Initial Management of Hypercortisolism

Diagnostic Confirmation

The Endocrine Society recommends confirming hypercortisolism using at least one of these screening tests: cortisol free urinary test, cortisol salivary nocturnal test, or dexamethasone suppression test 4
Determining ACTH-dependency status is crucial to classify the type of hypercortisolism and guide treatment approach 4
Ruling out exogenous glucocorticoid use is essential, as it is a common cause of hypercortisolism 4

For patients with mild disease and no visible tumor on MRI, the American College of Endocrinology recommends ketoconazole, osilodrostat, or metyrapone as first-line therapy, with cabergoline as an alternative for mild Cushing's disease 2, 3
For moderate disease with visible tumor, consider medications with potential for tumor shrinkage, such as cabergoline or pasireotide, with careful monitoring of biochemical control and tumor response 3
For severe disease, rapid normalization of cortisol is the primary goal, with options including osilodrostat, metyrapone, ketoconazole, or etomidate, and consideration of combination therapy with multiple steroidogenesis inhibitors 2, 3

The Endocrine Society recommends using multiple serial tests of both urinary free cortisol and salivary nocturnal cortisol to monitor treatment outcomes 3
For slight biochemical abnormalities without clinical features of hypercortisolism, close monitoring with repeat testing and treatment of comorbidities may be considered rather than treating the underlying disorder 1, 5

Cabergoline should be avoided in patients with a history of bipolar or impulse control disorder, and women desiring pregnancy may prefer cabergoline, though metyrapone may be considered with precautions in selected pregnant women 3
When using mifepristone, be aware that cortisol measurements are not reliable for dosing or safety monitoring 3

Ketoconazole with metyrapone can maximize adrenal blockade when monotherapy is ineffective, and a steroidogenesis inhibitor plus a tumor-targeting agent is rational when visible tumor is present 3

Not considering the severity of hypercortisolism when selecting initial therapy, and failing to monitor for drug-drug interactions, particularly with ketoconazole and mifepristone 1, 2, 3