What are the diagnostic criteria and current treatment guidelines for Cushing's disease in adults, particularly females, presenting with symptoms such as weight gain, hypertension, diabetes, and osteoporosis?

Diagnosis of Cushing's Disease

For adults presenting with weight gain, hypertension, diabetes, and osteoporosis, begin by ruling out exogenous glucocorticoid use, then perform 2-3 first-line screening tests including late-night salivary cortisol, 24-hour urinary free cortisol, and overnight 1 mg dexamethasone suppression test to confirm hypercortisolism. 1, 2, 3

Initial Screening Approach

First-Line Screening Tests (Perform 2-3 Tests)

• Late-night salivary cortisol (LNSC): Collect at least 2-3 samples on consecutive days at the patient's usual bedtime (typically 11 PM-midnight), with sensitivity of 95% and specificity of 93-100% 3, 4

  • This test is easiest for patient compliance and should be the starting point for low clinical suspicion 2
  • Critical contraindication: Do NOT use in night-shift workers or anyone with disrupted sleep-wake cycles 4
  • Avoid topical hydrocortisone contamination, which can falsely elevate results 4

• 24-hour urinary free cortisol (UFC): Collect at least 2-3 samples to account for variability, with sensitivity of 89% and specificity of 100% 3, 4

  • This measures overall cortisol production over 24 hours 3

• Overnight 1 mg dexamethasone suppression test (DST): Administer 1 mg dexamethasone at midnight, measure serum cortisol at 8 AM; normal response is cortisol <1.8 μg/dL (50 nmol/L), with sensitivity of 95% and specificity of 80% 3, 4

  • Measuring dexamethasone levels along with cortisol improves test interpretability 2, 4
  • Less useful in women taking estrogen-containing oral contraceptives 4

Interpretation of Screening Results

• If any test is abnormal: Repeat 1-2 screening tests to confirm the diagnosis 2, 3
• If all tests are normal and clinical suspicion is low-moderate: Cushing's syndrome is unlikely 2
• If results are inconsistent: Consider cyclic Cushing's syndrome and perform extended monitoring with multiple periodic sequential LNSC measurements 4

Common Pitfalls to Avoid

• Pseudo-Cushing's states can cause false-positive results in severe obesity, uncontrolled diabetes, depression, and alcoholism 2, 4
• Always exclude exogenous glucocorticoid use before any biochemical testing 2

Determining the Etiology

ACTH-Dependent vs. ACTH-Independent

• Measure morning plasma ACTH level to differentiate causes 2, 3, 4:
  • Normal or elevated ACTH (>5 ng/L or >1.1 pmol/L) indicates ACTH-dependent Cushing's syndrome (pituitary or ectopic source) 4
  • Low or undetectable ACTH indicates ACTH-independent Cushing's syndrome (adrenal source) 3, 4

Localizing ACTH-Dependent Disease

• Pituitary MRI with gadolinium enhancement: Perform for all ACTH-dependent cases, with sensitivity of 63% and specificity of 92% 2, 3

  • If pituitary lesion ≥10 mm is detected and dynamic testing is consistent with Cushing's disease, IPSS is not necessary 1, 2
  • If pituitary lesion is <6 mm, proceed with bilateral inferior petrosal sinus sampling (BIPSS) 1
  • For lesions 6-9 mm, expert opinion differs, but the majority recommend IPSS to confirm diagnosis 1

• Bilateral inferior petrosal sinus sampling (BIPSS): Perform if pituitary MRI is negative or equivocal 2, 3

  • Diagnostic criteria: central-to-peripheral ACTH ratio ≥2:1 before stimulation and ≥3:1 after CRH stimulation, with sensitivity of 100% 2, 3
  • IPSS has high diagnostic accuracy for localization to the pituitary gland but is not reliable for tumor lateralization 1

• Alternative testing: CRH stimulation test showing ≥20% increase in cortisol from baseline supports pituitary origin 4

Pre-Treatment Testing Requirements

• Before initiating treatment, obtain: fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), liver tests, electrocardiogram (ECG), gallbladder ultrasound, and serum potassium and magnesium levels 5

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Treatment Guidelines for Cushing's Disease

Transsphenoidal surgery is the first-line treatment for Cushing's disease, with medical therapy reserved for patients awaiting surgery, those with persistent disease after surgery, or when surgery is not an option. 1, 2, 6

First-Line Treatment: Transsphenoidal Surgery

• Transsphenoidal pituitary surgery is the treatment of choice for Cushing's disease caused by pituitary adenoma 2, 6
• After successful surgery, adrenal function typically recovers within 12 months, with an 80% recovery rate 2
• Important caveat: The risk of recurrence after initial surgery is high and remains elevated for many decades after surgery 7

Medical Therapy

When to Use Medical Therapy

• Indications: Patients awaiting surgery, persistent disease after surgery, or when surgery is not an option or has not been curative 2, 5

Adrenal Steroidogenesis Inhibitors

• Osilodrostat (11β-hydroxylase inhibitor): Achieves urinary free cortisol normalization in 86% of patients with a median time to response of 2 months 2

  • This is the most effective medical therapy based on recent evidence 2

• Ketoconazole or metyrapone: Alternative adrenal steroidogenesis inhibitors with response rates of approximately 70% 2

Somatostatin Receptor Ligands

• Pasireotide (SIGNIFOR): FDA-approved for adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative 5
  • Initial dosage: 0.6 mg or 0.9 mg subcutaneously twice daily; dosage range 0.3-0.9 mg twice daily 5
  • Titrate based on: Clinically meaningful reduction in 24-hour UFC and/or improvements in signs and symptoms 5
  • Hepatic impairment: Child-Pugh B patients start at 0.3 mg twice daily with maximum 0.6 mg twice daily; avoid use in Child-Pugh C patients 5

Critical Warnings for Medical Therapy

• Hypocortisolism: Decreases in cortisol may occur, requiring dose reduction, interruption, or adding low-dose short-term glucocorticoid 5
• Hyperglycemia and diabetes: Occurs with initiation; intensive glucose monitoring is required and may necessitate initiation or adjustment of anti-diabetic treatment 5
• Bradycardia and QT prolongation: Use with caution in at-risk patients; ECG testing required before and during treatment 5
• Cholelithiasis: Monitor periodically; discontinue if complications are suspected 5
• Steatorrhea and malabsorption: New onset steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss may occur; evaluate for pancreatic exocrine insufficiency if symptoms develop 5

Radiation Therapy

• Consider radiation therapy for persistent disease after surgery when medical therapy is inadequate or not tolerated 2
• Important limitation: Cortisol normalization may take months to years 2

Bilateral Adrenalectomy

• Reserved for: Patients not responsive to surgery and medication 6
• This is a definitive but last-resort option due to the need for lifelong glucocorticoid and mineralocorticoid replacement 1

Management of Comorbidities

Hypercoagulability and Thromboembolism

• VTE risk is >10-fold higher in Cushing's disease patients versus those with nonfunctioning adenomas 1
• VTE risk persists in the first few months after surgery, with 30-day post-adrenalectomy VTE risk of 3.4-4.75% 1
• Thromboprophylaxis: Data from retrospective studies indicate that thromboprophylaxis can decrease postoperative VTE incidence, particularly when extended to 30 days 1

Cardiovascular, Metabolic, and Skeletal Complications

• Address hypertension, diabetes, and osteoporosis concomitant with or even before Cushing's disease-specific treatments 1
• These comorbidities substantially impair health-related quality of life and contribute to increased mortality 7, 6

Treatment Algorithm

1. Confirm diagnosis with 2-3 screening tests and determine etiology with ACTH level and imaging 1, 2
2. Proceed with transsphenoidal surgery as first-line treatment 2, 6
3. If surgery is not curative or not an option: Initiate medical therapy with osilodrostat (preferred) or ketoconazole/metyrapone, or pasireotide 2, 5
4. If medical therapy is inadequate: Consider radiation therapy 2
5. If all else fails: Consider bilateral adrenalectomy 6

Special Considerations for Females of Reproductive Potential

• Advise premenopausal females of the potential for unintended pregnancy when using pasireotide 5