Exercise as a Stress Model and the Interplay Between the Hypothalamus-pituitary-adrenal and the Hypothalamus-pituitary-thyroid Axes

Abstract

Exercise represents a physical stress that challenges homeostasis. In response to this stressor, the autonomic nervous system and hypothalamus-pituitary-adrenal axis are known to react and participate in the maintenance of homeostasis and the development of physical fitness. This includes elevation of cortisol and catecholamines in plasma. However, physical conditioning is associated with a reduction in pituitary-adrenal activation in response to exercise. On the other hand, highly trained athletes exhibit chronic mild hypercortisolism at baseline that may be an adaptive change to chronic exercise. In addition the proinflammatory cytokine, IL-6 is also activated, probably via catecholamines. On the other hand, the stress of chronic exercise induces certain changes to the thyroid axis. Peripheral thyroid hormone metabolism suppression is observed, and the result is a hormonal status similar to that of euthyroid sick syndrome (ESS), with suppression of T₃ and elevation of rT₃ plasma levels. One mechanism proposed involves exercise-activated pathways participating in the pathogenesis of ESS. This is realized through norepinephrine’s activation of NF-κB. Neuroendocrine response to exercise stress involves activation of NF-κB resulting in inactivation of T₃-dependent 5’-deiodinase gene expression and enzyme activity. Thus, ESS is generated in the periphery. On the other hand, activation and nuclear translocation of NF-κB leads to increased transcription of proinflammatory genes responsible for the expression of proinflammatory cytokines such as TNF-α and IL-6. These cytokines could activate cortisol, which in turn inhibits NF-κB activation through IκB and finally shuts down this cycle.

Exercise - HPA axis - Thyroid and stress - Euthyroid sick syndrome

References

• 1 Chrousos G P. Regulation and dysregulation of the hypothalamic-pituitary-adrenal axis.  Endocrinol Metab Clin North Am. 1992;  21 833-858
• 2 Mastorakos G, Ilias I. Maternal and fetal hypothalamic-pituitary-adrenal axes during pregnancy and postpartum. Ann. N. Y. Acad.  Sci. 2003;  997 1-14
• 3 Kamal E H, Gold P W, Chrousos G P. Neuroendocrinology of stress.  Endocrinol Metab Clin North Am. 2001;  30 695-728
• 4 Larsen P J, Jessop D, Patel H, Lightman S L, Chowdrey H S. Substance P inhibits the release of anterior pituitary adrenocorticotrophin via a central mechanism involving corticotrophin-releasing factor-containing neurons in the hypoyhalamic paraventricular nucleus.  J Neuroendocrinol. 1993;  5 99-105
• 5 Chrousos G P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.  New Engl J Med. 2004;  332 1351-1362
• 6 Mastorakos G, Weber J S, Magiakou M A, Gunn H, Chrousos G P. Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion. J.  Clin Endocrinol.. Metab1994;  79 934-939
• 7 Mastorakos G, Chrousos G P, Weber J S. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans.  J Clin Endocrinol Metab. 1993;  77 1690-1694
• 8 Crofford L J, Kalogeras K T, Mastorakos G. et al . Circadian relationships between interleukin-6 (IL-6) and hypothalamic pituitary-adrenal axis hormones: Failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis.  J Clin Endocrinol. Metab1997;  82 1279-1283
• 9 Imura H, Fucata J, Mori T. Cytokines and endocrine functions: an interaction between the immune and neuroendocrine systems.  Clin Endocrinol. 1991;  35 107-115
• 10 Kelso T B, Herbert W G, Gwazdauskas F C, Goss F L, Hess J L. Exercise-thermoregulatory stress and increased plasma β-endorphin/β-lipotropin in humans. J.  Appl.. Physiol1984;  57 444-449
• 11 Luger A, Deuster P A, Kyle S B. et al . Acute hypothalamic-pituitary-adrenal responses to the stress of treadmill exercise.  N Engl J Med. 1987;  316 1309-1315
• 12 DeRijk R H, Boelen A, Tilders F JH, Berkenbosch F. 1994 Induction of plasma interleukin-6 by circulating adrenaline in the rat.  Psychoneuroendocrinology. 1987;  19 155-163
• 13 Papanicolaou D A, Petrides J S, Tsigos C. et al . Exercise stimulates interleukin-6 secretion: inhibition by glucocorticoids and correlation with catecholamines.  Endocrinol Metab. 1996;  34 E601-E605
• 14 Barder A E, Coyle S M, Marano E. Glucocorticoid therapy alters hormonal and cytokine responses to endotoxin in man. J.  Immunol. 1999;  150 1999-2006
• 15 Hogevold H E, Kierulf P, Ovstebo R, Reikeros O. Acute phase reactants and interleukin6 after total hip replacement; effects of high dose cortcosteroids.  Eur J Surg. 1992;  158 339-345
• 16 Terebuh P D, Otterness I G, Strieter R M. et al . Biologic and immunohistohemichal analysis of interleukin-6 expression in vivo. Constitutive and induced expression in murine polymorphonuclear and mononuclear phagocytes.  Am J Pathol. 1992;  140 649-657
• 17 Greenspan F S. The thyroid gland. Basic and Clinical Endocrinology 7th edition. Greenspan FS, Gardner DG (Ed) Lange/ Mc Graw-Hill 2004 7: 215-294
• 18 Reichlin S. Neuroendocrinology. Wilson JD, Foster DW, Krnonenberg HM, Larsen PR Williams Textbook of Endocrinology 9th edition. Philadelphia, PA; W. B Saunders Company 1998 8: 185-187, 203-206
• 19 Kelly G. Peripheral metabolism of thyroid hormones: a review.  Altern Med Rev. 2000;  5 306-333
• 20 Wirth A, Holm G, Lindstedt G, Lundberg P A, Bjorntorp P. Thyroid hormones and lipolysis in physically trained rats.  Metabolism. 1981;  30 237-241
• 21 Simsch C, Lormes W, Petersen K G. et al . Training intensity influences leptin and thyroid hormones in highly trained rowers.  Int J Sports Med. 2002;  23 422-427
• 22 Krotkiewski M, Sjostrom L, Sullivan L. et al . The effect of acute and chronic exercise on thyroid hormones in obesity.  Acta Med Scand. 1984;  216 269-275
• 23 Limanova Z, Sonka J, Kratochvil O. et al . Effects of exercise on serum cortisol and thyroids hormones.  Exp Clin Endocrinol. 1983;  81 308-314
• 24 Opstad K. Circadian rhythm of hormones is extinguished during prolonged physical stress, sleep and energy deficiency in young men.  Eur J Endocrinol. 1994;  131 56-66
• 25 O’Connell M, Robbins D C, Horton E S, Sims E A, Danforth E Jr. Changes in serum concentrations of 3,3’,5’-Triiodothyronine and 3,5,3’-Triiodothyronine during prolonged moderate exercise.  J Clin Endocrinol. Metab1979;  49 242-246
• 26 Loucks A B, Heath E M. Induction of low-T₃ syndrome in exercising women occurs at a threshold of energy availability.  Am J Physiol. 1994;  266 R817-R823
• 27 Baylor L S, Hackney A C. Resting thyroid and leptin hormone changes in women following intense, prolonged exercise training.  Eur J Appl Physiol. 2002;  88 480-484
• 28 Ghizzoni L, Mastorakos G, Ziveri M. et al . Interactions of leptin and thyrotropin 24-hour secretory profiles in short normal children.  J Clin Endocrinol Metab. 2001;  86 2065-2072
• 29 Bunt J C. Hormonal alterations due to exercise.  Sports Med. 1986;  3 331-345
• 30 Thornton J R. Hormonal responses to exercise and training.  Vet Clin North Am Equine Pract. 1985;  1 477-496
• 31 Mastorakos G, Pavlatou M, Diamanti-Kandarakis E. Chrousos GP. Exercise and the stress system.  Hormones. 2005;  4 73-89
• 32 Chopra I J. Euthyroid sick syndrome: is it a misnomer?.  The Journal of Clinical Endocrinology and Metabolism. 1997;  82 329-334
• 33 Fliers E, Alkemade A, Wiersinga W M. The hypothalamic-pituitary-thyroid axis in critical illness.  Best Practice and Research Clinical Endocrinology and Metabolism. 2001;  15 453-464
• 34 De Groot J L. Dangerous Dogmas in Medicine: The Nonthyroidal Illness Syndrome.  Journal of Clinical Endocrinology and Metabolism. 1999;  84 151-164
• 35 Kaptein E M. Thyroid hormone metabolism and thyroid diseases in chronic renal failure.  Endocr Rev. 1996;  17 45-63
• 36 Kaptein E M, Robinson W J, Grieb D A, Nicoloff J T. Peripheral serum thyroxine, triiodothyronine and reverse triodothyronine kinetics in the low thyronine state of acute nonthyroidal illnesses.  J Clin Invest. 1982;  69 526-535
• 37 Huang T S, Wu H P, Huang L S, Lai M Y, Ho S W, Chopra I J. A study of thyroidal response to thyrotropin (TSH) in decompensated liver cirrhosis.  Thyridology. 1989;  1 137-142
• 38 Bianco A C, Nunes M T, Hell N S, Maciel R MB. The role of glucocorticoids in the stress-induced reduction of extrathyroidal 3, 5, 3’-triiodothyronine generation in rats.  Endocrinology. 1987;  120 1033-1038
• 39 Van den Berghe G, de Zegher F, Bouillon R. Acute and prolonged critical illness as different neuroendocrine paradigms.  Journal of Clinical Endocrinology and Metabolism. 1998;  83 1827-1834
• 40 Van der Poll T, Romijin J A, Wiersinga W M, Sauerwein H P. Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome.  J Clin Endocrinol Metab. 1991;  71 1567-1572
• 41 Chopra I J, Sakane S, Chua T eco. A study of the serum concentration of tumor necrosis factor-α in thyroidal and nonthyroidal illness.  J Clin Endocrinol Metab. 1991;  72 1113-1116
• 42 Cannon J G, Tompkins R G, Gelfand J A. et al . Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever.  J Infect Dis. 1990;  161 79-84
• 43 Van der Poll T, Van Zee K J, Endert E. et al . Interleukin-1 receptor blockade does not affect endotoxin-induced changes in plasma thyroid hormone and thyrotropin concentrations in man.  J Clin Endocrinol Metab. 1995;  80 1341-1346
• 44 Boelen A, Platvoet-ter S chphorst, Wiersinga W M. Association between serum intrrleukin-6 and serum 3,5,3’-triiodothyronine in nonthyroidal illness.  J Clin Endocrinol. Metab1993;  77 1695-1699
• 45 Stouthard J M, van der Poll T, Endert E, Bakker P J. et al . Effects of acute and chronic interleukin-6 administration on thyroid hormone metabolism in humans.  J Clin Endocrinol Metab. 1994;  79 1342-1346
• 46 Michalaki M, Vagenakis A G, Makri M, Kalfarentzos F, Kyriazopoulou V. Dissociation of the early decline in serum T₃ concetration and serum IL-6 rise and TNFa in nonthyroidal illness syndrome induced by abdominal surgery.  The Journal of Clinical Endocrinology and Metabolism. 2001;  86 4198-4205
• 47 Boelen A, Platvoet-ter Schiphorst M C, Wiersinga W M. Immunoneutralization of interleukin-1, tumor necrosis factor, interleukin-6 or interferon does not prevent the LPS-induced sick euthyroid syndrome in mice.  J Endocrinol. 2001;  153 115-122
• 48 Pang X P, Hershman J M, Mirell C J, Pekary A E. Impairment of hypothalamic-pituitary-thyroid function in rats treated with human recombinant tumor necrosis factor-α (cachectin).  Endocrinology. 1989;  125 76-84
• 49 Nagaya T, Fujieda M, Otsuka G, Yang J P, Okamoto T, Seo H. A potential role of activated NF-κB in the pathogenesis of euthyroid sick syndrome.  J Clin Invest. 2000;  106 393-402
• 50 Perkins N D. Regulation of NF-κ B by cyclin-dependent kinases associated with the p300 coactivator.  Science. 1997;  275 523-527
• 51 Madrigal J L, Hurtado O, Moro M A. et al . The increase in TNF-α levels is implicated in NF-Kappa B activation inducible nitric oxide synthase expression in brain cortex after immobilization stress.  Neuropsychopharmagology. 2002;  26 155-163
• 52 Bierhaus A, Wolf J, Andrassy M, Rohleder N. A mechanism converting psychosocial stress into mononuclear cell activation.  PNAS. 2003;  100 1920-1925
• 53 Kirschbaum C, Pirke K M, Hellhammer D H. The ”Trier Social Stress Test” - a tool for investigating psychobiological stress responses in a laboratory setting.  Neuropsychobiology. 1993;  28 76-81
• 54 Karlamangla A S, Singer B H, McEwen B S, Rowe J W, Seeman T E. Allostatic load as a predictor of functional decline. MacArthur studies of successful aging.  J Clin Epidemiol. 2002;  55 696-710
• 55 Aljada A, Ghanim H, Assian E. et al . 1996 Increased IkB expression and diminished nuclear NF-kB in human mononuclear cells following hydrocortisone injection.  The Journal of Clinical Endocrinology and Metabolism. 2002;  84 3386-3389
• 56 De Bosscher K, Schmitz M L, Vanden B erghe, Plaisance S, Fiers W, Haegeman G. Glucocorticoid-mediated repression of nuclear factor-κB-dependent transcription involves direct interference with transactivation.  Proc Natl Acad Sci USA. 1997;  94 13 504-13 509
• 57 Auphan N, DiDonato J A, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-κ B activity through induction of I κ B synthesis.  Science. 1995;  270 286-290
• 58 Farmer P, Pugin J. Beta-adrenergic agonists exert their ”anti-inflammatory“ effects in monocytic cells through the I κ B/NF-κ B pathway.  Am J Physiol Lung Cell Mol Physiol. 2000;  279 L675-L682
• 59 Aksoy M O, Bin W, Yang Y, Yun-You D, Kelsen S G. Nuclear factor-Kappa B augments β (2)-adrenergic receptor expression in human airway epithelial cells. Am. J.  Physiol. 2001;  281 L1271-L1278