The 1microg short Synacthen test in chronic fatigue syndrome.
Hudson, M, Cleare, A J · Clinical endocrinology · 1999 · DOI
Quick Summary
This study tested whether people with ME/CFS have lower levels of cortisol (a stress hormone) or weaker adrenal gland responses compared to healthy people. Researchers gave small doses of a hormone called Synacthen to 20 ME/CFS patients and 20 healthy controls, then measured cortisol levels over an hour. They found no significant differences between the two groups, suggesting that reduced adrenal reserve may not explain ME/CFS symptoms.
Why It Matters
Many ME/CFS patients and researchers have hypothesized that abnormal stress hormone function contributes to fatigue and other symptoms. This study directly tested whether adrenal glands fail to respond adequately to stimulation, providing evidence against one proposed mechanism of ME/CFS pathophysiology. Understanding which biological systems are or are not dysfunctional helps guide future research and potential treatments.
Observed Findings
No significant differences in baseline cortisol levels between CFS patients and healthy controls.
No significant differences in peak cortisol response between groups following Synacthen injection.
No significant differences in cortisol incremental rise (delta value) or area-under-the-curve between groups.
Cortisol peak responses generally occurred earlier than the standard 30-minute sampling timepoint in both groups.
Overall cortisol responses were generally low in both patients and controls.
Inferred Conclusions
CFS patients do not have reduced adrenal gland reserve capacity as measured by acute Synacthen stimulation.
HPA axis abnormalities in CFS may involve factors upstream of the adrenal gland (e.g., reduced central drive) rather than adrenal insufficiency.
Heterogeneity in HPA axis findings across CFS studies may reflect uncontrolled confounding variables such as sleep disturbance, physical inactivity, altered circadian rhythmicity, and comorbid psychiatric conditions.
Remaining Questions
What causes the consistently low cortisol responses observed in both CFS patients and controls, and do these levels have clinical significance?
Does the timing of peak cortisol response (earlier than expected) reflect a methodological issue or a physiologically meaningful difference in HPA axis dynamics in CFS?
What This Study Does Not Prove
This study does not prove that HPA axis dysfunction plays no role in ME/CFS—it only shows that adrenal responsiveness to acute Synacthen stimulation is preserved. The authors note that HPA abnormalities in ME/CFS may be driven by other factors (sleep disruption, inactivity, circadian rhythm changes) rather than reduced adrenal capacity. A single negative finding does not rule out more subtle or context-dependent HPA axis alterations.
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 →
Which specific factors (sleep, circadian rhythm, inactivity, psychiatric comorbidity) most contribute to HPA axis alterations in ME/CFS, and how should future studies control for them?
Are there subtypes of CFS with different HPA axis profiles, and could more refined patient stratification reveal group differences missed in this analysis?