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

Molecular Psychiatry (2026)Cite this article

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Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a major clinical challenge as a complex multisystemic disorder with no well-established pathophysiological mechanism, characterized by persistent fatigue and post-exertional malaise, along with unrefreshing sleep, cognitive impairment, and impaired stress recovery. Despite decades of investigation into the hypothalamic-pituitary-adrenal (HPA) axis, a definitive neuroendocrine hallmark has remained elusive due to inconsistent findings across various cortisol matrices. Therefore, this systematic review and meta-analysis aimed to provide an integrated understanding of HPA-axis regulation in ME/CFS. We identified 46 case–control studies (comprising 46 independent datasets, including 12 pharmacological challenge studies), involving 1388 ME/CFS patients (71.9% female; mean age 37.3 ± 6.2 years) and 1349 matched healthy controls. Meta-analyses showed lower salivary cortisol at awakening and in the morning. Reductions were also observed in 24-h urinary cortisol and hair cortisol. In pharmacological challenge tests, patients exhibited impaired cortisol release in response to adrenocorticotropic hormone (ACTH) stimulation and exaggerated suppression following glucocorticoid administration. Collectively, these alterations indicate reduced free cortisol availability and enhanced HPA-axis negative feedback sensitivity, consistent with a hyporeactive endocrine state in ME/CFS. This neuroendocrine hypo-reactivity may underlie hallmark clinical features such as unrefreshing sleep, post-exertional malaise, and severe fatigue, as well as cognitive slowing, emotional blunting, and diminished stress resilience frequently observed in ME/CFS and related functional disorders. Integrating neuroendocrine and psychological perspectives may help clarify mechanisms of chronic stress maladaptation and inform psychobiological interventions for fatigue syndromes.

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Fig. 1: PRISMA flow diagram of study selection process.
The alternative text for this image may have been generated using AI.
Fig. 2: Meta-analysis of relative total blood cortisol levels in ME/CFS patients compared with healthy controls.
The alternative text for this image may have been generated using AI.
Fig. 3: Meta-analysis of relative salivary free cortisol levels in ME/CFS patients compared with healthy controls.
The alternative text for this image may have been generated using AI.
Fig. 4: Meta-analysis of relative free cortisol levels from 24-hour urine and hair in ME/CFS patients compared with healthy controls.
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Fig. 5: Meta-analysis of relative HPA-axis hormone responses to challenge tests in ME/CFS patients compared with healthy controls.
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Fig. 6: Meta-analysis of negative feedback regulation of cortisol and proposed model of ME/CFS pathophysiology.
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Data availability

The corresponding author makes available data extracted from the included studies, along with the R scripts used for the meta-analyses, upon reasonable request. The shared materials include all outcome data used to calculate effect sizes (log response ratios, lnRR) and heterogeneity statistics. Data will be available immediately after publication with no end date and may be provided to qualified researchers for methodologically sound proposals. No individual participant data were collected or analyzed in this study.

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Funding

This research was supported by National Research Foundation of Korea (NRF) grants funded by the Ministry of Science, ICT & Future Planning (NRF-2018R1A6A1A03025221).

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Authors and Affiliations

  1. Research Center for ME/CFS, Daejeon Hospital of Daejeon University, Daejeon, Republic of Korea

    Tae-Wook Woo, Jin-Seok Lee & Chang-Gue Son

  2. Institute of Bioscience & Integrative Medicine, Daejeon University, Daejeon, Republic of Korea

    Tae-Wook Woo, Yu-Jin Choi, Jun-Yeol Kim, Jin-Seok Lee & Chang-Gue Son

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  1. Tae-Wook Woo
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  2. Yu-Jin Choi
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Contributions

T.W.W. contributed to conceptualization, data curation, investigation, formal analysis, visualization, and drafting of the manuscript. Y.J.C. contributed to data curation, validation, and manuscript editing. J.Y.K. reviewed the meta-analytic procedures and cortisol data conversion. J.S.L. supervised the study design, provided methodological oversight, and critically revised the manuscript. C.G.S. supervised the project and contributed to interpretation of the findings. All authors had full access to the data in the study, take responsibility for the integrity of the data and the accuracy of the analyses, and approved the final version of the manuscript.

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Correspondence to Jin-Seok Lee or Chang-Gue Son.

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Woo, TW., Choi, YJ., Kim, JY. et al. Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03608-1

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