When is it recommended to check cortisol levels?

When to Check Cortisol Levels

Cortisol levels should be checked in patients with suspected adrenal hormone excess (Cushing's syndrome), adrenal insufficiency, or when evaluating adrenal incidentalomas, as these conditions significantly impact morbidity and mortality. 1

Indications for Cortisol Testing

1. Evaluation of Adrenal Incidentalomas

• All patients with adrenal incidentalomas should be screened for autonomous cortisol secretion using the 1 mg dexamethasone suppression test (DST) 1
• This is a strong recommendation with moderate quality evidence, as autonomous cortisol secretion can lead to significant metabolic complications

2. Suspected Cushing's Syndrome

Indicated when patients present with:

• Weight gain and central obesity
• Easy bruising
• Severe hypertension
• Diabetes
• Proximal muscle weakness
• Fatigue and depression
• Sleep disturbances
• Menstrual irregularities or virilization
• Physical findings: supraclavicular fat accumulation, dorsocervical fat pad, facial plethora, thinned skin, purple striae >1cm, acne, ecchymoses 1

3. Suspected Adrenal Insufficiency

Indicated when patients present with:

• Fatigue, weakness
• Weight loss
• Nausea, vomiting
• Anorexia
• Hypotension
• Electrolyte abnormalities (hyponatremia, hyperkalemia in primary adrenal insufficiency)
• History of pituitary disease, cranial irradiation/surgery/injury 2

4. Monitoring Immune Checkpoint Inhibitor Therapy

• Patients receiving immune checkpoint inhibitors (especially anti-CTLA-4 antibodies) should have routine monitoring with early morning ACTH and cortisol levels to detect hypophysitis 1
• Recommended schedule: monthly for 6 months, then every 3 months for 6 months, then every 6 months for 1 year

Specific Cortisol Tests and Their Interpretation

1. Morning Serum Cortisol

• Best collected around 8:00 AM
• Interpretation:
  • <5 μg/dL (<138 nmol/L): Suggestive of adrenal insufficiency 2
  • 5-10 μg/dL (138-275 nmol/L): Intermediate, requires further testing 2

  • 10 μg/dL (>275 nmol/L): Generally excludes adrenal insufficiency in outpatients 3

2. 1 mg Dexamethasone Suppression Test (DST)

• Preferred screening test for autonomous cortisol secretion 1
• Protocol: 1 mg dexamethasone taken at 11 PM, serum cortisol measured at 8 AM
• Interpretation:
  • ≤50 nmol/L (≤1.8 μg/dL): Normal suppression, excludes cortisol hypersecretion
  • 51-138 nmol/L (1.8-5 μg/dL): Possible autonomous cortisol secretion

  • 138 nmol/L (>5 μg/dL): Evidence of cortisol hypersecretion 1

3. Late Night Salivary Cortisol (LNSC)

• Measures loss of normal circadian rhythm in cortisol secretion
• Collect at bedtime
• High specificity for Cushing's syndrome
• At least 2-3 samples recommended 1
• Not useful in night-shift workers or those with disrupted sleep cycles

4. 24-hour Urinary Free Cortisol (UFC)

• Measures overall cortisol production
• At least 2-3 collections recommended
• Less reliable in patients with renal impairment (CrCl <60mL/min) or significant polyuria (>5 L/24h) 1

5. ACTH Stimulation Test (Cosyntropin Test)

• Gold standard for diagnosing adrenal insufficiency
• Measures cortisol before and 60 minutes after administration of 250 μg cosyntropin
• Normal response: stimulated cortisol >18 μg/dL (>500 nmol/L) 2, 4

Important Considerations and Pitfalls

Factors Affecting Cortisol Results

• False positive DST results may occur with:

  • Rapid absorption/malabsorption of dexamethasone
  • Medications that induce CYP3A4 (phenobarbital, carbamazepine)
  • Increased corticosteroid binding globulin levels (oral estrogens, pregnancy) 1

• False negative DST results may occur with:

  • Medications that inhibit dexamethasone metabolism (fluoxetine, cimetidine)
  • Decreased binding proteins (nephrotic syndrome) 1

Differentiating Primary vs. Secondary Adrenal Insufficiency

Type	ACTH Level	Cortisol Level	Electrolytes	Hyperpigmentation
Primary	High	Low	↓Na, ↑K	Present
Secondary	Low	Low	Generally normal	Absent
[5]

Algorithm for Cortisol Testing

1. For adrenal incidentalomas:

   • Perform 1 mg DST in all patients
   • If DST >138 nmol/L, consider adrenalectomy
   • If DST 51-138 nmol/L, monitor for metabolic complications 1

2. For suspected Cushing's syndrome:

   • Start with 1 mg DST or late night salivary cortisol
   • If abnormal, confirm with 24-hour UFC or additional tests
   • Determine ACTH dependency with plasma ACTH 1

3. For suspected adrenal insufficiency:

   • Check morning serum cortisol (8 AM)
   • If <275 nmol/L in outpatients or <250 nmol/L in afternoon samples, proceed with ACTH stimulation test 3
   • If clinical suspicion is high despite normal morning cortisol, perform ACTH stimulation test

By following these guidelines for cortisol testing, clinicians can appropriately diagnose conditions affecting the hypothalamic-pituitary-adrenal axis, leading to timely treatment and improved patient outcomes.