This study looks at whether a hormone system called the HPA axis—which controls stress responses and cortisol production—might explain why people with ME/CFS experience severe fatigue. Researchers found that some patients have lower cortisol levels and changes in how their bodies respond to stress, and that giving cortisol replacement therapy in some cases improved fatigue. However, the changes weren't the same in all patients, suggesting multiple different factors may be contributing to fatigue rather than one single problem.
Why It Matters
Understanding whether hormonal imbalances drive ME/CFS fatigue is crucial for developing targeted treatments. This study's finding that cortisol replacement helped some patients suggests HPA axis dysfunction could be a therapeutic target, while the heterogeneity of findings indicates that ME/CFS likely involves multiple biological pathways that future research should address.
Observed Findings
Some ME/CFS patients show reduced cortisol output compared to controls.
Impaired ACTH and cortisol responses to various physiological and psychological challenges are evident in some patients.
Randomized controlled trials showed improvements in fatigue and disability following glucocorticoid replacement therapy in certain patients.
HPA axis disturbances vary among patients and are not uniform across the ME/CFS population.
Inferred Conclusions
HPA axis dysfunction may contribute to fatigue in a subset of ME/CFS patients but is not a universal or primary feature of the condition.
Multiple factors—including physical inactivity, sleep disruption, psychiatric symptoms, medications, and ongoing stress—likely shape HPA axis changes in ME/CFS rather than a single underlying defect.
The heterogeneous pattern of HPA axis abnormalities and variable response to glucocorticoid therapy suggests ME/CFS involves multiple distinct biological pathways to fatigue.
Remaining Questions
Why do some ME/CFS patients show HPA axis dysfunction while others do not?
What mechanisms link cortisol imbalance to the symptom of fatigue in responders to glucocorticoid therapy?
What This Study Does Not Prove
This review does not establish that HPA axis dysfunction is the primary cause of ME/CFS—it may be a secondary consequence of other disease processes. The improvements seen with cortisol replacement do not prove causation, as the mechanism by which cortisol helps fatigue remains unclear. The absence of uniform HPA axis changes across all patients suggests that this dysfunction, if present, is not necessary or sufficient to explain all cases of ME/CFS.
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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