Comparison of the effects of growth hormone-releasing hormone and hexarelin, a novel growth hormone-releasing peptide-6 analog, on growth hormone secretion in humans with or without glucocorticoid excess

Giustina, Andrea; Bussi, Anna Rosa; Deghenghi, Romano; Imbimbo, Bruno P.; Licini, Massimo; Poiesi, Claudio; Wehrenberg, W B

doi:10.1677/joe.0.1460227

Cited by 36 publications

(17 citation statements)

References 12 publications

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“…Concerning GH release, our data, showing that pretreatment with 1 mg DEXA on the previous night does not modify the somatotrope responsiveness to HEX, do not disagree with previous data showing that the GH response to GHRPs is only blunted after exposure to exogenous corticosteroids [23, 24, 30], while it is more clearly inhibited in patients with Cushing’s syndrome [8, 44]. Moreover, glucocorticoids are even able to stimulate GH secretion in different experimental conditions, and it has been clearly demonstrated that their effects on somatotrope secretion depend on dose, time and length of exposure [30, 31].…”

Section: Discussioncontrasting

confidence: 47%

“…In fact, the GH-releasing effect of GHRPs is strongly reduced, though not lost, in presence of hypothalamo-pituitary disconnection [15, 19, 20]. On the other hand, it has also been shown that the stimulatory effect of GHRPs on GH secretion is, at least partially, refractory to inhibitory influences including neurotransmitters, glucocorticoids, glucose, lipids and even exogenous somatostatin and rhGH [21, 22, 23, 24, 25, 26]. …”

Section: Introductionmentioning

confidence: 99%

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Effects of Dexamethasone and Alprazolam, a Benzodiazepine, on the Stimulatory Effect of Hexarelin, a Synthetic GHRP, on ACTH, Cortisol and GH Secretion in Humans

et al. 1998

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Hexarelin (HEX) is a synthetic GHRP which acts on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in humans. Like other GHRPs, HEX possesses also acute ACTH and cortisol-releasing activity similar to that of hCRH. The mechanisms underlying the stimulatory effect of GHRPs on hypothalamo-pituitary-adrenal (HPA) axis are still unclear, although a CNS-mediated action has been demonstrated. In 6 normal healthy young women (26–34 years) we studied the effects on ACTH and cortisol secretion of HEX (2.0 µg/kg i.v. at 0 min) alone and preceded by dexamethasone (DEXA, 1 mg p.o. at 23.00 h on the previous night) or alprazolam (ALP, 0.02 mg/kg p.o. at –90 min), a benzodiazepine which binds to GABA receptors and possesses CRH-mediated inhibitory activity on HPA axis. ACTH and cortisol secretion after saline administration as well as the GH response to HEX alone and preceded by DEXA or ALP were also studied. HEX administration elicited an increase in ACTH (peak vs. baseline, mean ± SEM: 28.0 ± 6.7 vs. 11.7 ± 2.2 pg/ml, p < 0.05) and cortisol secretion (162.6 ± 15.0 vs. 137.7 ± 12.6 µg/l, p < 0.05). DEXA pretreatment strongly inhibited basal ACTH (3.2 ± 0.7 pg/ml, p < 0.01) and cortisol levels (11.3 ± 2.5 µg/l, p < 0.001) and abolished the ACTH and cortisol responses to HEX (3.6 ± 0.9 pg/ml, p < 0.01 and 10.7 ± 2.0 µg/l, p < 0.001), respectively. On the other hand, ALP pretreatment did not significantly modify basal ACTH (7.9 ± 2.0 pg/ml) and cortisol levels (127.6 ± 14.5 µg/l) but abolished the HEX-induced ACTH and cortisol secretions (8.6 ± 2.4 pg/ml, p < 0.05 and 111.0 ± 6.0 µg/l, p < 0.05), respectively. ACTH and cortisol levels after HEX when preceded by ALP overlapped with those recorded during saline. HEX induced a clear GH response (peak at 15 min vs. baseline: 65.5 ± 20.5 vs. 2.2 ± 0.7 µg/l, p < 0.03) which was blunted by ALP (peak at 15 min: 21.5 ± 5.5 µg/l, p < 0.05) while it was not modified by DEXA pretreatment (78.7 ± 7.6 µg/l). In conclusion, our present data demonstrate that the ACTH- and cortisol-releasing effect of HEX is abolished by either dexamethasone or alprazolam, a benzodiazepine, which is even able to blunt the GH-releasing activity of the hexapeptide. These findings suggest that, in physiological conditions, the stimulatory effect of GHRPs on HPA axis is sensitive to the negative glucocorticoid feedback and could be mediated by GABAergic mechanisms; the latter seem also involved in the GH-releasing activity of GHRPs.

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Section: Discussioncontrasting

confidence: 47%

Section: Introductionmentioning

confidence: 99%

Effects of Dexamethasone and Alprazolam, a Benzodiazepine, on the Stimulatory Effect of Hexarelin, a Synthetic GHRP, on ACTH, Cortisol and GH Secretion in Humans

et al. 1998

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“…We found that the GH response to HEX in hypocortisolemic patients with AD is preserved and similar to that in NS even after metyrapone or RU-486 pretreatment. There is evidence that the GH response to GHS is not affected by acute dexamethasone pretreatment [30]while it is only blunted by prolonged and chronic corticosteroid exposure [44, 45]. These findings agree with the assumption that the GH-releasing activity of GHS is generally refractory to inhibitory and stimulatory inputs [2, 23], which are very active in inhibiting and enhancing, respectively, the GH response to GHRH [46].…”

Section: Discussionsupporting

confidence: 59%

Corticotropin-Releasing Effect of Hexarelin, a Peptidyl GH Secretagogue, in Normal Subjects Pretreated with Metyrapone or RU-486, a Glucocorticoid Receptor Antagonist, and in Patients with Addison’s Disease

et al. 1999

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GH secretagogues (GHS) are peptidyl and nonpeptidyl molecules which possess strong GH-releasing activity but also stimulatory effect on hypothalamo-pituitary-adrenal axis. The ACTH and cortisol responses to Hexarelin (HEX), a peptidyl GHS, are abolished by low-dose dexamethasone pretreatment in normal subjects but are exaggerated and higher than those after hCRH in patients with pituitary ACTH-dependent Cushing’s disease, in spite of their hypercortisolism. Based on the foregoing, we studied the ACTH, cortisol and GH responses to HEX (2.0 µg/kg i.v. at 0 min) alone and after metyrapone (2 g p.o. at 23:00 h the night before) or RU-486 (400 mg p.o. at 02:00 h), a glucocorticoid receptor antagonist, in 6 normal women (NS, age 26–34 years). The endocrine responses (mean ± SEM) to HEX alone were also studied in 8 patients with Addison’s disease (AD, 6 males, 2 females, age 30–77 years; last hydrocortisone administration the day before testing). In NS, HEX stimulated basal ACTH (peak, mean ± SEM: 26.0 ± 7.8 vs. 10.7 ± 2.0 pg/ml, p < 0.05), cortisol (163.2 ± 18.3 vs. 137.4 ± 15.4 µg/l, p < 0.05) and GH (72.6 ± 23.5 vs. 3.7 ± 1.3 µg/l, p < 0.01) levels. Metyrapone markedly increased basal ACTH (294.4 ± 61.6 pg/ml, p < 0.05), reduced basal cortisol (19.6 ± 7.2 µg/l, p < 0.05), while it did not modify GH levels. After metyrapone pretreatment the ACTH response to HEX was clearly increased (ΔAUC: 2,857.4 ± 901.9 vs. 367.3 ± 274.0 pg/ml/h, p < 0.05), while the GH response was not modified. HEX did not stimulate the low cortisol levels after metyrapone pretreatment. RU-486 significantly increased basal ACTH (76.6 ± 12.5 pg/ml, p < 0.05) and cortisol (312.7 ± 22.2 µg/l, p < 0.05), while it did not modify basal GH levels. RU-486 pretreatment did not modify the ACTH, cortisol and GH responses to HEX. In AD, HEX elicited a marked ACTH response (6,619.4 ± 3,365.8 pg/ml/h; p < 0.01), which was clearly higher (p < 0.01) than that in NS after HEX alone but not significantly different from that after HEX+MET. The GH response to HEX in AD (1,325.6 ± 284.1 µg/l/h) was similar to that in NS (1,519.7 ± 483.8 µg/l/h). In conclusion, our present data demonstrate that the ACTH-releasing activity of HEX is increased in primary hypoadrenalism as well as in normal subjects after metyrapone but not after RU-486 pretreatment. These findings indicate that in normal subjects as well as in hypocortisolemic patients the ACTH-releasing activity of GHS is enhanced by the lack of negative glucocorticoid feedback.

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“…It is a classic observation that chronic hypercortisolism inhibits somatic growth as well as GH secretion [25, 26]. In Cushing’s syndrome, GH responses appear blunted towards all stimuli tested so far [27, 28]; ghrelin can now be added to this list.…”

Section: Discussionmentioning

confidence: 99%

Ghrelin Is No Longer Able to Stimulate Growth Hormone Secretion in Patients with Cushing’s Syndrome but Instead Induces Exaggerated Corticotropin and Cortisol Responses

et al. 2002

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Growth and growth hormone (GH) secretion are blunted or severely impeded in chronic hypercortisolism and in patients with Cushing’s syndrome. A mechanistic explanation for the effect however has yet to be provided. On the other hand, several properties of ghrelin, a new peptide recently identified as the endogenous ligand of the GH secretagogue receptor, are still largely unknown. The two aims of this study were to observe whether ghrelin-mediated GH secretion was altered, and to characterize the corticotropin (ACTH) and cortisol response to this new stimulus in patients with Cushing’s disease. Ten patients with active Cushing’s disease (6 harboring microadenomas and 4 with macroadenomas) and 10 sex- and age-matched controls were studied. Ghrelin was administered at a dose of 1 µg/kg i.v. and GH, ACTH and cortisol analyzed in duplicate. In control women, ghrelin induced GH secretion to levels of 74.4 ± 12.8 µg/l, while chronic hypercortisolism severely reduced the ghrelin-mediated GH release in all patients with Cushing’s disease (peak values 17.7 ± 5.2 µg/l). The slightly, but significantly higher adiposity of patients vs. controls may have contributed to the effect, since a significant negative correlation (r = 0.639) was found between the amplitude of the GH peak and body mass index. In control women, ghrelin increased ACTH and cortisol levels, with peaks at 57.4 ± 19.0 ng/l and 162 ± 16 µg/l, respectively. This secretion was enhanced in Cushing’s syndrome patients, with ACTH and cortisol values of 380.7 ± 109.8 ng/l and 338 ± 81 µg/l respectively, both significantly higher than in controls. In conclusion, ghrelin-induced GH secretion was severely blunted in patients with active Cushing’s syndrome, in addition to a remarkable hyper-response in ACTH and cortisol secretion. These findings could have implications for the understanding of the physiology and physiopathology of interactions between GH and ACTH regulation.

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Comparison of the effects of growth hormone-releasing hormone and hexarelin, a novel growth hormone-releasing peptide-6 analog, on growth hormone secretion in humans with or without glucocorticoid excess

Cited by 36 publications

References 12 publications

Effects of Dexamethasone and Alprazolam, a Benzodiazepine, on the Stimulatory Effect of Hexarelin, a Synthetic GHRP, on ACTH, Cortisol and GH Secretion in Humans

Effects of Dexamethasone and Alprazolam, a Benzodiazepine, on the Stimulatory Effect of Hexarelin, a Synthetic GHRP, on ACTH, Cortisol and GH Secretion in Humans

Corticotropin-Releasing Effect of Hexarelin, a Peptidyl GH Secretagogue, in Normal Subjects Pretreated with Metyrapone or RU-486, a Glucocorticoid Receptor Antagonist, and in Patients with Addison’s Disease

Ghrelin Is No Longer Able to Stimulate Growth Hormone Secretion in Patients with Cushing’s Syndrome but Instead Induces Exaggerated Corticotropin and Cortisol Responses

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