What are the treatment options for hypercortisolism?

Treatment of Hypercortisolism

The treatment of high cortisol depends critically on identifying the underlying cause through ACTH measurement, with surgical resection being the definitive treatment for most cases, while medical management with adrenal steroidogenesis inhibitors (ketoconazole 400-1200 mg/d or metyrapone) serves as first-line pharmacotherapy when surgery is not feasible or for rapid preoperative control. 1

Diagnostic Algorithm to Guide Treatment

Before initiating treatment, you must determine the source of hypercortisolism through a systematic approach 1:

• Measure ACTH levels to distinguish ACTH-dependent from ACTH-independent causes 1

  • Elevated ACTH: Indicates pituitary tumors (Cushing's disease) or ectopic ACTH production from lung, thyroid, pancreas, or bowel tumors 1
  • Low/undetectable ACTH: Indicates primary adrenal pathology (adenoma, carcinoma, or bilateral hyperplasia) 1

• Obtain imaging based on ACTH results 1:

  • Pituitary MRI if ACTH is elevated
  • Adrenal CT/MRI if ACTH is suppressed
  • Chest/abdomen/pelvis imaging to evaluate for ectopic sources and metastases 1

Surgical Treatment (Definitive Therapy)

For ACTH-Independent Disease (Adrenal Source)

Benign adrenal adenoma 1:

• Laparoscopic adrenalectomy is the treatment of choice when feasible 1
• Postoperative corticosteroid supplementation is mandatory until HPA axis recovery 1

Malignant adrenal tumors (suspect if >5 cm, irregular margins, or inhomogeneous) 1:

• Open adrenalectomy with removal of adjacent lymph nodes is recommended 1
• May require en bloc resection of liver, kidney, pancreas, spleen, or diaphragm for complete resection 1
• Laparoscopic approach should be avoided due to increased risk of local recurrence and peritoneal spread 1

Bilateral multinodular hyperplasia 1:

• Perform adrenal vein sampling to assess cortisol production lateralization 1
• If asymmetric production: unilateral adrenalectomy of the most active side 1
• If symmetric production: medical management is indicated 1

For ACTH-Dependent Disease

Ectopic ACTH-producing tumors 1:

• Surgical removal of the ectopic tumor if resectable 1
• If unresectable: bilateral laparoscopic adrenalectomy or medical management 1

Pituitary tumors (Cushing's disease) 1:

• Transsphenoidal surgery is the primary treatment (not detailed in provided evidence but standard of care)
• Repeat surgery may be considered for recurrent disease if tumor visible on MRI 1

Medical Management

First-Line Adrenal Steroidogenesis Inhibitors

Ketoconazole 1:

• Most commonly used at doses of 400-1200 mg/d due to easy availability and relatively tolerable toxicity 1
• Achieves UFC normalization in approximately 64% of patients 1
• Monitor liver function tests regularly; mild stable elevations do not necessarily require discontinuation 1
• Common pitfall: Under-dosing due to fear of hepatotoxicity—do not hesitate to use adequate doses with appropriate monitoring 1
• Men may experience hypogonadism and gynecomastia, which can limit prolonged treatment 1

Metyrapone 1:

• Provides rapid cortisol control within hours 1
• Often combined with ketoconazole to maximize adrenal blockade or allow lower doses of both drugs 1
• Not limited by liver function test monitoring or hypogonadism concerns 1

Osilodrostat 1:

• Recently approved agent with rapid response (typically within hours) 1
• Expected to be increasingly used as it becomes widely available 1
• Not limited by hepatotoxicity or hypogonadism concerns 1

Mitotane 1:

• Slower-acting agent that may be included for synergistic effect 2
• Useful for preventing escape phenomenon with fast-acting drugs during prolonged follow-up 2

Alternative Medical Therapies

Octreotide 1:

• Can be considered for ectopic Cushing syndrome if tumor is Octreoscan-positive 1
• May be less effective in controlling ectopic ACTH secretion than in other contexts 1

Pasireotide 1, 3:

• Targets pituitary somatostatin receptors 1
• May be preferred when visible tumor is present due to potential for tumor shrinkage 1
• Critical limitation: High rate of hyperglycemia makes patient selection critical 1
• Requires monitoring for liver enzyme elevations, cholelithiasis (33% incidence), and QT prolongation 3

Cabergoline 1:

• May be used for mild disease with slower onset of action 1
• Preferred in young women desiring pregnancy 1
• Contraindicated in patients with bipolar disorder or impulse control disorders 1

Mifepristone (glucocorticoid receptor blocker) 1:

• Improves hyperglycemia and weight gain 1
• Major limitation: No reliable biochemical markers for monitoring cortisol levels, increasing risk of adrenal insufficiency 1
• Should only be used by clinicians with extensive experience in Cushing's disease 1
• Often worsens hypokalemia 1

Severe Hypercortisolism Requiring Urgent Treatment

For patients with life-threatening complications (severe infections, cardiovascular/thromboembolic events, uncontrolled hyperglycemia, psychiatric crisis) 1, 2:

• Rapid cortisol normalization is the most important goal 1
• Use osilodrostat or metyrapone (response within hours) or ketoconazole (response within days) 1
• Etomidate can be used if patient is hospitalized and cannot take oral medications 1
• Combination therapy with steroidogenesis inhibitors may be necessary 1
• If medical therapy fails: bilateral adrenalectomy should be performed as a life-saving measure 1, 2

Critical point for ectopic ACTH syndrome: Severe opportunistic infections occur after chemotherapy induction in patients with uncontrolled hypercortisolism, causing mortality before anticancer benefit can be realized 1. Laparoscopic bilateral adrenalectomy can rapidly decrease cortisol to allow timely chemotherapy initiation 1.

Combination Therapy Strategies

When monotherapy fails to normalize cortisol after 2-3 months at maximum tolerated doses 1:

Rational combinations 1:

• Ketoconazole + metyrapone: Maximizes adrenal blockade 1
• Ketoconazole + osilodrostat: Alternative adrenal blockade combination 1
• Ketoconazole + cabergoline or pasireotide: When visible tumor is present 1
• Triple therapy: Cabergoline + pasireotide + ketoconazole 1
• Metyrapone + ketoconazole + mitotane: For refractory cases 1

Monitor for overlapping toxicities, particularly QTc prolongation and drug-drug interactions 1

Monitoring Treatment Response

Biochemical monitoring 1:

• Measure urinary free cortisol (UFC) regularly, except when using mifepristone 1
• UFC is not useful if adrenal insufficiency is a concern 1
• Late-night salivary cortisol and morning cortisol can be measured, though significance of targeting diurnal rhythm alone is unclear 1

Clinical monitoring 1:

• Assess improvement in phenotype, weight, hypertension, glucose metabolism, and quality of life 1
• Clinical endpoints alone when using glucocorticoid receptor blockers 1

Tumor surveillance with adrenal-targeting agents 1:

• Monitor ACTH levels as significant elevations may indicate tumor growth 1
• 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

Symptomatic Management

While pursuing definitive treatment, manage complications of hypercortisolism 1:

• Hypertension, hyperglycemia, hypokalemia, and muscle atrophy require treatment for symptom palliation 1
• Correct hypokalemia and hypomagnesemia before initiating certain medical therapies 3
• Consider VTE prophylaxis given increased clotting factors and 2-4% VTE risk 1