What is the most specific test for establishing a diagnosis of Cushing's disease?

The most specific test for establishing a diagnosis of Cushing's disease is petrosal sinus sampling following corticotropin-releasing hormone stimulation. This highly specialized procedure directly assesses the source of ACTH production, which is critical in differentiating between Cushing's disease caused by a pituitary adenoma and ectopic ACTH production or adrenal tumors.

In this test, blood samples are taken from the petrosal sinus, which drains the pituitary gland, allowing for the measurement of ACTH levels before and after the administration of corticotropin-releasing hormone (CRH). A significant increase in ACTH levels from the petrosal sinus compared to peripheral blood indicates that the source of ACTH is likely the pituitary gland, confirming a diagnosis of Cushing's disease. This targeted approach provides higher specificity than other tests, making it the gold standard for differentiation and diagnosis.

Other tests such as low-dose and high-dose dexamethasone suppression tests assess the feedback mechanism and can indicate Cushing's syndrome but are less reliable in pinpointing whether the cause is pituitary or ectopic. The twenty-four-hour urinary free cortisol test measures cortisol levels over a full day and helps in screening for hypercortisolism but lacks the specificity