What is the appropriate diagnostic and treatment approach for a 40-year-old female suspected of having Cushing's disease?

Diagnostic and Treatment Approach for Cushing's Disease in a 40-Year-Old Female

For a 40-year-old female with suspected Cushing's disease, begin screening with late-night salivary cortisol (LNSC) or 24-hour urinary free cortisol (UFC), followed by transsphenoidal surgery as first-line definitive treatment if confirmed, with medical therapy reserved for surgical failures or as bridging therapy. 1

Initial Diagnostic Workup

Screening Tests

• Start with LNSC (at least 2-3 tests on consecutive days) or UFC (average of 2-3 collections) as these are the most practical first-line screening tests 1
• The 1-mg dexamethasone suppression test (DST) is also acceptable, but avoid DST if the patient is taking oral estrogen-containing contraceptives as this causes false-positive results due to elevated corticosteroid binding globulin 1
• Multiple LNSC collections may be easier for patient compliance than UFC 1
• Measuring dexamethasone levels alongside morning cortisol improves DST interpretability if false-positive results are suspected 1

Ruling Out Pseudo-Cushing's

• If screening tests show mild elevations (UFC within 3-fold of normal), consider pseudo-Cushing's syndrome from psychiatric disorders, alcohol use, obesity, or polycystic ovary syndrome 1
• Repeat testing after 3-6 months or treat underlying conditions (such as depression) to see if symptoms resolve 1
• The combined dexamethasone-CRH test or desmopressin test can distinguish true Cushing's from pseudo-Cushing's if needed 1

Confirming ACTH-Dependent Disease

• Once hypercortisolism is confirmed, measure plasma ACTH levels to distinguish pituitary/ectopic sources (mid-normal to elevated ACTH) from adrenal causes (suppressed ACTH) 2, 3
• Obtain pituitary MRI to identify corticotroph adenoma 2, 3
• Bilateral inferior petrosal sinus sampling (IPSS) is indicated if MRI is negative or equivocal, or if ACTH levels suggest ectopic source—but IPSS should never be used to diagnose hypercortisolism itself 1

Treatment Algorithm

First-Line: Transsphenoidal Surgery

• Transsphenoidal pituitary surgery is the definitive first-line treatment for Cushing's disease, achieving remission in approximately 78% of patients 4, 3
• Surgery should be performed by an experienced pituitary neurosurgeon 2
• Monitor for recurrence as approximately 13% relapse within 10 years, meaning nearly one-third ultimately fail surgical treatment 4

Preoperative Considerations

• Consider preoperative medical therapy only if surgery is delayed due to scheduling or external factors 1
• Patients with severe, life-threatening complications (severe metabolic derangements, psychiatric crises, infections, cardiovascular/thromboembolic events) may benefit from preoperative medical therapy in select cases 1
• Prophylactic anticoagulation with low molecular weight heparin should be considered for patients at high VTE risk, including those with severe hypercortisolism, history of thromboembolism, current estrogen use, or poor mobility 1
• Hold estrogen therapy preoperatively if used for contraception (though pregnancy also increases thrombosis risk) 1

Second-Line: Medical Therapy

Medical therapy is indicated for: 1, 4

• Persistent hypercortisolism after incomplete surgical resection
• Recurrent disease
• Bridging therapy while awaiting radiotherapy effects
• Preoperative stabilization in severe cases
• Primary therapy when surgery is not an option

Adrenal Steroidogenesis Inhibitors (Most Commonly Used)

Ketoconazole: 1

• Dosing: 400-1200 mg/day orally, divided twice daily
• Achieves ~65% UFC normalization initially
• Favored for ease of dose titration but requires monitoring for hepatotoxicity with regular liver function tests
• Needs gastric acid for absorption—avoid proton pump inhibitors
• Monitor for drug-drug interactions and hypogonadism in men

Osilodrostat (FDA-approved for Cushing's disease): 1

• Dosing: 2-7 mg twice daily (maximum 30 mg twice daily)
• Achieves highest rates of cortisol normalization (86% in Phase 3 trials)
• Rapid decrease in UFC
• Monitor for hyperandrogenism (hirsutism), hypertension, hypokalemia, and adrenal insufficiency
• More convenient dosing schedule than metyrapone

Metyrapone: 1

• Dosing: 500 mg/day to 6 g/day, divided every 6-8 hours
• Achieves ~70% UFC normalization
• Rapid onset (typically within first month)
• Monitor for hyperandrogenism in women with long-term use
• Not limited by hypogonadism in men (unlike ketoconazole)

Pituitary-Directed Therapy

Pasireotide (FDA-approved for Cushing's disease): 1, 4

• Immediate-release: 0.3-0.9 mg twice daily (15-26% UFC normalization)
• Long-acting release: 10-30 mg monthly (40% UFC normalization)
• High risk for hyperglycemia and diabetes mellitus requires careful patient selection—avoid in patients with poorly controlled diabetes
• Also causes diarrhea, nausea, abdominal pain, cholelithiasis

Cabergoline: 1, 4

• Dosing: 0.5-7 mg weekly
• Achieves ~40% UFC normalization
• Decreases tumor volume in up to 50% of patients initially
• Avoid in patients with history of bipolar disorder or impulse control disorders 1
• Consider for pregnant women or those desiring pregnancy (though not approved for pregnancy) 1
• Monitor for treatment-induced impulse-control disorders

Glucocorticoid Receptor Blocker

Mifepristone (FDA-approved for hyperglycemia in Cushing's syndrome): 1, 4

• Dosing: 300-1200 mg/day orally
• Highly effective for controlling glucose intolerance (~60% improvement in glycemia)—particularly useful when Cushing's disease is associated with diabetes
• Cannot use cortisol levels to monitor treatment response or adrenal insufficiency—must rely on clinical endpoints only 1
• Use cautiously without expert pituitary endocrinologist monitoring 1
• Requires careful review for drug-drug interactions
• Monitor for hypokalemia, hypertension, vaginal bleeding

Monitoring Medical Therapy

• Define response using both clinical improvement (weight, hypertension, glucose metabolism, quality of life) and biochemical endpoints (UFC for all agents except mifepristone) 1
• Obtain pituitary MRI 6-12 months after initiating medical therapy and repeat every few years to monitor for tumor growth 1
• Monitor ACTH levels as progressive elevations may signal tumor growth requiring MRI, though ACTH fluctuates and doesn't necessarily reflect tumor progression 1
• Consider changing treatment if cortisol remains persistently elevated after 2-3 months on maximum tolerated doses 1
• If partial response with some clinical improvement, consider combination therapy 1
• Switch to different therapy if clear resistance despite dose escalation 1

Third-Line: Radiotherapy

• Stereotactic radiosurgery (SRS) or conventional radiotherapy is used for persistent hypercortisolism after incomplete tumor resection, particularly for aggressive/invasive tumors 1
• SRS achieves biochemical control in approximately 80% at 5.6 years, with tumor control in ~95% 1
• Requires 3-5 mm distance between tumor and optic chiasm with chiasm dose <8 Gy to prevent optic damage 1
• Adjuvant medical therapy is needed during the latency period (months to years) until radiotherapy takes effect 1
• Hypopituitarism occurs in 25-50% of patients and increases over time—requires lifelong monitoring 1
• Periodically withdraw medical therapy to assess radiotherapy response 1

Fourth-Line: Bilateral Adrenalectomy

• Reserve bilateral adrenalectomy for severe, refractory Cushing's disease after all other options have failed 1, 5
• Consider earlier for patients with life-threatening complications requiring rapid, definitive cortisol control (severe cardiac dysfunction, cirrhosis, uncontrolled infections) 1, 5
• Many expert centers recommend bilateral adrenalectomy earlier for females desiring pregnancy 1
• Provides immediate control of cortisol excess 1, 5
• Requires lifelong glucocorticoid and mineralocorticoid replacement 1, 5
• Monitor for Nelson syndrome (corticotroph tumor progression) in 25-40% of patients after 5-10 years using plasma ACTH and serial pituitary MRI every 6 months initially 1, 5

Critical Pitfalls to Avoid

• Do not use IPSS to diagnose hypercortisolism—only use it for localization after confirming cortisol excess 1
• Do not rely on single screening test—obtain multiple collections (2-3 LNSC or UFC) to account for variability 1
• Do not use DST in women on oral contraceptives—false-positives are common 1
• Do not use cortisol to monitor mifepristone therapy—only clinical endpoints are valid 1
• Do not under-dose ketoconazole due to hepatotoxicity concerns—this leads to treatment failure 1
• Do not ignore tumor growth monitoring on medical therapy—obtain MRI 6-12 months after starting treatment 1
• Do not forget thromboprophylaxis in high-risk patients—Cushing's disease carries significant VTE risk 1