When should serum cortisol be measured (indications for checking cortisol levels)?

When to Check Cortisol Levels

Check cortisol levels in any patient presenting with unexplained hypotension, collapse, persistent vomiting or diarrhea, unexplained fatigue, weight loss, hyperpigmentation, or electrolyte abnormalities (hyponatremia, hyperkalemia, hypoglycemia). 1, 2, 3

Clinical Scenarios Requiring Immediate Cortisol Assessment

High-Risk Emergency Presentations

• Unexplained hypotension or shock requiring vasopressors – particularly when refractory to standard treatment, presume adrenal insufficiency until proven otherwise 1
• Unexplained collapse with hypotension and gastrointestinal symptoms (vomiting, diarrhea) – immediately raises suspicion for adrenal crisis 1, 2
• Critically ill patients with treatment-resistant hypotension – consider screening or empiric stress-dose hydrocortisone 1
• Any patient taking ≥20 mg/day prednisone or equivalent for ≥3 weeks who develops unexplained hypotension – presume adrenal insufficiency 1

Critical pitfall: Never delay treatment of suspected acute adrenal crisis for diagnostic procedures; give 100 mg IV hydrocortisone immediately plus 0.9% saline infusion at 1 L/hour, drawing blood for cortisol and ACTH before treatment if possible 1, 2, 3

Outpatient Indications for Cortisol Testing

Suspected Adrenal Insufficiency

• Persistent unexplained fatigue (present in 50-95% of adrenal insufficiency cases) with associated symptoms 3
• Nausea, vomiting, or poor appetite (occurs in 20-62% of cases) 1, 3
• Unintentional weight loss (43-73% of cases) 3
• Salt craving – specific clue for primary adrenal insufficiency 1
• Hyperpigmentation of skin creases, scars, or mucous membranes – strongly suggests primary adrenal insufficiency due to elevated ACTH 1
• Orthostatic hypotension – reflects mineralocorticoid deficiency in primary adrenal insufficiency 1
• Hyponatremia – present in 90% of newly diagnosed adrenal insufficiency cases 1

Important caveat: The absence of hyperkalemia cannot rule out adrenal insufficiency, as it occurs in only ~50% of cases 1, 2

Suspected Cushing's Syndrome

• Clinical features of hypercortisolism – central obesity, facial plethora, proximal muscle weakness, wide purple striae, easy bruising 4
• Screening tests include: late-night salivary cortisol (>3.6 nmol/L abnormal), 24-hour urinary free cortisol (>100 μg/24h diagnostic), or overnight 1-mg dexamethasone suppression test (cortisol ≥1.8 μg/dL abnormal) 4, 2
• Obtain 2-3 measurements of each test due to substantial intra-patient variability and possibility of cyclic Cushing's 4, 2

Patients on Chronic Glucocorticoid Therapy

• Before tapering or discontinuing glucocorticoids – to assess for iatrogenic secondary adrenal insufficiency 1, 3
• Wait until corticosteroids are discontinued with adequate washout time before attempting diagnostic testing; hydrocortisone requires 24-hour washout, other steroids require longer 1
• Testing for HPA axis recovery 3 months after weaning from maintenance glucocorticoid therapy 1

Critical pitfall: Morning cortisol measurements in patients actively taking corticosteroids are not diagnostic due to assay cross-reactivity with therapeutic steroids 1

Special Populations

Hyponatremia Workup

• Adrenal insufficiency must be excluded before diagnosing SIADH – both present with euvolemic hypo-osmolar hyponatremia and similar laboratory findings 1
• Perform cosyntropin stimulation test (0.25 mg with cortisol at baseline and 30 minutes) to rule out adrenal insufficiency in patients with hypo-osmolality and hyponatremia 1

Pituitary Disease or Incidentaloma

• Any patient with pituitary lesion or surgery – to assess for secondary adrenal insufficiency from ACTH deficiency 1
• Adrenal incidentaloma workup – to screen for autonomous cortisol secretion 2

Diagnostic Algorithm Based on Clinical Context

Morning Cortisol Interpretation (8 AM sample)

• >14 μg/dL (>386 nmol/L) – effectively rules out adrenal insufficiency 1, 2, 3
• <5 μg/dL (<140 nmol/L) with high ACTH – diagnostic of primary adrenal insufficiency 3
• 5-10 μg/dL (140-275 nmol/L) – indeterminate, requires cosyntropin stimulation test 1, 3, 5
• <10 μg/dL (<275 nmol/L) in setting of hypotension or electrolyte abnormalities – strongly suggests adrenal insufficiency, proceed to confirmatory testing 2, 5

Cosyntropin Stimulation Test Protocol

• Administer 0.25 mg (250 μg) cosyntropin IV or IM 1, 6, 3
• Measure cortisol at baseline, 30 minutes, and optionally 60 minutes 1, 6
• Peak cortisol <500 nmol/L (<18 μg/dL) – confirms adrenal insufficiency 1, 6, 3
• Peak cortisol >550 nmol/L (>18-20 μg/dL) – excludes adrenal insufficiency 1, 2

Important consideration: The test should be performed preferably in the morning, though not strictly necessary 1

Distinguishing Primary from Secondary Adrenal Insufficiency

• Measure paired morning cortisol and plasma ACTH 1, 3
• Primary AI: low cortisol (<5 μg/dL) with markedly elevated ACTH (>300 pg/mL), often with hyponatremia and hyperkalemia 1, 3
• Secondary AI: low cortisol (5-10 μg/dL) with low or inappropriately normal ACTH, hyponatremia without hyperkalemia 1, 3

Etiologic Workup After Confirming Primary Adrenal Insufficiency

• Measure 21-hydroxylase autoantibodies – positive in ~85% of autoimmune Addison's disease in Western populations 1
• If antibodies negative, obtain adrenal CT imaging – to evaluate for hemorrhage, tumor, tuberculosis, or infiltrative disease 1
• In males with negative antibodies, measure very-long-chain fatty acids – to screen for adrenoleukodystrophy 1

Common Pitfalls to Avoid

• Do not rely solely on electrolyte abnormalities – 10-20% of patients have mild or normal electrolytes at presentation 1
• Do not attempt diagnostic testing while patient is on corticosteroids – wait for adequate washout period 1
• Do not use dexamethasone suppression test in shift workers or patients with disrupted circadian rhythm – may not be reliable 4
• Do not measure cortisol in patients on oral estrogen/contraceptives without considering CBG elevation – can falsely elevate total cortisol while free cortisol remains normal 2
• Do not use IPSS to diagnose hypercortisolism – only for localization after biochemical confirmation 4
• Avoid topical hydrocortisone before salivary cortisol collection – can contaminate samples and cause false elevation 2

Drug Interactions Affecting Cortisol Testing

Medications Increasing Cortisol Requirements

• CYP3A4 inducers (phenytoin, carbamazepine, rifampin, barbiturates) – increase cortisol clearance 1

Medications Decreasing Cortisol Requirements

• CYP3A4 inhibitors (grapefruit juice, licorice) – decrease cortisol clearance 1, 2

Medications Affecting Dexamethasone Suppression Test

• CYP3A4 inducers – accelerate dexamethasone metabolism, causing false-positive DST 2
• Inhaled fluticasone – can suppress HPA axis and confound DST interpretation 2