Does Increased Cortisol Increase Fatigue?
No, increased cortisol does not increase fatigue—the opposite is true: decreased cortisol levels are consistently associated with fatigue, particularly in chronic fatigue syndrome and cancer-related fatigue.
The Cortisol-Fatigue Relationship
The evidence demonstrates a clear inverse relationship between cortisol and fatigue:
Low Cortisol is Associated with Fatigue
Fatigued cancer survivors had significantly lower cortisol levels compared to non-fatigued survivors, along with higher inflammatory markers 1.
Chronic fatigue syndrome (CFS) patients demonstrate mild hypocortisolism, with reduced basal evening glucocorticoid levels (89.0 vs. 148.4 nmol/L in controls, P<0.01) and low 24-hour urinary free cortisol excretion (122.7 vs. 203.1 nmol/24h in controls, P<0.0002) 2.
Low waking salivary cortisol and a flat diurnal cortisol slope are associated with both current fatigue and future onset of fatigue in community-dwelling adults (odds ratio 1.50 for lowest vs. highest tertile, 95% CI 1.08-2.09) 3.
Variance from the expected diurnal pattern of cortisol was associated with increased levels of fatigue, with fatigue and pain correlating with altered salivary cortisol levels 4.
The Mechanism: HPA Axis Dysfunction
The pathophysiology involves blunted hypothalamic-pituitary-adrenal (HPA) axis function:
During chronic exposure to proinflammatory cytokines (as occurs in cancer and cancer therapies), the sensitivity of the HPA axis becomes blunted, and this decrease in cortisol production has been associated with cancer-related fatigue 1.
Current evidence supports mild hypocortisolism, attenuated diurnal variation of cortisol, enhanced negative feedback to the HPA axis, and blunted HPA axis responsiveness in CFS patients 5.
The data are most compatible with a mild central adrenal insufficiency secondary to either a deficiency of CRH or some other central stimulus to the pituitary-adrenal axis 2.
Clinical Implications
Cortisol's Normal Function
In the normal physiologic environment, cortisol is released in a circadian pattern and functions to inhibit proinflammatory cytokine production and activity during acute stressful events 1.
Robust synchronized circadian rhythms with appropriate cortisol patterns are important to health and well-being 1.
When to Suspect Low Cortisol in Fatigue
Look for these specific features in patients with primary adrenal insufficiency:
Weight loss, postural hypotension (reflecting insufficient mineralocorticoid therapy), and low salt intake 1.
Subclinical thyroid disease can contribute to fatigue and should be screened with TSH, FT4, and TPO-Ab every 12 months 1.
B12-deficiency due to autoimmune gastritis is common and should be monitored annually 1.
Important Caveats
The Exception: Cushing's Syndrome
While the question asks about "increased cortisol," it's important to note that pathologically elevated cortisol in diseases like Cushing's syndrome can cause fatigue through different mechanisms 6. However, this represents frank hypercortisolism (a disease state), not the physiological variations discussed in most fatigue research.
Stress and Depression Context
Chronic psychological stress and depression activate the HPA axis, producing physiological hypercortisolism, but this is distinct from the hypocortisolism seen in established chronic fatigue states 7.
Low activity levels, depression, and early-life stress appear to reduce cortisol levels, whereas psychotropic medication can increase cortisol 5.
Measurement Considerations
If cortisol is within normal range at 0800h or 1700h, it has been considered normal, without realizing that swings at immunosuppressive levels might occur during its 24-hour circadian rhythm 6.
A morning test of cortisol absorption and elimination (cortisol serum or saliva day curve before and 2,4, and 6 hours following the morning dose) can be useful when suspecting under-replacement 1.