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Original Studies |
Division of Endocrinology and Metabolism, Department of Internal Medicine (E.A., M.M., L.D.V., F.B., A.B., C.G., F.C., E.G.), Department of Biomedical Sciences and Oncology (M.P.), Department of Anatomy, Pharmacology and Forensic Medicine (G.M.), University of Turin, 10126 Turin, Italy; Department of Physiology (C.D.) and Department of Medicine (F.F.C.), Faculty of Medicine, Santiago de Compostela University, Santiago de Compostela E-15780, Spain; and Europeptides (R.D.), Argenteuil 95108 Cedex, France
Address all correspondence and requests for reprints to: E. Ghigo, M.D., Divisione di Endocrinologia, Ospedale Molinette, Corso Dogliotti 14, 10126 Torino, Italy. E-mail: ezio.ghigo{at}unito.it
| Abstract |
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| Introduction |
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The existence of another major, unknown factor involved in the control of somatotroph function had been hypothesized, based on the evidence that synthetic, nonnatural peptidyl, and nonpeptidyl molecules [named GH secretagogues (GHSs)] possess strong GH-releasing activity acting on the pituitary, but mainly on the hypothalamus, where specific receptors [GHS receptors (GHS-Rs)] are present (3, 4, 5, 6, 7, 8). The endogenous ligand of this so-called orphan receptor was thought to be another hypothalamic neuropeptide (8).
Surprisingly, an endogenous ligand for the GHS-R has recently been purified, from both the rat and the human stomach, and named ghrelin (9). It is a 28-amino-acid peptide showing a unique structure with an n-octanoyl ester at its third serine residue, which is essential for its potent stimulatory activity on somatotroph secretion. In fact, it has been shown that ghrelin specifically stimulates GH secretion from both rat pituitary cells in culture and rats in vivo (9). More recently, another ligand, showing the same activity, has been purified from the rat stomach; it is a 27-amino-acid peptide named des-Gln14-ghrelin, the sequence of which is identical to ghrelin except for one glutamine (10). Therefore, there is evidence that GH release is regulated by two gastric peptides secreted by endocrine cells, even if brain ghrelin immunoreactive neurons have also been localized in the hypothalamic arcuate nucleus (9).
Human ghrelin is homologous to rat ghrelin, apart from two amino acids, and circulates in human blood at considerable plasma concentrations (9, 11).
We have recently shown that human ghrelin inhibits the binding of 125I-Tyr-Ala-hexarelin from pituitary and hypothalamic membranes in humans (12); and in a preliminary study, we demonstrated, in a few normal subjects, that the administration of 1.0 µg/kg human ghrelin elicits a strong increase in circulating GH levels (13).
The aim of the present study was to compare, in humans, the GH-releasing activity of ghrelin with that of either GHRH or hexarelin (HEX), a nonnatural, synthetic hexapeptide belonging to the GHS family (5). Because nonnatural GHSs generally possess strong GH-releasing activity, but also a significant stimulatory effect on PRL, ACTH, and cortisol secretion (4, 14), the effect of ghrelin administration on these hormones was also verified and compared with that of HEX. To clarify the mechanisms of action underlying the endocrine activity of ghrelin in humans, its interaction with GHRH and HEX was also studied.
| Materials and Methods |
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Vials containing 100 µg lyophilized human ghrelin (Mwt 3370.5) were kindly provided by Europeptides (Argenteuil, France). Human ghrelin was prepared under Good Manufactory Practice conditions by Neosystem (Strasbourg, France) and purified to more than 98%. Sterility was guaranteed by filtration on individual Millipore Corp. (Bedford, MA) filters at injection. Absorption of ghrelin on filters was determined experimentally and found not to exceed 10%.
Vials containing 100 µg lyophilized HEX (Mwt 887.06) were kindly provided by Europeptides.
Vials containing 50 µg GHRH-29 (Mwt 5039.7) were kindly provided by Serono (Roma, Italy).
Subjects and study protocol
Seven healthy young male volunteers (age, mean ± SEM, 28.6 ± 2.9 yr; body mass index, 22.1 ± 0.8 kg/m2) were studied. All subjects gave their written informed consent to participate in the study, which had previously been approved by the independent Ethical Committee of the University of Turin.
All subjects underwent the following four testing sessions, in single-blind, random order, and at least 3 days apart: 1) placebo (2 mL isotonic saline iv at 0 min); 2) ghrelin (1.0 µg/kg iv at 0 min); 3) HEX (1.0 µg/kg iv at 0 min); and 4) GHRH-29 (1.0 µg/kg iv at 0 min). Six subjects also underwent two further testing sessions in which they received the combined administration of ghrelin and HEX or ghrelin and GHRH.
After overnight fasting, the tests were begun at 08300900 h, 30 min after an indwelling catheter had been inserted in an antecubital vein of the forearm, kept patent by slow infusion of isotonic saline.
Blood samples were taken every 15 min, from -15 up to +180 min. GH levels were assayed at each time point in all sessions; PRL, ACTH, cortisol, and aldosterone levels were also assayed after ghrelin and/or HEX administration.
Serum GH levels (µg/L) were measured in duplicate by immunoradiometric assay (hGH-CTK IRMA, SORIN, Saluggia, Italy). The sensitivity of the assay was 0.15 µg/L. The inter- and intraassay variation coefficients were 2.94.5% and 2.44.0%, respectively.
Serum PRL levels (µg/L) were measured in duplicate by immunoradiometric assay (PRL-CTK, IRMA, SORIN). The sensitivity of the assay was 0.15 µg/L. The inter- and intraassay variation coefficients ranged between 3.9 and 6.8% and between 3.3 and 7.5%, respectively.
Plasma ACTH levels (pmol/L) were measured in duplicate by immunoradiometric assay (Allegro HS-ACTH, Nichols Institute Diagnostics, San Juan Capistrano, CA). The sensitivity of the assay was 0.22 pmol/L. The inter- and intraassay variation coefficients ranged between 6.9 and 8.9% and between 1.1 and 3.0%, respectively.
Serum cortisol levels (nmol/L) were measured in duplicate by RIA (CORT-CTK 125, IRMA, SORIN). The sensitivity of the assay was 11.0 nmol/L. The inter- and intraassay variation coefficients ranged between 6.6 and 7.5% and between 3.8 and 6.6%, respectively.
Serum aldosterone levels (pmol/L) were measured in duplicate by RIA (CORT-CTK 125, IRMA, SORIN). The sensitivity of the assay was 16.2 pmol/L. The inter- and intraassay variation coefficients ranged between 6.6 and 7.5% and between 3.8 and 6.6%, respectively.
All samples from an individual subject were analyzed together.
The hormonal responses are expressed as mean ± SEM absolute values and areas under curves (AUCs, from 0180 min), calculated by trapezoidal integration.
The statistical analysis was carried out using nonparametric ANOVA (Friedman test) and later by a Wilcoxon matched-pairs test.
| Results |
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Placebo administration did not modify GH levels (Fig. 1
).
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The GH response to ghrelin was clearly higher (P <
0.01) than the one recorded after GHRH (Cmax, 26.7 ± 8.7 µg/L;
AUC, 619.6 ± 174.4 µg/L·h; Tmax, 25.7 ± 4.3 min) and
even significantly higher (P < 0.05) than that after
HEX (Cmax, 68.4 ± 14.7 µg/L; AUC, 1546.9 ± 380.0
µg/L·h; Tmax, 30.0 ± 3.3 min) (Fig. 1
).
Placebo administration did not modify PRL and aldosterone levels,
whereas a trend toward decrease in ACTH and cortisol levels, after its
administration, was present (Fig. 2
).
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The PRL response to ghrelin was higher (P < 0.05) than
the one recorded after HEX (Cmax, 10.9 ± 0.9 µg/L; AUC,
438.2 ± 31.4 µg/L·h; Tmax, 17.5 ± 2.5 min)
administration (Fig 2
). Similarly, both ACTH and cortisol responses to
ghrelin were higher (P < 0.02) than those recorded
after HEX (Cmax: 10.2 ± 2.5 pmol/L, AUC: 264.5 ± 30.6
pmol/L·h, Tmax: 15.0 ± 0.0 min; and Cmax: 394.8 ± 30.0
nmol/L, AUC: 15228.8 ± 1414.8 nmol/L·h, Tmax: 22.5 ± 3.4
min) (Fig 2
). On the other hand, differently from ghrelin, HEX did not
stimulate aldosterone release (Fig. 2
).
The endocrine responses to ghrelin were not modified by the
coadministration with HEX. In fact, in six subjects, the GH
response to ghrelin plus HEX was similar to that recorded after ghrelin
alone (Cmax, 99.7 ± 12.9 vs. 100.3 ± 17.3
µg/L; AUC, 2265.9 ± 201.8 vs. 2066.0 ± 358.3
µg/L·h) (Fig. 3
). Similarly, the PRL
(Cmax, 15.9 ± 2.7 vs. 15.6 ± 2.4 µg/L; AUC,
570.7 ± 61.6 vs. 554.8 ± 49.7 µg/L·h), ACTH
(Cmax, 24.2 ± 4.4 vs. 20.2 ± 5.0 pmol/L; AUC,
485.0 ± 87.3 vs. 407.2 ± 81.0 pmol/L·h),
cortisol (Cmax, 620.4 ± 59.9 vs. 495.0 ± 43.4
nmol/L; AUC, 24537.4 ± 2575.6 vs. 20616 ± 2769.0
nmol/L·h), and aldosterone (Cmax, 534.7 ± 112.9 vs.
507.2 ± 106.9 pmol/L; AUC, 23958.9 ± 4501.3 vs.
22173.8 ± 4398.0 pmol/L·h) responses to ghrelin plus HEX
overlapped with those after ghrelin alone.
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Side effects
No changes in heart rate and blood pressure were recorded after ghrelin administration, though three out of seven subjects were hungry at the end of the ghrelin testing session. Transient facial flushing was recorded in four out of seven subjects after GHRH administration and in two out of seven subjects after HEX administration. The coadministration of ghrelin and HEX or ghrelin and GHRH did not modify the side effects recorded after the administration of various peptides alone.
| Discussion |
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It has been demonstrated that the strong GH-releasing activity of nonnatural GHS is mediated by actions on the pituitary and, mainly, on the hypothalamus, probably via the activation of GHRH-secreting neurons and/or via functional antagonism of somatostatin action (3, 4, 6, 14, 15). GHSs bind and activate both pituitaric and hypothalamic GHS-R (3, 8, 15, 16, 17, 18), though receptor subtypes have been shown in the pituitary, in the brain, and in peripheral tissues (7, 12, 16, 18). Evidence that nonnatural GHSs act via specific orphan receptors suggested the existence of a natural GHS-like ligand (8). Both rat and human ghrelin have recently been isolated and proposed as an endogenous ligand of the GHS-R. In fact, this peptide is able to selectively stimulate GH secretion from both rat pituitary cells in culture and rat in vivo (9) and has recently been shown to inhibit the binding of 125I-Tyr-Ala-hexarelin from pituitary and hypothalamic membranes in humans (12). More recently, another ligand, showing the same activity, has been purified from the rat stomach; it is a 27-amino-acid peptide named des-Gln14-ghrelin, whose sequence is identical to ghrelin except for one glutamine (10).
In a previous preliminary study, we showed that in four normal young subjects, the administration of 1.0 µg/kg human ghrelin elicits a strong increase in circulating GH levels (13). The marked stimulatory effect of ghrelin on somatotroph secretion in humans is definitively demonstrated in the present study, in which it was compared with the one recorded after the administration of 1.0 µg/kg HEX hexapeptide, the effects of which had been extensively described in humans (4, 5, 6), or 1.0 µg/kg GHRH, the specific hypophysio-tropic neurohormone (19). In agreement with evidence that nonnatural GHSs release more GH than GHRH (4, 6, 14), ghrelin (a 28-amino-acid peptide) released much more GH than GHRH-29, suggesting that ghrelin, a natural ligand of GHS-R, possesses a more potent GH-releasing activity than GHRH. It has also to be noted that ghrelin induced an even greater GH response than that elicited by the same absolute dose of HEX, known as one of the most potent peptidyl GHSs (4, 6). When considered on a molar basis, the present results suggest that ghrelin is more potent in releasing GH than synthetic nonnatural GHS.
This evidence is well suited to the hypothesis that ghrelin may be a true natural ligand of GHS-R (9, 15). This assumption is confirmed by evidence that human ghrelin does not show any interaction with HEX on GH secretion. The present findings in humans agree with preliminary results in rats showing that rat ghrelin and GHRP-2 have no interaction on somatotroph secretion (20). Interestingly, evidence that the GH response to ghrelin is not modified by the coadministration of HEX also indicates that the somatotroph responsiveness to ghrelin is reproducible; this property could have clinical implication whenever ghrelin is considered as a provocative test of GH secretion.
On the other hand, the evidence that human ghrelin and GHRH have a synergistical effect on GH secretion agrees with the well-known synergism between nonnatural GHS and GHRH (4, 6, 8). As previously hypothesized, based on the effect of nonnatural GHS, the synergistical interaction between ghrelin and GHRH indicates that these peptides act, at least partially, via different mechanisms.
In all, the present results emphasize the importance of ghrelin in the control of somatotroph function in humans and indicate that, actually, nonnatural GHSs were imitating its GH-releasing effect.
Our study also shows that the activity of ghrelin is not fully specific for GH release, at least in humans. In fact, different from what was recorded in the rat (9), the acute administration of human ghrelin induced increase in both lactotroph and corticotroph secretion.
Just as with nonnatural GHS, evidence that ghrelin also possesses PRL-, ACTH- and cortisol-releasing activity indicates that testing with nonnatural GHS really reflects the activities of the endogenous GHS-like ligand. Therefore, it is unlikely that the stimulatory effect of nonnatural GHS on lactotroph and corticotroph secretion could merely reflect loss of specificity of small synthetic molecules. In fact, in the present study, ghrelin and HEX had no interaction on both lactotroph and corticotroph secretion; and this evidence once again supports the hypothesis that ghrelin is a true natural ligand of GHS-R (9, 15).
The PRL-releasing activity of nonnatural GHS has been explained by direct action on the pituitary on somatomammotroph cells (21).
On the contrary, at least in physiological conditions, the ACTH-releasing effect of nonnatural GHS mainly depends on central nervous system-mediated mechanisms, possibly involving CRH- and/or AVP-mediated mechanisms (22, 23) but also partially independent of them (24). In fact, GABAergic pathways could play a major role in the GHS-induced ACTH release (25). Whether these mechanisms of action also explain the PRL- and ACTH-releasing activity of ghrelin is to be demonstrated.
In agreement with the results on GH secretion, the stimulatory effect of ghrelin on lactotroph and corticotroph secretion is more pronounced than nonnatural GHSs, such as HEX. The more marked ACTH-releasing activity of ghrelin is likely to explain the significant increase in aldosterone levels, which was not observed after HEX. In fact, it has been demonstrated that aldosterone levels are increased even by extremely low ACTH doses (26); moreover, the aldosterone response to some peptidyl GHSs endowed with marked ACTH-releasing effect has already been shown in humans (27). Based on the existence of specific GHS binding sites in the human adrenal gland (12), a direct action of ghrelin at this level cannot be ruled out.
In conclusion, the results of this study show that, in humans, ghrelin possesses very strong GH-releasing activity, beside a clear stimulatory effect also on lactotroph and corticotroph secretion. The endocrine responses to ghrelin are not modified by its coadministration with nonnatural GHS, whereas the GH-releasing effect of ghrelin and GHRH is synergistical. These findings indicate that the effects of nonnatural GHS were mimicking those of ghrelin, which is a new hormone playing a major role in the control of somatotroph function as well as other endocrine activities.
| Acknowledgments |
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| Footnotes |
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Received August 8, 2000.
Accepted November 13, 2000.
| References |
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M. Misra, K. K. Miller, V. Stewart, E. Hunter, K. Kuo, D. B. Herzog, and A. Klibanski Ghrelin and Bone Metabolism in Adolescent Girls with Anorexia Nervosa and Healthy Adolescents J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5082 - 5087. [Abstract] [Full Text] [PDF] |
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P. Zizzari, H. Halem, J. Taylor, J. Z. Dong, R. Datta, M. D. Culler, J. Epelbaum, and M. T. Bluet-Pajot Endogenous Ghrelin Regulates Episodic Growth Hormone (GH) Secretion by Amplifying GH Pulse Amplitude: Evidence from Antagonism of the GH Secretagogue-R1a Receptor Endocrinology, September 1, 2005; 146(9): 3836 - 3842. [Abstract] [Full Text] [PDF] |
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M. Misra, K. K. Miller, K. Kuo, K. Griffin, V. Stewart, E. Hunter, D. B. Herzog, and A. Klibanski Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents Am J Physiol Endocrinol Metab, August 1, 2005; 289(2): E347 - E356. [Abstract] [Full Text] [PDF] |
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P. J. Currie, A. Mirza, R. Fuld, D. Park, and J. R. Vasselli Ghrelin is an orexigenic and metabolic signaling peptide in the arcuate and paraventricular nuclei Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R353 - R358. [Abstract] [Full Text] [PDF] |
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J. D. Veldhuis, A. Iranmanesh, and C. Y. Bowers Joint Mechanisms of Impaired Growth-Hormone Pulse Renewal in Aging Men J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4177 - 4183. [Abstract] [Full Text] [PDF] |
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G Natalucci, S Riedl, A Gleiss, T Zidek, and H Frisch Spontaneous 24-h ghrelin secretion pattern in fasting subjects: maintenance of a meal-related pattern Eur. J. Endocrinol., June 1, 2005; 152(6): 845 - 850. [Abstract] [Full Text] [PDF] |
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M. Groschl, H. G. Topf, J. Bohlender, J. Zenk, S. Klussmann, J. Dotsch, W. Rascher, and M. Rauh Identification of Ghrelin in Human Saliva: Production by the Salivary Glands and Potential Role in Proliferation of Oral Keratinocytes Clin. Chem., June 1, 2005; 51(6): 997 - 1006. [Abstract] [Full Text] [PDF] |
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L. S. Farhy and J. D. Veldhuis Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1649 - R1663. [Abstract] [Full Text] [PDF] |
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S. Kanumakala, R. Greaves, C. C. Pedreira, S. Donath, G. L. Warne, M. R. Zacharin, and M. Harris Fasting Ghrelin Levels Are Not Elevated in Children with Hypothalamic Obesity J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2691 - 2695. [Abstract] [Full Text] [PDF] |
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M. Kojima and K. Kangawa Ghrelin: Structure and Function Physiol Rev, April 1, 2005; 85(2): 495 - 522. [Abstract] [Full Text] [PDF] |
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C. Soares-Welch, L. Farhy, K. L. Mielke, F. H. Mahmud, J. M. Miles, C. Y. Bowers, and J. D. Veldhuis Complementary Secretagogue Pairs Unmask Prominent Gender-Related Contrasts in Mechanisms of Growth Hormone Pulse Renewal in Young Adults J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2225 - 2232. [Abstract] [Full Text] [PDF] |
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V. Popovic, D. Miljic, S. Pekic, P. Pesko, M. Djurovic, M. Doknic, S. Damjanovic, D. Micic, G. Cvijovic, J. Glodic, et al. Low Plasma Ghrelin Level in Gastrectomized Patients Is Accompanied by Enhanced Sensitivity to the Ghrelin-Induced Growth Hormone Release J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2187 - 2191. [Abstract] [Full Text] [PDF] |
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F. Gaytan, C. Morales, M. L. Barreiro, P. Jeffery, L. K. Chopin, A. C. Herington, F. F. Casanueva, E. Aguilar, C. Dieguez, and M. Tena-Sempere Expression of Growth Hormone Secretagogue Receptor Type 1a, the Functional Ghrelin Receptor, in Human Ovarian Surface Epithelium, Mullerian Duct Derivatives, and Ovarian Tumors J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1798 - 1804. [Abstract] [Full Text] [PDF] |
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U. Espelund, T. K. Hansen, K. Hojlund, H. Beck-Nielsen, J. T. Clausen, B. S. Hansen, H. Orskov, J. O. L. Jorgensen, and J. Frystyk Fasting Unmasks a Strong Inverse Association between Ghrelin and Cortisol in Serum: Studies in Obese and Normal-Weight Subjects J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 741 - 746. [Abstract] [Full Text] [PDF] |
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P. C. Ng, C. H. Lee, C. W. K. Lam, E. Wong, I. H. S. Chan, and T. F. Fok Plasma Ghrelin and Resistin Concentrations Are Suppressed in Infants of Insulin-Dependent Diabetic Mothers J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5563 - 5568. [Abstract] [Full Text] [PDF] |
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G. Rindi, A. Torsello, V. Locatelli, and E. Solcia Ghrelin Expression and Actions: A Novel Peptide for an Old Cell Type of the Diffuse Endocrine System Experimental Biology and Medicine, November 1, 2004; 229(10): 1007 - 1016. [Abstract] [Full Text] [PDF] |
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M. L. Barreiro, F. Gaytan, J. M. Castellano, J. S. Suominen, J. Roa, M. Gaytan, E. Aguilar, C. Dieguez, J. Toppari, and M. Tena-Sempere Ghrelin Inhibits the Proliferative Activity of Immature Leydig Cells in Vivo and Regulates Stem Cell Factor Messenger Ribonucleic Acid Expression in Rat Testis Endocrinology, November 1, 2004; 145(11): 4825 - 4834. [Abstract] [Full Text] [PDF] |
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A. Iranmanesh, C. Y. Bowers, and J. D. Veldhuis Activation of Somatostatin-Receptor Subtype-2/-5 Suppresses the Mass, Frequency, and Irregularity of Growth Hormone (GH)-Releasing Peptide-2-Stimulated GH Secretion in Men J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4581 - 4587. [Abstract] [Full Text] [PDF] |
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R. J. A. James, R. F. Drewett, and T. D. Cheetham Low Cord Ghrelin Levels in Term Infants Are Associated with Slow Weight Gain Over the First 3 Months of Life J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3847 - 3850. [Abstract] [Full Text] [PDF] |
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J.-P. Chanoine and A. C. K. Wong Ghrelin Gene Expression Is Markedly Higher in Fetal Pancreas Compared with Fetal Stomach: Effect of Maternal Fasting Endocrinology, August 1, 2004; 145(8): 3813 - 3820. [Abstract] [Full Text] [PDF] |
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R. M. Luque, R. D. Kineman, S. Park, X.-D. Peng, F. Gracia-Navarro, J. P. Castano, and M. M. Malagon Homologous and Heterologous Regulation of Pituitary Receptors for Ghrelin and Growth Hormone-Releasing Hormone Endocrinology, July 1, 2004; 145(7): 3182 - 3189. [Abstract] [Full Text] [PDF] |
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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] |
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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] |
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S. Lall, N. Balthasar, D. Carmignac, C. Magoulas, A. Sesay, P. Houston, K. Mathers, and I. Robinson Physiological Studies of Transgenic Mice Overexpressing Growth Hormone (GH) Secretagogue Receptor 1A in GH-Releasing Hormone Neurons Endocrinology, April 1, 2004; 145(4): 1602 - 1611. [Abstract] [Full Text] [PDF] |
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M. E. Davis, C. J. Pemberton, T. G. Yandle, J. G. Lainchbury, M. T. Rademaker, M. G. Nicholls, C. M. Frampton, and A. M. Richards Urocortin-1 Infusion in Normal Humans J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1402 - 1409. [Abstract] [Full Text] [PDF] |
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F. Gaytan, M. L. Barreiro, J. E. Caminos, L. K. Chopin, A. C. Herington, C. Morales, L. Pinilla, R. Paniagua, M. Nistal, F. F. Casanueva, et al. Expression of Ghrelin and Its Functional Receptor, the Type 1a Growth Hormone Secretagogue Receptor, in Normal Human Testis and Testicular Tumors J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 400 - 409. [Abstract] [Full Text] [PDF] |
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D. H. St-Pierre, L. Wang, and Y. Tache Ghrelin: A Novel Player in the Gut-Brain Regulation of Growth Hormone and Energy Balance Physiology, December 1, 2003; 18(6): 242 - 246. [Abstract] [Full Text] [PDF] |
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J. Q. Purnell, D. S. Weigle, P. Breen, and D. E. Cummings Ghrelin Levels Correlate with Insulin Levels, Insulin Resistance, and High-Density Lipoprotein Cholesterol, But Not with Gender, Menopausal Status, or Cortisol Levels in Humans J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5747 - 5752. [Abstract] [Full Text] [PDF] |
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M. M. Malagon, R. M. Luque, E. Ruiz-Guerrero, F. Rodriguez-Pacheco, S. Garcia-Navarro, F. F. Casanueva, F. Gracia-Navarro, and J. P. Castano Intracellular Signaling Mechanisms Mediating Ghrelin-Stimulated Growth Hormone Release in Somatotropes Endocrinology, December 1, 2003; 144(12): 5372 - 5380. [Abstract] [Full Text] [PDF] |
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X. Qi, J. Reed, E. W. Englander, V. Chandrashekar, A. Bartke, and G. H. Greeley Jr. Evidence That Growth Hormone Exerts a Feedback Effect on Stomach Ghrelin Production and Secretion Experimental Biology and Medicine, October 1, 2003; 228(9): 1028 - 1032. [Abstract] [Full Text] [PDF] |
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J. Farquhar, M. Heiman, A. C. K. Wong, R. Wach, P. Chessex, and J.-P. Chanoine Elevated Umbilical Cord Ghrelin Concentrations in Small for Gestational Age Neonates J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4324 - 4327. [Abstract] [Full Text] [PDF] |
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J. C. Bunt, A. D. Salbe, M. H. Tschop, A. DelParigi, P. Daychild, and P. A. Tataranni Cross-Sectional and Prospective Relationships of Fasting Plasma Ghrelin Concentrations with Anthropometric Measures in Pima Indian Children J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3756 - 3761. [Abstract] [Full Text] [PDF] |
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C. Holdstock, B. E. Engstrom, M. Ohrvall, L. Lind, M. Sundbom, and F. A. Karlsson Ghrelin and Adipose Tissue Regulatory Peptides: Effect of Gastric Bypass Surgery in Obese Humans J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3177 - 3183. [Abstract] [Full Text] [PDF] |
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A. Torsello, E. Bresciani, G. Rossoni, R. Avallone, G. Tulipano, D. Cocchi, I. Bulgarelli, R. Deghenghi, F. Berti, and V. Locatelli Ghrelin Plays a Minor Role in the Physiological Control of Cardiac Function in the Rat Endocrinology, May 1, 2003; 144(5): 1787 - 1792. [Abstract] [Full Text] [PDF] |
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M.L. Barreiro, J.S. Suominen, F. Gaytan, L. Pinilla, L.K. Chopin, F.F. Casanueva, C. Dieguez, E. Aguilar, J. Toppari, and M. Tena-Sempere Developmental, Stage-Specific, and Hormonally Regulated Expression of Growth Hormone Secretagogue Receptor Messenger RNA in Rat Testis Biol Reprod, May 1, 2003; 68(5): 1631 - 1640. [Abstract] [Full Text] [PDF] |
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F. Broglio, A. Benso, C. Castiglioni, C. Gottero, F. Prodam, S. Destefanis, C. Gauna, A. J. van der Lely, R. Deghenghi, M. Bo, et al. The Endocrine Response to Ghrelin as a Function of Gender in Humans in Young and Elderly Subjects J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1537 - 1542. [Abstract] [Full Text] [PDF] |
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K. Choi, S.-G. Roh, Y.-H. Hong, Y. B. Shrestha, D. Hishikawa, C. Chen, M. Kojima, K. Kangawa, and S.-I. Sasaki The Role of Ghrelin and Growth Hormone Secretagogues Receptor on Rat Adipogenesis Endocrinology, March 1, 2003; 144(3): 754 - 759. [Abstract] [Full Text] [PDF] |
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F. Gaytan, M. L. Barreiro, L. K. Chopin, A. C. Herington, C. Morales, L. Pinilla, F. F. Casanueva, E. Aguilar, C. Dieguez, and M. Tena-Sempere Immunolocalization of Ghrelin and Its Functional Receptor, the Type 1a Growth Hormone Secretagogue Receptor, in the Cyclic Human Ovary J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 879 - 887. [Abstract] [Full Text] [PDF] |
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M. Volante, E. Allia, E. Fulcheri, P. Cassoni, E. Ghigo, G. Muccioli, and M. Papotti Ghrelin in Fetal Thyroid and Follicular Tumors and Cell Lines: Expression and Effects on Tumor Growth Am. J. Pathol., February 1, 2003; 162(2): 645 - 654. [Abstract] [Full Text] [PDF] |
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J. C. Weikel, A. Wichniak, M. Ising, H. Brunner, E. Friess, K. Held, S. Mathias, D. A. Schmid, M. Uhr, and A. Steiger Ghrelin promotes slow-wave sleep in humans Am J Physiol Endocrinol Metab, February 1, 2003; 284(2): E407 - E415. [Abstract] [Full Text] [PDF] |
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A. M. Haqq, I. S. Farooqi, S. O'Rahilly, D. D. Stadler, R. G. Rosenfeld, K. L. Pratt, S. H. LaFranchi, and J. Q. Purnell Serum Ghrelin Levels Are Inversely Correlated with Body Mass Index, Age, and Insulin Concentrations in Normal Children and Are Markedly Increased in Prader-Willi Syndrome J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 174 - 178. [Abstract] [Full Text] [PDF] |
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H. Hosoda, M. Kojima, and K. Kangawa Ghrelin and the Regulation of Food Intake and Energy Balance Mol. Interv., December 1, 2002; 2(8): 494 - 503. [Abstract] [Full Text] |
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A. DelParigi, M. Tschop, M. L. Heiman, A. D. Salbe, B. Vozarova, S. M. Sell, J. C. Bunt, and P. A. Tataranni High Circulating Ghrelin: A Potential Cause for Hyperphagia and Obesity in Prader-Willi Syndrome J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5461 - 5464. [Abstract] [Full Text] [PDF] |
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M.L. Barreiro, F. Gaytan, J.E. Caminos, L. Pinilla, F.F. Casanueva, E. Aguilar, C. Dieguez, and M. Tena-Sempere Cellular Location and Hormonal Regulation of Ghrelin Expression in Rat Testis Biol Reprod, December 1, 2002; 67(6): 1768 - 1776. [Abstract] [Full Text] [PDF] |
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P. Lucidi, G. Murdolo, C. Di Loreto, A. De Cicco, N. Parlanti, C. Fanelli, F. Santeusanio, G. B. Bolli, and P. De Feo Ghrelin Is Not Necessary for Adequate Hormonal Counterregulation of Insulin-Induced Hypoglycemia Diabetes, October 1, 2002; 51(10): 2911 - 2914. [Abstract] [Full Text] [PDF] |
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H. Kaiya, S. van der Geyten, M. Kojima, H. Hosoda, Y. Kitajima, M. Matsumoto, S. Geelissen, V. M. Darras, and K. Kangawa Chicken Ghrelin: Purification, cDNA Cloning, and Biological Activity Endocrinology, September 1, 2002; 143(9): 3454 - 3463. [Abstract] [Full Text] [PDF] |
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M. Volante, E. Fulcheri, E. Allia, M. Cerrato, A. Pucci, and M. Papotti Ghrelin Expression in Fetal, Infant, and Adult Human Lung J. Histochem. Cytochem., August 1, 2002; 50(8): 1013 - 1021. [Abstract] [Full Text] [PDF] |
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F. Broglio, E. Arvat, A. Benso, C. Gottero, F. Prodam, S. Grottoli, M. Papotti, G. Muccioli, A. J. van der Lely, R. Deghenghi, et al. Endocrine Activities of Cortistatin-14 and Its Interaction with GHRH and Ghrelin in Humans J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3783 - 3790. [Abstract] [Full Text] [PDF] |
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W. A. Banks, M. Tschop, S. M. Robinson, and M. L. Heiman Extent and Direction of Ghrelin Transport Across the Blood-Brain Barrier Is Determined by Its Unique Primary Structure J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 822 - 827. [Abstract] [Full Text] [PDF] |
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S. Ishizaki, T. Murase, Y. Sugimura, S. Kakiya, H. Yokoi, K. Tachikawa, H. Arima, Y. Miura, and Y. Oiso Role of Ghrelin in the Regulation of Vasopressin Release in Conscious Rats Endocrinology, May 1, 2002; 143(5): 1589 - 1593. [Abstract] [Full Text] [PDF] |
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V. Tolle, M.-H. Bassant, P. Zizzari, F. Poindessous-Jazat, C. Tomasetto, J. Epelbaum, and M.-T. Bluet-Pajot Ultradian Rhythmicity of Ghrelin Secretion in Relation with GH, Feeding Behavior, and Sleep-Wake Patterns in Rats Endocrinology, April 1, 2002; 143(4): 1353 - 1361. [Abstract] [Full Text] [PDF] |
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M. Volante, E. AllIa, P. Gugliotta, A. Funaro, F. Broglio, R. Deghenghi, G. Muccioli, E. Ghigo, and M. Papotti Expression of Ghrelin and of the GH Secretagogue Receptor by Pancreatic Islet Cells and Related Endocrine Tumors J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1300 - 1308. [Abstract] [Full Text] [PDF] |
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C. Ghe, P. Cassoni, F. Catapano, T. Marrocco, R. Deghenghi, E. Ghigo, G. Muccioli, and M. Papotti The Antiproliferative Effect of Synthetic Peptidyl GH Secretagogues in Human CALU-1 Lung Carcinoma Cells Endocrinology, February 1, 2002; 143(2): 484 - 491. [Abstract] [Full Text] [PDF] |
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T. L. Horvath, S. Diano, P. Sotonyi, M. Heiman, and M. Tschop Minireview: Ghrelin and the Regulation of Energy Balance--A Hypothalamic Perspective Endocrinology, October 1, 2001; 142(10): 4163 - 4169. [Abstract] [Full Text] [PDF] |
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