Recent challenges in the diagnosis of Cushing's syndrome

Background: The diagnosis of Cushing's syndrome still represents a challenge for the endocrinologist. Correct implementation and interpretation of diagnostic procedures require expertise and a high degree of clinical knowledge. The diagnosis should be established based on results of two or more concordant first-line tests (e. g., urinary free cortisol, midnight serum cortisol and low-dose dexamethasone testing); otherwise, second-line tests such as the dexamethasone-suppressed corticotrophin-releasing hormone (CRH) test, desmopressin stimulation or later reevaluation can confirm/exclude the diagnosis. Aetiological diagnosis requires measurement of plasma corticotrophin (ACTH) to distinguish between ACTH-dependent (pituitary or extrapituitary ACTH-secreting tumors) and ACTH-independent Cushing's syndrome (adrenal cortisol-secreting lesions), and the possible detection of normal ACTH levels in patients with adrenal Cushing's syndrome must be kept in mind. Lastly, the differential diagnosis between pituitary and ectopic ACTH secretion can be performed using CRH testing, high-dose dexamethasone suppression and inferior petrosal sinus sampling. Conclusions: The different epidemiology of the two entities and the incomplete diagnostic accuracy of diagnostic procedures mandate careful evaluation of test results.