Serum Cortisol in Cushing's Disease
Yes, serum cortisol is elevated in Cushing's disease, though the elevation is best demonstrated through specific testing patterns rather than random serum measurements alone. 1, 2
Understanding Cortisol Elevation Patterns
Cushing's disease is characterized by chronic hypercortisolism with loss of normal circadian rhythm, which is the hallmark diagnostic feature. 1 The key abnormality is not simply that cortisol is high, but that it remains inappropriately elevated when it should be suppressed—particularly at night. 1
Specific Cortisol Patterns in Cushing's Disease
Morning serum cortisol levels may appear deceptively normal or only mildly elevated in some patients, as the normal reference range is 5-23 μg/dL (138-635 nmol/L). 3 This overlap with normal values makes random morning cortisol a poor screening test.
Late-night cortisol levels are the most diagnostically useful, as they should normally be <1.8 μg/dL (<50 nmol/L) in sleeping individuals. 3 Values of 290 and 275 nmol/L at night are significantly elevated and highly suggestive of Cushing's syndrome with loss of normal circadian rhythm. 1
24-hour urinary free cortisol is markedly elevated, with mean total daily cortisol production reaching 46 mg (range 13.4-154 mg) in Cushing's disease patients compared to 12.8 mg (range 6.7-20 mg) in healthy controls. 4
Mechanism of Cortisol Elevation
The cortisol elevation in Cushing's disease results from both amplified pulsatile secretion and dramatically increased basal secretion rates. 4 Specifically:
Basal cortisol secretion rates are increased 7-fold above normal values in Cushing's disease patients. 4
Pulsatile cortisol secretion shows increased mass per pulse due to higher maximal secretion rates, with patients having more cortisol pulses per 24 hours (24 vs. 17 in controls). 4
The underlying cause is ACTH hypersecretion from a pituitary corticotroph adenoma, which drives the adrenal glands to overproduce cortisol. 2, 5
Diagnostic Testing Algorithm
To confirm elevated cortisol in suspected Cushing's disease, use the following approach:
Screen with at least 2-3 of these tests (never rely on a single test): 1, 3
Measure morning plasma ACTH once hypercortisolism is confirmed to determine if it's ACTH-dependent (>5 ng/L) or ACTH-independent (suppressed). 1, 6 In Cushing's disease, ACTH is detectable or elevated, with levels >29 ng/L having 70% sensitivity and 100% specificity for pituitary disease. 1, 6
Proceed to pituitary MRI if ACTH is elevated, followed by bilateral inferior petrosal sinus sampling if imaging is inconclusive. 1, 6
Critical Pitfalls to Avoid
Do not rely on random morning serum cortisol alone, as values may overlap with normal ranges and miss the diagnosis. 3 The loss of circadian rhythm is more diagnostic than absolute cortisol levels.
Beware of false positives from oral contraceptives (which increase cortisol-binding globulin and falsely elevate total cortisol), severe obesity, depression, and alcoholism. 1, 3
Always obtain multiple screening tests (2-3 collections of each modality) due to substantial intra-patient variability and the possibility of cyclic Cushing's syndrome. 1, 3
Measure dexamethasone levels concomitantly during suppression testing to confirm adequate drug absorption and exclude false-positive results from CYP3A4 inducers. 1, 3
Rare Exception
In extremely rare cases, a patient with Cushing's disease may have a defect in 11β-hydroxysteroid dehydrogenase type 1 activity, which impairs cortisone-to-cortisol conversion and increases cortisol clearance, potentially masking the typical biochemical picture. 7 However, this is exceptionally uncommon and should not alter standard diagnostic approaches.