This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Van den Berghe, G. Articles by Bowers, C. Y. Search for Related Content PubMed PubMed Citation Articles by Van den Berghe, G. Articles by Bowers, C. Y.

Neuroendocrinology of Prolonged Critical Illness: Effects of Exogenous Thyrotropin-Releasing Hormone and Its Combination with Growth Hormone Secretagogues¹

Departments of Intensive Care Medicine (G.VdB., P.W., M.S., C.V., E.VdV., P.L.), Pediatrics (F.dZ.), and Endocrinology (R.B.), University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium; Kolling Institute of Medical Research, Royal Shore Hospital (R.C.B.), St. Leonards New South Wales 2065, Australia; Department of Medicine, Division of Endocrinology, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 29908; and Department of Medicine, Division of Endocrinology, Tulane University Medical Center (C.Y.B.), New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: Greet Van den Berghe, Department of Intensive Care Medicine, University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium. E-mail: greta.vandenberghe{at}uz.kuleuven.ac.be

The catabolic state of prolonged critical illness is associated with a low activity of the thyrotropic and the somatotropic axes. The neuroendocrine component in the pathogenesis of these low activity states was assessed by investigating the effects of continuous intravenous infusions of TRH, GH-releasing peptide-2 (GHRP-2), and GHRH. Twenty adult patients, critically ill for several weeks, were studied during two consecutive nights. They had been randomly allocated to one of three combinations of peptide infusions, each administered in random order: TRH (one night) and placebo (other night), TRH + GHRP-2 (one night) and GHRP-2 (other night), or TRH + GHRH + GHRP-2 (one night) and GHRH + GHRP-2 (other night). The peptide infusions were started after a 1-µg/kg bolus and infused (1 µg/kg per h) until 0600 h. Blood sampling was performed every 20 min, and pituitary hormone secretion was quantified by deconvolution analysis. Reduced pulsatile fraction of TSH, GH, and PRL secretion and low serum concentrations of T₄, T₃, in-sulin growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were documented in the untreated state.

Infusion of TRH alone or in combination with GH secretagogues augmented nonpulsatile TSH release 2- to 5-fold; only TRH + GHRP-2 increased pulsatile TSH secretion (4-fold). Average rises in T₄ (40–54%) and in T₃ (52–116%) were obtained with all three combinations, whereas reverse T₃ levels did not increase, except when TRH was infused alone. Pulsatile GH secretion was amplified >6- and >10-fold, respectively, by GHRP-2 and GHRH + GHRP-2 infusions, generating mean increases of serum IGF-I (66% and 106%), IGFBP-3 (50% and 56%), and ALS (65% and 97%) within 45 h. The addition of TRH did not alter the GH secretory patterns. TRH infusion increased PRL release only when combined with GH secretagogues. No effects on serum cortisol were detected.

In conclusion, the pathogenesis of the low activity state of the thyrotropic and somatotropic axes in prolonged critical illness appears to have a neuroendocrine component, because these axes are both readily activated by coinfusion of TRH and GH secretagogues.

This article has been cited by other articles:

				Y. Debaveye, B. Ellger, L. Mebis, T. J. Visser, V. M. Darras, and G. Van den Berghe Effects of Substitution and High-Dose Thyroid Hormone Therapy on Deiodination, Sulfoconjugation, and Tissue Thyroid Hormone Levels in Prolonged Critically Ill Rabbits Endocrinology, August 1, 2008; 149(8): 4218 - 4228. [Abstract] [Full Text] [PDF]

				M. Granado, A. I. Martin, M. Lopez-Menduina, A. Lopez-Calderon, and M. A. Villanua GH-releasing peptide-2 administration prevents liver inflammatory response in endotoxemia Am J Physiol Endocrinol Metab, January 1, 2008; 294(1): E131 - E141. [Abstract] [Full Text] [PDF]

				J. Svensson, G. Johannsson, A. Iranmanesh, K. Albertsson-Wikland, J. D Veldhuis, and B.-A. Bengtsson GH secretory pattern in young adults who discontinued GH treatment for GH deficiency and decreased longitudinal growth in childhood. Eur. J. Endocrinol., July 1, 2006; 155(1): 91 - 99. [Abstract] [Full Text] [PDF]

				Y. Debaveye, B. Ellger, L. Mebis, E. Van Herck, W. Coopmans, V. Darras, and G. Van den Berghe Tissue Deiodinase Activity during Prolonged Critical Illness: Effects of Exogenous Thyrotropin-Releasing Hormone and Its Combination with Growth Hormone-Releasing Peptide-2 Endocrinology, December 1, 2005; 146(12): 5604 - 5611. [Abstract] [Full Text] [PDF]

				G. Marchesini, G. Bianchi, P. Lucidi, N. Villanova, M. Zoli, and P. De Feo Plasma Ghrelin Concentrations, Food Intake, and Anorexia in Liver Failure J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2136 - 2141. [Abstract] [Full Text] [PDF]

				E. S. Nylen and B. Muller Endocrine Changes in Critical Illness J Intensive Care Med, March 1, 2004; 19(2): 67 - 82. [Abstract] [PDF]

				A. INUI, A. ASAKAWA, C. Y. BOWERS, G. MANTOVANI, A. LAVIANO, M. M. MEGUID, and M. FUJIMIYA Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ FASEB J, March 1, 2004; 18(3): 439 - 456. [Abstract] [Full Text] [PDF]

				S. K. Andersen, J. Gjedsted, C. Christiansen, and E. Tonnesen The roles of insulin and hyperglycemia in sepsis pathogenesis J. Leukoc. Biol., March 1, 2004; 75(3): 413 - 421. [Abstract] [Full Text] [PDF]

				F. Weekers, M. Michalaki, W. Coopmans, E. Van Herck, J. D. Veldhuis, V. M. Darras, and G. Van den Berghe Endocrine and Metabolic Effects of Growth Hormone (GH) Compared with GH-Releasing Peptide, Thyrotropin-Releasing Hormone, and Insulin Infusion in a Rabbit Model of Prolonged Critical Illness Endocrinology, January 1, 2004; 145(1): 205 - 213. [Abstract] [Full Text] [PDF]

				R. A. Frost and C. H. Lang Alteration of somatotropic function by proinflammatory cytokines J Anim Sci, January 1, 2004; 82(13_suppl): E100 - 109. [Abstract] [Full Text] [PDF]

				Y. Hataya, T. Akamizu, H. Hosoda, N. Kanamoto, K. Moriyama, K. Kangawa, K. Takaya, and K. Nakao Alterations of Plasma Ghrelin Levels in Rats with Lipopolysaccharide-Induced Wasting Syndrome and Effects of Ghrelin Treatment on the Syndrome Endocrinology, December 1, 2003; 144(12): 5365 - 5371. [Abstract] [Full Text] [PDF]

				F. Weekers, E. Van Herck, W. Coopmans, M. Michalaki, C. Y. Bowers, J. D. Veldhuis, and G. Van den Berghe A Novel in Vivo Rabbit Model of Hypercatabolic Critical Illness Reveals a Biphasic Neuroendocrine Stress Response Endocrinology, March 1, 2002; 143(3): 764 - 774. [Abstract] [Full Text] [PDF]

				G. Van den Berghe, F. Weekers, R. C. Baxter, P. Wouters, A. Iranmanesh, R. Bouillon, and J. D. Veldhuis Five-Day Pulsatile Gonadotropin-Releasing Hormone Administration Unveils Combined Hypothalamic-Pituitary-Gonadal Defects Underlying Profound Hypoandrogenism in Men with Prolonged Critical Illness J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3217 - 3226. [Abstract] [Full Text] [PDF]

				N. Yamakita, T. Komaki, T. Takao, T. Murai, K. Hashimoto, and K. Yasuda Usefulness of Thyrotropin (TSH)-Releasing Hormone Test and Nocturnal Surge of TSH for Diagnosis of Isolated Deficit of TSH Secretion J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1054 - 1060. [Abstract] [Full Text]

				K. J. Osterziel, R. Dietz, M. B. Ranke, G. Van den Berghe, J. Takala, and C. J. Hinds Increased Mortality Associated with Growth Hormone Treatment in Critically Ill Adults N. Engl. J. Med., January 13, 2000; 342(2): 134 - 136. [Full Text]

				G. Van den Berghe, R. C. Baxter, F. Weekers, P. Wouters, C. Y. Bowers, and J. D. Veldhuis A Paradoxical Gender Dissociation within the Growth Hormone/Insulin-Like Growth Factor I Axis during Protracted Critical Illness J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 183 - 192. [Abstract] [Full Text]

				N. Shah, W. S. Evans, C. Y. Bowers, and J. D. Veldhuis Tripartite Neuroendocrine Activation of the Human Growth Hormone (GH) Axis in Women by Continuous 24-Hour GH-Releasing Peptide Infusion: Pulsatile, Entropic, and Nyctohemeral Mechanisms J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 2140 - 2150. [Abstract] [Full Text]

				R. C. Jenkins, A. Meguid El Nahas, M. E. Wilkie, C. B. Brown, J. Jones, E. Ghigo, and R. J. M. Ross The Effects of Dose, Nutrition, and Age on Hexarelin-Induced Anterior Pituitary Hormone Secretion in Adult Patients on Maintenance Hemodialysis J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1220 - 1225. [Abstract] [Full Text]

				G. Van den Berghe, P. Wouters, F. Weekers, S. Mohan, R. C. Baxter, J. D. Veldhuis, C. Y. Bowers, and R. Bouillon Reactivation of Pituitary Hormone Release and Metabolic Improvement by Infusion of Growth Hormone-Releasing Peptide and Thyrotropin-Releasing Hormone in Patients with Protracted Critical Illness J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1311 - 1323. [Abstract] [Full Text]

				L. J. De Groot Dangerous Dogmas in Medicine: The Nonthyroidal Illness Syndrome J. Clin. Endocrinol. Metab., January 1, 1999; 84(1): 151 - 164. [Full Text]

				A. Giustina and J. D. Veldhuis Pathophysiology of the Neuroregulation of Growth Hormone Secretion in Experimental Animals and the Human Endocr. Rev., December 1, 1998; 19(6): 717 - 797. [Abstract] [Full Text]

				G. Van den Berghe, P. Wouters, L. Carlsson, R. C. Baxter, R. Bouillon, and C. Y. Bowers Leptin Levels in Protracted Critical Illness: Effects of Growth Hormone-Secretagogues and Thyrotropin-Releasing Hormone J. Clin. Endocrinol. Metab., September 1, 1998; 83(9): 3062 - 3070. [Abstract] [Full Text]

				G. Van den Berghe, F. de Zegher, and R. Bouillon Acute and Prolonged Critical Illness as Different Neuroendocrine Paradigms J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 1827 - 1834. [Full Text]