What is the initial approach to a patient with Cushing's disease?

Approach to Patient with Cushing's Disease

Initial Diagnostic Workup

Begin with 2-3 first-line screening tests to confirm hypercortisolism: late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC), and/or overnight 1 mg dexamethasone suppression test (DST). 1, 2, 3

Screening Tests Selection

• Late-night salivary cortisol: Collect ≥2 samples on consecutive days; this test may be easier for patient collection and can detect recurrence earlier than other tests 1, 3
• 24-hour urinary free cortisol: Obtain 2-3 collections to account for variability (sensitivity 95%, specificity 98%) 1, 2
• Overnight 1 mg dexamethasone suppression test: Normal response is serum cortisol <1.8 μg/dL at 8 AM (sensitivity 95%, specificity 90%); particularly useful in shift workers, but avoid in women on estrogen-containing oral contraceptives 1, 2
• Measuring dexamethasone level along with morning cortisol improves test interpretability 1

Exclude Non-Neoplastic Hypercortisolism

Before proceeding, rule out physiologic causes that can mimic Cushing's syndrome: 1

• Severe obesity
• Pregnancy
• Polycystic ovary syndrome (PCOS)
• Uncontrolled diabetes mellitus
• Anorexia/malnutrition
• Recent illness or surgery
• Excessive exercise

Determining Etiology

ACTH Measurement

Measure morning plasma ACTH to differentiate ACTH-dependent from ACTH-independent causes (sensitivity 80%, specificity 90%). 2, 3

• Low ACTH: Indicates adrenal Cushing's syndrome → proceed to adrenal CT or MRI 1, 2
• Normal or elevated ACTH: Indicates ACTH-dependent Cushing's syndrome (Cushing's disease or ectopic ACTH) → proceed to pituitary MRI 1, 2

Pituitary MRI Interpretation

Order pituitary MRI to detect pituitary adenoma (sensitivity 63%, specificity 92%). 2, 3

The size of the lesion determines next steps: 1, 2

• Lesions ≥10 mm: Cushing's disease is presumed (positive predictive value 90%); proceed directly to surgical planning 1, 2
• Lesions 6-9 mm: Gray zone where expert opinions differ; consider inferior petrosal sinus sampling (IPSS) or additional dynamic testing (CRH, DDAVP) 1
• Lesions <6 mm or no visible adenoma: Perform IPSS to differentiate Cushing's disease from ectopic ACTH syndrome 1, 2

Additional Testing When Diagnosis Unclear

• Inferior petrosal sinus sampling (IPSS): Gold standard for differentiating pituitary from ectopic ACTH sources when imaging is equivocal 1, 3
• Whole-body CT: Necessary when ectopic ACTH syndrome is suspected to localize the source 1

Pre-Treatment Evaluation

Before initiating any treatment, obtain baseline assessments: 1, 4

• Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c)
• Liver function tests
• Electrocardiogram (ECG)
• Gallbladder ultrasound
• Serum potassium and magnesium levels

Treatment Algorithm

First-Line Treatment: Transsphenoidal Surgery

Transsphenoidal surgery by an experienced neurosurgeon at a Pituitary Tumor Center of Excellence is the first-line treatment, with remission rates of approximately 80% for microadenomas and 60% for macroadenomas. 3

• Remission is defined as postoperative serum cortisol <55 nmol/L 3
• Patients achieving remission require glucocorticoid replacement until hypothalamic-pituitary-adrenal axis recovery (typically within 12 months) 2, 3
• Complication rates are low (<5%) and include new-onset hypopituitarism, diabetes insipidus, CSF leak, and venous thromboembolism 3
• Critical pitfall: Recurrence rates range from 5-35%, requiring lifelong monitoring 3

Medical Therapy Indications

Medical therapy is indicated for: 1, 3

• Patients with persistent or recurrent disease after surgery
• Patients awaiting surgery or effects of radiation therapy
• Patients who are not surgical candidates
• Severe hypercortisolism requiring rapid cortisol normalization

Medical Therapy Selection by Disease Severity

Mild Disease (No Visible Tumor on MRI)

Start with ketoconazole, osilodrostat, or metyrapone as first-line agents. 1

• Ketoconazole: 400-1200 mg/day PO divided BID; normalizes UFC in ~65% initially (EMA approved for endogenous Cushing's syndrome, off-label in US) 1
• Osilodrostat: 2-7 mg/day BID (maximum 30 mg/day BID); normalizes UFC in 86% (FDA approved for Cushing's disease) 1, 2
• Metyrapone: 500 mg/day to 6 g/day divided every 6-8 hours; normalizes UFC in ~70% 1, 3
• Cabergoline may be considered for mild disease but is less effective with slower onset 1

Mild-to-Moderate Disease with Residual Tumor

Consider cabergoline or pasireotide due to potential for tumor shrinkage, though pasireotide carries high risk of hyperglycemia. 1, 4

• Pasireotide: 0.6-0.9 mg subcutaneously BID (FDA approved for Cushing's disease when surgery is not an option or has not been curative) 4
• Patient selection is critical due to high rate of hyperglycemia requiring intensive glucose monitoring 1, 4

Severe Disease

For severe hypercortisolism, use rapid-acting adrenal steroidogenesis inhibitors (osilodrostat or metyrapone) with response typically within hours. 1, 3

• Ketoconazole shows response within a few days 1
• Etomidate can be used if patient is hospitalized and cannot take oral medications 1
• Combination therapy with multiple steroidogenesis inhibitors may be necessary 1, 3
• If hypercortisolism is very severe and not responsive to optimized medical therapy, bilateral adrenalectomy should be considered to avoid worsening outcomes 1

Combination Therapy Regimens

When monotherapy fails: 1, 3

• Ketoconazole + metyrapone: Maximizes adrenal blockade or allows lower doses of both drugs 1, 3
• Ketoconazole + cabergoline or pasireotide: Rational when visible tumor is present 1, 3
• Triple therapy (cabergoline + pasireotide + ketoconazole): Reserved for resistant cases 3

Special Considerations for Medical Therapy

Mifepristone (glucocorticoid receptor blocker): 1

• Improves hyperglycemia and weight gain specifically
• Should only be used by clinicians with extensive Cushing's disease experience
• No reliable biochemical markers for monitoring cortisol levels
• High risk of adrenal insufficiency due to inability to monitor cortisol
• Often worsens hypokalemia

Patient-specific factors: 1

• Avoid cabergoline in patients with bipolar disorder or impulse control disorders
• Cabergoline may be preferred in young women desiring pregnancy
• Metyrapone may be considered with precautions in pregnant women (use higher cortisol target of 1.5 × ULN)

Monitoring Treatment Response

Assess response using multiple serial tests of both UFC and LNSC along with clinical improvement. 1, 3

• Consider changing treatment if cortisol levels remain elevated after 2-3 months on maximum tolerated doses 3
• If cortisol is reduced but not normalized with some clinical improvement, consider combination therapy 3
• Annual evaluation after hypothalamic-pituitary-adrenal axis recovery 3

Key Monitoring Parameters During Medical Therapy

• Ketoconazole: Regular liver function tests (risk of serious hepatotoxicity), ECG for QTc prolongation, testosterone levels in men, avoid proton pump inhibitors 1
• Osilodrostat: Monitor for hyperandrogenism in women (hirsutism), hypertension, hypokalemia, QTc prolongation; cross-reaction with 11-deoxycortisol in routine assays 1
• Metyrapone: Monitor for hyperandrogenism, hypertension, hypokalemia 1
• Pasireotide: Intensive glucose monitoring required, monitor thyroid function, ECG, gallbladder ultrasound 1, 4

Pediatric Considerations

Children with Cushing's syndrome should be referred to multidisciplinary centers with pediatric endocrinology expertise. 2, 3

• Medical therapy in children should be limited to normalizing cortisol in preparation for surgery or while awaiting radiotherapy response 3
• Metyrapone and ketoconazole have limited long-term use due to adverse effects 3
• Bilateral adrenalectomy reserved for severe refractory cases or life-threatening emergencies 3
• Evaluate for growth hormone deficiency 3-6 months postoperatively (prevalence 20%) 2

Critical Pitfalls to Avoid

• Do not rely on single screening test: Always perform 2-3 tests to confirm hypercortisolism 1, 2
• Do not skip IPSS for small lesions: All lesions <6 mm require IPSS; lesions 6-9 mm are controversial but many experts recommend IPSS 1, 2
• Do not underestimate recurrence risk: Lifelong monitoring is essential as recurrence can occur decades after "cure" 3
• Do not use mifepristone without extensive experience: Inability to monitor cortisol creates high risk of adrenal insufficiency 1
• Do not delay bilateral adrenalectomy in severe refractory cases: This can be life-saving when medical therapy fails 1, 3