What is the initial approach to managing a patient with hypercortisolism?

Initial Management of Hypercortisolism

For patients with hypercortisolism, the initial approach should be individualized based on disease severity, with adrenal steroidogenesis inhibitors as first-line medical therapy for most patients due to their reliable effectiveness and rapid action. 1

Diagnostic Confirmation

• Before initiating treatment, confirm hypercortisolism using at least one of these screening tests: cortisol free urinario de 24 horas (UFC), cortisol salival nocturno (LNSC), or prueba de supresión con dexametasona (1 mg overnight) 2
• Determine ACTH-dependency status to classify the type of hypercortisolism and guide treatment approach 2
• Rule out exogenous glucocorticoid use, which is a common cause of hypercortisolism 2, 3

Initial Treatment Selection Based on Disease Severity

For Mild Disease

• For patients with mild disease and no visible tumor on MRI, preferred options include:
  • Ketoconazole, osilodrostat, or metyrapone as first-line therapy 1
  • Cabergoline may be used for mild Cushing's disease but has slower onset of action 1
• Use a titration approach with progressive dose increases to achieve eucortisolism 4

For Moderate Disease with Visible Tumor

• Consider medications with potential for tumor shrinkage:
  • Cabergoline or pasireotide may be preferred, though pasireotide has high risk of hyperglycemia 1
• Monitor for both biochemical control and tumor response 1

For Severe Disease

• Rapid normalization of cortisol is the primary goal 1, 5
• Options with fastest onset include:
  • Osilodrostat or metyrapone (response within hours) 1
  • Ketoconazole (response within days) 1
  • Etomidate (for hospitalized patients unable to take oral medications) 1, 6
• Consider combination therapy with multiple steroidogenesis inhibitors for severe hypercortisolism 1
• If medical therapy fails to control severe hypercortisolism, bilateral adrenalectomy should be considered 1, 5

Monitoring Treatment Response

• Use multiple serial tests of both UFC and LNSC to monitor treatment outcomes 1
• 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

Special Considerations

Patient-Specific Factors

• Cabergoline should be avoided in patients with history of bipolar or impulse control disorder 1
• For women desiring pregnancy, cabergoline may be preferred, though metyrapone may be considered with precautions in selected pregnant women 1
• When using mifepristone, be aware that cortisol measurements are not reliable for dosing or safety monitoring 1

Combination Therapy Approaches

• Ketoconazole with metyrapone can maximize adrenal blockade when monotherapy is ineffective 1
• A steroidogenesis inhibitor plus a tumor-targeting agent (e.g., ketoconazole plus cabergoline) is rational when visible tumor is present 1

Pitfalls to Avoid

• Not considering the severity of hypercortisolism when selecting initial therapy 1
• Failing to monitor for adrenal insufficiency when using steroidogenesis inhibitors 7
• Overlooking drug-drug interactions, particularly with ketoconazole and mifepristone 1
• Delaying definitive treatment in severe hypercortisolism, which is a medical emergency requiring prompt intervention 5, 6