparin infusion (35).

In conclusion, our results demonstrate that in normal subjects, HEX is endowed with an ACTH- and cortisol-releasing activity similar to that of hCRH, whereas in Cushing’s disease, the effect of HEX is clearly enhanced and higher than that of hCRH. On the other hand, both HEX and hCRH are unable to change ACTH and cortisol levels in patients with Cushing’s syndrome due to adrenal adenoma or ectopic ACTH. These findings point to the usefulness of GHRPs to investigate the activity of the hypothalamo-pituitary-adrenal axis in various pathophysiological conditions and to differentiate pituitary from ectopic ACTH-dependent Cushing’s syndrome.


   Acknowledgments
 
The authors thank Drs. R. Giordano, L. DiVito, B. Maccagno, and F. Broglio for their participation in the study, and Dr. A. Bertagna, Mrs. A. Barberis, and M. Taliano for their skillful technical assistance.


   Footnotes
 
1 This work was supported by grants from Ministero dell’Universitá della Ricerca Scientifica e Tecnologica, Fondazione per lo Studio delle Malattie Endocrino-Metaboliche, and Europeptides. Back

Received January 6, 1997.

Revised March 19, 1997.

Accepted April 22, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Bowers CY, Veeraragavan K, Sethumadhavan K. 1993 Atypical growth hormone releasing peptides. In: Bercu BB, Walker RF, eds. Growth hormone. II. basic and clinical aspects. New York: Springer-Verlag; 203–222.
  2. Ghigo E, Arvat E, Gianotti L, et al. 1996 Aging and GH-releasing peptides. In: Bercu B, Walker R, eds. Growth hormone secretagogues. New York: Serono Symposia; 415–431.
  3. Deghenghi R. 1993 Growth hormone releasing peptides. In: Bercu B, Walker R, eds. Growth hormone secretagogues. New York: Serono Symposia; 85–102.
  4. Korbonits M, Grossman AB. 1995 Growth hormone-releasing peptide and its analogues. Novel stimuli to growth hormone release. Trends Endocrinol Metab. 6:43–49.
  5. DeVita RJ, Wyratt MJ. 1996 Benzolactam growth hormone secretagogues. Drugs Future. 21:273–81.
  6. Gertz BJ, Barrett JS, Eisenhandler R, et al. 1993 Growth hormone response in man to L-692,429, a novel non peptide mimic of growth hormone-releasing peptide-6. J Clin Endocrinol Metab. 77:1393–1397.[Abstract]
  7. Smith RG, Cheng K, Pong SS, Hickey G, Jacks T, Butler B, et al. 1993 A non-peptidyl GH secretagogue. Science. 260:1640–1643.[Abstract/Free Full Text]
  8. Jacks T, Hickey G, Judith F, et al. 1994 Effects of acute and repeated intravenous administration of L-692,585, a novel non-peptidyl growth hormone secretagogue, on plasma growth hormone, IGF-I, ACTH, cortisol, prolactin, insulin, and thyroxine levels in beagles. J Endocrinol. 143:399–406.[Abstract/Free Full Text]
  9. Chang CH, Rickes EL, Marsilio F, et al. 1995 Activity of a novel non peptidyl GH secretagogue, L-700,653, in swine. Endocrinology. 136:1065–1071.[Abstract]
  10. Hickey GJ, Jacks T, Judith F, et al. 1994 Efficacy and specificity of L-692,429, a novel nonpeptidyl growth hormone secretagogue, in beagles. Endocrinology. 134:695–701.[Abstract/Free Full Text]
  11. Bowers CY, Reynolds GA, Durham D, Barrera CM, Pezzoli SS, Thorner MO. 1990 Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J Clin Endocrinol Metab. 70:975–982.[Abstract/Free Full Text]
  12. Imbimbo BP, Mant T, Edward M, et al. 1994 Growth hormone releasing activity of hexarelin in humans: a dose-response study. Eur J Clin Pharmacol. 46:421–425.[Medline]
  13. Ghigo E, Arvat E, Gianotti L, et al. 1994 Growth hormone-releasing activity of Hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal and oral administration in man. J Clin Endocrinol Metab. 78:693–698.[Abstract]
  14. Korbonits M, Trainer PJ, Besser GM. 1995 The effect of an opiate antagonist on the hormonal changes induced by hexarelin. Clin Endocrinol (Oxf). 43:365–371.[Medline]
  15. Copinschi G, van Onderbergen A, L’hermite-Baleriaux M, et al. 1996 Effects of 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24-hour GH profiles, insulin-like growth factor I, and adrenocortical function in normal young men. J Clin Endocrinol Metab. 81:2776–2782.[Abstract/Free Full Text]
  16. Codd EE, Shu AYL, Walker RF. 1989 Binding of a growth hormone releasing hexapeptide to specific hypothalamic and pituitary binding sites. Neuropharmacology. 28:1139–1144.[CrossRef][Medline]
  17. Veeraragavan K, Sethumadhavan K, Bowers CY. 1992 Growth hormone-releasing peptide (GHRP) binding to porcine anterior pituitary and hypothalamic membranes. Life Sci. 50:1149–1155.[CrossRef][Medline]
  18. Pong SS, Chaung LYP, Dean DC, Nargunt RP, Patchett AA, Smith RG. 1996 Identification of a new G-protein-linked receptor for growth hormone secretagogues. Mol Endocrinol. 10:57–61.[Abstract/Free Full Text]
  19. Howard AD, Feighner SD, Cully DF, et al. 1996 A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 273:974–977.[Abstract]
  20. Mallo F, Alvarez CV, Benitez L, Burguera B, Coya R, Casanueva FF. 1992 Regulation of His-dTRP-Ala-Trp-dPhe-Lys-NH2 (GHRP6)-induced GH secretion in the rat. Neuroendocrinology. 57:247–251.
  21. Hickey GJ, Drisko J, Faidley T, et al. 1996 Mediation by the central nervous system is critical to the in vivo activity of the GH secretagogue L-692,585. J Endocrinol. 148:371–380.[Abstract/Free Full Text]
  22. Bowers CY, Momany FA, Reynolds GA, Hong A. 1984 On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 114:1537–1545.
  23. Momany FA, Bowers CY, Reynolds GA, Hong A, Newlander K. 1984 Conformational energy studies and in vitro and in vivo activity data on active GH releasing peptides. Endocrinology 114:1531–1536.
  24. Orth DN. 1992 Corticotropin-releasing hormone in humans. Endocr Rev. 13:164–191.[Abstract/Free Full Text]
  25. Arvat E, Maccagno B, Gianotti L, et al. Effects of histaminergic antagonists on the GH-releasing activity of GHRH or hexarelin, a synthetic hexapeptide, in man. J Endocrinol Invest. 20:122–127.
  26. Chapman IM, Bach MA, van Cauter E, et al. 1996 Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretagogue (MK-677) in healthy elderly subjects. J Clin Endocrinol Metab. 81:4249–4257.[Abstract]
  27. Leal Cerro A, Pumar A, Garcia-Garcia E, Dieguez C, Casanueva FF. 1994 Inhibition of growth hormone release after the combined administration of GHRH and GHRP-6 in patients with Cushing’s syndrome. Clin Endocrinol (Oxf). 41:649–654.[Medline]
  28. Magiakou MA, Mastorakos G, Gomez MT, Rose SR, Chrousos GP. 1994 Suppressed spontaneous and stimulated growth hormone secretion in Cushing’s disease before and after surgical cure. J Clin Endocrinol Metab. 78:131–137.[Abstract]
  29. Giustina A, Bossoni S, Bodini C, et al. 1991 Pyridostigmine enhances even if it does not normalize the growth hormone responses to growth hormone-releasing hormone in patients with Cushing’s disease. Horm Res. 35:99–103.[Medline]
  30. Procopio M, Invitti C, Maccario M, et al. 1995 Effect of arginine and pyridostigmine on the GHRH-induced GH rise in obesity and Cushing’s syndrome. Int J Obesity. 19:108–112.
  31. Goth MI, Lyons CE, Canny BY, Thorner MO. 1992 Pituitary adenilate cyclase activating polypeptide, growth hormone (GH)-releasing peptide and GH-releasing hormone stimulate GH release through distinct pituitary receptors. Endocrinology. 130:939–944.[Abstract/Free Full Text]
  32. Fairhall KM, Mynett A, Robinson ICAF. 1995 Central effects of growth hormone-releasing hexapeptide (GHRP-6) on growth hormone release are inhibited by central somatostatin action. J Endocrinol. 144:555–560.[Abstract/Free Full Text]
  33. Dieguez C, Mallo F, Senaris R, et al. 1996 Role of glucocorticoids in the neuroregulation of growth hormone secretion. J Pediatr Endocrinol Metab. 9:255–260.
  34. Cordido F, Peino R, Penalva A, Alvarez CV, Casanueva FF, Dieguez C. 1996 Impaired growth hormone secretion in obese subjects is partially reversed by acipimox-mediated plasma free fatty acid depression. J Clin Endocrinol Metab. 81:914–918.[Abstract]
  35. Maccario M, Arvat E, Procopio M, et al. 1995 Metabolic modulation of the growth hormone-releasing activity of hexarelin in man. Metabolism. 44:134–138.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Eur J EndocrinolHome page
M. C. Machado, S. Valeria de Sa, M. L. Correa-Giannella, R. R. Giorgi, M. A. A. Pereira, V. A. S Cescato, D. Giannella-Neto, and L. R. Salgado
Association between tumoral GH-releasing peptide receptor type 1a mRNA expression and in vivo response to GH-releasing peptide-6 in ACTH-dependent Cushing's syndrome patients
Eur. J. Endocrinol., May 1, 2008; 158(5): 605 - 613.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
L. R. Salgado, M. C. B V. Fragoso, M. Knoepfelmacher, M. C. Machado, S. Domenice, M. A. A. Pereira, and B. B. de Mendonca
Ectopic ACTH syndrome: our experience with 25 cases.
Eur. J. Endocrinol., November 1, 2006; 155(5): 725 - 733.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. J. Martinez-Fuentes, J. Moreno-Fernandez, R. Vazquez-Martinez, M. Duran-Prado, A. de la Riva, M. Tena-Sempere, C. Dieguez, L. Jimenez-Reina, S. M. Webb, A. Pumar, et al.
Ghrelin Is Produced by and Directly Activates Corticotrope Cells from Adrenocorticotropin-Secreting Adenomas
J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2225 - 2231.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
R. Giordano, A. Picu, U. Pagotto, R. De Iasio, L. Bonelli, F. Prodam, F. Broglio, L. Marafetti, R. Pasquali, M. Maccario, et al.
The negative association between total ghrelin levels, body mass and insulin secretion is lost in hypercortisolemic patients with Cushing's disease
Eur. J. Endocrinol., October 1, 2005; 153(4): 535 - 543.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
A. J. van der Lely, M. Tschop, M. L. Heiman, and E. Ghigo
Biological, Physiological, Pathophysiological, and Pharmacological Aspects of Ghrelin
Endocr. Rev., June 1, 2004; 25(3): 426 - 457.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. Y. Bowers, R. Granda, S. Mohan, J. Kuipers, D. Baylink, and J. D. Veldhuis
Sustained Elevation of Pulsatile Growth Hormone (GH) Secretion and Insulin-Like Growth Factor I (IGF-I), IGF-Binding Protein-3 (IGFBP-3), and IGFBP-5 Concentrations during 30-Day Continuous Subcutaneous Infusion of GH-Releasing Peptide-2 in Older Men and Women
J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2290 - 2300.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
G. Arnaldi, T. Mancini, B. Kola, G. Appolloni, S. Freddi, C. Concettoni, I. Bearzi, A. Masini, M. Boscaro, and F. Mantero
Cyclical Cushing's Syndrome in a Patient with a Bronchial Neuroendocrine Tumor (Typical Carcinoid) Expressing Ghrelin and Growth Hormone Secretagogue Receptors
J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5834 - 5840.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
P. L. M. Dahia and A. B. Grossman
The Molecular Pathogenesis of Corticotroph Tumors
Endocr. Rev., April 1, 1999; 20(2): 136 - 155.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
H. G. Maheshwari, A. Rahim, S. M. Shalet, and G. Baumann
Selective Lack of Growth Hormone (GH) Response to the GH-Releasing Peptide Hexarelin in Patients with GH-Releasing Hormone Receptor Deficiency
J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 956 - 959.
[Abstract] [Full Text]

Home page
 Endocr. Rev.Home page
A. Giustina and J. D. Veldhuis
Pathophysiology of the Neuroregulation of Growth Hormone Secretion in Experimental Animals and the Human
Endocr. Rev., December 1, 1998; 19(6): 717 - 797.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
E. Arvat, R. Giordano, J. Ramunni, G. Arnaldi, A. Colao, R. Deghenghi, G. Lombardi, F. Mantero, F. Camanni, and E. Ghigo
Adrenocorticotropin and Cortisol Hyperresponsiveness to Hexarelin in Patients with Cushing's Disease Bearing a Pituitary Microadenoma, But Not in Those with Macroadenoma
J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4207 - 4211.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. M. Skinner, R. Nass, B. Lopes, E. R. Laws, and M. O. Thorner
Growth Hormone Secretagogue Receptor Expression in Human Pituitary Tumors
J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4314 - 4320.
[Abstract] [Full Text]

Home page
 Endocr. Rev.Home page
J. Newell-Price, P. Trainer, M. Besser, and A. Grossman
The Diagnosis and Differential Diagnosis of Cushing's Syndrome and Pseudo-Cushing's States
Endocr. Rev., October 1, 1998; 19(5): 647 - 672.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. Korbonits, R. A. Jacobs, S. J. B. Aylwin, J. M. Burrin, P. L. M. Dahia, J. P. Monson, J. Honegger, R. Fahlbush, P. J. Trainer, S. L. Chew, et al.
Expression of the Growth Hormone Secretagogue Receptor in Pituitary Adenomas and Other Neuroendocrine Tumors
J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3624 - 3630.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
D. F. Carmignac, P. A. Bennett, and I. C. A. F. Robinson
Effects of Growth Hormone Secretagogues on Prolactin Release in Anesthetized Dwarf (dw/dw) Rats
Endocrinology, August 1, 1998; 139(8): 3590 - 3596.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ghigo, E.
Right arrow Articles by Camanni, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ghigo, E.
Right arrow Articles by Camanni, F.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals