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Physiol. Rev. 79: 511-607, 1999;
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Physiological Reviews, Vol. 79, No. 2, April 1999, pp. 511-607
Copyright ©1999 by the American Physiological Society

Neuroendocrine Control of Growth Hormone Secretion

Eugenio E. Müller, Vittorio Locatelli, and Daniela Cocchi

Department of Pharmacology, Chemotherapy, and Toxicology, University of Milan, Milan; and Department of Biomedical and Biotechnology Sciences, University of Brescia, Brescia, Italy

Müller, Eugenio E., Vittorio Locatelli, and Daniela Cocchi. The secretion of growth hormone (GH) is regulated through a complex neuroendocrine control system, especially by the functional interplay of two hypothalamic hypophysiotropic hormones, GH-releasing hormone (GHRH) and somatostatin (SS), exerting stimulatory and inhibitory influences, respectively, on the somatotrope. The two hypothalamic neurohormones are subject to modulation by a host of neurotransmitters, especially the noradrenergic and cholinergic ones and other hypothalamic neuropeptides, and are the final mediators of metabolic, endocrine, neural, and immune influences for the secretion of GH. Since the identification of the GHRH peptide, recombinant DNA procedures have been used to characterize the corresponding cDNA and to clone GHRH receptor isoforms in rodent and human pituitaries. Parallel to research into the effects of SS and its analogs on endocrine and exocrine secretions, investigations into their mechanism of action have led to the discovery of five separate SS receptor genes encoding a family of G protein-coupled SS receptors, which are widely expressed in the pituitary, brain, and the periphery, and to the synthesis of analogs with subtype specificity. Better understanding of the function of GHRH, SS, and their receptors and, hence, of neural regulation of GH secretion in health and disease has been achieved with the discovery of a new class of fairly specific, orally active, small peptides and their congeners, the GH-releasing peptides, acting on specific, ubiquitous seven-transmembrane domain receptors, whose natural ligands are not yet known.




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Estradiol Supplementation in Postmenopausal Women Doubles Rebound-Like Release of Growth Hormone (GH) Triggered by Sequential Infusion and Withdrawal of Somatostatin: Evidence that Estrogen Facilitates Endogenous GH-Releasing Hormone Drive
J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 121 - 127.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
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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J. Clin. Endocrinol. Metab.Home page
S.-G. Ren, S. Kim, J. Taylor, J. Dong, J.-P. Moreau, M. D. Culler, and S. Melmed
Suppression of Rat and Human Growth Hormone and Prolactin Secretion by a Novel Somatostatin/Dopaminergic Chimeric Ligand
J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5414 - 5421.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
J. E. Caminos, R. Nogueiras, M. Blanco, L. M. Seoane, S. Bravo, C. V. Alvarez, T. Garcia-Caballero, F. F. Casanueva, and C. Dieguez
Cellular Distribution and Regulation of Ghrelin Messenger Ribonucleic Acid in the Rat Pituitary Gland
Endocrinology, November 1, 2003; 144(11): 5089 - 5097.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
D. L. Hurley, D. V. Birch, M. C. Almond, I. J. Estrada, and C. J. Phelps
Reduced Hypothalamic Neuropeptide Y Expression in Growth Hormone- and Prolactin-Deficient Ames and Snell Dwarf Mice
Endocrinology, November 1, 2003; 144(11): 4783 - 4789.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
E. B. Klerman, G. K. Adler, M. Jin, A. M. Maliszewski, and E. N. Brown
A statistical model of diurnal variation in human growth hormone
Am J Physiol Endocrinol Metab, November 1, 2003; 285(5): E1118 - E1126.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
L. S. Farhy and J. D. Veldhuis
Joint pituitary-hypothalamic and intrahypothalamic autofeedback construct of pulsatile growth hormone secretion
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1240 - R1249.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
L. Liu, C. E. Dean, and T. E. Porter
Thyroid Hormones Interact with Glucocorticoids to Affect Somatotroph Abundance in Chicken Embryonic Pituitary Cells in Vitro
Endocrinology, September 1, 2003; 144(9): 3836 - 3841.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
W. K. Yunker, S. Smith, C. Graves, P. J. Davis, S. Unniappan, J. E. Rivier, R. E. Peter, and J. P. Chang
Endogenous Hypothalamic Somatostatins Differentially Regulate Growth Hormone Secretion from Goldfish Pituitary Somatotropes in Vitro
Endocrinology, September 1, 2003; 144(9): 4031 - 4041.
[Abstract] [Full Text] [PDF]


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J ANIM SCIHome page
R. Draghia-Akli, K. K. Cummings, A. S. Khan, P. A. Brown, and R. H. Carpenter
Effects of plasmid-mediated growth hormone releasing hormone supplementation in young, healthy Beagle dogs
J Anim Sci, September 1, 2003; 81(9): 2301 - 2310.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
S. N. Sauter, E. Ontsouka, B. Roffler, Y. Zbinden, C. Philipona, M. Pfaffl, B. H. Breier, J. W. Blum, and H. M. Hammon
Effects of dexamethasone and colostrum intake on the somatotropic axis in neonatal calves
Am J Physiol Endocrinol Metab, August 1, 2003; 285(2): E252 - E261.
[Abstract] [Full Text] [PDF]


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Mol. Endocrinol.Home page
J. Gent, M. van den Eijnden, P. van Kerkhof, and G. J. Strous
Dimerization and Signal Transduction of the Growth Hormone Receptor
Mol. Endocrinol., May 1, 2003; 17(5): 967 - 975.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
H. Hosoda, M. Kojima, T. Mizushima, S. Shimizu, and K. Kangawa
Structural Divergence of Human Ghrelin. IDENTIFICATION OF MULTIPLE GHRELIN-DERIVED MOLECULES PRODUCED BY POST-TRANSLATIONAL PROCESSING
J. Biol. Chem., January 3, 2003; 278(1): 64 - 70.
[Abstract] [Full Text] [PDF]


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Mol. Interv.Home page
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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J. Physiol.Home page
R. Xu, Y. Zhao, and C. Chen
Growth hormone-releasing peptide-2 reduces inward rectifying K+ currents via a PKA-cAMP-mediated signalling pathway in ovine somatotropes
J. Physiol., December 1, 2002; 545(2): 421 - 433.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Renal Physiol.Home page
P. H. Lane
Diabetic kidney disease: impact of puberty
Am J Physiol Renal Physiol, October 1, 2002; 283(4): F589 - F600.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
R. Busto, A. V. Schally, J. L. Varga, M. O. Garcia-Fernandez, K. Groot, P. Armatis, and K. Szepeshazi
The expression of growth hormone-releasing hormone (GHRH) and splice variants of its receptor in human gastroenteropancreatic carcinomas
PNAS, September 3, 2002; 99(18): 11866 - 11871.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
M. Gasperi, E. Cecconi, L. Grasso, L. Bartalena, R. Centoni, G. Aimaretti, F. Broglio, P. Miccoli, C. Marcocci, E. Ghigo, et al.
GH Secretion Is Impaired in Patients with Primary Hyperparathyroidism
J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 1961 - 1964.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
G. Tulipano, D. Soldi, M. Bagnasco, M. D. Culler, J. E. Taylor, D. Cocchi, and A. Giustina
Characterization of New Selective Somatostatin Receptor Subtype-2 (sst2) Antagonists, BIM-23627 and BIM-23454. Effects of BIM-23627 on GH Release in Anesthetized Male Rats after Short-Term High-Dose Dexamethasone Treatment
Endocrinology, April 1, 2002; 143(4): 1218 - 1224.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
P. van Kerkhof, M. Smeets, and G. J. Strous
The Ubiquitin-Proteasome Pathway Regulates the Availability of the GH Receptor
Endocrinology, April 1, 2002; 143(4): 1243 - 1252.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
G. Diaz-Torga, C. Feierstein, C. Libertun, D. Gelman, M. A. Kelly, M. J. Low, M. Rubinstein, and D. Becu-Villalobos
Disruption of the D2 Dopamine Receptor Alters GH and IGF-I Secretion and Causes Dwarfism in Male Mice
Endocrinology, April 1, 2002; 143(4): 1270 - 1279.
[Abstract] [Full Text] [PDF]


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Mol. Endocrinol.Home page
R. Salvatori, X. Fan, P. E. Mullis, A. Haile, and M. A. Levine
Decreased Expression of the GHRH Receptor Gene Due to a Mutation in a Pit-1 Binding Site
Mol. Endocrinol., March 1, 2002; 16(3): 450 - 458.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
L. S. Farhy, M. Straume, M. L. Johnson, B. Kovatchev, and J. D. Veldhuis
Unequal autonegative feedback by GH models the sexual dimorphism in GH secretory dynamics
Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2002; 282(3): R753 - R764.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
M. Murata, Y. Okimura, K. Iida, M. Matsumoto, H. Sowa, H. Kaji, M. Kojima, K. Kangawa, and K. Chihara
Ghrelin Modulates the Downstream Molecules of Insulin Signaling in Hepatoma Cells
J. Biol. Chem., February 8, 2002; 277(7): 5667 - 5674.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
A. Gentili, T. Mulligan, M. Godschalk, J. Clore, J. Patrie, A. Iranmanesh, and J. D. Veldhuis
Unequal Impact of Short-Term Testosterone Repletion on the Somatotropic Axis of Young and Older Men
J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 825 - 834.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
J. D. Veldhuis, W. S. Evans, and C. Y. Bowers
Impact of Estradiol Supplementation on Dual Peptidyl Drive of GH Secretion in Postmenopausal Women
J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 859 - 866.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
S. M. Anderson, L. Wideman, J. T. Patrie, A. Weltman, C. Y. Bowers, and J. D. Veldhuis
E2 Supplementation Selectively Relieves GH's Autonegative Feedback on GH-Releasing Peptide-2-Stimulated GH Secretion
J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5904 - 5911.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
J. Schwartz
Editorial: Pulsatile Hormone Patterns Governing Transcription Factor Function
Endocrinology, November 1, 2001; 142(11): 4595 - 4598.
[Full Text] [PDF]


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Mol. Endocrinol.Home page
T. C. Voss, M. P. Flynn, and D. L. Hurley
IGF-I Causes an Ultrasensitive Reduction in GH mRNA Levels via an Extracellular Mechanism Involving IGF Binding Proteins
Mol. Endocrinol., September 1, 2001; 15(9): 1549 - 1558.
[Abstract] [Full Text] [PDF]


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J. Neurosci.Home page
F. Van Goor, Y.-X. Li, and S. S. Stojilkovic
Paradoxical Role of Large-Conductance Calcium-Activated K+ (BK) Channels in Controlling Action Potential-Driven Ca2+ Entry in Anterior Pituitary Cells
J. Neurosci., August 15, 2001; 21(16): 5902 - 5915.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
M. J. Bray, T. M. Vick, N. Shah, S. M. Anderson, L. W. Rice, A. Iranmanesh, W. S. Evans, and J. D. Veldhuis
Short-Term Estradiol Replacement in Postmenopausal Women Selectively Mutes Somatostatin's Dose-Dependent Inhibition of Fasting Growth Hormone Secretion
J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3143 - 3149.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
R. G. Gondo, M. H. Aguiar-Oliveira, C. Y. Hayashida, S. P. A. Toledo, N. Abelin, M. A. Levine, C. Y. Bowers, A. H. O. Souza, R. M. C. Pereira, N. L. Santos, et al.
Growth Hormone-Releasing Peptide-2 Stimulates GH Secretion in GH-Deficient Patients with Mutated GH-Releasing Hormone Receptor
J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3279 - 3283.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
J. D. Veldhuis, M. Bidlingmaier, S. M. Anderson, Z. Wu, and C. J. Strasburger
Lowering Total Plasma Insulin-Like Growth Factor I Concentrations by Way of a Novel, Potent, and Selective Growth Hormone (GH) Receptor Antagonist, Pegvisomant (B2036-Peg), Augments the Amplitude of GH Secretory Bursts and Elevates Basal/Nonpulsatile GH Release in Healthy Women and Men
J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3304 - 3310.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
L. S. Farhy, M. Straume, M. L. Johnson, B. Kovatchev, and J. D. Veldhuis
A construct of interactive feedback control of the GH axis in the male
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2001; 281(1): R38 - R51.
[Abstract] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
V. ROELFSEMA and R. G. CLARK
The Growth Hormone and Insulin-Like Growth Factor Axis: Its Manipulation for the Benefit of Growth Disorders in Renal Failure
J. Am. Soc. Nephrol., June 1, 2001; 12(6): 1297 - 1306.
[Abstract] [Full Text]


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J. Neurosci.Home page
F. Obal Jr, J. Fang, P. Taishi, B. Kacsoh, J. Gardi, and J. M. Krueger
Deficiency of Growth Hormone-Releasing Hormone Signaling Is Associated with Sleep Alterations in the Dwarf Rat
J. Neurosci., April 15, 2001; 21(8): 2912 - 2918.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
Y. Takatsu, H. Matsumoto, T. Ohtaki, S. Kumano, C. Kitada, H. Onda, O. Nishimura, and M. Fujino
Distribution of Galanin-Like Peptide in the Rat Brain
Endocrinology, April 1, 2001; 142(4): 1626 - 1634.
[Abstract] [Full Text]


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J. Clin. Endocrinol. Metab.Home page
W. S. Evans, S. M. Anderson, L. T. Hull, P. P. Azimi, C. Y. Bowers, and J. D. Veldhuis
Continuous 24-Hour Intravenous Infusion of Recombinant Human Growth Hormone (GH)-Releasing Hormone-(1-44)-Amide Augments Pulsatile, Entropic, and Daily Rhythmic GH Secretion in Postmenopausal Women Equally in the Estrogen-Withdrawn and Estrogen-Supplemented States
J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 700 - 712.
[Abstract] [Full Text]




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