Abstract
Hexarelin (HEX) is a peptidyl GH sec-retagogue (GHS) which markedly stimulates GH release but, like other GHS, possesses also CNS-mediated ACTH- and cortisol-releasing activity. Interestingly, the stimulatory effect of HEX on ACTH and cortisol release is exaggerated and higher than that of hCRH in patients with Cushing’s disease (CD). To further clarify the mechanisms by which HEX stimulates the activity of hypothalamo-pituitary-adrenal (HPA) axis in man, in 6 patients with CD (6 women, 38–68 yr old) and in 7 control subjects (CS, 7 women, 22–29 yr old) we studied the effects of HEX (2.0 ώg/kg iv) and/or hCRH (2.0 ώg/kg iv) on ACTH and cortisol (F) secretion. The GH responses to HEX alone and combined with hCRH were also studied in all subjects. Basal ACTH and F levels in CD were higher than in CS (66.3±5.1 vs 16.5±0.6 pg/ml and 217.8±18.5 vs 134.4±4.6 ώg/l, respectively; p<0.02). In CS, the ACTH and F responses to HEX, evaluated as △AUC (mean±SE: 128.7±39.2 pg*min/ml and 328.5±93.2 ώg*min/l, respectively) were lower, though not significantly, than those after hCRH (375.8±128.4 pg*min/ml and 1714.2±598.0 ώg*min/l, respectively), though the peak ACTH and F responses to both stimuli were similar. The co-administration of HEX and hCRH had an additive effect on both ACTH (1189.6±237.2 pg*min/ml) and F secretion (3452.9±648.6 ώg*min/l). In fact, the ACTH and F responses to HEX+hCRH were significantly higher (p<0.01) than those elicited by single stimuli. In CD, HEX induced ACTH and F responses (3603.8±970.7 pg*min/ml and 10955.9±6184.6 ώg*min/l, respectively) clearly higher (p<0.002) than those in CS. The HEX-induced ACTH and F responses in CD were higher, though not significantly, than those recorded after hCRH (1432.7 ±793.5 pg*min/ml and 4832.7±2146.5 ώg*min/l, respectively). On the other hand, the hCRH-induced ACTH and F responses in CD were similar to those in CS. In CD, the coadministration of HEX and hCRH had an additive effect on ACTH (8035.7±1191.1 pg*min/ml) but not on F (10985.4 ±3900.8 ώg*min/l) secretion. In fact, the ACTH, but not the F response to HEX+hCRH was significantly higher (p<0.02) than that elicited by single stimuli. In conclusion, the present study demonstrates that in patients with Cushing’s disease as well as in subjects control Hexarelin and hCRH have an additive effect on ACTH secretion. Considering that, at least in humans, differently from hCRH, GHS have no interaction with AVP, our present findings further agree with the hypothesis that the ACTH-releasing activity of GHS is, at least partially, independent of CRH-mediated mechanisms.
Similar content being viewed by others
References
Bowers C.Y., Veeraragavan K., Sethumadhavan K. Atypical growth hormone releasing peptides. In: Bercu B.B., Walker R.F. (Eds.), Growth hormone II, basic and clinical aspects. Springer-Verlag, New York, 1993, p. 203–222.
Ghigo E., Arvat E., Muccioli G., Camanni F. Growth hormone-releasing peptides. Eur. J. Endocrinol., 136: 445, 1997.
Smith R.G., Van der Ploeg L.X.T., Howard A.D., Feighner S.D., Cheng K., Hickey G.J., Wyvratt M.J., Fisher M.H., Nargund R.P., Patchett A.A. Peptidomimetic regulation of growth hormone secretion. Endocr. Rev., 18: 621, 1997.
Deghenghi R., Boutignon F., Luoni M., Grilli R., Guidi M., Locatelli V. Small peptides as potent releasers of growth hormone. J. Ped. Endocrinol. Metab., 8: 311, 1995.
Korbonits M., Grossman A.B. Growth hormone-releasing peptide and its analogues. Novel stimuli to growth hormone release. Trends Endocrinol. Metab., 6: 43, 1995.
Codd E.E., Shu A.Y.L., Walker R.F. Binding of a growth hormone releasing hexapeptide to specific hypothalamic and pituitary binding sites. Neuropharmacology, 28: 1139, 1989.
Pong S.S., Chaung L.Y.P., Dean D.C., Nargunt R.P., Patchett A.A., Smith R.G. Identification of a new G-protein-linked receptor for growth hormone secretagogues. Mol. Endocrinol., 10: 57, 1996.
Ong H., McNicoll N., Escher E., Collu R., Deghenghi R., Locatelli V., Ghigo E., Muccioli G., Boghen M., Nillson M.H.L. Identification of a pituitary GHRP receptor subtype by the photoaffinity labeling approach using [125I] p-benzoyl-phenylalanine Hexarelin derivative. Endocrinology, 139: 432, 1998.
Muccioli G, Ghè C., Ghigo M.C., Papotti M., Arvat E., Boghen M.F., Nilsson M.H.L., Deghenghi R., Ong H., Ghigo E. Specific receptors for synthetic GH secretagogues in the human brain and pituitary gland. J. Endocrinol., 157: 99, 1998.
Howard A.D., Feighner S.D., Cully D.F., Arena J.P., Liberator P.A., Rosenblum C.I., Uamelin M., Ureniuk D.I., Palyhe O.C., Anderson J., Paress P.S., Diaz C., Chou N., Liu K.K., McKee K.K., Pong S.S., Cheung L.Y., Elbrecth A., Dashkeviez M., Keavehs R., Rishy M., Siringjhsinghji D.J.S., Dean D.C., Melillo D.G., Patchett A.A., Nergund R., Srillin P.R. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273: 974, 1996.
Goth M.I., Lyons C.E., Canny B.Y., Thorner M.O. Pituitary adenylate cyclase activating polypeptide, growth hormone (GH)-releasing peptide and GH-releasing hormone stimulate GH release through distinct pituitary receptors. Endocrinology 130: 939, 1992.
Fairhall K.M., Mynett A., Robinson I.C.A.F. Central effects of growth hormone-releasing hexapeptide (GHRP-6) on growth hormone release are inhibited by central somatostatin action. J. Endocrinol. 144: 555, 1995.
Dickson S.L., Luckman S.M. Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6. Endocrinology 138: 771, 1997.
Popovic V., Damjanovic S., Micic D., Djurovic M., Dieguez C., Casanueva F.F. Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: evidence that GHRP-6 main action is exerted at the hy-pothalamic level. J. Clin. Endocrinol. Metab. 80: 942, 1995.
Pombo M., Barreiro J., Penalva A., Peino R., Dieguez C., Casanueva F.F. Absence of growth hormone (GH) secretion after the administration of either GH releasing hormone (GHRH), GH-releasing peptide (GHRP-6), or GHRH plus GHRP-6 in children with neonatal pituitary stalk transection. J. Clin. Endocrinol. Metab. 80: 3180, 1995.
Loche S., Cambiaso P., Merola B., Colao A., Feadda A., Imbimbo B.P., Deghenghi R., Lombardi G., Cappa M. The effect of Hexarelin on growth hormone (GH) secretion in patients with GH deficiency. J. Clin. Endocrinol. Metab. 80: 2692, 1995.
Hickey G.J., Drisko J., Faidley T., Chang C., Anderson L., Nicolich S., McGuire L., Riches E., Kripe D., Feeney W., Friscino R., Cunnighan P., Frazier E., Chen H., Leroque P., Smith R.G. Mediation by the central nervous system is critical to the in vivo activity of the GH secretagogue L-692,585. J. Endocrinol. 148: 371, 1996.
De Keyzer Y., Lenne F., Bertagna X. Widespread transcription of the growth hormone-releasing peptide receptor gene in neuroendocrine human tumors. Eur. J. Endocrinol. 137: 715, 1997.
Jansson J.O., Svensson J., Bengtsson B.A., Frohman L.A., Ahlmant H., Wangberg B., Nilsson O., Nilsson M. Acromegaly and Cushing’s syndrome due to ec-topic production of GHRH and ACTH by a thymic carcinoid tumour: in vitro responses to GHRH and GHRP-6. Clin. Endocrinol. (Oxf.) 48: 243, 1998.
Thomas G.B., Fairhall K.M., Robinson I.C.A.F. Activation of the hypothalamo-pituitary-adrenal axis by the growth hormone (GH) secretagogue, GH-releasing peptide-6, in rats. Endocrinology 138: 1585, 1997.
Korbonits M., Trainer P.J., Besser G.M. The effect of an opiate antagonist on the hormonal changes induced by hexarelin. Clin. Endocrinol. (Oxf.) 43: 365, 1995.
Arvat E., Maccagno B., Ramunni J., Di Vito L., Broglio F., Deghenghi R., Camanni F., Ghigo E. Hexarelin, a synthetic growth-hormone releasing peptide, shows no interaction with corticotropin-re-leasing hormone and vasopressin on adrenocorti-cotropin and cortisol secretion in humans. Neuroendocrinology 66: 432, 1997.
Ghigo E., Arvat E., Ramunni J., Colao A., Gianotti L., Deghenghi R., Lombardi G., Camanni F. Adrenocorticotropin- and cortisol-releasing effect of hexarelin, a synthetic growth hormone-releasing peptide, in normal subjects and patients with Cushing’s syndrome. J. Clin. Endocrinol. Metab. 82: 2439, 1997.
Orth D.N. Corticotropin-releasing hormone in humans. Endocr. Rev. 13: 164, 1992.
Copinschi G., van Onderbergen A., L’hermite-Baleriaux M., Mendel C.M., Caufriez A., Leproult R., Bolognese J.A., De Smet M., Thorner M.O., Van Cauter E. Effects of 7-day treatment with a novel, orally active, growth hormone (GH) secretagogue, MK-677, on 24hour GH profiles, Insulin-like growth factor I, and adrenocortical function in normal young men. J. Clin. Endocrinol. Metab. 81: 2776, 1996.
Jacks T., Hickey G., Judith F., Taylor J., Chen H., Krupa D., Feeney W., Schoen W., Fisher M., Wyratt M., Smith R. 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, 1994.
Arvat E., Maccagno B., Ramunni J., Di Vito L., Gianotti L., Broglio F., Benso A., Deghenghi R., Camanni F., Ghigo E. Effects of dexamethasone and alprazolam, a benzo-diazepine, on the stimulatory effect of Hexarelin, a synthetic GHRP, on ACTH, cortisol and GH secretion in humans. Neuroendocrinology, 67: 310, 1998.
Grottoli S., Arvat E., MAccario M., Ramunni J., Procopio M., Gianotti L., Deghenghi R., Ghigo E. Effects of alprazolam, a benzodiazepine, on the ACTH and cortisol response to Hexarelin, a synthetic GHRP, in normal subjects and in obese patients with Cushing’s disease. 8th European Congress on obesity Dublin, 1997. Int. J. Obes., 21: 181 (Abstract) S61, 1997.
Korbonits M., Little J.A., Forling M., Trainer G.M., Besser G.M., Grossman A.B. The effect of growth hormone secretagogues on GHRH and arginine vasopressin release from the rat hypothalamus in vitro. 79th Ann. Meet. Endocr. Soc., Minneapolis, 1997, p. 153.
Arvat E., Maccagno B., Ramunni J., Gianotti L., Di Vito L., Deghenghi R., Camanni F., Ghigo E. Effects of histaminergic antagonists on the GH-releasing activity of GHRH or hexarelin, a synthetic hexapeptide, in man. J. Endocrinol. Invest. 20: 122, 1997.
Di Vito L., Arvat E., Gianotti L., Broglio F., Sortino G., Lanfranco F., Deghenghi R., Ghigo E. Influence of galanin and serotonin on the GH, PRL, ACTH and cortisol response to Hexarelin, a synthetic GHRP, in humans. Ann. Endocr, 58: 86 (Abstract) P1–6, 1997.
Barlier A., Gunz G., Morange-Ramos I., Dufour H., Jaquet P., Enjalbert A. Functional expression of growth hormone secreta-gogue receptors (GHS-R) in human pituitary adenomas. 5th international Pituitary Congress, 1998. Abstract book p. 60.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Arvat, E., Ramunni, J., Giordano, R. et al. Effects of the combined administration of hexarelin, a synthetic peptidyl GH secretagogue, and hCRH on ACTH, cortisol and GH secretion in patients with Cushing’s disease. J Endocrinol Invest 22, 23–28 (1999). https://doi.org/10.1007/BF03345474
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF03345474