A Low Dose of Ghrelin Stimulates Growth Hormone (GH) Release Synergistically with GH-Releasing Hormone in Humans
Abstract
The synergistic relationship between GH-releasing secretagogue (GHS) and GH-releasing hormone (GHRH) with respect to GH secretion is well known. In the present study, we report a similar relationship between GHRH and ghrelin, a recently identified endogenous ligand for the GHS receptor. In normal male adults, various doses of ghrelin were intravenously administered alone or together with 1.0 microg/kg GHRH. At small doses of 0.08 and 0.2 microg/kg ghrelin, combined administration of the two peptides significantly stimulated GH release in a synergistic manner; the mean GH response values of the two peptide combinations were more than the summed mean GH response values of each peptide alone (P < 0.05). In addition, at 1.0 microg/kg ghrelin, the tendency of the synergistic effect was observed, although the comparison was not statistically significant probably due to a submaximal dose ceiling effect. No synergistic effects with respect to ACTH or prolactin secretion were observed. In conclusion, the synergistic interaction between ghrelin and GHRH was clearly shown and might be useful for a provocation test to diagnose GH deficiency.
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Ghrelin has the opposite effect on the arcuate nucleus, stimulating appetite, and prolonging postprandial glucose responses, while stimulating growth hormone release.
“Ghrelin has the opposite effect on the arcuate nucleus, stimulating appetite, and prolonging postprandial glucose responses, while stimulating GH release.79”
From Interacting epidemics? Sleep curtailment, insulin resistance, and obesity (2012) · cites this paper as [79]
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“Coadministration of ghrelin and GHRH had a synergistic effect on GH secretion; that is, coadministration results in more GH release than does either GHRH or ghrelin alone (13, 101).”
BackgroundSelf-citationBiological, Physiological, Pathophysiological, and Pharmacological Aspects of Ghrelin
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“The gastric hormone ghrelin was identified as an endogenous ligand for the former orphan receptor GHS-R 1a (1, 13, 14); the discovery of this receptor followed by 20 yr that of synthetic GHS, which specifically binds it (1, 14, 17, 19–21, Abbreviations: AGRP, Agouti-related protein; CNS, central nervous system; CST, c…”
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“An overwhelming amount of pharmacological data suggests that ghrelin has significant impact on body fat content (12, 20, 21, 35, 40), but our body composition study showed that the fat contents as a percentage of body mass of ghrelin / and wild-type littermates were identical (Fig.”
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“Furthermore, ghrelin and GHRH synergistically increases GH release [141].”
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“This observation is in contrast to previous studies that were performed with the same size of groups (each group, n ¼ 6); the 1mg/kg dose was observed to elicit a significantly lower response than the 5mg/kg dose (12, 17 ).”
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Engström, B. E., Burman, P., Holdstock, C., & Karlsson, F. A. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030713 · Cited by 146 · see citing works
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“, 2002) and that ghrelin and GHRH exert synergic effects on somatotroph secretion (Arvat et al., 2001; Hataya et al., 2001; Cunha & Mayo, 2002), an increased GH response to ghrelin could have been foreseen.”
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Self-citationIs irritable bowel syndrome an organic disorder?
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“It is produced by approximately 20% of the neuroendocrine cell population of oxyntic glands, by cells different from enterochromaffin-like, enterochromaffin or D cells and probably of the X-like cells (7, 8). Ghrelin potentially stimulates GH release (9, 10 ) and it may also play a role in different aspects of food in…”
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“... in several regions of the hypothalamus, raising the possibility that growth hormone (GH) secretion may be under the control of ghrelin released from the arcuate nucleus (2, 3). In this view, ghrelin probably stimulates GH secretion by triggering multiple signals that include modulation of somatostatin and GHreleas…”
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“Furthermore, ghrelin and GHRH synergistically increases GH release [30].”
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“Coadministration of ghrelin and GHRH has a synergistic effect on GH secretion; that is, coadministration results in more GH release than does either GHRH or ghrelin alone”
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Broglio, F., Arvat, E., Benso, A. S., Gottero, C., Prodam, F., Grottoli, S., Papotti, M., Muccioli, G., van der Lely, A. J., Deghenghi, R., et al. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.8.8749 · Cited by 76 · see citing works
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“, and is the only known circulating orexigenic hormone. Ghrelin increases growth hormone (GH) release, stimulates appetite, and induces fat deposition”
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“However, subsequent studies revealed growth hormone releasing hormone (GHRH) to be the main antagonist for the inhibitory effect of somatostatin on GH release, since efficient GH release upon ghrelin GHSR1a stimulation requires GHRH [8,9].”
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“…actions, including vasorelaxation (Nagaya et al. 2001, Shimizu et al. 2003) and stimulation of GH secretion (Takaya et al. 2000, Arvat et al. 2001, Hataya et al. 2001), appetite (Korbonits et al. 2004, van der Lely et al. 2004) and gastrointestinal motility (Masuda et al. 2000, Trudel et al.…”
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Baudet, M., & Harvey, S. (2003) · Journal of Endocrinology · doi:10.1677/joe.0.1790097 · Cited by 67 · see citing works
“This contrasts with the in vivo GH-releasing activity of TRH in chickens, which is known to be partly due to stimulatory actions at CNS sites ( Harvey et al. 1990 ).”
BackgroundCardiovascular actions of the ghrelin gene-derived peptides and growth hormone-releasing hormone
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“Thus, it will be of interest in the future to determine the effect of these diets on the 24-hour integrated GH concentration as well as a potential effect on the ghrelin concentration, an independent stimulator of GH secretion [14,15].”
BackgroundGhrelin Expression and Actions: A Novel Peptide for an Old Cell Type of the Diffuse Endocrine System
Rindi, G., Torsello, A., Locatelli, V., et al. (2004) · Experimental Biology and Medicine · doi:10.1177/153537020422901004 · Cited by 61 · see citing works
Pusztai, P., Sármán, B., Ruzicska, É., Tõke, J., Rácz, K., Somogyi, A., & Tulassay, Z. (2008) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.830 · Cited by 60 · see citing works
“Ghrelin appears to be more effective than GHRH itself [21].”
BackgroundRegulation of Ghrelin Secretion and Action
Camiña, J. P., Carreira, M. C., Micić, D., Pombo, M., Keleştimur, F., Diéguez, C., & Casanueva, F. F. (2003) · Endocrine · doi:10.1385/endo:22:1:5 · Cited by 59 · see citing works
Bowers, C. Y., Granda, R., Mohan, S., Kuipers, J., Baylink, D., & Veldhuis, J. D. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031799 · Cited by 57 · see citing works
Recent Developments in Ghrelin Receptor Ligands
Moulin, A., Ryan, J. L., Martínez, J., & Fehrentz, J. (2007) · ChemMedChem · doi:10.1002/cmdc.200700015 · Cited by 59 · see citing works
Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a
Casanueva, F. F., Camiña, J. P., Carreira, M. C., Pazos, Y., Varga, J. L., & Schally, A. V. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811680106 · Cited by 57 · see citing works
Kluge, M., SCHÜSSLER, P., Bleninger, P., Kleyer, S., Uhr, M., Weikel, J. C., Yassouridis, A., Zuber, V., & Steiger, A. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.01.008 · Cited by 56 · see citing works
“GHRH enhanced the ghrelin-induced GH secretion and CRH enhanced the ghrelin-induced cortisol secretion as previously reported (Hataya et al., 2001; Veldhuis et al., 2006; Iranmanesh et al., 2007).”
ResultIntegrating GHS into the Ghrelin System
Veldhuis, J. D., & Bowers, C. Y. (2010) · International Journal of Peptides · doi:10.1155/2010/879503 · Cited by 57 · see citing works
“Synergism is not observed after combined stimulation with either maximal GHRH and maximal GHS or submaximal GHRH and maximal GHS stimulation [65, 254].”
BackgroundNocturnal ghrelin pulsatility and response to growth hormone secretagogues in healthy men
Koutkia, P., Hron, B. M., Breu, J. J., Johnson, M. L., & Grinspoon, S. K. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00548.2003 · Cited by 56 · see citing works
“Ghrelin has dual actions to stimulate both food intake and GH secretion (4, 26, 30, 41, 46).”
BackgroundFernández-Fernández, R., Tena‐Sempere, M., Roa, J., Castellano, J. M., Navarro, V. M., Aguilar, E., & Pinilla, L. (2007) · Reproduction · doi:10.1530/rep-06-0227 · Cited by 54 · see citing works
“…et al. 1999, 2001) and stimulates food intake and growth hormone (GH) secretion in humans and rats (Kojima et al. 1999, 2001, Seoane et al. 2000, Wren et al. 2000, Ahnfelt-Ronne et al. 2001, Arvat et al. 2001a, 2001b, Ghigo et al. 2001, Hataya et al. 2001, Tayaka et al. 2001, Pinilla et al. 2003).”
BackgroundEl-Eshmawy, M. M., Aal, I. A. A., & El-Hawary, A. K. (2010) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-8-153 · Cited by 53 · see citing works
“Together, ghrelin and growth hormone releasing hormone (GHRH) synergistically increase GH levels [16].”
Stimulatory Effect of Ghrelin on Isolated Porcine Somatotropes
Glavaski‐Joksimovic, A., Jeftinija, K., Scanes, C. G., et al. (2003) · Neuroendocrinology · doi:10.1159/000071309 · Cited by 53 · see citing works
ThidarMyint, H., Yoshida, H., Ito, T., et al. (2006) · Journal of Endocrinology · doi:10.1677/joe.1.06746 · Cited by 51 · see citing works
“3 and Table 1) and this is consistent with the results of previous work in humans and rats (Takaya et al. 2000, Hataya et al. 2001, Tolle et al. 2001).”
ResultGrinspoon, S. K., Miller, K. K., Herzog, D. B., Grieco, K. A., & Klibanski, A. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0287 · Cited by 51 · see citing works
Reichenbach, A., Steyn, F. J., Sleeman, M. W., & Andrews, Z. B. (2012) · Endocrinology · doi:10.1210/en.2012-1622 · Cited by 47 · see citing works
“However, ghrelin can also initiate GH release through the activation of GHRH neurons in the hypothalamic arcuate nucleus (55, 56), and GHRH increases GHSR mRNA in the pituitary, highlighting synergistic actions of ghrelin on GH secretion at the hypothalamus and pituitary (57).”
BackgroundSeoane, L. M., Al–Massadi, O., Barreiro, F. J. J., Diéguez, C., & Casanueva, F. F. (2007) · Journal of Endocrinological Investigation · doi:10.1007/bf03350806 · Cited by 46 · see citing works
Structure of Mammalian and Nonmammalian Ghrelins
Kojima, M., Ida, T., & Sato, T. (2007) · Vitamins and hormones · doi:10.1016/s0083-6729(06)77003-0 · Cited by 46 · see citing works
Self-citationPhysiology of ghrelin and related peptides
Anderson, L. L., Jeftinija, S., Scanes, C. G., Stromer, M. H., Lee, J.-S., Jeftinija, K., & Glavaski‐Joksimovic, A. (2005) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2005.02.033 · Cited by 46 · see citing works
The ups and downs of growth hormone secretagogue receptor signaling
Cornejo, M. P., Mustafá, E. R., Cassano, D., Banères, J., Raingo, J., & Perelló, M. (2021) · FEBS Journal · doi:10.1111/febs.15718 · Cited by 46 · see citing works
Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion
Farhy, L. S., & Veldhuis, J. D. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00451.2004 · Cited by 44 · see citing works
“greater in the female than in the male rodent and human (1, 2, 10, 11, 55, 71), and GHS and GHRH were found to act in synergy (3, 10, 14, 37, 78).”
BackgroundLall, S., Balthasar, N., Carmignac, D. F., Magoulas, C., Sesay, A. K., Houston, P. A., Mathers, K., & Robinson, I. C. A. F. (2004) · Endocrinology · doi:10.1210/en.2003-1509 · Cited by 44 · see citing works
Cornejo, M. P., Mustafá, E. R., Barrile, F., Cassano, D., Francesco, P. N. D., Raingo, J., & Perelló, M. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.10.017 · Cited by 43 · see citing works
Endocrine cells in the ileum of patients with irritable bowel syndrome
El‐Salhy, M. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i9.2383 · Cited by 41 · see citing works
- Authors
- Hataya, Y., Akamizu, T., Takaya, K., Kanamoto, N., Ariyasu, H., Saijo, M., Moriyama, K., Shimatsu, A., Kojima, M., Kangawa, K., & Nakao, K.
- Affiliations
- Kyoto University (JP)
- Kyoto Medical Center (JP)
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2001-09
- Volume
- 86
- Issue
- 9
- Pages
- 4552-4552
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2148006619
- Cited by
- 293
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 9 · 2017: 8 · 2016: 5 · 2015: 8 · 2014: 13 · 2013: 18 · 2012: 16
- FWCI
- 17.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- ghrelin, growth hormone-releasing hormone, growth hormone secretion, synergistic hormone interaction, GHS receptor, provocation tests, ACTH, prolactin
- MeSH terms
- Adrenocorticotropic Hormone, Adult, Dose-Response Relationship, Drug, Drug Synergism, Humans, Hydrocortisone, Male, Middle Aged, Peptides, Pituitary Hormones, Anterior, Prolactin, Growth Hormone-Releasing Hormone, Human Growth Hormone, Peptide Hormones, Ghrelin
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