When is it appropriate to order cortisol levels in patients, particularly those with symptoms such as weight gain, hypertension, fatigue, or changes in skin pigmentation, and those with a history of pituitary or adrenal gland disorders, or taking corticosteroid medications like metyrapone (metyrapone) or ketoconazole (ketoconazole)?

When to Order Cortisol Levels

Order cortisol levels when patients present with unexplained weight gain accompanied by growth deceleration in children, or when adults exhibit symptoms of hypercortisolism (hypertension, central obesity, skin changes) or adrenal insufficiency (unexplained hypotension, fatigue, weight loss, hyponatremia), particularly in those with pituitary/adrenal disorders or taking medications that affect cortisol metabolism.

Screening for Cushing Syndrome (Hypercortisolism)

Pediatric Patients

• Order cortisol testing only when unexplained weight gain occurs with either growth rate deceleration or declining height percentile over time, as this combination has high sensitivity and specificity for Cushing syndrome in children and adolescents 1
• Growth failure reliably discriminates simple obesity from Cushing syndrome in prepubertal children, but post-pubertal adolescents require assessment according to adult guidelines 1
• Not all children with Cushing syndrome have obesity, and few obese children prove to have Cushing syndrome—the key discriminator is the growth pattern 1

Adult Patients with Suspected Hypercortisolism

• Order initial screening tests when patients present with multiple features suggestive of Cushing syndrome: hypertension, hyperglycemia, central obesity with thin extremities, wide purple striae, easy bruising, proximal muscle weakness, or facial plethora 1, 2
• Multiple tests on separate occasions are required because episodic hypercortisolism is highly prevalent in mild Cushing syndrome—92% of patients with confirmed Cushing syndrome had at least one normal salivary cortisol, 88% had normal 24-hour urinary free cortisol, and 86% had normal 17-hydroxycorticosteroids 3
• A single normal test does not exclude Cushing syndrome; repeat testing when patients experience active symptoms of hypercortisolism 3

Recommended Initial Screening Protocol for Cushing Syndrome

• 24-hour urinary free cortisol collection for 3 consecutive days (diagnostic cutoff >193 nmol/24h or >70 μg/m²) with 89% sensitivity and 100% specificity 1
• Late-night salivary cortisol based on local assay cutoff (95% sensitivity, 100% specificity) 1
• Serum cortisol circadian rhythm study at 09:00h, 18:00h, and midnight while sleeping (midnight cortisol ≥50 nmol/L or ≥1.8 μg/dL has 100% sensitivity) 1
• Low-dose dexamethasone suppression test: 0.5 mg every 6 hours for 48 hours (dose 30 μg/kg/day for patients <40 kg), with serum cortisol ≥50 nmol/L at 48 hours indicating non-suppression (95% sensitivity, 80% specificity) 1

Screening for Adrenal Insufficiency

High-Risk Clinical Scenarios Requiring Immediate Cortisol Assessment

• Any patient on ≥20 mg/day prednisone or equivalent for ≥3 weeks who develops unexplained hypotension should be presumed to have adrenal insufficiency until proven otherwise 4
• Unexplained collapse, hypotension requiring vasopressors, or refractory shock warrants immediate cortisol assessment 4
• Hyponatremia with hypo-osmolality requires cortisol testing to exclude adrenal insufficiency before diagnosing SIADH, as 90% of newly diagnosed adrenal insufficiency cases present with hyponatremia and both conditions are clinically indistinguishable 4
• Unexplained gastrointestinal symptoms (nausea, vomiting, abdominal pain) with hypotension, especially in patients with prior steroid exposure 4, 5

Patients with Specific Risk Factors

• History of pituitary adenoma or other pituitary disorders requiring assessment for secondary adrenal insufficiency 1, 4
• Patients taking medications that inhibit cortisol synthesis: ketoconazole (inhibits 11β-hydroxylase and 17,20-lyase) or metyrapone 6, 7, 8
• Patients on immune checkpoint inhibitors with symptoms of fatigue, nausea, or hypotension should have morning ACTH and cortisol measured (if cortisol <3 mg/dL, adrenal insufficiency is likely) 1
• Recent discontinuation of chronic corticosteroids (risk of secondary adrenal insufficiency from HPA axis suppression) 4, 5

Diagnostic Protocol for Suspected Adrenal Insufficiency

• Measure morning (08:00-09:00h) serum cortisol and plasma ACTH simultaneously as first-line testing 1, 4
• Interpretation of morning cortisol:
  • <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 4
  • <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion 4
  • <3 mg/dL warrants immediate evaluation 1
  • 5-18 μg/dL requires ACTH stimulation testing for definitive diagnosis 4
• Basic metabolic panel to assess for hyponatremia, hyperkalemia (present in only ~50% of cases), and hypoglycemia 1, 4
• Renin and aldosterone levels if primary adrenal insufficiency is suspected 1

ACTH Stimulation Test (Cosyntropin/Synacthen Test)

• Perform when morning cortisol is indeterminate (between 3-15 mg/dL or 140-400 nmol/L) 1, 4
• Protocol: Administer 0.25 mg (250 mcg) cosyntropin IV or IM, measure serum cortisol at baseline, 30 minutes, and 60 minutes 4
• Interpretation: Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency; >550 nmol/L (>18-20 μg/dL) excludes it 4
• The high-dose (250 mcg) test is preferred over low-dose (1 mcg) due to easier administration, comparable accuracy, and FDA approval 4

Critical Pitfalls to Avoid

Do Not Delay Treatment for Testing

• 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 if the patient is clinically unstable 1, 4, 5
• Draw blood for cortisol and ACTH before treatment if possible, but do not wait for results 1, 4
• If you need to treat but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 4

Testing Limitations in Patients on Corticosteroids

• Do not order morning cortisol in patients actively taking corticosteroids—the assay measures both endogenous and therapeutic steroids with variable cross-reactivity, making results uninterpretable 4
• Laboratory confirmation should not be attempted until corticosteroid treatment is discontinued and sufficient washout time has elapsed 4
• Hydrocortisone must be held for 24 hours before testing; other steroids require longer washout periods 4
• Approximately one-third to one-half of patients on 5-20 mg prednisone daily fail ACTH stimulation testing even with adequate adrenal reserve 4

Electrolyte Abnormalities Are Unreliable

• Do not rely on hyperkalemia to diagnose adrenal insufficiency—it is present in only ~50% of cases 4, 5
• Hyponatremia is present in 90% of cases but is not specific 4, 5
• When vomiting is present, hypokalemia (not hyperkalemia) may occur due to gastrointestinal losses masking aldosterone deficiency 5

Distinguishing Primary from Secondary Adrenal Insufficiency

• Primary adrenal insufficiency: Low cortisol with high ACTH, often with both hyponatremia and hyperkalemia, requires both glucocorticoid and mineralocorticoid replacement 1, 4
• Secondary adrenal insufficiency: Low cortisol with low or inappropriately normal ACTH, typically only hyponatremia (no hyperkalemia), requires only glucocorticoid replacement 1, 4

Special Considerations for Hyponatremia

• The standard 0.25 mg cosyntropin stimulation test is medically necessary to rule out adrenal insufficiency in patients with hypo-osmolality and hyponatremia, as adrenal insufficiency presents nearly identically to SIADH 4
• Both conditions show euvolemic hypo-osmolar hyponatremia with inappropriately high urine osmolality and elevated urinary sodium 4
• Correct diagnosis is crucial because treatment differs significantly: adrenal insufficiency requires glucocorticoid replacement, while SIADH requires fluid restriction 4