How should hypercortisolism be managed?

Management of Hypercortisolism

For confirmed hypercortisolism, transsphenoidal surgery at a specialized Pituitary Tumor Center of Excellence is first-line treatment for Cushing's disease, while unilateral laparoscopic adrenalectomy is first-line for ACTH-independent disease from adrenal adenoma. 1, 2, 3

Initial Referral and Diagnostic Confirmation

• Refer immediately to an endocrinologist when screening tests show abnormal late-night salivary cortisol, 1-mg dexamethasone suppression test failure, or elevated 24-hour urinary free cortisol, as subsequent diagnostic testing requires considerable expertise and specialist referral is associated with better outcomes. 2

• Confirm hypercortisolism using 24-hour urinary free cortisol, late-night salivary cortisol, or overnight dexamethasone suppression test before proceeding with treatment decisions. 3, 4

• Measure plasma ACTH to distinguish ACTH-dependent (Cushing's disease, ectopic ACTH) from ACTH-independent (adrenal) causes—low or undetectable ACTH indicates adrenal disease. 3, 5

Surgical Management: First-Line Treatment

For ACTH-Dependent Disease (Cushing's Disease)

• Transsphenoidal surgery should be performed at specialized Pituitary Tumor Centers of Excellence with experienced neurosurgeons, as high-volume centers show better outcomes, fewer complications, shorter hospital stays, and lower costs. 2

• After incomplete tumor resection with persistent hypercortisolism, radiation therapy is used, particularly for aggressive or invasive unresectable tumors, with lifelong monitoring for pituitary hormone deficiencies required. 1

For ACTH-Independent Disease (Adrenal Adenoma)

• Laparoscopic unilateral adrenalectomy is the recommended treatment for adrenal adenoma causing ACTH-independent Cushing's syndrome. 3

• Postoperative corticosteroid supplementation is required until recovery of the hypothalamic-pituitary-adrenal axis, which may take months. 3

Medical Therapy: When Surgery Fails or Is Not Feasible

First-Line Medical Agents

Osilodrostat is the preferred first-line medical therapy due to highest efficacy based on prospective clinical trials, with rapid onset within hours. 6, 7

• Osilodrostat dosing requires careful titration with regular monitoring of urinary free cortisol and late-night salivary cortisol to assess efficacy. 6

• Common adverse reactions with osilodrostat include: adrenal insufficiency (43%), fatigue (39%), nausea (37%), headache (31%), and edema (21%), with hypocortisolism manageable by dose reduction and/or short-term glucocorticoid therapy. 7

• QT prolongation occurs in 4% of patients, requiring baseline and periodic ECG monitoring, particularly when QTcF increases >60 ms from baseline or exceeds 450 ms. 7

• Accumulation of adrenal hormone precursors causes hypertension (14%), hypokalemia (17%), and hyperandrogenism in females (hirsutism 12%, acne 11%), requiring potassium supplementation and/or mineralocorticoid antagonist therapy. 7

Alternative First-Line Agents

• Metyrapone has rapid onset within hours, is not limited by liver function monitoring requirements, and does not cause hypogonadism in men, making it suitable when osilodrostat is contraindicated. 6, 8

• Ketoconazole is effective within days and favored for ease of dose titration, though often under-dosed due to hepatotoxicity concerns requiring regular liver function monitoring. 6, 8

• Liver function tests should be regularly monitored for ketoconazole, but treatment does not necessarily require discontinuation if liver enzymes are mildly elevated yet stable. 6

For Mild Hypercortisolism

• For patients with mild hypercortisolism and no visible tumor on MRI, ketoconazole, osilodrostat, or metyrapone are typically preferred. 6

• Cabergoline may be used for mild disease, though it is less effective and has slower onset of action. 6

Combination Therapy

• Combination therapy should be used when monotherapy fails or to allow lower doses of individual drugs, maximizing adrenal blockade for patients with persistent hypercortisolism. 6

Severe Hypercortisolism: Urgent Management

• Immediate endocrinology consultation is necessary for severe hypercortisolism with life-threatening complications such as severe opportunistic infections, particularly in ectopic ACTH syndrome from small cell lung cancer. 2, 8

• Hypercortisolism must be controlled before cancer chemotherapy or surgery to reduce therapy-induced complications and mortality. 2, 6

• Adrenal steroidogenesis inhibitors (etomidate, ketoconazole, metyrapone), alone or in combination, are first-line treatment for severe hypercortisolemia due to rapid action, good efficacy, and safety profile. 8

Bilateral Adrenalectomy: Last Resort or Definitive Option

• Bilateral adrenalectomy is considered treatment of last resort after all other options have failed in most centers. 1

• However, bilateral adrenalectomy may be warranted earlier in patients with severe hypercortisolism requiring rapid, definitive cortisol control to avoid prolonged systemic effects of uncontrolled disease. 1

• Many expert centers recommend bilateral adrenalectomy earlier for females with Cushing's disease desiring pregnancy, as corticotroph tumor progression after bilateral adrenalectomy does not appear influenced by pregnancy. 1

• Laparoscopic bilateral adrenalectomy using transperitoneal or posterior retroperitoneal approach has 10-18% complication rate and <1% mortality, with clinical improvement in BMI, diabetes, hypertension, and muscle weakness in >80% of patients. 1

• After bilateral adrenalectomy, plasma ACTH and serial pituitary imaging are required for monitoring at 6-month intervals, as corticotroph tumor progression occurs in 25-40% of patients after 5-10 years. 1

Critical Monitoring Requirements

• Regular monitoring for treatment efficacy requires multiple serial tests of urinary free cortisol and late-night salivary cortisol. 6

• Lifelong monitoring for pituitary hormone deficiencies and recurrence is required in all patients undergoing radiation therapy. 1

• More frequent evaluation is necessary if there is clinical suspicion of corticotroph tumor progression after bilateral adrenalectomy. 1