When should cortisol levels be checked?

When to Check Cortisol

Check cortisol immediately in any patient with unexplained hypotension, collapse, or shock—especially when accompanied by vomiting, diarrhea, or altered mental status—as these presentations suggest acute adrenal crisis requiring urgent treatment. 1, 2

Emergency/Acute Settings Requiring Immediate Cortisol Assessment

• Unexplained hypotension or shock refractory to standard therapy warrants urgent cortisol evaluation, as adrenal insufficiency should be presumed until ruled out 1
• Unexplained collapse with hypotension plus gastrointestinal symptoms (vomiting or diarrhea) mandates immediate assessment for adrenal crisis 1, 2
• Patients on ≥20 mg/day prednisone (or equivalent) for ≥3 weeks who develop unexplained hypotension should be assumed to have adrenal insufficiency 2
• Critically ill patients with treatment-resistant hypotension should be screened for adrenal insufficiency or receive empiric stress-dose hydrocortisone 1

Critical pitfall: Do not postpone treatment while awaiting cortisol results—administer 100 mg IV hydrocortisone plus rapid saline infusion immediately, drawing blood for cortisol and ACTH beforehand only if feasible 1, 2

Outpatient Clinical Scenarios Prompting Cortisol Evaluation

Classic Symptoms of Adrenal Insufficiency

• Persistent unexplained fatigue (present in 50-95% of cases), especially when accompanied by weight loss or salt craving 1, 3
• Nausea and vomiting (20-62% of cases), particularly morning nausea with poor appetite 2, 3
• Anorexia and weight loss (43-73% of cases) that cannot be explained by other conditions 3
• Hyperpigmentation of skin creases, scars, or mucous membranes strongly suggests primary adrenal insufficiency due to elevated ACTH 1, 2
• Orthostatic hypotension reflects mineralocorticoid deficiency in primary adrenal insufficiency 4, 1, 2

Laboratory Abnormalities Triggering Evaluation

• Hyponatremia is present in approximately 90% of newly diagnosed adrenal insufficiency cases 1, 2
• Hyperkalemia occurs in only about 50% of cases, so its absence does not exclude the diagnosis 1, 2, 5
• Hypoglycemia, particularly in children, warrants cortisol assessment 2

Screening for Cushing's Syndrome

Clinical Features Prompting Evaluation

• Central obesity, facial plethora, proximal muscle weakness, wide purple striae (>1 cm), and easy bruising are key signs that should trigger cortisol measurement 1, 5

Recommended Screening Tests

• Late-night salivary cortisol collected between 11 PM–midnight; abnormal if >3.6 nmol/L 4, 1, 5
• 24-hour urinary free cortisol; abnormal if >100 µg/24 hours 4, 1, 5
• Overnight 1-mg dexamethasone suppression test; abnormal if morning cortisol ≥1.8 µg/dL 4, 1, 5
• Obtain 2-3 measurements of each screening test because of substantial intra-patient variability and the possibility of cyclic disease 4, 1, 5

Assessment of Adrenal Incidentalomas

• All patients with incidentally discovered adrenal masses should be screened for autonomous cortisol secretion using a 1-mg overnight dexamethasone suppression test 1
• Post-test cortisol <1.8 µg/dL excludes autonomous cortisol excess 1
• Post-test cortisol >5 µg/dL indicates clear hypercortisolism 1

Before Tapering or Stopping Glucocorticoid Therapy

• Evaluate for iatrogenic secondary adrenal insufficiency before reducing or stopping chronic glucocorticoid therapy 1
• Test HPA axis recovery approximately 3 months after cessation of maintenance glucocorticoids 1, 2
• Ensure adequate wash-out period: 24 hours for hydrocortisone, longer for longer-acting steroids 1, 2

Critical pitfall: Do not attempt diagnostic testing while the patient is still on corticosteroids or immediately after stopping—this will yield false-positive results showing "adrenal insufficiency" that simply reflects expected HPA suppression 2

Interpretation of Morning Serum Cortisol

When to Proceed Directly to Treatment or Further Testing

• Morning cortisol >14 µg/dL (>386 nmol/L) effectively excludes adrenal insufficiency 1, 5
• Morning cortisol <5 µg/dL (<140 nmol/L) with clinical suspicion strongly suggests adrenal insufficiency and warrants immediate treatment consideration 3
• Morning cortisol 5-10 µg/dL (140-275 nmol/L) is indeterminate and requires a cosyntropin stimulation test 1, 3, 6
• Morning cortisol <10 µg/dL (<275 nmol/L) in the context of hypotension or electrolyte disturbances strongly suggests adrenal insufficiency 1, 6

Cosyntropin Stimulation Test Protocol

• Administer 0.25 mg (250 µg) cosyntropin intravenously or intramuscularly 1, 2, 7
• Measure cortisol at baseline, 30 minutes, and 60 minutes after administration 1, 2, 7
• Peak cortisol <500 nmol/L (<18 µg/dL) confirms adrenal insufficiency 1, 2, 7
• Peak cortisol >550 nmol/L (>18-20 µg/dL) excludes adrenal insufficiency 1, 2
• Testing is preferably performed in the morning but is not mandatory 4, 1

Differentiating Primary vs. Secondary Adrenal Insufficiency

• Measure paired morning cortisol and plasma ACTH 1, 2
• Primary adrenal insufficiency: cortisol <5 µg/dL with markedly elevated ACTH (>300 pg/mL), often with hyponatremia and hyperkalemia 1, 2
• Secondary adrenal insufficiency: cortisol 5-10 µg/dL with low or inappropriately normal ACTH, hyponatremia without hyperkalemia 1, 2

Special Populations and Situations

Hyponatremia Work-up

• Exclude adrenal insufficiency before diagnosing SIADH, as both present with euvolemic hypo-osmolar hyponatremia 1, 2
• Perform a cosyntropin stimulation test to rule out adrenal insufficiency in patients with hypo-osmolar hyponatremia 1, 2

Pituitary Lesions or Post-surgical Status

• Patients with pituitary lesions or post-surgical status should be evaluated for secondary adrenal insufficiency due to possible ACTH deficiency 1

Patients on Chronic Glucocorticoids

• Morning cortisol measurements in patients actively taking corticosteroids are not diagnostic because the assay measures both endogenous cortisol and therapeutic steroids 2
• Laboratory confirmation should not be attempted until treatment is ready to be discontinued with adequate washout time 2

Common Pitfalls to Avoid

• Do not rely solely on electrolyte abnormalities—10-20% of patients present with normal electrolytes 1, 2
• Avoid diagnostic testing while the patient is receiving corticosteroids—wait for appropriate wash-out period 1, 2
• Do not use dexamethasone suppression test in shift workers or individuals with disrupted circadian rhythms 1
• When measuring serum cortisol in patients on oral estrogen/contraceptives, consider the effect of increased cortisol-binding globulin, which can falsely raise total cortisol levels 1, 5
• Avoid topical hydrocortisone before collecting salivary cortisol specimens to prevent sample contamination 1