How do I differentiate between the various causes of Cushing's syndrome, such as pituitary adenoma versus adrenal causes?

Differentiating the causes of Cushing's syndrome, such as pituitary adenoma (Cushing's disease) versus adrenal causes, involves a combination of biochemical testing and imaging studies.

Initially, biochemical screening tests confirm hypercortisolism, typically using 24-hour urinary free cortisol, late-night salivary cortisol, or low-dose dexamethasone suppression tests. Once endogenous Cushing's syndrome is confirmed, plasma ACTH measurement helps distinguish ACTH-dependent from ACTH-independent causes.

In ACTH-dependent Cushing's syndrome (usually pituitary adenoma or ectopic ACTH secretion), plasma ACTH levels are normal or elevated. In contrast, ACTH levels are suppressed in ACTH-independent causes such as adrenal adenomas or carcinomas, where cortisol secretion is autonomous ¹.

For pituitary adenomas (Cushing's disease), further tests include high-dose dexamethasone suppression and CRH stimulation tests, which typically show cortisol suppression or increased ACTH, respectively, supporting a pituitary source. Inferior petrosal sinus sampling (IPSS) may be used to confirm pituitary origin when imaging is inconclusive ¹.

Imaging studies are essential: pituitary MRI is used to identify adenomas, although small microadenomas may be missed. Adrenal imaging (CT or MRI) identifies adrenal adenomas, hyperplasia, or carcinomas. Unilateral adrenal masses with suppressed ACTH suggest adrenal cause, while bilateral adrenal hyperplasia may be seen in ACTH-dependent cases ¹.

Management differs by cause: pituitary adenomas are treated primarily with transsphenoidal surgery, adrenal adenomas with adrenalectomy, and adrenal carcinomas with surgical resection, often challenging due to aggressiveness ¹.

Recent literature emphasizes the complexity and potential pitfalls in diagnosis, highlighting that biochemical tests can have false positives/negatives and that ectopic ACTH secretion can mimic pituitary disease, necessitating careful interpretation and sometimes repeated or advanced testing (Vilar et al., 2007; Chabre, 2014).