How are abnormal cortisol levels treated?

Treatment of Abnormal Cortisol Levels

Hypercortisolism (Cushing Syndrome)

For hypercortisolism, treatment selection depends on disease severity and tumor presence, with adrenal steroidogenesis inhibitors as first-line medical therapy and surgery reserved for pituitary or ectopic sources. 1

Surgical Management

• Transsphenoidal surgery is first-line treatment for pituitary tumors causing Cushing's disease 1
• Surgical removal of ectopic ACTH-producing tumors is recommended when the primary tumor is resectable 1
• Bilateral laparoscopic adrenalectomy should be considered for unresectable primary tumors or when medical therapy fails to control severe hypercortisolism 2, 1

Medical Therapy by Disease Severity

Mild Disease (no visible tumor on MRI):

• Start with ketoconazole, osilodrostat, or metyrapone as first-line agents 2, 3
• Cabergoline is an alternative option but has slower onset and lower efficacy; requires less frequent dosing 2

Mild-to-Moderate Disease (with residual tumor):

• Consider cabergoline or pasireotide due to potential for tumor shrinkage 2, 3
• Exercise caution with pasireotide given high rates of hyperglycemia requiring careful patient selection 2

Severe Disease:

• Rapid cortisol normalization is the primary goal 2, 3
• Osilodrostat and metyrapone produce response within hours; ketoconazole within days 2
• Etomidate can be used for hospitalized patients unable to take oral medications 2, 3
• Combination therapy with multiple steroidogenesis inhibitors may be necessary 2
• If severe hypercortisolism remains unresponsive to optimized medical therapy including combinations, proceed to bilateral adrenalectomy to prevent worsening outcomes 2

Specific Medical Agents

Adrenal Steroidogenesis Inhibitors (ranked by efficacy for UFC normalization):

• Osilodrostat has highest efficacy based on prospective trials 2
• Metyrapone (retrospective and prospective data) 2
• Ketoconazole 400-1200 mg/day (retrospective data) 2, 1
• Pasireotide (prospective data) 2
• Cabergoline (retrospective and prospective data) 2
• Mitotane for adrenal carcinoma 1

Mifepristone:

• Improves clinical features including hyperglycemia and weight gain regardless of hypercortisolism etiology 3
• Should only be used by clinicians with extensive experience in Cushing's disease 2
• Cortisol measurements are not reliable for monitoring; cannot assess for adrenal insufficiency biochemically 2
• Long half-life requires several days of stress-dose glucocorticoid (preferably dexamethasone) if adrenal insufficiency develops 2
• Often worsens hypokalemia 2

Octreotide:

• Consider for ectopic Cushing syndrome if tumor is Octreoscan-positive 1

Combination Therapy

• Combine ketoconazole with metyrapone to maximize adrenal blockade when monotherapy fails 2, 3
• Alternative: steroidogenesis inhibitor plus tumor-targeting agent (ketoconazole plus cabergoline) when visible tumor present 2
• Triplet combinations include cabergoline, pasireotide, plus ketoconazole 2
• Monitor for overlapping toxicities, particularly QTc prolongation 2

Monitoring Treatment Response

• Measure urinary free cortisol (UFC) regularly; this test is not useful for diagnosing adrenal insufficiency 2
• Morning cortisol and/or late-night salivary cortisol may be used as alternatives 2
• Patients normalizing both UFC and late-night salivary cortisol show better clinical outcomes than those normalizing UFC alone 2
• Monitor patient symptoms, comorbidities (weight, glycemia, blood pressure), and quality of life through patient-reported outcomes 2
• Change treatment if cortisol levels remain persistently elevated after 2-3 months on maximum tolerated doses 2, 3
• If cortisol reduces but doesn't normalize with some clinical improvement, consider combination therapy 2
• Switch to different therapy if clear resistance occurs, but ensure insufficient control is not due to under-dosing 2

Tumor Monitoring with Medical Therapy

• Obtain MRI typically 6-12 months after initiating treatment, then repeat every few years 2, 3
• Monitor ACTH levels as significant elevations may indicate tumor growth, though ACTH has short half-life and fluctuates 2, 3
• If progressive tumor size increase occurs, suspend treatment and reassess management 2, 3
• With adrenal-targeting agents, tumor growth may occur due to ACTH-cortisol feedback interruption 2

Special Patient Populations

• Pregnancy: Metyrapone may be considered with precautions; use higher cortisol target of 1.5 × upper limit of normal 2
• Young women desiring pregnancy: Cabergoline may be preferred 2
• Bipolar or impulse control disorder: Avoid cabergoline 2
• Cirrhosis: Impaired response to metyrapone may occur 3

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Adrenal Insufficiency (Low Cortisol)

For adrenal insufficiency, glucocorticoid replacement with hydrocortisone 15-25 mg daily in divided doses is the cornerstone of treatment, with mineralocorticoid replacement added for primary adrenal insufficiency. 1

Primary Adrenal Insufficiency

• Glucocorticoid replacement: hydrocortisone 15-25 mg daily in divided doses 1
• Mineralocorticoid replacement: fludrocortisone 0.05-0.1 mg/day, adjusted based on volume status, sodium level, and renin response 1

Secondary Adrenal Insufficiency

• Glucocorticoid replacement: hydrocortisone 15-20 mg daily in divided doses 1
• Mineralocorticoid replacement is not required 1

Stress Dosing and Crisis Management

• Increase glucocorticoid dose to 2-3 times maintenance dose during illness or physical stress 1
• Adrenal crisis is life-threatening and requires immediate IV hydrocortisone and fluid resuscitation 1
• Educate patients on steroid stress dosing and emergency injections 1
• Patients should wear medical alert bracelet or necklace 1

Monitoring

• Regular follow-up of clinical symptoms and electrolytes 1
• For functioning tumors, follow-up imaging and biomarkers every 3-6 months 1
• Monitor thyroid function and adjust thyroid hormone replacement as needed in patients taking mifepristone 3

Critical Diagnostic Caveat

• Approximately 10% of patients with primary adrenal insufficiency present with normal cortisol concentrations 4
• Normal to high basal cortisol in presence of clearly elevated corticotropin (ACTH >300 pg/ml) is indicative of primary adrenal insufficiency when case history is suggestive 4
• Do not rule out adrenal insufficiency based solely on normal morning cortisol values if clinical suspicion is high 4