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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.


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  		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).



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  		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).



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  		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).



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  		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).



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  		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).



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  		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.

 

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  		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
 

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