What does an evening cortisol level of more than 60 indicate?

Evening Cortisol Level Above 60: Diagnostic Implications

An evening cortisol level above 60 nmol/L (>1.8 μg/dL) strongly suggests Cushing syndrome and requires further diagnostic evaluation to confirm hypercortisolism and determine its etiology. 1

Diagnostic Significance

• Evening cortisol levels should normally be at their nadir due to the circadian rhythm of cortisol secretion; levels above 50 nmol/L (≥1.8 μg/dL) at midnight or late evening indicate loss of this normal rhythm, a hallmark of Cushing syndrome 1
• Late-night salivary cortisol measurements have high sensitivity (95%) and specificity (100%) for diagnosing Cushing syndrome 1, 2
• Evening cortisol elevation is one of the earliest and most consistent biochemical abnormalities in Cushing syndrome, occurring before other manifestations become apparent 1
• High evening cortisol levels are associated with increased mortality risk, particularly in women 3

Diagnostic Algorithm

Step 1: Confirm Hypercortisolism

Perform at least two of the following tests to confirm the diagnosis:

• Repeat late-night salivary cortisol measurements on 2-3 occasions 1
• 24-hour urinary free cortisol (UFC) measurements (at least 2-3 collections) 1
• Low-dose dexamethasone suppression test (1 mg overnight or 2-day test) 1

Step 2: Determine Etiology of Hypercortisolism

Once hypercortisolism is confirmed, determine if it is ACTH-dependent or ACTH-independent:

• Measure morning plasma ACTH level 1
  • Elevated or normal ACTH (>5 ng/L or >1.1 pmol/L): ACTH-dependent Cushing syndrome (pituitary or ectopic source) 1
  • Low or undetectable ACTH: ACTH-independent Cushing syndrome (adrenal tumor) 1

Step 3: Localize Source of Excess Cortisol

For ACTH-dependent Cushing syndrome:

• Perform pituitary MRI 1
• Consider CRH stimulation test (cortisol increase ≥20% suggests pituitary source) 1
• If MRI is negative or inconclusive, consider bilateral inferior petrosal sinus sampling (BIPSS) 1

For ACTH-independent Cushing syndrome:

• Perform adrenal imaging (CT or MRI) 1
• Look for features suggesting malignancy: tumor >5 cm, irregular margins, local invasion 1

Common Pitfalls and Caveats

• False positive results can occur in:

  • Pseudo-Cushing states (depression, alcoholism, obesity) 1
  • Night-shift workers (disrupted circadian rhythm) 1
  • Severe stress, illness, or hospitalization 1
  • Pregnancy (increased CBG levels) 1

• False negative results can occur in:

  • Cyclical Cushing syndrome (periods of normal cortisol production) 1
  • Patients taking medications that affect cortisol metabolism 1

• A single elevated evening cortisol value is not diagnostic; confirmation with additional tests is essential 1

• Cortisol values may vary by assay method; laboratory-specific reference ranges should be used 1

Clinical Implications

• Untreated Cushing syndrome is associated with significant morbidity and mortality from complications including hypertension, diabetes mellitus, osteoporosis, and immunosuppression 1, 3

• Early diagnosis and treatment are critical to prevent these complications 1

• Treatment depends on etiology:

  • Pituitary adenoma: transsphenoidal surgery 1
  • Adrenal adenoma: laparoscopic adrenalectomy 1
  • Ectopic ACTH: removal of source tumor if possible 1
  • Medical therapy (ketoconazole, metyrapone, osilodrostat) if surgery contraindicated 1