Diagnostic and Treatment Algorithm for Hypercortisolism

Initial Screening and Diagnosis

The Endocrine Society recommends ruling out exogenous glucocorticoid use as a common cause of hypercortisolism, and performing at least one screening test, preferably two tests if clinical suspicion is intermediate or high 1, 2
For suspected Cushing's disease, the American College of Endocrinology suggests starting with 24-hour urinary free cortisol (UFC) and/or late night salivary cortisol (LNSC); the overnight 1mg dexamethasone suppression test (DST) is also an option 1, 3, 4
The European Society of Endocrinology recommends considering the following when selecting initial tests: for suspected adrenal tumor, start with DST (LNSC has lower specificity); for shift workers or disrupted circadian rhythm, DST may be preferred; for patients on estrogen-containing medications, avoid DST (false positives) 1, 3, 5

Normal results with low clinical suspicion indicate that Cushing's syndrome (CS) is unlikely; abnormal results require confirmation and exclusion of non-neoplastic hypercortisolism 1, 3
The American Association of Clinical Endocrinologists recommends considering conditions that can cause false positive results, such as severe obesity, uncontrolled diabetes, pregnancy, alcoholism, depression/psychiatric disorders, and chronic kidney disease 3, 5

Measuring plasma ACTH levels helps determine the etiology of confirmed hypercortisolism: low ACTH indicates ACTH-independent CS (adrenal source), while normal or high ACTH indicates ACTH-dependent CS (pituitary or ectopic source) 1, 4, 5
For ACTH-independent CS, adrenal CT or MRI is recommended to identify adrenal adenoma, carcinoma, or bilateral disease 1

For Cushing's disease (ACTH-dependent, pituitary source), the first-line treatment is transsphenoidal surgery (TSS); for persistent/recurrent disease after TSS, options include second TSS, radiation therapy, medical therapy, or bilateral adrenalectomy 1, 5
Medical therapy options for Cushing's disease include ketoconazole, osilodrostat, or metyrapone for mild disease; medications with tumor-shrinking potential (cabergoline, pasireotide) for moderate disease; and rapid cortisol normalization with osilodrostat, metyrapone, ketoconazole, or etomidate for severe disease 1, 6

The Endocrine Society recommends using multiple serial tests of both UFC and LNSC to monitor treatment response; monitoring for resolution of clinical features and specific adverse effects of medical therapy is also essential 4, 6
Children with CS should be referred to multidisciplinary centers with pediatric endocrinology expertise; genetic testing should be considered, especially in children and young adults 1, 7