What is the most sensitive initial screening test for Cushing syndrome?

• A. Late-night salivary cortisol
• B. Overnight dexamethasone suppression test
• C. 24-hour urinary free cortisol
• D. Plasma ACTH

Answer: (A)

Cortisol’s daily rhythm is a key clue: it normally stays low at night. In Cushing syndrome, this nocturnal dip is lost, so cortisol is elevated when it should be minimal. Measuring cortisol in saliva late at night directly captures this loss of diurnal variation because saliva reflects the free, biologically active cortisol fraction that isn’t influenced by binding proteins.

This makes late-night salivary cortisol a highly sensitive and convenient screen. It’s noninvasive, easy to collect at home, and reduces preanalytic variability, which helps detect even mild hypercortisolism that might be missed by other tests.

Other tests have important roles but come with limitations. The overnight dexamethasone suppression test depends on proper adherence and can be affected by drug interactions, potentially causing false results. The 24-hour urinary free cortisol requires accurate urine collection and can miss mild cases or be influenced by day-to-day variability. Plasma ACTH helps distinguish ACTH-dependent from ACTH-independent causes but is not a screening test for hypercortisolism itself.