What are the next steps for a 57-year-old male with elevated morning (am) cortisol levels, indicating hypercortisolism?

Management of Elevated Morning Cortisol (648) in a 57-Year-Old Male

The next step for a 57-year-old male with an elevated morning cortisol of 648 should be confirmatory testing with 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), and 1mg overnight dexamethasone suppression test (DST) to establish the diagnosis of Cushing's syndrome. 1

Diagnostic Approach for Elevated Cortisol

Initial Assessment

• A single elevated morning cortisol value (648) is insufficient for diagnosing Cushing's syndrome
• Morning cortisol normally ranges from 200-650 nmol/L 2
• The Endocrine Society recommends using multiple tests to confirm hypercortisolism 1, 3

Recommended First-Line Tests

1. 24-hour Urinary Free Cortisol (UFC)

   • Reflects integrated tissue exposure to free cortisol over 24 hours 4
   • Patient instructions:
     • Avoid strenuous physical activity for 48 hours before and during collection 1
     • Ensure complete collection with appropriate total volume 4
   • At least 2-3 samples should be collected to confirm diagnosis 1

2. Late-Night Salivary Cortisol (LNSC)

   • Measures disruption of normal circadian rhythm (cortisol should be low at night) 1
   • Highest sensitivity (>90%) and specificity (100%) among screening tests 1
   • Collect ≥2 samples on consecutive days for improved accuracy 1
   • Simple collection method suitable for outpatients 4

3. 1mg Overnight Dexamethasone Suppression Test (DST)

   • Evaluates feedback inhibition of the hypothalamic-pituitary-adrenal axis 2
   • Procedure: Dexamethasone 1mg orally at midnight, measure plasma cortisol at 8 AM
   • Normal response: Morning cortisol suppressed to <80 nmol/L 2
   • Absence of suppression suggests Cushing's syndrome 2

Further Diagnostic Steps

If Initial Tests Are Positive

• Refer to an endocrinologist for further evaluation 1, 3
• Determine ACTH status to differentiate between ACTH-dependent and ACTH-independent causes 1
  • Low ACTH: Suggests adrenal cause (adrenal adenoma/carcinoma) (~20% of cases) 2
  • Normal/elevated ACTH: Suggests pituitary Cushing's disease (70%) or ectopic ACTH syndrome (10%) 2
• Pituitary MRI if ACTH-dependent Cushing's is suspected 5
• Consider inferior petrosal sinus sampling for equivocal MRI results 5

If Initial Tests Are Discordant

• Consider cyclic Cushing's syndrome 3
• May need CRH stimulation test following low-dose dexamethasone to rule out pseudo-Cushing states 5

Important Considerations

Potential Confounding Factors

• Medications: Some drugs can interfere with cortisol measurement 1
  • Consider using liquid chromatography-tandem mass spectrometry (LC-MS/MS) instead of immunoassays for more accurate measurement 1
• Pseudo-Cushing states: Severe depression or stress can cause false positives on DST 2
• Sample collection issues: Ensure proper collection techniques, especially for UFC and LNSC 4

Clinical Features to Evaluate

• Look for specific signs of Cushing's syndrome:
  • Abnormal fat distribution (supraclavicular and temporal fossae)
  • Proximal muscle weakness
  • Wide purple striae
  • Hypertension, diabetes, obesity, osteoporosis
  • Facial rounding, dorsocervical fat pad ("buffalo hump")
  • Thin skin, easy bruising 6, 4

Treatment Considerations

If Cushing's syndrome is confirmed, treatment will depend on the cause:

• Pituitary Cushing's disease: Transsphenoidal surgery (first-line) 1
• Adrenal adenoma: Laparoscopic unilateral adrenalectomy 1
• Ectopic ACTH syndrome: Surgical resection of the tumor 1
• Medical therapy (if surgery contraindicated or unsuccessful): Steroidogenesis inhibitors like ketoconazole, metyrapone, or osilodrostat 1

Monitoring During Treatment

• Liver function should be monitored, especially if medical therapy is initiated 7
• Monitor for adrenal insufficiency after successful treatment 1
• Regular assessment of pituitary function during treatment 7