E0ReviewPEM ?
Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity.
2026Woo, Tae-Wook et al.·Molecular psychiatry·Meta-Analysis
← Research Hub
Endocrine
Endocrine Disruption
131 studies in the atlas
The hypothalamic-pituitary-adrenal (HPA) axis has been extensively studied in ME/CFS. Patterns suggestive of HPA-axis alterations have been reported in multiple studies — including mild hypocortisolism, attenuated diurnal cortisol variation, enhanced negative feedback, and blunted HPA-axis responsiveness — though findings are not uniform across cohorts. These neuroendocrine signals are associated with worse symptoms and poorer treatment outcomes in some clinical studies. HPA-axis alterations may reflect adjustments at the level of the central nervous system, the adrenal cortex, or both, and may interact with the immune and autonomic abnormalities reported in the illness.
What we know
- Some studies have reported blunted cortisol responses and altered HPA axis function in ME/CFS
- Thyroid function abnormalities have been observed in subsets of patients, though most have normal standard thyroid tests
- Sex-specific differences in ME/CFS prevalence suggest hormonal factors may play a role
- Endocrine findings are generally subtle and not consistent across studies
What remains uncertain
- Whether HPA axis changes are a primary feature or a secondary adaptation to chronic illness
- Whether subclinical thyroid dysfunction contributes meaningfully to symptoms
- The role of sex hormones in the 2-4x higher prevalence of ME/CFS in women
- Whether hormonal interventions could benefit specific patient subgroups
What is emerging
- The mechanisms linking endocrine function to immune and metabolic abnormalities in ME/CFS
- Whether endocrine profiles predict disease trajectory
- The interaction between endocrine disruption and autonomic dysfunction
- Whether menstrual cycle-related symptom fluctuations reflect underlying endocrine mechanisms
Start here
E0 ConsensusPEM not required
Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis.
Zhang, Yi-Dan, Wang, Li-Na·Frontiers in endocrinology·2024
This review examines how ME/CFS affects the body's stress-response system, called the HPA axis, which controls cortisol (a stress hormone). Research shows that people with ME/CFS tend to have lower cortisol levels, less natural variation in cortisol throughout the day, and a weaker response to stress compared to healthy people. Understanding these hormone changes may help explain why ME/CFS patients experience extreme fatigue and other symptoms, and could guide new treatments.
Research Momentum
130 publications over 32 years. Recent trend: steady (2/year over the last 3 years).
Top Studies
60 of 131, sorted by evidence level and year
E0ReviewPEM ✗
Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis.
2024Zhang, Yi-Dan et al.·Frontiers in endocrinology·Review-Narrative
E0ReviewPEM ✗
Potential causal factors of CFS/ME: a concise and systematic scoping review of factors researched.
2020Muller, Ashley Elizabeth et al.·Journal of translational medicine·Systematic-Review
E0ReviewPEM ✗
A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome.
2013Tomas, Cara et al.·ISRN neuroscience·Review-Narrative
E0ReviewPEM ✗
Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta-analysis.
2013Powell, Daniel J H et al.·Psychoneuroendocrinology·Systematic-Review
E0ReviewPEM ?
Sleep abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a review.
2012Jackson, Melinda L et al.·Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine·Review-Narrative
E0ReviewPEM ✗
Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome.
2011Papadopoulos, Andrew S et al.·Nature reviews. Endocrinology·Systematic-Review
E0ReviewPEM ✗
The genetics and epigenetics of fatigue.
2010Landmark-Høyvik, Hege et al.·PM & R : the journal of injury, function, and rehabilitation·Systematic-Review
E0ReviewPEM ✗
Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome.
2007Van Den Eede, Filip et al.·Neuropsychobiology·Review-Narrative
E0ReviewPEM ✗
[Chronic fatigue syndrome--a functional somatic syndrome].
2007Linde, Andreas·Therapeutische Umschau. Revue therapeutique·Editorial
E0ReviewPEM ✗
The neuroendocrinology of chronic fatigue syndrome.
2003Cleare, Anthony J·Endocrine reviews·Review-Narrative
E0ReviewPEM ✗
The neuroendocrinology of chronic fatigue syndrome and fibromyalgia.
2001Parker, A J et al.·Psychological medicine·Review-Narrative
E0ReviewPEM ✗
Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders.
2011Tak, Lineke M et al.·Biological psychology·Meta-Analysis
E0ReviewPEM ✗
[Overlap between atypical depression, seasonal affective disorder and chronic fatigue syndrome].
2007Juruena, Mario Francisco et al.·Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)·Review-Narrative
E0ReviewPEM ?
The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders.
2000Heim, C et al.·Psychoneuroendocrinology·Systematic-Review
E0ReviewPEM ✗
[Neuro-endocrine correlates of burnout].
2012Verhaeghe, J et al.·Tijdschrift voor psychiatrie·Systematic-Review
E1TrialPEM ✗
Disease mechanisms and clonidine treatment in adolescent chronic fatigue syndrome: a combined cross-sectional and randomized clinical trial.
2014Sulheim, Dag et al.·JAMA pediatrics·RCT
E1TrialPEM ✗
Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome.
2004Cleare, A J et al.·Psychoneuroendocrinology·RCT
E1TrialPEM ✗
Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy.
2001Cleare, A J et al.·The Journal of clinical endocrinology and metabolism·RCT
E1TrialPEM ✗
Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial.
1998McKenzie, R et al.·JAMA·RCT
E1TrialPEM ?
Lower hair cortisol concentration in adolescent and young adult patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Q-Fever Fatigue Syndrome compared to controls.
2024Vroegindeweij, Anouk et al.·Psychoneuroendocrinology·RCT
E2CohortPEM ✗
Clinical characteristics of patients with unexplainable hypothalamic disorder diagnosed by the corticotropin-releasing hormone challenge test: a retrospective study.
2022Hataya, Yuji et al.·BMC endocrine disorders·Observational
E2CohortPEM ✗
Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patients.
2018Vangeel, Elise Beau et al.·Journal of psychosomatic research·Case-Control
E2CohortPEM ✗
Neuroendocrine disorder in chronic fatigue syndrome.
2017Tomic, Slavica et al.·Turkish journal of medical sciences·Cross-Sectional
E2BehavioralPEM ✗
Self-critical perfectionism predicts lower cortisol response to experimental stress in patients with chronic fatigue syndrome.
2016Kempke, Stefan et al.·Health psychology : official journal of the Division of Health Psychology, American Psychological Association·Cross-Sectional
E2CohortPEM ✗
Chronic Fatigue Syndrome and DNA Hypomethylation of the Glucocorticoid Receptor Gene Promoter 1F Region: Associations With HPA Axis Hypofunction and Childhood Trauma.
2015Vangeel, Elise et al.·Psychosomatic medicine·Observational
E2BehavioralPEM ✗
Effects of early childhood trauma on hypothalamic-pituitary-adrenal (HPA) axis function in patients with Chronic Fatigue Syndrome.
2015Kempke, Stefan et al.·Psychoneuroendocrinology·Cross-Sectional
E2BehavioralPEM ✗
Cortisol output in adolescents with chronic fatigue syndrome: pilot study on the comparison with healthy adolescents and change after cognitive behavioural guided self-help treatment.
2014Rimes, Katharine A et al.·Journal of psychosomatic research·Observational
E2BehavioralPEM ✗
Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction.
2009Heim, Christine et al.·Archives of general psychiatry·Case-Control
E2CohortPEM ✗
Glucocorticoid receptor mediated negative feedback in chronic fatigue syndrome using the low dose (0.5 mg) dexamethasone suppression test.
2009Papadopoulos, Andrew et al.·Journal of affective disorders·Cross-Sectional
E2BehavioralPEM ✗
Salivary cortisol output before and after cognitive behavioural therapy for chronic fatigue syndrome.
2009Roberts, Amanda D L et al.·Journal of affective disorders·Longitudinal
E2BehavioralPEM ✗
Chronic fatigue syndrome and high allostatic load: results from a population-based case-control study in Georgia.
2009Maloney, Elizabeth M et al.·Psychosomatic medicine·Case-Control
E2CohortPEM ✗
Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls.
2008Nater, Urs M et al.·The Journal of clinical endocrinology and metabolism·Case-Control
E2CohortPEM ✗
Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome.
2008Van Den Eede, F et al.·Psychological medicine·Case-Control
E2CohortPEM ✗
Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome.
2007Rajeevan, M S et al.·Genes, brain, and behavior·Case-Control
E2CohortPEM ✗
Urinary cortisol and cortisol metabolite excretion in chronic fatigue syndrome.
2006Jerjes, Walid K et al.·Psychosomatic medicine·Case-Control
E2CohortPEM ✗
Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome.
2006Jerjes, Walid K et al.·Journal of psychosomatic research·Cross-Sectional
E2CohortPEM ✗
Chronic fatigue syndrome and high allostatic load.
2006Maloney, Elizabeth M et al.·Pharmacogenomics·Case-Control
E2CohortPEM ✗
Disturbed adrenal function in adolescents with chronic fatigue syndrome.
2005Segal, T Y et al.·Journal of pediatric endocrinology & metabolism : JPEM·Case-Control
E2CohortPEM ✗
24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome.
2005Di Giorgio, Annabella et al.·Psychosomatic medicine·Observational
E2CohortPEM ?
Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome.
2005Jerjes, W K et al.·Journal of affective disorders·Cross-Sectional
E2CohortPEM ✗
Normal opioid tone and hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome despite marked functional impairment.
2005Inder, Warrick J et al.·Clinical endocrinology·Case-Control
E2CohortPEM ?
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.
2004Cevik, Remzi et al.·BMC musculoskeletal disorders·Case-Control
E2CohortPEM ✗
Salivary cortisol response to awakening in chronic fatigue syndrome.
2004Roberts, Amanda D L et al.·The British journal of psychiatry : the journal of mental science·Cross-Sectional
E2CohortPEM ✗
Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism.
2004Torpy, David J et al.·Endocrine research·Case-Control
E2CohortPEM ✗
Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome.
2004Gaab, Jens et al.·Journal of psychosomatic research·Cross-Sectional
E2CohortPEM ?
Is hypercortisolaemia a factor in chronic fatigue syndrome?
2003Renan, M J·Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme·Observational
E2CohortPEM ✗
[Disorder of adrenal gland function in chronic fatigue syndrome].
2003Zarković, Milos et al.·Srpski arhiv za celokupno lekarstvo·Observational
E2CohortPEM ✗
Association between serotonin transporter gene polymorphism and chronic fatigue syndrome.
2003Narita, Masaaki et al.·Biochemical and biophysical research communications·Case-Control
E2CohortPEM ✗
Low-dose dexamethasone suppression test in chronic fatigue syndrome and health.
2002Gaab, Jens et al.·Psychosomatic medicine·Case-Control
E2CohortPEM ✗
Urinary free cortisol in chronic fatigue syndrome.
2001Cleare, A J et al.·The American journal of psychiatry·Cross-Sectional
E2CohortPEM ✗
Characterization of pituitary function with emphasis on GH secretion in the chronic fatigue syndrome.
2000Moorkens, G et al.·Clinical endocrinology·Observational
E2CohortPEM ✗
Differences in adrenal steroid profile in chronic fatigue syndrome, in depression and in health.
1999Scott, L V et al.·Journal of affective disorders·Cross-Sectional
E2MechanismPEM ✗
Desmopressin augments pituitary-adrenal responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers.
1999Scott, L V et al.·Biological psychiatry·Mechanistic
E2CohortPEM ✗
The 1microg short Synacthen test in chronic fatigue syndrome.
1999Hudson, M et al.·Clinical endocrinology·Cross-Sectional
E2CohortPEM ✗
Naloxone-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome.
1998Scott, L V et al.·Psychological medicine·Case-Control
E2CohortPEM ?
Secretion of growth hormone in patients with chronic fatigue syndrome.
1998Berwaerts, J et al.·Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society·Cross-Sectional
E2CohortPEM ✗
Diurnal variation of adrenocortical activity in chronic fatigue syndrome.
1998MacHale, S M et al.·Neuropsychobiology·Cross-Sectional
E2CohortPEM ✗
A comparison of salivary cortisol in chronic fatigue syndrome, community depression and healthy controls.
1998Strickland, P et al.·Journal of affective disorders·Cross-Sectional
E2CohortPEM ✗
The low dose ACTH test in chronic fatigue syndrome and in health.
1998Scott, L V et al.·Clinical endocrinology·Cross-Sectional
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