There is evidence for a hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in a proportion of the patients with chronic fatigue syndrome (CFS), despite the negative studies and methodological difficulties. In this review, we focus on challenge studies and on the role of the HPA axis in the pathogenesis of CFS. Mild hypocortisolism, blunted adrenocorticotropin response to stressors and enhanced negative feedback sensitivity to glucocorticoids are the main findings. Several underlying mechanisms have been proposed. Currently, it is a matter of debate whether these disturbances have a primary role in the pathogenesis of CFS. However, even if the HPA axis dysfunctions are secondary to other factors, they are probably a relevant factor in symptom propagation in CFS.
© 2007 S. Karger AG, Basel
- Challenge test
- Corticotropin-releasing factor
- Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: 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.
- Cleare AJ: The neuroendocrinology of chronic fatigue syndrome. Endocr Rev 2003;24:236–252.
- Poteliakhoff A: Adrenocortical activity and some clinical findings in acute and chronic fatigue. J Psychosom Res 1981;25:91–95.
- Afari N, Buchwald D: Chronic fatigue syndrome: a review. Am J Psychiatry 2003;160:221–236.
- Hatcher S, House A: Life events, difficulties and dilemmas in the onset of chronic fatigue syndrome: a case-control study. Psychol Med 2003;33:1185–1192.
- Heim C, Wagner D, Maloney E, Papanicolaou DA, Solomon L, Jones JF, Unger ER, Reeves WC: Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study. Arch Gen Psychiatry 2006;63:1258–1266.
- Kato K, Sullivan PF, Evengard B, Pedersen NL: Premorbid predictors of chronic fatigue. Arch Gen Psychiatry 2006;63:1267–1272.
- Prins JB, van der Meer JW, Bleijenberg G: Chronic fatigue syndrome. Lancet 2006;367:346–355.
- Theorell T, Blomkvist V, Lindh G, Evengard B: Critical life events, infections, and symptoms during the year preceding chronic fatigue syndrome (CFS): an examination of CFS patients and subjects with a nonspecific life crisis. Psychosom Med 2005;61:304–310.
- Van Houdenhove B, Neerinckx E, Lysens R, Vertommen H, Van Houdenhove L, Onghena P, Westhovens R, D’Hooghe MB: Victimization in chronic fatigue syndrome and fibromyalgia in tertiary care: a controlled study on prevalence and characteristics. Psychosomatics 2001;42:21–28.
- Van Houdenhove B, Neerinckx E, Onghena P, Lysens R, Vertommen H: Premorbid ‘overactive’ lifestyle in chronic fatigue syndrome and fibromyalgia. An etiological factor or proof of good citizenship? J Psychosom Res 2001;51:571–576.
- Fries E, Hesse J, Hellhammer J, Hellhammer DH: A new view on hypocortisolism. Psychoneuroendocrinology 2005;30:1010–1016.
- Gold PW, Chrousos GP: Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 2002;7:254–275.
- Heim C, Ehlert U, Hellhammer DH: The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology 2000;25:1–35.
- Parker AJ, Wessely S, Cleare AJ: The neuroendocrinology of chronic fatigue syndrome and fibromyalgia. Psychol Med 2001;31:1331–1345.
- Wood B, Wessely S, Papadopoulos A, Poon L, Checkley S: Salivary cortisol profiles in chronic fatigue syndrome. Neuropsychobiology 1998;37:1–4.
- 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.
- 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.
- Di Giorgio A, Hudson M, Jerjes W, Cleare AJ: 24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome. Psychosom Med 2005;67:433–440.
- Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ, Chrousos, GP, Gold PW: Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 1991;73:1224–1234.
- Demitrack MA, Crofford LJ: Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome. Ann NY Acad Sci 1998;840:684– 697.
- Fish HR, Chernow B, O’Brian JT: Endocrine and neurophysiologic responses of the pituitary to insulin-induced hypoglycemia: a review. Metabolism 1986;35:763–780.
- Gaab J, Huster D, Peisen R, Engert V, Heitz V, Schad T, Schurmeyer TH, Ehlert U: Hypothalamic-pituitary-adrenal axis reactivity in chronic fatigue syndrome and health under psychological, physiological, and pharmacological stimulation. Psychosom Med 2002;64:951–962.
- Cleare AJ, Miell J, Heap E, Sookdeo S, Young L, Malhi GS, O’Keane V: 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.
- Moorkens G, Berwaerts J, Wynants H, Abs R: Characterization of pituitary function with emphasis on GH secretion in the chronic fatigue syndrome. Clin Endocrinol 2000;53:99–106.
- Bearn J, Allain T, Coskeran P, Munro N, Butler J, McGregor A, Wessely S: Neuroendocrine responses to d-fenfluramine and insulin-induced hypoglycemia in chronic fatigue syndrome. Biol Psychiatry 1995;37:245–252.
- Scott LV, Medbak S, Dinan TG: Blunted adrenocorticotropin and cortisol responses to corticotropin-releasing hormone stimulation in chronic fatigue syndrome. Acta Psychiatr Scand 1998;97:450–457.
- Inder WJ, Prickett TC, Mulder RT: Normal opioid tone and hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome despite marked functional impairment. Clin Endocrinol 2005;62:343–348.
- Altemus M, Dale JK, Michelson D, Demitrack MA, Gold PW, Straus SE: Abnormalities in response to vasopressin infusion in chronic fatigue syndrome. Psychoneuroendocrinology 2001;26:175–188.
- Scott LV, Medbak S, Dinan TG: Desmopressin augments pituitary-adrenal responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers. Biol Psychiatry 1999;45:1447–1454.
- Scott LV, Burnett F, Medbak S, Dinan TG: Naloxone-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. Psychol Med 1998;28:285–293.
- Gaab J, Huster D, Peisen R, Engert V, Schad T, Schurmeyer TH, Schurmeyer TH, Ehlert U: Low-dose dexamethasone suppression test in chronic fatigue syndrome and health. Psychosom Med 2002;64:311–318.
- Gaab J, Huster D, Peisen R, Engert V, Heitz V, Schad T, Schurmeyer TH, Ehlert U: Assessment of cortisol response with low-dose and high-dose ACTH in patients with chronic fatigue syndrome and healthy comparison subjects. Psychosomatics 2003;44:113–119.
- Hudson M, Cleare AJ: The 1microg short Synacthen test in chronic fatigue syndrome. Clin Endocrinol 1999;51:625–630.
- Scott LV, Medbak S, Dinan TG: The low dose ACTH test in chronic fatigue syndrome and in health. Clin Endocrinol 1998;48:733–777.
- Scott LV, The J, Reznek R, Martin A, Sohaib A, Dinan TG: Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study. Psychoneuroendocrinology 1999;24:759–768.
- Cleare AJ: The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrinol Metab 2004;15:55–59.
- Claes SJ: CRH, stress, and major depression: a psychobiological interplay. Vitam Horm 2004;69:117–150.
- Heim C, Plotsky PM, Nemeroff CB: Importance of studying the contributions of early adverse experience to neurobiological findings in depression. Neuropsychopharmacology 2004;29:641–648.
- Van Houdenhove B, Egle UT: Fibromyalgia: a stress disorder? Piecing the biopsychosocial puzzle together. Psychother Psychosom 2004;73:267–275.
- Crofford LJ, Pillemer SR, Kalogeras KT, Cash JM, Michelson D, Kling MA, Sternberg EM, Gold PW, Chrousos GP, Wilder RL: Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia. Arthritis Rheum 1994;37:1583–1592.
- Griep EN, Boersma JW, de Kloet ER: Altered reactivity of the hypothalamic-pituitary-adrenal axis in the primary fibromyalgia syndrome. J Rheumatol 1993;20:469–474.
- Griep EN, Boersma JW, Lentjes EG, Prins AP, van der Korst JK, de Kloet ER: Function of the hypothalamic-pituitary-adrenal axis in patients with fibromyalgia and low back pain. J Rheumatol 1998;25:1374–1381.
- Crofford LJ, Young EA, Engleberg NC, Korszun A, Brucksch CB, McClure LA, Brown MB, Demitrack MA: Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav Immun 2004;18:314–325.
- Gaab J, Engert V, Heitz V, Schad T, Schurmeyer TH, Ehlert U: Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome. J Psychosom Res 2004;56:419–424.
- Kirschbaum C, Kudielka BM, Gaab J, Schommer NC, Hellhammer DH: Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. Psychosom Med 1999;61:154–162.
- Gaab J, Rohleder N, Heitz V, Schad T, Engert V, Schürmeyer TH, Ehlert U: Enhanced glucocorticoid sensitivity in patients with chronic fatigue syndrome. Acta Neuropsychiatr 2003;15:184–191.
- Visser J, Blauw B, Hinloopen B, Brommer E, de Kloet ER, Kluft C, Nagelkerken L: CD4 T lymphocytes from patients with chronic fatigue syndrome have decreased interferon-gamma production and increased sensitivity to dexamethasone. J Infect Dis 1998;177:451–454.
- Visser J, Graffelman W, Blauw B, Haspels I, Lentjes E, de Kloet ER, Nagelkerken L: LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone. J Neuroimmunol 2001;119:343–349.
- Visser J, Lentjes E, Haspels I, Graffelman W, Blauw B, de Kloet R, Nagelkerken L: 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.
- Chrousos GP, Gold PW: The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 1992;267:1244–1252.
- Heim C, Nemeroff CB: The impact of early adverse experiences on brain systems involved in the pathophysiology of anxiety and affective disorders. Biol Psychiatry 1999;46:1509–1522.
- Yehuda R, Southwick SM, Krystal JH, Bremner D, Charney DS, Mason JW: Enhanced suppression of cortisol following dexamethasone administration in posttraumatic stress disorder. Am J Psychiatry 1993;150:83–86.
- Rinne T, de Kloet ER, Wouters L, Goekoop JG, DeRijk RH, van den Brink W: Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse. Biol Psychiatry 2002;52:1102–1112.
- Newport DJ, Heim C, Bonsall R, Miller AH, Nemeroff CB: Pituitary-adrenal responses to standard and low-dose dexamethasone suppression tests in adult survivors of child abuse. Biol Psychiatry 2004;55:10–20.
- Stein MB, Yehuda R, Koverola C, Hanna C: Enhanced dexamethasone suppression of plasma cortisol in adult women traumatized by childhood sexual abuse. Biol Psychiatry 1997;42:680–686.
- De Souza EB: Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. Psychoneuroendocrinology 1995;20:789–819.
- Brown MR, Fisher LA, Spiess J, Rivier C, Rivier J, Vale W: Corticotropin-releasing factor: actions on the sympathetic nervous system and metabolism. Endocrinology 1982;111:928–931.
- Sutton RE, Koob GF, Le Moal M, Rivier J, Vale W: Corticotropin releasing factor produces behavioural activation in rats. Nature 1992;297:331–333.
- Chang FC, Opp MR: Corticotropin-releasing hormone (CRH) as a regulator of waking. Neurosci Biobehav Rev 2001;25:445–453.
- Lariviere WR, Melzack R: The role of corticotropin-releasing factor in pain and analgesia. Pain 2000;84:1–12.
- Steiger A: Neurochemical regulation of sleep. J Psychiatr Res 2007;41:537–552.
- Reeves WC, Heim C, Maloney EM, Youngblood LS, Unger ER, Decker MJ: Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: results from a population-based study. BMC Neurol 2006;6:41.
- Gerrity TR, Papanicolaou DA, Amsterdam JD, Bingham S, Grossman A, Hedrick T, Herberman, RB, Krueger G, Levine S, Mohagheghpour N, Moore RC, Oleske J, Snell CR; CFIDS Association of America: Immunologic aspects of chronic fatigue syndrome. Report on a Research Symposium convened by The CFIDS Association of America and co-sponsored by the US Centers for Disease Control and Prevention and the National Institutes of Health. Neuroimmunomodulation 2004;11:351–357.
- Dantzer R: Somatization: a psychoneuroimmune perspective. Psychoneuroendocrinology 2005;30:947–952.
- Chalder T, Godfrey E, Ridsdale L, King M, Wessely S: Predictors of outcome in a fatigued population in primary care following a randomized controlled trial. Psychol Med 2003;33:283–287.
- Rubin GJ, Hotopf M, Papadopoulos A, Cleare AJ: Salivary cortisol as a predictor of postoperative fatigue. Psychosom Med 2005;67:441–447.
- Glass JM, Lyden AK, Petzke F, Stein P, Whalen G, Ambrose K, Chrousos G, Clauw DJ: The effect of brief exercise cessation on pain, fatigue, and mood symptom development in healthy, fit individuals. J Psychosom Res 2004;57:391–398.
- Van Houdenhove B: Premorbid ‘overactive’ lifestyle and stress-related pain/fatigue syndromes. J Psychosom Res 2005;58:389–390.
- McEwen BS: Mood disorders and allostatic load. Biol Psychiatry 2003;54:200–207.
- Houshyar H, Galigniana MD, Pratt WB, Woods JH: Differential responsivity of the hypothalamic-pituitary-adrenal axis to glucocorticoid negative-feedback and corticotropin releasing hormone in rats undergoing morphine withdrawal: possible mechanisms involved in facilitated and attenuated stress responses. J Neuroendocrinol 2001;13:875–886.
- Claes SJ, Villafuerte S, Forsgren T, Sluijs S, Del-Favero J, Adolfsson R, Van Broeckhoven C: The corticotropin-releasing hormone binding protein is associated with major depression in a population from Northern Sweden. Biol Psychiatry 2003;54:867–872.
- van Rossum EF, Binder EB, Majer M, Koper JW, Ising M, Modell S, Salyakina D, Lamberts SW, Holsboer F: Polymorphisms of the glucocorticoid receptor gene and major depression. Biol Psychiatry 2006;59:681–688.
- van West D, Del-Favero J, Aulchenko Y, Oswald P, Souery D, Forsgren T, Sluijs S, Bel Kacem S, Adolfsson R, Mendlewicz J, Van Duijn C, Deboutte D, Van Broeckhoven C, Claes SJ: A major SNP haplotype of the arginine vasopressin 1B receptor protects against recurrent major depression. Mol Psychiatry 2004;9:287–292.
- van West D, Van Den Eede F, Del-Favero J, Souery D, Norrback KF, Van Duijn C, Sluijs S, Adolfsson R, Mendlewicz J, Deboutte D, Van Broeckhoven C, Claes SJ: Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression. Neuropsychopharmacology 2006;31:620–627.
- Goertzel BN, Pennachin C, de Souza Coelho L, Gurbaxani B, Maloney EM, Jones JF: Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. Pharmacogenomics 2006;7:475– 483.
- Kaiser J: Biomedicine. Genes and chronic fatigue: how strong is the evidence? Science 2006;312:669–671.
- Rajeevan MS, Smith AK, Dimulescu I, Unger ER, Vernon SD, Heim C, Reeves WC: Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome. Genes Brain Behav 2007;6:167–176.
- Halbreich U: Major depression is not a diagnosis, it is a departure point to differential diagnosis – clinical and hormonal considerations (a commentary and elaboration on Antonejevic’s paper). Psychoneuroendocrinology 2006;31:16–22.
- Baschetti R: Chronic fatigue syndrome: a form of Addison’s disease. J Intern Med 2000;247:737–739.
- McKenzie R, O’Fallon A, Dale J, Demitrack M, Sharma G, Deloria M, Garcia-Borreguero D, Blackwelder W, Straus SE: Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA 1998;280:1061–1066.
- Cleare AJ, Heap E, Malhi GS, Wessely S, O’Keane V, Miell J: Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet 1999;353:455–458.
- Blockmans D, Persoons P, Van Houdenhove B, Lejeune M, Bobbaers H: Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study. Am J Med 2003;114:736–741.
Filip Van Den Eede, PhD
Department of Psychiatry, University Hospital Antwerp (UZA)
BE–2650 Edegem (Belgium)
Tel. +32 3 821 49 11, Fax +32 3 825 16 41, E-Mail email@example.com
Received: August 29, 2006
Accepted after revision: March 17, 2007
Published online: June 27, 2007
Number of Print Pages : 9
Number of Figures : 1, Number of Tables : 1, Number of References : 83
Neuropsychobiology (International Journal of Experimental and Clinical Research in Biological Psychiatry, Pharmacopsychiatry, Biological Psychology/Pharmacopsychology and Pharmacoelectroencephalography)
Vol. 55, No. 2, Year 2007 (Cover Date: July 2007)
Journal Editor: Strik, W. (Bern)
ISSN: 0302–282X (print), 1423–0224 (Online)
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