The role of hypocortisolism in chronic fatigue syndrome

BACKGROUND There is accumulating evidence of hypothalamic-pituitary-adrenal (HPA) axis hypofunction in chronic fatigue syndrome (CFS). However, knowledge of this hypofunction has so far come exclusively from research in adulthood, and its clinical significance remains unclear. The objective of the current study was to assess the role of the HPA-axis in adolescent CFS and recovery from adolescent CFS. METHOD Before treatment, we compared the salivary cortisol awakening response of 108 diagnosed adolescent CFS patients with that of a reference group of 38 healthy peers. Salivary cortisol awakening response was measured again after 6 months of treatment in CFS patients. RESULTS Pre-treatment salivary cortisol levels were significantly lower in CFS-patients than in healthy controls. After treatment recovered patients had a significant rise in salivary cortisol output attaining normalization, whereas non-recovered patients improved slightly, but not significantly. The hypocortisolism found in CFS-patients was significantly correlated to the amount of sleep. Logistic regression analysis showed that an increase of one standard deviation in the difference between pre- and post-treatment salivary cortisol awakening response was associated with a 93% higher odds of recovery (adjusted OR 1.93 (1.18 to 3.17), p=0.009). Pre-treatment salivary cortisol did not predict recovery. CONCLUSIONS Hypocortisolism is associated with adolescent CFS. It is not pre-treatment cortisol but its change to normalization that is associated with treatment success. We suggest that this finding may have clinical implications regarding the adaptation of future treatment strategies.

[1]  C. Kirschbauma,et al.  Awakening cortisol responses are influenced by health status and awakening time but not by menstrual cycle phase , 2002 .

[2]  G. Bleijenberg,et al.  Fatigue In Teenagers on the interNET - The FITNET Trial. A randomized clinical trial of web-based cognitive behavioural therapy for adolescents with chronic fatigue syndrome: study protocol. [ISRCTN59878666] , 2011, BMC neurology.

[3]  C. Kirschbaum,et al.  Familial influences on basal salivary cortisol in an adult population , 2005, Psychoneuroendocrinology.

[4]  G. Bleijenberg,et al.  Clinical assessment of the physical activity pattern of chronic fatigue syndrome patients: a validation of three methods , 2009, Health and quality of life outcomes.

[5]  C. Kirschbaum,et al.  Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity. , 1997, Life sciences.

[6]  D. Jessop,et al.  Measurement and meaning of salivary cortisol: A focus on health and disease in children , 2008, Stress.

[7]  Ian Hickie,et al.  The Chronic Fatigue Syndrome: A Comprehensive Approach to Its Definition and Study , 1994, Annals of Internal Medicine.

[8]  G. Bleijenberg,et al.  Efficacy of Cognitive Behavioral Therapy for Adolescents With Chronic Fatigue Syndrome: Long-term Follow-up of a Randomized, Controlled Trial , 2008, Pediatrics.

[9]  T. Chalder,et al.  Family-focused cognitive behaviour therapy versus psycho-education for chronic fatigue syndrome in 11- to 18-year-olds: a randomized controlled treatment trial , 2009, Psychological Medicine.

[10]  M. Demitrack,et al.  Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. , 1998, JAMA.

[11]  G. Chrousos,et al.  Evaluation of the Hypothalamic-Pituitary-Adrenal Axis Function in Childhood and Adolescence , 2009, Neuroimmunomodulation.

[12]  G. Bleijenberg,et al.  Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. , 2000, Journal of psychosomatic research.

[13]  A. Steptoe,et al.  Smoking, cortisol and nicotine. , 2004, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[14]  G. Bleijenberg,et al.  Effectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): a randomised controlled trial , 2012, The Lancet.

[15]  G. Bleijenberg,et al.  Internet-Based Therapy for Adolescents With Chronic Fatigue Syndrome: Long-term Follow-up , 2013, Pediatrics.

[16]  A. Cleare The HPA axis and the genesis of chronic fatigue syndrome , 2004, Trends in Endocrinology & Metabolism.

[17]  I. Hickie,et al.  The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. , 1994, Annals of internal medicine.

[18]  Patrick Luyten,et al.  Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a 'crash' in the stress system? , 2009, Medical hypotheses.

[19]  C. Kirschbaum,et al.  Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change , 2003, Psychoneuroendocrinology.

[20]  C. Törnhage Salivary Cortisol for Assessment of Hypothalamic-Pituitary-Adrenal Axis Function , 2009, Neuroimmunomodulation.

[21]  Dirk H. Hellhammer,et al.  The cortisol awakening response - normal values and confounds. , 2000, Noise & health.

[22]  G. Bleijenberg,et al.  Dimensional assessment of chronic fatigue syndrome. , 1994, Journal of psychosomatic research.

[23]  Simon Wessely,et al.  Salivary cortisol response to awakening in chronic fatigue syndrome , 2004, British Journal of Psychiatry.

[24]  P Evans,et al.  The Awakening Cortisol Response: Methodological Issues and Significance , 2004, Stress.

[25]  A M Hansen,et al.  Long‐term stability of salivary cortisol , 2005, Scandinavian journal of clinical and laboratory investigation.

[26]  M. Kovacs The Children's Depression, Inventory (CDI). , 1985, Psychopharmacology bulletin.

[27]  Clemens Kirschbaum,et al.  The cortisol awakening response (CAR): facts and future directions. , 2009, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[28]  D. Hellhammer,et al.  A new view on hypocortisolism , 2005, Psychoneuroendocrinology.

[29]  H. Kley,et al.  [The effect of storage and temperature on the analysis of steroids in plasma and blood]. , 1984, Journal of clinical chemistry and clinical biochemistry. Zeitschrift fur klinische Chemie und klinische Biochemie.

[30]  A. Cleare,et al.  Glucocorticoid receptor mediated negative feedback in chronic fatigue syndrome using the low dose (0.5 mg) dexamethasone suppression test. , 2009, Journal of affective disorders.

[31]  J. Violanti,et al.  Area Under the Curve and Other Summary Indicators of Repeated Waking Cortisol Measurements , 2007, Psychosomatic medicine.

[32]  R. Engelbert,et al.  Mirrored Symptoms in Mother and Child With Chronic Fatigue Syndrome , 2006, Pediatrics.

[33]  S. Wessely,et al.  Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial , 1999, The Lancet.

[34]  L. Lipsitt,et al.  Long-term stability of maternal prenatal steroid hormones from the National Collaborative Perinatal Project: Still valid after all these years , 2007, Psychoneuroendocrinology.

[35]  G. Bonsel,et al.  Reliability and validity of the child health questionnaire-child form (CHQ-CF87) in a Dutch adolescent population , 2002, Quality of Life Research.

[36]  S. Wessely,et al.  Does hypocortisolism predict a poor response to cognitive behavioural therapy in chronic fatigue syndrome? , 2009, Psychological Medicine.

[37]  L. Coffeng,et al.  Cortisol and severe fatigue: A longitudinal study in adolescent girls , 2007, Psychoneuroendocrinology.

[38]  R. J. Bakker,et al.  Adolescent chronic fatigue syndrome: a follow-up study. , 2010, Archives of pediatrics & adolescent medicine.

[39]  S. Wessely,et al.  Salivary cortisol output before and after cognitive behavioural therapy for chronic fatigue syndrome. , 2009, Journal of affective disorders.

[40]  A. Cleare,et al.  The neuroendocrinology of chronic fatigue syndrome. , 2003, Endocrine reviews.

[41]  D. Bell,et al.  Thirteen-year follow-up of children and adolescents with chronic fatigue syndrome. , 2001, Pediatrics.

[42]  C. Kirschbaum,et al.  Free cortisol awakening responses are influenced by awakening time , 2004, Psychoneuroendocrinology.

[43]  J. Rosmalen,et al.  Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders , 2010, Biological Psychology.

[44]  Gijs Bleijenberg,et al.  Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial , 2004, BMJ : British Medical Journal.

[45]  D. Hellhammer,et al.  The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders , 2000, Psychoneuroendocrinology.

[46]  G. Bleijenberg,et al.  Adolescent Chronic Fatigue Syndrome: Prevalence, Incidence, and Morbidity , 2011, Pediatrics.

[47]  M. Demitrack,et al.  Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. , 1991, The Journal of clinical endocrinology and metabolism.