PM&R
Volume 2, Issue 5 , Pages 338-346 , May 2010

Neuroendocrine and Immune Contributors to Fatigue

  • Marni N. Silverman, PhD

      Affiliations

    • Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Rockville, MD
  • ,
  • Christine M. Heim, PhD

      Affiliations

    • Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA
  • ,
  • Urs M. Nater, PhD

      Affiliations

    • Department of Clinical Psychology and Psychotherapy, University of Zurich, Switzerland, Centers for Disease Control and Prevention, Atlanta, GA§
  • ,
  • Andrea H. Marques, MD, PhD

      Affiliations

    • Genetic Epidemiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD
  • ,
  • Esther M. Sternberg, MD

      Affiliations

    • Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Integrative Neural Immune Program, 5625 Fishers Lane (MSC-9401), Rockville, MD 20852
    • Corresponding Author InformationAddress correspondence to E.M.S.

References 

  1. Guymer EK, Clauw DJ. Treatment of fatigue in fibromyalgia. Rheum Dis Clin N Am. 2002;28:367–378
  2. Swain MG. Fatigue in chronic disease. Clin Sci (Lond). 2000;99:1–8
  3. Demmyttenaere K, De Fruyt J, Stahl SM. The many faces of fatigue in major depressive disorder. Int J Neuropsychopharmacol. 2005;8:93–105
  4. Bower JE. Behavioral symptoms in patients with breast cancer and survivors. J Clin Oncol. 2008;26:768–777
  5. Silverman MN, Pearce BD, Biron CA, Miller AH. Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol. 2005;18:41–78
  6. Silverman MN, Sternberg EM. Neuroendocrine-immune interactions in rheumatoid arthritis: mechanisms of glucocorticoid resistance. Neuroimmunomodulation. 2008;15:19–28
  7. Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol. 2006;6:318–328
  8. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000;52:595–638
  9. Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system. Brain Behav Immun. 2007;21:736–745
  10. Tracey KJ. Physiology and immunology of the cholinergic anti-inflammatory pathway. J Clin Invest. 2007;117:289–296
  11. Thayer JF. Vagal tone and the inflammatory reflex. Cleve Clin J Med. 2009;76:S23–S26
  12. Goehler LE, Gaykema RPA, Hansen MK, Anderson K, Maier SF, Watkins LR. Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton Neurosci. 2000;85:49–59
  13. Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol. 2009;5:374–381
  14. McEwen BS, Biron CA, Brunson KW, et al. The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res Brain Res Rev. 1997;23:79–133
  15. Dhabhar FS. Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation. 2009;16:300–317
  16. Kvetnansky R, Pacak K, Fukuhara K, et al. Sympathoadrenal system in stress: interaction with the hypothalamic-pituitary-adrenocortical system. Ann NY Acad Sci. 1995;771:131–158
  17. Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. 2003;160:1554–1565
  18. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31
  19. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–57
  20. Maes M. Inflammatory and oxidative and nitrostative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry. 2008;22:75–83
  21. Maes M, Yirmaya R, Noraberg J, et al. The inflammatory and neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis. 2009;24:27–53
  22. Capuron L, Miller AH. Cytokines and psychopathology: lessons from interferon-α. Biol Psychiatry. 2004;56:819–824
  23. Cleeland CS, Bennett GJ, Dantzer R, et al. Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? (A cytokine-immunologic model of cancer symptoms). Caner. 2003;97:2919–2925
  24. Bower JE. Cancer-related fatigue: links with inflammation in cancer patients and survivors. Brain Behav Immun. 2007;21:863–871
  25. Miller AH, Ancoli-Israel S, Bower JE, Capuron L, Irwin MR. Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J Clin Oncol. 2008;26:971–982
  26. Meeusen R, Watson P, Hasegawa H, Roelands B, Piacentini MF. Central fatigue: the serotonin hypothesis and beyond. Sports Med. 2006;36:881–909
  27. Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms. Neuroimmunomodulation. 1997;4:134–153
  28. Hayley S, Merali Z, Anisman H. Stress and cytokine-elicited neuroendocrine and neurotransmitter sensitization: implications for depressive illness. Stress. 2003;6:19–32
  29. Fukada K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study (International Chronic Fatigue Syndrome Study Group). Ann Intern Med. 1994;121:953–959
  30. Poteliakhoff A. Adrenocortical activity and some clinical findings in acute and chronic fatigue. J Psychosom Res. 1981;25:91–95
  31. Demitrack MA, Dale JK, Straus SE, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 1991;73:1224–1234
  32. Hamilos DL, Nutter D, Gershtenson J, et al. Core body temperature is normal in chronic fatigue syndrome. Biol Psychiatry. 1998;43:293–302
  33. MacHale SM, Cavanagh JT, Bennie J, Carroll S, Goodwin GM, Lawrie SM. Diurnal variation of adrenocortical activity in chronic fatigue syndrome. Neuropsychobiology. 1998;38:213–217
  34. Strickland P, Morriss R, Wearden A, Deakin B. A comparison of salivary cortisol in chronic fatigue syndrome, community depression and healthy controls. J Affect Disord. 1998;47:191–194
  35. Cevik R, Gur A, Acar S, Nas K, Sarac AJ. Hypothalamic-pituitary-gonadal axis hormones and cortisol in both menstrual phases of women with chronic fatigue syndrome and effect of depressive mood on these hormones. BMC Musculoskelet Disord. 2004;5:47
  36. Gur A, Cevik R, Nas K, Colpan L, Sarac S. Cortisol and hypothalamic-pituitary-gonadal axis hormones in follicular-phase women with fibromyalgia and chronic fatigue syndrome and effect of depressive symptoms on these hormones. Arthritis Res Ther. 2004;6:R232–R238
  37. Roberts AD, Wessely S, Chalder T, Papadopoulos A, Cleare AJ. Salivary cortisol response to awakening in chronic fatigue syndrome. Br J Psychiatry. 2004;184:136–141
  38. Jerjes WK, Cleare AJ, Wessely S, Wood PJ, Taylor NF. Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome. J Affect Disord. 2005;87:299–304
  39. Nater UM, Maloney E, Boneva RS, et al. Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls. J Clin Endocrinol Metab. 2008;93:703–709
  40. Nater UM, Youngblood LS, Jones JF, et al. Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome. Psychosom Med. 2008;70:298–305
  41. Cleare AJ, Blair D, Chambers S, Wessely S. Urinary free cortisol in chronic fatigue syndrome. Am J Psychiatry. 2001;158:641–643
  42. Cleare AJ, Miell J, Heap E, et al. Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy. J Clin Endocrinol Metab. 2001;86:3545–3554
  43. Jerjes WK, Peters TJ, Taylor NF, Wood PJ, Wessely S, Cleare AJ. Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome. J Psychosom Res. 2006;60:145–153
  44. Scott LV, Dinan TG. Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers. J Affect Disord. 1998;47:49–54
  45. Cleare AJ. The neuroendocrinology of chronic fatigue syndrome. Endocr Rev. 2003;24:236–252
  46. Nater UM, Heim C, Raison CL. Chronic fatigue syndrome. In: Aminoff MJ, Boller F, Swaab D, eds. Handbook of Clinical Neurology. 3rd series. Amsterdam: Elsevier. In press.
  47. Gaab J, Huster D, Peisen R, et al. Low-dose dexamethasone suppression test in chronic fatigue syndrome and health. Psychosom Med. 2002;64:311–318
  48. Segal TY, Hindmarsh PC, Viner RM. Disturbed adrenal function in adolescents with chronic fatigue syndrome. J Pediatr Endocrinol Metab. 2005;18:295–301
  49. Jerjes WK, Taylor NF, Wood PJ, Cleare AJ. Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome. Psychoneuroendocrinology. 2007;32:192–198
  50. Van Den Eede F, Moorkens G, Hulstijn W, et al. Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome. Psychol Med. 2008;38:963–973
  51. Scott LV, Medbak S, Dinan TG. The low dose ACTH test in chronic fatigue syndrome and in health. Clin Endocrinol (Oxf). 1998;48:733–737
  52. ter Wolbeek M, van Doornen LJ, Schedlowski M, Janssen OE, Kavelaars A, Heijnen CJ. Glucocorticoid sensitivity of immune cells in severely fatigued adolescent girls: a longitudinal study. Psychoneuroendocrinology. 2008;33:375–385
  53. Visser J, Lentjes E, Haspels I, et al. Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors. J Investig Med. 2001;49:195–204
  54. Heim C, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC. Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction. Arch Gen Psychiatry. 2009;66:72–80
  55. Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology. 2000;25:1–35
  56. Cleare AJ. The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrinol Metab. 2004;15:55–59
  57. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. 1995;274:961–967
  58. Rowe PC, Bou-Holaigah I, Kan JS, Calkins H. Is neurally mediated hypotension an unrecognised cause of chronic fatigue?. Lancet. 1995;345:623–624
  59. Tanaka H, Matsushima R, Tamai H, Kajimoto Y. Impaired postural cerebral hemodynamics in young patients with chronic fatigue with and without orthostatic intolerance. J Pediatr. 2002;140:412–417
  60. De Lorenzo F, Hargreaves J, Kakkar VV. Possible relationship between chronic fatigue and postural tachycardia syndromes. Clin Auton Res. 1996;6:263–264
  61. Schondorf R, Benoit J, Wein T, Phaneuf D. Orthostatic intolerance in the chronic fatigue syndrome. J Auton Nerv Syst. 1999;75:192–201
  62. Stewart J, Weldon A, Arlievsky N, Li K, Munoz J. Neurally mediated hypotension and autonomic dysfunction measured by heart rate variability during head-up tilt testing in children with chronic fatigue syndrome. Clin Auton Res. 1998;8:221–230
  63. Stewart JM, Gewitz MH, Weldon A, Munoz J. Patterns of orthostatic intolerance: the orthostatic tachycardia syndrome and adolescent chronic fatigue. J Pediatr. 1999;135:218–225
  64. Yataco A, Talo H, Rowe P, Kass DA, Berger RD, Calkins H. Comparison of heart rate variability in patients with chronic fatigue syndrome and controls. Clin Auton Res. 1997;7:293–297
  65. Duprez DA, De Buyzere ML, Drieghe B, et al. Long- and short-term blood pressure and RR-interval variability and psychosomatic distress in chronic fatigue syndrome. Clin Sci (Lond). 1998;94:57–63
  66. Jones JF, Nicholson A, Nisenbaum R, et al. Orthostatic instability in a population-based study of chronic fatigue syndrome. Am J Med. 2005;118:1415
  67. LaManca JJ, Peckerman A, Walker J, et al. Cardiovascular response during head-up tilt in chronic fatigue syndrome. Clin Physiol. 1999;19:111–120
  68. Poole J, Herrell R, Ashton S, Goldberg J, Buchwald D. Results of isoproterenol tilt table testing in monozygotic twins discordant for chronic fatigue syndrome. Arch Intern Med. 2000;160:3461–3468
  69. Freeman R, Komaroff AL. Does the chronic fatigue syndrome involve the autonomic nervous system?. Am J Med. 1997;102:357–364
  70. Karas B, Grubb BP, Boehm K, Kip K. The postural orthostatic tachycardia syndrome: a potentially treatable cause of chronic fatigue, exercise intolerance, and cognitive impairment in adolescents. Pacing Clin Electrophysiol. 2000;23:344–351
  71. Naschitz JE, Rozenbaum M, Rosner I, et al. Cardiovascular response to upright tilt in fibromyalgia differs from that in chronic fatigue syndrome. J Rheumatol. 2001;28:1356–1360
  72. Streeten DH, Thomas D, Bell DS. The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci. 2000;320:1–8
  73. van de Luit L, van der Meulen J, Cleophas TJ, Zwinderman AH. Amplified amplitudes of circadian rhythms and nighttime hypotension in patients with chronic fatigue syndrome: improvement by inopamil but not by melatonin. Angiology. 1998;49:903–908
  74. Winkler AS, Blair D, Marsden JT, Peters TJ, Wessely S, Cleare AJ. Autonomic function and serum erythropoietin levels in chronic fatigue syndrome. J Psychosom Res. 2004;56:179–183
  75. Cordero DL, Sisto SA, Tapp WN, LaManca JJ, Pareja JG, Natelson BH. Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome. Clin Auton Res. 1996;6:329–333
  76. Sisto SA, Tapp W, Drastal S, et al. Vagal tone is reduced during paced breathing in patients with the chronic fatigue syndrome. Clin Auton Res. 1995;5:139–143
  77. Stewart JM. Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Pediatr Res. 2000;48:218–226
  78. De Becker P, Dendale P, De Meirleir K, Campine I, Vandenborne K, Hagers Y. Autonomic testing in patients with chronic fatigue syndrome. Am J Med. 1998;105:22S–26S
  79. Pagani M, Lucini D, Mela GS, Langewitz W, Malliani A. Sympathetic overactivity in subjects complaining of unexplained fatigue. Clin Sci (Lond). 1994;87:655–661
  80. Boneva RS, Decker MJ, Maloney EM, et al. Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome: a population-based study. Auton Neurosci. 2007;137:94–101
  81. Lyall M, Peakman M, Wessely S. A systematic review and critical evaluation of the immunology of chronic fatigue syndrome. J Psychosom Res. 2003;55:79–90
  82. Lorusso L, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G. Immunological aspects of chronic fatigue syndrome. Autoimmun Rev. 2009;8:287–291
  83. Klimas NG, Koneru AO. Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions. Curr Rheumatol Rep. 2007;9:482–487
  84. Jones JF. An extended concept of altered self: chronic fatigue and post-infection syndromes. Psychoneuroendocrinology. 2008;33:119–129
  85. Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006;333:575
  86. Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG. Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors. Appl Neuropsychol. 2001;8:51–64
  87. Patarca R. Cytokines and chronic fatigue syndrome. Ann N Y Acad Sci. 2001;933:185–200
  88. Borish L, Schmaling K, DiClementi JD, Streib J, Negri J, Jones JF. Chronic fatigue syndrome: identification of distinct subgroups on the basis of allergy and psychologic variables. J Allergy Clin Immunol. 1998;102:222–230
  89. Straus SE, Dale JK, Peter JB, Dinarello CA. Circulating lymphokine levels in the chronic fatigue syndrome. J Infect Dis. 1989;160:1085–1086
  90. Cannon JG, Angel JB, Abad LW, et al. Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome. J Clin Immunol. 1997;17:253–261
  91. Mawle AC, Nisenbaum R, Dobbins JG, et al. Immune responses associated with chronic fatigue syndrome: a case-control study. J Infect Dis. 1997;175:136–141
  92. Skowera A, Cleare A, Blair D, Bevis L, Wessely SC, Peakman M. High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clin Exp Immunol. 2004;135:294–302
  93. von Mikecz A, Konstantinov K, Buchwald DS, Gerace L, Tan EM. High frequency of autoantibodies to insoluble cellular antigens in patients with chronic fatigue syndrome. Arthritis Rheum. 1997;40:295–305
  94. Whiteside TL, Friberg D. Natural killer cells and natural killer cell activity in chronic fatigue syndrome. Am J Med. 1998;105:27S–34S
  95. Steinau M, Unger ER, Vernon SD, Jones JF, Rajeevan MS. Differential-display PCR of peripheral blood for biomarker discovery in chronic fatigue syndrome. J Mol Med. 2004;82:750–755
  96. Bounous G, Molson J. Competition for glutathione precursors between the immune system and the skeletal muscle: pathogenesis of chronic fatigue syndrome. Med Hypotheses. 1999;53:347–349
  97. Raison CL, Lin JMS, Reeves WC. Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain Behav Immun. 2009;23:327–337
  98. Danese A, Moffit TE, Pariante CM, Ambler A, Poulton R, Caspi A. Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry. 2008;65:409–415
  99. Pace TW, Mletzko TC, Alagbe O, et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163:1630–1633
  100. Clow A, Thorn L, Evans P, Hucklebridge F. The awakening cortisol response: methodological issues and significance. Stress. 2004;7:29–37
  101. Kirschbaum C, Hellhammer DH. Salivary Cortisol. In:  Fink G editors. Encyclopedia of Stress. Volume 3:San Diego, CA: Academic Press; 2000;p. 379–383
  102. Kennedy B, Dillon E, Mills PJ, Ziegler MG. Catecholamines in human saliva. Life Sci. 2001;69:87–99
  103. Baum BJ. Principles of saliva secretion. Ann NY Acad Sci. 1993;694:17–23
  104. Nater UM, Rohleder N. Salivary alpha-amylase as a non-invasive biomarker for the sympathetic nervous system: current state of research. Psychoneuroendocrinology. 2009;34:486–496
  105. Thayer JF, Sternberg EM. Beyond heart rate variability: vagal regulation of allostatic systems. Ann NY Acad Sci. 2006;1088:361–372
  106. Marques-Deak AH, Cizza G, Eskandari F, et al. Measurement of cytokines in sweat patches and plasma in healthy women: validation in a controlled study. J Immunol Methods. 2006;315:99–109
  107. Cizza G, Marques AH, Eskandari F, et al. Elevated neuroimmune biomarkers in sweat patches and plasma of premenopausal women with major depressive disorder in remission: the POWER study. Biol Psychiatry. 2008;64:907–911
  108. Fries E, Hesse J, Hellhammer J, Hellhammer DH. A new view of hypocortisolism. Psychoneuroendocrinology. 2005;30:1010–1016
  109. van Houdenhove B, van den Eede F, Luyten P. Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a “crash” in the stress system?. Med Hypoth. 2009;72:701–705

PII: S1934-1482(10)00328-X

doi: 10.1016/j.pmrj.2010.04.008

PM&R
Volume 2, Issue 5 , Pages 338-346 , May 2010