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Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity. — ME/CFS Atlas

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Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity.

Woo, Tae-Wook, Choi, Yu-Jin, Kim, Jun-Yeol et al. · Molecular psychiatry · 2026 · DOI

Quick Summary

A review of 46 studies involving 1,388 ME/CFS patients found that people with ME/CFS were observed to have lower cortisol (a stress hormone) measured in saliva, urine, and hair, and showed altered responses when given hormone-stimulation tests. The authors propose these findings may be associated with some ME/CFS symptoms like fatigue and sleep problems, though the clinical significance and how this relates to individual patient outcomes remains unclear.

Why It Matters

This meta-analysis consolidates two decades of inconsistent cortisol findings into a coherent neuroendocrine pattern, strengthening the biological plausibility of ME/CFS as a disorder involving dysregulated stress-response physiology. If replicated, it could support the development of neuroendocrine-informed clinical phenotyping and mechanistically targeted interventions beyond current symptom management.

Observed Findings

Lower salivary cortisol at awakening and in the morning observed across multiple studies
Reduced 24-h urinary cortisol and hair cortisol concentrations observed in ME/CFS cohorts
Blunted cortisol release in response to ACTH stimulation observed in pharmacological challenge tests
Exaggerated cortisol suppression following glucocorticoid administration observed in ME/CFS patients
These alterations correlated with reduced free cortisol availability and enhanced HPA-axis negative feedback sensitivity

Inferred Conclusions

The authors propose that ME/CFS is characterised by a hyporeactive neuroendocrine state rather than hyperactivity of the stress-response system.
The authors interpret enhanced negative feedback sensitivity as consistent with central or peripheral glucocorticoid receptor hypersensitivity.
The authors hypothesise that this neuroendocrine hypo-reactivity may be one candidate mechanism underlying unrefreshing sleep, post-exertional malaise, and impaired stress resilience in ME/CFS.
The authors suggest integrating neuroendocrine and psychological perspectives may clarify chronic stress maladaptation pathways.

Remaining Questions

Do these cortisol abnormalities precede ME/CFS onset (predictive biomarkers) or emerge as secondary adaptations to illness?

What This Study Does Not Prove

This meta-analysis does not establish that cortisol abnormalities cause ME/CFS symptoms or that restoring cortisol will treat the disease. It does not clarify whether these neuroendocrine changes are primary pathological features or secondary adaptations to chronic illness. The study cannot determine which individual patients will exhibit these patterns or how cortisol status predicts clinical outcomes.

Topics

Endocrine Disruption Biomarkers Sleep Cognitive Impairment Post-Exertional Malaise

Metadata

DOI: 10.1038/s41380-026-03608-1
PMID: 42026257
Evidence level: Higher-level evidence type — systematic reviews, meta-analyses, guidelines, or major syntheses (study type, not a quality guarantee)
Last updated: 24 April 2026

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About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →

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The first block is for the primary paper and is the citation you should use in research work. The atlas-snapshot line only applies if you are specifically referring to this atlas’s reading of the paper on the date shown.

Primary citation

Woo, Tae-Wook, Choi, Yu-Jin, Kim, Jun-Yeol, Lee, Jin-Seok, & Son, Chang-Gue (2026). Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity.. Molecular psychiatry. https://doi.org/10.1038/s41380-026-03608-1

BibTeX

@article{mecfsatlas-woo-2026-neuroendocrine-signature,
  author  = {Woo, Tae-Wook and Choi, Yu-Jin and Kim, Jun-Yeol and Lee, Jin-Seok and Son, Chang-Gue},
  title   = {Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity.},
  journal = {Molecular psychiatry},
  year    = {2026},
  doi     = {10.1038/s41380-026-03608-1},
  note    = {PubMed: 42026257},
  url     = {https://www.mecfsatlas.com/evidence/woo-2026-neuroendocrine-signature},
}

Atlas snapshot reference

ME/CFS Atlas. Generator v1 / Scanner v1.4 / policy v0.1. Accessed 2026-04-26. https://www.mecfsatlas.com/evidence/woo-2026-neuroendocrine-signature

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