What is the difference between checking morning (am) cortisol levels and a dexamethasone suppression test for diagnosing Cushing's syndrome?

Morning Cortisol vs Dexamethasone Suppression Test for Cushing's Syndrome

The dexamethasone suppression test (DST) is the superior screening test for Cushing's syndrome compared to a simple morning cortisol measurement, as morning cortisol alone has wide overlap between normal and Cushing's patients and provides little diagnostic value. 1

Why Morning Cortisol Alone is Inadequate

• Morning (8-9 AM) cortisol levels show extensive overlap between patients with Cushing's syndrome and those without the condition, making it unreliable as a standalone diagnostic test 1
• Morning cortisol can be elevated in many physiologic states (stress, illness, obesity) and normal in some patients with mild Cushing's syndrome 2
• A single morning cortisol measurement does not assess the hypothalamic-pituitary-adrenal (HPA) axis feedback mechanism, which is the fundamental defect in Cushing's syndrome 2

Why the Dexamethasone Suppression Test is Superior

The overnight 1 mg DST is the procedure of choice for screening Cushing's syndrome because it directly tests the integrity of the HPA axis feedback mechanism with excellent sensitivity (100%) and specificity (92-94%) 3, 4

Test Performance Characteristics

• Using a cortisol cutoff of 200 nmol/L (7.24 μg/dL), the overnight DST achieves 100% sensitivity with only 7.3% false positive rate 3
• The lowest plasma cortisol level achieved in confirmed Cushing's syndrome patients after overnight DST was 259 nmol/L (9.39 μg/dL), establishing a clear separation from normal suppressors 3
• The test is simpler for both patients and medical personnel compared to 24-hour urine collections or other screening procedures 3

How the DST Works

• The patient takes 1 mg dexamethasone orally at 11 PM-midnight, and plasma cortisol is measured at 8-9 AM the next morning 2, 3
• In normal individuals, dexamethasone suppresses ACTH secretion, leading to cortisol suppression to <1.8 μg/dL (50 nmol/L) 2
• In Cushing's syndrome, the HPA axis is resistant to negative feedback, and cortisol fails to suppress appropriately 2

Critical Pitfalls and How to Avoid Them

Measuring Dexamethasone Levels

Measuring serum dexamethasone concentration simultaneously with cortisol dramatically improves test specificity from 67.5% to 92.4% by identifying false positives from inadequate dexamethasone absorption or non-compliance 5

• The lower limit of normal for dexamethasone is 1.8 ng/mL (4.6 nmol/L) 5
• Only 4% of patients have undetectable dexamethasone, suggesting true non-compliance 5
• Decreased glomerular filtration rate and diabetes mellitus are associated with higher serum dexamethasone concentrations 5

Drug Interactions That Cause False Negatives

Phenytoin, phenobarbital, ephedrine, and rifampin enhance the metabolic clearance of dexamethasone, resulting in false negative DST results that should be interpreted with caution 6

• Indomethacin has been reported to cause false negative results in the DST 6
• These medications accelerate dexamethasone metabolism, preventing adequate HPA axis suppression even in normal individuals 6

False Positive Considerations

• Severe obesity, alcoholism, depression, and disrupted sleep-wake cycles can cause mild hypercortisolism (pseudo-Cushing's states) with false positive DST results 7
• Pseudo-Cushing's states typically show UFC <3-fold above normal, whereas true Cushing's syndrome usually shows higher elevations 2

The Role of Morning Cortisol in the Diagnostic Algorithm

While morning cortisol alone is inadequate for screening, it plays a critical role AFTER Cushing's syndrome is confirmed biochemically—specifically, measuring morning (8-9 AM) plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes 8, 2

ACTH Measurement Protocol

• Morning ACTH >5 ng/L (>1.1 pmol/L) indicates ACTH-dependent Cushing's syndrome (pituitary or ectopic source) 8, 2
• Low or undetectable ACTH (<5 ng/L) indicates ACTH-independent Cushing's syndrome (adrenal source) 8, 2
• Morning timing is essential because cortisol follows a diurnal rhythm with highest levels in the morning, providing standardization across patients 8

Recommended Diagnostic Algorithm

1. Screen with overnight 1 mg DST using cortisol cutoff of 1.8 μg/dL (50 nmol/L) 2
2. Measure dexamethasone level simultaneously; exclude results if dexamethasone <1.8 ng/mL 5
3. If DST is abnormal, repeat 1-2 screening tests (including 24-hour UFC or late-night salivary cortisol) to confirm hypercortisolism 2
4. Once hypercortisolism is confirmed, measure morning (8-9 AM) plasma ACTH to determine etiology 8, 2
5. Proceed with appropriate imaging (pituitary MRI for ACTH-dependent, adrenal CT for ACTH-independent) 2

The combination of midnight cortisol measurement with overnight DST provides even better diagnostic accuracy than either test alone, with virtually no false positives except in anorexia nervosa 1