What are the management options for hypercortisolism (high cortisol)?

Management of High Cortisol (Hypercortisolism)

The management of hypercortisolism depends critically on disease severity and ACTH-dependency status, with treatment ranging from surgical resection for tumor-related causes to medical therapy using steroidogenesis inhibitors like ketoconazole, metyrapone, or osilodrostat, with the primary goal being rapid normalization of cortisol to prevent life-threatening complications. 1

Initial Diagnostic Steps

Before initiating treatment, confirm the diagnosis and determine the underlying cause:

• Confirm hypercortisolism using at least one screening test: 24-hour urinary free cortisol (UFC), late-night salivary cortisol, or low-dose dexamethasone suppression test 1, 2
• Measure ACTH levels to classify as ACTH-dependent (pituitary or ectopic source) versus ACTH-independent (adrenal source), as this fundamentally determines treatment approach 3, 2
• Rule out exogenous glucocorticoid use, which is a common and reversible cause 1

Treatment Strategy Based on Disease Severity

Mild Disease (No Visible Tumor on MRI)

• First-line options: Ketoconazole (400-1200 mg/day), osilodrostat, or metyrapone 3, 1
• Alternative for mild Cushing's disease: Cabergoline, particularly if the patient has a history of bipolar disorder or impulse control issues where cabergoline should be avoided 3, 1
• Cabergoline may be preferred in women desiring pregnancy, though metyrapone can be considered with precautions in selected pregnant patients 1

Moderate Disease (Visible Tumor Present)

• Consider tumor-targeting agents: Pasireotide or cabergoline, which have potential for tumor shrinkage in addition to biochemical control 3, 1
• Monitor both biochemical parameters and tumor response on serial imaging 3
• Be aware that pasireotide carries significant risks of hyperglycemia requiring intensive glucose monitoring and potential initiation of antidiabetic therapy 4

Severe Disease (Life-Threatening Hypercortisolism)

Rapid cortisol normalization is the primary goal to prevent mortality from opportunistic infections, thromboembolic events, and metabolic complications. 3, 5

• Medical options for rapid control: Osilodrostat, metyrapone, ketoconazole, or continuous etomidate infusion for critically ill patients 3, 1, 5
• Consider combination therapy with multiple steroidogenesis inhibitors (e.g., ketoconazole plus metyrapone) to maximize adrenal blockade 3, 1
• Bilateral laparoscopic adrenalectomy can rapidly decrease cortisol levels in patients with rapidly progressive disease (especially ectopic ACTH from small cell lung cancer) who cannot wait for medical therapy to take effect 3

Specific Clinical Scenarios

ACTH-Dependent Cushing's (Elevated ACTH)

Pituitary source (Cushing's disease):

• Transsphenoidal surgery is definitive treatment, but medical therapy may be needed preoperatively if surgery is delayed or for persistent disease 3, 1
• Preoperative medical therapy with steroidogenesis inhibitors should be considered for patients with severe disease or life-threatening complications (metabolic, psychiatric, infectious, cardiovascular/thromboembolic) 3

Ectopic ACTH secretion (lung, thyroid, pancreas, bowel tumors):

• Surgical removal of the ectopic tumor is primary therapy if resectable 3
• If unresectable, options include bilateral laparoscopic adrenalectomy or medical management 3
• Medical control of hypercortisolism is critical before chemotherapy, as severe opportunistic infections cause high mortality in patients with small cell lung cancer and ectopic Cushing's syndrome 3

ACTH-Independent Cushing's (Low ACTH)

Adrenal adenoma (benign, typically <5 cm):

• Laparoscopic adrenalectomy is the treatment of choice 3
• Postoperative corticosteroid supplementation is required until recovery of the hypothalamic-pituitary-adrenal axis 3

Adrenal carcinoma (malignant, typically >5 cm with irregular margins):

• Open adrenalectomy with complete resection and evaluation for metastases 3
• Medical management with mitotane for advanced disease 3

Bilateral multinodular hyperplasia:

• Adrenal vein sampling determines lateralization of cortisol production 3
• If asymmetric production: unilateral adrenalectomy of the most active side 3
• If symmetric production: medical management 3

Medical Therapy Details

Steroidogenesis Inhibitors (Most Commonly Used)

• Ketoconazole: 400-1200 mg/day, most commonly used due to availability and relatively tolerable toxicity profile 3, 6
• Metyrapone: Effective for rapid control, often combined with ketoconazole 3, 6
• Osilodrostat: Newer agent for rapid normalization 1
• Mitotane: Used for adrenal carcinoma and refractory cases 3
• Etomidate: Continuous infusion for critically ill patients requiring immediate cortisol reduction 3, 5

Glucocorticoid Receptor Antagonist

• Mifepristone: Blocks cortisol action at the receptor level 3
• Critical caveat: Cortisol measurements are not reliable for dosing or safety monitoring when using mifepristone, so clinical endpoints must guide therapy 1

Tumor-Targeting Agents

• Pasireotide: Somatostatin analog for Cushing's disease with visible tumor 3, 4
• Cabergoline: Dopamine agonist for mild Cushing's disease 3, 1
• Octreotide: Can be considered for ectopic Cushing's if tumor is Octreoscan-positive, though less effective than for other indications 3

Combination Therapy Approaches

When monotherapy fails to normalize cortisol after 2-3 months at maximum tolerated doses, consider: 3

• Ketoconazole plus metyrapone to maximize adrenal blockade 3, 1
• Ketoconazole plus osilodrostat to allow lower doses of both drugs 3
• Steroidogenesis inhibitor plus tumor-targeting agent (e.g., ketoconazole plus cabergoline or pasireotide) when visible tumor is present 3, 1
• Triple therapy: Cabergoline, pasireotide, plus ketoconazole, or ketoconazole, metyrapone, plus mitotane for refractory cases 3

Monitoring Treatment Response

• Use multiple serial tests: Both UFC and late-night salivary cortisol to monitor treatment outcomes 1
• Clinical endpoints: Improved phenotype, weight, hypertension, glucose metabolism, and quality of life 3
• Timing: Assess response after 2-3 months on maximum tolerated doses before changing therapy 3
• For slight biochemical abnormalities without clinical features: Close monitoring with repeat testing and treatment of comorbidities may be sufficient rather than treating the underlying disorder 1

Special Monitoring Considerations

• With pasireotide: Intensive glucose monitoring is mandatory due to high risk of hyperglycemia and diabetes mellitus; ECG monitoring for bradycardia and QT prolongation; liver function tests; monitoring for cholelithiasis 4
• After bilateral adrenalectomy: Monitor ACTH levels, as progressive elevations may signal tumor growth (Nelson's syndrome) requiring MRI and reassessment 3

Critical Pitfalls to Avoid

• Failing to assess disease severity before selecting initial therapy—severe disease requires rapid normalization to prevent mortality 1, 5
• Not monitoring for drug-drug interactions, particularly with ketoconazole (affects cyclosporine, bromocriptine) and mifepristone 1, 4
• Overlooking thromboembolic risk: Patients with Cushing's syndrome have increased clotting factors and VTE risk of 2% without surgery and 4% after surgery 3
• Delaying treatment in ectopic ACTH syndrome: Severe opportunistic infections after chemotherapy cause high mortality if hypercortisolism is not controlled first 3
• Using cortisol levels to guide mifepristone dosing: This is unreliable and can lead to dangerous over- or under-treatment 1
• Not providing glucocorticoid replacement after bilateral adrenalectomy or when medical therapy causes hypocortisolism 3

Managing Hypocortisolism from Treatment

• Reduce SIGNIFOR (pasireotide) dose or interrupt treatment if hypocortisolism develops 4
• Add low-dose short-term glucocorticoid therapy to bridge until dose adjustment takes effect 3, 4
• Monitor for adrenal insufficiency with any steroidogenesis inhibitor, particularly during dose escalation 3