Hypothalamic–pituitary–adrenal axis dysfunction in chronic fatigue syndrome

This article has been updated


The weight of current evidence supports the presence of the following factors related to hypothalamic–pituitary–adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS): mild hypocortisolism; attenuated diurnal variation of cortisol; enhanced negative feedback to the HPA axis; and blunted HPA axis responsiveness. Furthermore, HPA axis changes seem clinically relevant, as they are associated with worse symptoms and/or disability and with poorer outcomes to standard treatments for CFS. Regarding etiology, women with CFS are more likely to have reduced cortisol levels. Studies published in the past 8 years provide further support for a multifactorial model in which several factors interact to moderate HPA axis changes. In particular, low activity levels, depression and early-life stress appear to reduce cortisol levels, whereas the use of psychotropic medication can increase cortisol. Addressing these factors—for example, with cognitive behavioral therapy—can increase cortisol levels and is probably the first-line approach for correcting HPA axis dysfunction at present, as steroid replacement is not recommended. Given what is now a fairly consistent pattern of findings for the type of HPA axis changes found in CFS, we recommend that future work focuses on improving our understanding of the cause and relevance of these observed changes.

Key Points

  • The bulk of evidence points to modest reductions in cortisol levels in some cohorts of patients with chronic fatigue syndrome (CFS), and these changes are more apparent in women than in men

  • Underlying the reduction in cortisol levels is a hypothalamic–pituitary–adrenal (HPA) axis with attenuated diurnal variation, enhanced negative feedback and blunted response to challenges

  • Low cortisol levels have clinical relevance as they might contribute to symptoms—along with other factors—and are associated with a worsened outcome of currently recommended treatments for CFS

  • A multidimensional etiological model remains most probable, with low cortisol levels occurring at a later stage of the illness, moderated by factors such as activity levels, depression, early-life stress and psychotropic medication

  • Cortisol levels can be increased by treatment with cognitive behavioral therapy, potentially because of reversal of some moderating factors

  • Further improvements in research designs remain necessary to fully understand HPA axis dysfunction in CFS

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Figure 1: Schematic representation of the hypothalamic–pituitary–adrenal (HPA) axis.

Change history

  • 26 June 2012

    In the version of this article initially published online in Table 3 the findings in relation to the study by Van den Eede et al. should have read "Patients without early-life stress had lower mean cortisol post DEX and lower AUC total post DEX plus CRH than both controls and patients with early-life stress". The error has been corrected for the HTML and PDF versions of the article.


  1. 1

    Fukuda, K. et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann. Intern. Med. 121, 953–959 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. 2

    Cho, H. J., Skowera, A., Cleare, A. & Wessely, S. Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology. Curr. Opin. Psychiatry 19, 67–73 (2006).

    Article  Google Scholar 

  3. 3

    Dinos, S. et al. A systematic review of chronic fatigue, its syndromes and ethnicity: prevalence, severity, co-morbidity and coping. Int. J. Epidemiol. 38, 1554–1570 (2009).

    Article  Google Scholar 

  4. 4

    Cleare, A. J. & Wessely, S. Chronic fatigue syndrome. eLS doi:10.1038/npg.els.0002207.

  5. 5

    Demitrack, M. A. et al. Evidence for impaired activation of the hypothalamic–pituitary–adrenal axis in patients with chronic fatigue syndrome. J. Clin. Endocrinol. Metab. 73, 1224–1234 (1991).

    Article  CAS  Google Scholar 

  6. 6

    Cleare, A. J. The neuroendocrinology of chronic fatigue syndrome. Endocr. Rev. 24, 236–252 (2003).

    Article  CAS  Google Scholar 

  7. 7

    Cleare, A. J. The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrinol. Metab. 15, 55–59 (2004).

    Article  CAS  Google Scholar 

  8. 8

    Cleare, A. J. in Handbook of Chronic Fatigue Syndrome 1st edn Ch. 16 (eds Jason, L. A., Fennell, P. A. & Taylor, R. R.) 331–362 (John Wiley & Sons, Hoboken, 2003).

    Google Scholar 

  9. 9

    Roberts, A. D., Wessely, S., Chalder, T., Papadopoulos, A. & Cleare, A. J. Salivary cortisol response to awakening in chronic fatigue syndrome. Br. J. Psychiatry 184, 136–141 (2004).

    Article  Google Scholar 

  10. 10

    Papadopoulos, A. et al. Glucocorticoid receptor mediated negative feedback in chronic fatigue syndrome using the low dose (0.5 mg) dexamethasone suppression test. J. Affect. Disord. 112, 289–294 (2009).

    Article  CAS  Google Scholar 

  11. 11

    Cleare, A. J., O'Keane, V. & Miell, J. P. Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome. Psychoneuroendocrinology 29, 724–732 (2004).

    Article  CAS  Google Scholar 

  12. 12

    Cevik, R., Gur, A., Acar, S., Nas, K. & Sarac, A. J. 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. 5, 47 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Inder, W. J., Prickett, T. C. & Mulder, R. T. Normal opioid tone and hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome despite marked functional impairment. Clin. Endocrinol. (Oxf.) 62, 343–348 (2005).

    Article  CAS  Google Scholar 

  14. 14

    Turan, T. et al. The effects of galantamine hydrobromide treatment on dehydroepiandrosterone sulfate and cortisol levels in patients with chronic fatigue syndrome. Psychiatry Investig. 6, 204–210 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Izgi, H. B. et al. Investigation of the hypothalamopituitary-adrenal axis by low-dose (1 μg) adrenocorticotrophic hormone test and metyrapone test in patients with chronic fatigue syndrome. Endocrinologist 15, 89–92 (2005).

    Article  CAS  Google Scholar 

  16. 16

    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. 6, R232–R238 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Maes, M., Mihaylova, I. & De Ruyter, M. Decreased dehydroepiandrosterone sulfate but normal insulin-like growth factor in chronic fatigue syndrome (CFS): relevance for the inflammatory response in CFS. Neuro. Endocrinol. Lett. 26, 487–492 (2005).

    CAS  PubMed  Google Scholar 

  18. 18

    Meeus, M., Nijs, J., Van de Wauwer, N., Toeback, L. & Truijen, S. Diffuse noxious inhibitory control is delayed in chronic fatigue syndrome: an experimental study. Pain 139, 439–448 (2008).

    Article  Google Scholar 

  19. 19

    Crofford, L. J. et al. Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain Behav. Immun. 18, 314–325 (2004).

    Article  CAS  Google Scholar 

  20. 20

    Di Giorgio, A., Hudson, M., Jerjes, W. & Cleare, A. J. 24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome. Psychosom. Med. 67, 433–440 (2005).

    Article  CAS  Google Scholar 

  21. 21

    Jerjes, W. K., Cleare, A. J., Wessely, S., Wood, P. J. & Taylor, N. F. Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome. J. Affect. Disord. 87, 299–304 (2005).

    Article  CAS  Google Scholar 

  22. 22

    Nater, U. M. et al. Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome. Psychosom. Med. 70, 298–305 (2008).

    Article  CAS  Google Scholar 

  23. 23

    Jerjes, W. K., Taylor, N. F., Peters, T. J., Wessely, S. & Cleare, A. J. Urinary cortisol and cortisol metabolite excretion in chronic fatigue syndrome. Psychosom. Med. 68, 578–582 (2006).

    Article  CAS  Google Scholar 

  24. 24

    Jerjes, W. K. et al. Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome. J. Psychosom. Res. 60, 145–153 (2006).

    Article  Google Scholar 

  25. 25

    Jerjes, W. K., Taylor, N. F., Wood, P. J. & Cleare, A. J. Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome. Psychoneuroendocrinology 32, 192–198 (2007).

    Article  CAS  Google Scholar 

  26. 26

    Tak, L. M. et al. Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis acitivity in functional somatic disorders. Biol. Psychol. 87, 183–194 (2011).

    Article  Google Scholar 

  27. 27

    Roberts, A. D. et al. Does hypocortisolism predict a poor response to cognitive behavioural therapy in chronic fatigue syndrome? Psychol. Med. 40, 515–522 (2010).

    Article  CAS  Google Scholar 

  28. 28

    Roberts, A. D., Papadopoulos, A. S., Wessely, S., Chalder, T. & Cleare, A. J. Salivary cortisol output before and after cognitive behavioural therapy for chronic fatigue syndrome. J. Affect. Disord. 115, 280–286 (2009).

    Article  CAS  Google Scholar 

  29. 29

    Torres-Harding, S. et al. The associations between basal salivary cortisol and illness symptomatology in chronic fatigue syndrome. J. Appl. Biobehav. Res. 13, 157–180 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    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 28, 76–81 (1993).

    Article  CAS  Google Scholar 

  31. 31

    Melmed, S. & Kleinberg, D. in Williams Textbook of Endocrinology 10th edn Ch. 8 (eds Larsen, P. R., Kronenberg, H. M., Melmed, S. & Polonsky, K. S.) 177–260 (Saunders, 2003).

    Google Scholar 

  32. 32

    Pruessner, J. C. et al. Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity. Life Sci. 61, 2539–2549 (1997).

    Article  CAS  Google Scholar 

  33. 33

    Schmidt-Reinwald, A. et al. The cortisol response to awakening in relation to different challenge tests and a 12-hour cortisol rhythm. Life Sci. 64, 1653–1660 (1999).

    Article  CAS  Google Scholar 

  34. 34

    Gaab, J. et al. Associations between neuroendocrine responses to the insulin tolerance test and patient characteristics in chronic fatigue syndrome. J. Psychosom. Res. 56, 419–424 (2004).

    Article  Google Scholar 

  35. 35

    Gaab, J. et al. Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome. Psychoneuroendocrinology 30, 188–198 (2005).

    Article  CAS  Google Scholar 

  36. 36

    Nater, U. M. 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. 93, 703–709 (2008).

    Article  CAS  Google Scholar 

  37. 37

    Heim, C. et al. Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction. Arch. Gen. Psychiatry 66, 72–80 (2009).

    Article  PubMed  Google Scholar 

  38. 38

    Gaab, J. et al. Low-dose dexamethasone suppression test in chronic fatigue syndrome and health. Psychosom. Med. 64, 311–318 (2002).

    Article  CAS  Google Scholar 

  39. 39

    Pruessner, J. C., Hellhammer, D. H. & Kirschbaum, C. Burnout, perceived stress, and cortisol responses to awakening. Psychosom. Med. 61, 197–204 (1999).

    Article  CAS  Google Scholar 

  40. 40

    Yehuda, R., Boisoneau, D., Lowy, M. T. & Giller, E. L. Jr . Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. Arch. Gen. Psychiatry 52, 583–593 (1995).

    Article  CAS  Google Scholar 

  41. 41

    Goenjian, A. K. et al. Basal cortisol, dexamethasone suppression of cortisol, and MHPG in adolescents after the 1998 earthquake in Armenia. Am. J. Psychiatry 153, 929–934 (1996).

    Article  CAS  Google Scholar 

  42. 42

    Stein, M. B., Yehuda, R., Koverola, C. & Hanna, C. Enhanced dexamethasone suppression of plasma cortisol in adult women traumatized by childhood sexual abuse. Biol. Psychiatry 42, 680–686 (2011).

    Article  Google Scholar 

  43. 43

    Heim, C., Ehlert, U., Hanker, J. P. & Hellhammer, D. H. Abuse-related posttraumatic stress disorder and alterations of the hypothalamic–pituitary–adrenal axis in women with chronic pelvic pain. Psychosom. Med. 60, 309–318 (1998).

    Article  CAS  Google Scholar 

  44. 44

    Gaab, J. et al. Enhanced glucocorticoid sensitivity in patients with chronic fatigue syndrome. Acta Neuropsychiatr. 15, 184–191 (2003).

    Article  Google Scholar 

  45. 45

    Visser, J. et al. CD4 T lymphocytes from patients with chronic fatigue syndrome have decreased interferon-g production and increased sensitivity to dexamethasone. J. Infect. Dis. 177, 451–454 (1998).

    Article  CAS  Google Scholar 

  46. 46

    Visser, J. 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. 49, 195–204 (2001).

    Article  CAS  Google Scholar 

  47. 47

    Van Den Eede, F. et al. Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome. Psychol. Med. 38, 963–973 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. 48

    Juruena, M. F., Pariante, C. M., Papadopoulos, A. & Cleare, A. J. The development and application of the prednisolone suppression test in psychiatry: a novel tool for assessing glucocorticoid and mineralocorticoid receptor function. Mind Brain 1, 115–122 (2010).

    Google Scholar 

  49. 49

    Cleare, A. J., O'Keane, V. & Miell, J. Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low-dose hydrocortisone on leptin secretion Clin. Endocrinol. (Oxf.) 55, 113–119 (2001).

    Article  CAS  Google Scholar 

  50. 50

    Baulieu, E. E. Dehydroepiandrosterone (DHEA): a fountain of youth? J. Clin. Endocrinol. Metab. 81, 3147–3151 (1996).

    Article  CAS  Google Scholar 

  51. 51

    Kalimi, M., Shafagoj, Y., Loria, R., Padgett, D. & Regelson, W. Anti-glucocorticoid effects of dehydroepiandrosterone (DHEA). Mol. Cell Biochem. 131, 99–104 (1994).

    Article  CAS  Google Scholar 

  52. 52

    Kroboth, P. D., Salek, F. S., Pittenger, A. L., Fabian, T. J. & Frye, R. F. DHEA and DHEA-S: a review. J. Clin. Pharmacol. 39, 327–348 (1999).

    Article  CAS  Google Scholar 

  53. 53

    Maninger, N., Wolkowitz, O. M., Reus, V. I., Epel, E. S. & Mellon, S. H. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front. Neuroendocrinol. 30, 65–91 (2009).

    Article  CAS  Google Scholar 

  54. 54

    Ngai, L.-Y. & Herbert, J. in DHEA and the Brain 1st edn Ch. 3 (ed. Morfin, R.) 44–71 (Taylor and Francis, London and New York, 2002).

    Google Scholar 

  55. 55

    Burtis, C. A., Ashwood, E. R. & Bruns, D. E. Tietz textbook of clinical chemistry and molecular diagnostics (Saunders, Pennsylvania, USA, 2005).

    Google Scholar 

  56. 56

    Rosenfeld, R. S., Rosenberg, B. J., Fukushima, D. K. & Hellman, L. 24-Hour secretory pattern of dehydroisoandrosterone and dehydroisoandrosterone sulfate. J. Clin. Endocrinol. Metab. 40, 850–855 (1975).

    Article  CAS  Google Scholar 

  57. 57

    Nieschlag, E. et al. The secretion of dehydroepiandrosterone and dehydroepiandrosterone sulphate in man. J. Endocrinol. 57, 123–134 (1973).

    Article  CAS  Google Scholar 

  58. 58

    Salek, F. S., Bigos, K. L. & Kroboth, P. D. The influence of hormones and pharmaceutical agents on DHEA and DHEA-S. concentrations: a review of clinical studies. J. Clin. Pharmacol. 42, 247–266 (2002).

    Article  CAS  Google Scholar 

  59. 59

    Kroboth, P. D. et al. Influence of DHEA administration on 24-hour cortisol concentrations. J. Clin. Psychopharmacol. 23, 96–99 (2003).

    Article  CAS  Google Scholar 

  60. 60

    Wolf, O. T. et al. A single administration of dehydroepiandrosterone does not enhance memory performance in young healthy adults, but immediately reduces cortisol levels. Biol. Psychiatry 42, 845–848 (1997).

    Article  CAS  Google Scholar 

  61. 61

    Kalimi, M., Shafagoj, Y., Loria, R., Padgett, D. & Regelson, W. Anti-glucocorticoid effects of dehydroepiandrosterone (DHEA). Mol. Cell Biochem. 131, 99–104 (1994).

    Article  CAS  Google Scholar 

  62. 62

    Hechter, O., Grossman, A. & Chatterton, R. T. Jr . Relationship of dehydroepiandrosterone and cortisol in disease. Med. Hypotheses 49, 85–91 (1997).

    Article  CAS  Google Scholar 

  63. 63

    Goodyer, I. M., Herbert, J. & Altham, P. M. Adrenal steroid secretion and major depression in 8- to 16-year-olds, III. Influence of cortisol/DHEA ratio at presentation on subsequent rates of disappointing life events and persistent major depression. Psychol. Med. 28, 265–273 (1998).

    Article  CAS  Google Scholar 

  64. 64

    Reid, S. F., Chalder, T., Cleare, A., Hotopf, M. & Wessely, S. Chronic fatigue syndrome. Clin. Evid. (Online) pii, 1101 (2011).

  65. 65

    Jason, L. et al. Baseline cortisol levels predict treatment outcomes in chronic fatigue syndrome non-pharmacologic clinical trial. J. Chronic Fatigue Syndr. 14, 39–59 (2007).

    Article  Google Scholar 

  66. 66

    Tak, L. M. et al. As good as it gets? A meta-analysis and systematic review of methodological quality of heart rate variability studies in functional somatic disorders. Biol. Psychol. 82, 101–110 (2009).

    Article  Google Scholar 

  67. 67

    von Elm, E. et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Plos Med. 4, e296 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Altman, D. G. & Lyman, G. H. Methodological challenges in the evaluation of prognostic factors in breast cancer. Breast Cancer Res. Treat. 52, 289–303 (1998).

    Article  CAS  Google Scholar 

  69. 69

    Candy, B. et al. Predictors of fatigue following the onset of infectious mononucleosis. Psychol. Med. 33, 847–855 (2003).

    Article  CAS  Google Scholar 

  70. 70

    Rubin, G. J., Hotopf, M., Papadopoulos, A. & Cleare, A. Salivary cortisol as a predictor of postoperative fatigue. Psychosom. Med. 67, 441–447 (2005).

    Article  CAS  Google Scholar 

  71. 71

    Fries, E., Hesse, J., Hellhammer, J. & Hellhammer, D. H. A new view on hypocortisolism. Psychoneuroendocrinology 30, 1010–1016 (2005).

    Article  CAS  Google Scholar 

  72. 72

    Fries, E in Stress. The brain–body connection. (eds Hellhammer, D. H. & Hellhammer, J.) 60–77 (Karger, Basel, 2008). [Series Eds Riecher-Rössler, A. & Steiner, M. Key issues in mental health Vol. 174].

    Google Scholar 

  73. 73

    Miller, G. E., Chen, E. & Zhou, E. S. If it goes up, must it come down? Chronic stress and the hypothalamic–pituitary-–adrenocortical axis in humans. Psychol. Bull. 133, 25–45 (2007).

    Article  Google Scholar 

  74. 74

    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. Hypotheses 72, 701–705 (2009).

    Article  CAS  Google Scholar 

  75. 75

    Gold, P. W., Licinio, J., Wong, M. L. & Chrousos, G. P. Corticotropin releasing hormone in the pathophysiology of melancholic and atypical depression and in the mechanism of action of antidepressant drugs. Ann. N. Y. Acad. Sci. 771, 716–729 (1995).

    Article  CAS  Google Scholar 

  76. 76

    Carruthers, B. M. Definitions and aetiology of myalgic encephalomyelitis: how the Canadian consensus clinical definition of myalgic encephalomyelitis works. J. Clin. Pathol. 60, 117–119 (2007).

    Article  CAS  Google Scholar 

  77. 77

    Cryer, P. E., Davis, S. N. & Shamoon, H. Hypoglycemia in diabetes. Diabetes Care 26, 1902–1912 (2003).

    Article  CAS  Google Scholar 

  78. 78

    Kirschbaum, C., Tietze, A., Skoluda, N. & Dettenborn, L. Hair as a retrospective calendar of cortisol production-Increased cortisol incorporation into hair in the third trimester of pregnancy. Psychoneuroendocrinology 34, 32–37 (2009).

    Article  CAS  Google Scholar 

  79. 79

    Thomson, S. et al. Hair analysis provides a historical record of cortisol levels in Cushing's syndrome. Exp. Clin. Endocrinol. Diabetes 118, 133–138 (2010).

    Article  CAS  Google Scholar 

  80. 80

    Dettenborn, L., Tietze, A., Bruckner, F. & Kirschbaum, C. Higher cortisol content in hair among long-term unemployed individuals compared to controls. Psychoneuroendocrinology 35, 1404–1409 (2010).

    Article  CAS  Google Scholar 

  81. 81

    Warnock, F. et al. Measuring cortisol and DHEA in fingernails: a pilot study. Neuropsychiatr. Dis. Treat. 6, 1–7 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Steudte, S. et al. Decreased hair cortisol concentrations in generalised anxiety disorder. Psychiatry Res. 186, 310–314 (2011).

    Article  CAS  Google Scholar 

  83. 83

    Gow, R., Thomson, S., Rieder, M., Van, U. S. & Koren, G. An assessment of cortisol analysis in hair and its clinical applications. Forensic Sci. Int. 196, 32–37 (2010).

    Article  CAS  Google Scholar 

  84. 84

    Koper, J. W., Manenschijn, L., Lamberts, S. W. & van Rossum, E. F. Evaluation of a method to measure long term cortisol levels. Steroids 76, 1032–1036 (2011).

    Article  CAS  Google Scholar 

  85. 85

    Gold, P. W. & Chrousos, G. P. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol. Psychiatry 7, 254–275 (2002).

    Article  CAS  Google Scholar 

  86. 86

    Juruena, M. F. & Cleare, A. J. Overlap between atypical depression, seasonal affective disorder and chronic fatigue syndrome [Portuguese]. Rev. Bras. Psiquiatr. 29 (Suppl. 1), S19–S26 (2007).

    Article  Google Scholar 

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The authors' work was supported by the NIHR Biomedical Research Centre at South London and Maudsley NHS Trust & Institute of Psychiatry (King's College London).

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Both authors contributed equally to all aspects of this manuscript.

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Correspondence to Anthony J. Cleare.

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Papadopoulos, A., Cleare, A. Hypothalamic–pituitary–adrenal axis dysfunction in chronic fatigue syndrome. Nat Rev Endocrinol 8, 22–32 (2012). https://doi.org/10.1038/nrendo.2011.153

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