E3 PreliminaryModerate confidencePEM ?Cross-SectionalPeer-reviewedMachine draft
Assessment of cortisol response with low-dose and high-dose ACTH in patients with chronic fatigue syndrome and healthy comparison subjects.
Gaab, Jens, Hüster, D, Peisen, R et al. · Psychosomatics · 2003 · DOI
Quick Summary
This study tested whether ME/CFS patients have problems with cortisol, a stress hormone made by the adrenal glands. Researchers gave 18 ME/CFS patients and 18 healthy people a hormone called ACTH (in both low and high doses) to stimulate cortisol production. The results showed no difference between the two groups, suggesting that ME/CFS is unlikely caused by faulty adrenal glands.
Why It Matters
Many ME/CFS patients and some researchers have hypothesized that low cortisol levels drive symptoms, making this question clinically relevant. This study provides evidence against a primary adrenal dysfunction mechanism, helping refocus research on other potential HPA axis abnormalities or entirely different pathways in ME/CFS pathophysiology.
Observed Findings
- No significant differences in salivary cortisol response between ME/CFS and healthy controls after low-dose ACTH stimulation.
- No significant differences in plasma cortisol response between ME/CFS and healthy controls after low-dose ACTH stimulation.
- No significant differences in salivary or plasma cortisol response between groups after high-dose ACTH stimulation.
- Adrenocortical sensitivity to ACTH was similar in both groups.
Inferred Conclusions
- Primary adrenal insufficiency is unlikely to be a significant cause of ME/CFS symptoms.
- The adrenal glands' ability to respond to stimulation is intact in ME/CFS patients.
- If HPA axis dysfunction exists in ME/CFS, it is not due to primary adrenal disease.
Remaining Questions
- Do ME/CFS patients have abnormal baseline cortisol levels or abnormal circadian cortisol patterns?
- Is there dysregulation at the pituitary or hypothalamic level of the HPA axis that wouldn't be detected by ACTH stimulation testing?
- Could other hormonal or immune system abnormalities explain ME/CFS symptoms independent of cortisol pathways?
What This Study Does Not Prove
This study does not rule out HPA axis dysfunction in ME/CFS—it only excludes primary adrenal insufficiency. It does not address whether patients have abnormal cortisol patterns at baseline, abnormal circadian rhythms, or problems at the pituitary or hypothalamic level. Absence of difference in acute ACTH response does not exclude other endocrine or immune mechanisms underlying ME/CFS.
Tags
Symptom:Fatigue
Biomarker:Blood Biomarker
Method Flag:PEM Not DefinedSmall Sample
Metadata
- DOI
- 10.1176/appi.psy.44.2.113
- PMID
- 12618533
- Review status
- Machine draft
- Evidence level
- Early hypothesis, preprint, editorial, or weak support
- Last updated
- 8 April 2026