How to treat hypercortisolism?

Treatment of Elevated Cortisol Levels

The treatment of hypercortisolism requires first measuring ACTH levels to distinguish the underlying cause, followed by surgical resection as definitive therapy when feasible, or medical management with adrenal steroidogenesis inhibitors (ketoconazole, osilodrostat, or metyrapone) when surgery is not possible or for rapid preoperative control. 1

Initial Diagnostic Steps

Before initiating treatment, you must determine the etiology of hypercortisolism through specific testing:

• Measure ACTH levels to distinguish ACTH-dependent (pituitary tumors or ectopic ACTH production) from ACTH-independent causes (primary adrenal pathology), with elevated ACTH indicating the former and low/undetectable ACTH indicating the latter 1
• Rule out exogenous glucocorticoid use, as this is a common and reversible cause of hypercortisolism 2
• Confirm hypercortisolism using urinary free cortisol, late-night salivary cortisol, or dexamethasone suppression testing 2

Treatment Algorithm Based on Disease Severity

Mild Disease (No Visible Tumor on MRI)

• First-line options: ketoconazole, osilodrostat, or metyrapone 2
• Cabergoline may be used as an alternative specifically for mild Cushing's disease, but avoid in patients with bipolar disorder or impulse control disorders 2

Moderate Disease (Visible Tumor Present)

• Consider medications with tumor-shrinking potential such as cabergoline or pasireotide, with careful monitoring of both biochemical control and tumor response 2
• Combination of a steroidogenesis inhibitor plus a tumor-targeting agent is rational when visible tumor is present 2

Severe Disease (Medical Emergency)

• Rapid cortisol normalization is the primary goal using osilodrostat, metyrapone, ketoconazole, or etomidate 2
• Etomidate infusion can be life-saving in critically ill patients with severe hypercortisolism requiring urgent intervention 3
• Consider combination therapy with multiple steroidogenesis inhibitors for maximal adrenal blockade 2

Surgical Treatment (Definitive Therapy)

ACTH-Independent Disease

• Laparoscopic adrenalectomy is the treatment of choice for benign adrenal adenoma when feasible 1
• Postoperative corticosteroid supplementation is mandatory until HPA axis recovery occurs 1
• For malignant adrenal tumors, open adrenalectomy with removal of adjacent lymph nodes is recommended, potentially requiring en bloc resection of liver, kidney, pancreas, spleen, or diaphragm 1

Bilateral Adrenalectomy

• May be needed as a rescue procedure when medical management fails or surgery is not feasible for the primary lesion 3

Medical Management Details

Ketoconazole

• Most commonly used agent at doses of 400-1200 mg/day, achieving urinary free cortisol normalization in approximately 64% of patients 1
• Monitor liver function tests regularly due to hepatotoxicity risk 1
• Be aware of significant drug-drug interactions 2

Metyrapone

• Provides rapid cortisol control within hours 1
• Often combined with ketoconazole to maximize adrenal blockade or allow lower doses of both drugs 1
• May be considered in selected pregnant women with precautions 2

Osilodrostat

• Recently approved agent with rapid response and expected increasing use 1
• Advantage: no limitations by hepatotoxicity or hypogonadism concerns 1

Combination Therapy Strategies

• Ketoconazole + metyrapone or ketoconazole + osilodrostat can maximize adrenal blockade when monotherapy is ineffective 1, 2
• Monitor for overlapping toxicities and drug-drug interactions 1

Monitoring Treatment Response

Biochemical Monitoring

• Measure urinary free cortisol (UFC) regularly to assess treatment response 1
• Use multiple serial tests of both urinary free cortisol and late-night salivary cortisol 2
• Exception: cortisol measurements are not reliable when using mifepristone for dosing or safety monitoring 2

Clinical Monitoring

• Assess improvement in phenotype, weight, hypertension, glucose metabolism, and quality of life 1

Tumor Surveillance

• Monitor ACTH levels and perform MRI 6-12 months after initiating treatment, then every few years 1
• If progressive tumor growth occurs, suspend medical treatment and reassess management 1

Critical Pitfalls to Avoid

• Do not fail to consider disease severity when selecting initial therapy, as severe hypercortisolism is a medical emergency requiring urgent intervention 2, 3
• Do not overlook drug-drug interactions, particularly with ketoconazole and mifepristone 2
• Do not delay treatment while awaiting definitive surgery, as hypercortisolism itself modifies future prognosis even after cure 4
• Do not use dexamethasone or betamethasone for alternate-day therapy due to prolonged HPA axis suppression 5