What are the clinical indications for ordering cortisol testing?

Clinical Indications for Cortisol Testing

Screening for Cushing's Syndrome (Hypercortisolism)

Test patients who present with central obesity plus growth deceleration, as this combination is highly sensitive and specific for Cushing's syndrome. 1

High-Risk Clinical Features Requiring Testing

• Proximal muscle weakness and easy bruising are strong indicators that warrant cortisol testing 1
• Hypertension and diabetes with unexplained weight gain should prompt screening 1
• Moon facies, acne, purple striae, peripheral edema, and metabolic alkalosis with hypokalemia are classic features of Cushing's syndrome 2
• Skin hyperpigmentation is more prominent with ectopic ACTH production 2

Specific Tumor-Related Indications

• All patients with adrenal incidentalomas should be tested for autonomous cortisol secretion 1
• Small cell lung cancer (SCLC) or bronchial carcinoid tumors require screening, as ectopic Cushing syndrome occurs in 1.6-4.5% of SCLC cases and is associated with poor prognosis 2
• Testing should occur before chemotherapy or surgery in these patients, as hypercortisolism increases risk of therapy-induced complications and opportunistic infections 2

Critical Exclusion Before Testing

Always exclude iatrogenic Cushing's syndrome by obtaining a comprehensive medication history before any biochemical testing. 2, 3 This includes:

• Oral glucocorticoids (prednisolone, dexamethasone) 3
• Inhaled steroids (fluticasone) 3
• Topical hydrocortisone preparations 3
• Intra-articular or epidural corticosteroid injections 3
• Over-the-counter supplements that may contain undeclared corticosteroids 3

The Endocrine Society emphasizes that failure to exclude exogenous glucocorticoid use leads to unnecessary testing without clinical benefit. 3

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Screening for Adrenal Insufficiency (Hypocortisolism)

Order cortisol testing in any patient presenting with unexplained collapse, hypotension, persistent vomiting or diarrhea, hyperpigmentation, hyponatremia, hyperkalemia, or hypoglycemia. 2, 3

Specific Clinical Scenarios

• Morning serum cortisol <275 nmol/L (<10 µg/dL) in the setting of hypotension or electrolyte abnormalities strongly suggests primary adrenal insufficiency and requires confirmatory ACTH stimulation testing 2, 3
• Patients tapering or discontinuing exogenous steroid therapy should be tested for secondary adrenal insufficiency 1
• Coexistence of autoimmune thyroid disease (anti-TPO antibodies) increases likelihood of polyglandular autoimmune syndrome including adrenal insufficiency 2, 3

Emergency Situations

In suspected acute adrenal crisis, immediately administer 100 mg hydrocortisone IV and 0.9% saline infusion—do not delay treatment for diagnostic testing. 2 Draw blood for cortisol and ACTH before the first dose if possible, but treatment takes absolute priority 2, 3

• Cortisol <250 nmol/L with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 3
• Cortisol <400 nmol/L with elevated ACTH in acute illness generates strong suspicion 3

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First-Line Testing Algorithm

For Suspected Cushing's Syndrome

Start with one of three screening tests, obtaining 2-3 measurements of each to account for biological variability: 2, 1

1. 24-hour urinary free cortisol (UFC): Collect 2-3 separate 24-hour collections; values >100 µg/24h are diagnostic 2
2. Late-night salivary cortisol (LNSC): Collect at 11 PM-midnight on 2-3 separate nights; values >3.6 nmol/L are abnormal with >90% sensitivity 2, 4
3. 1-mg overnight dexamethasone suppression test (DST): Give 1 mg at 11 PM-midnight, measure cortisol at 8 AM; values ≥1.8 µg/dL (≥50 nmol/L) indicate abnormal suppression 2

If one test is abnormal, confirm with a second different test before proceeding to further evaluation. 1

Test Selection Nuances

• DST is preferred for shift workers with disrupted circadian rhythm, but may be unreliable in women taking oral estrogens 2, 1
• LNSC is preferred when renal impairment or polyuria would invalidate UFC results 3
• Multiple measurements are essential because UFC can vary by 50% between collections, and cyclic Cushing's can produce weeks of normal cortisol interspersed with hypercortisolism 2

For Suspected Adrenal Insufficiency

Measure morning (8-9 AM) serum cortisol as the initial test: 2, 3

• >14 µg/dL (>386 nmol/L) effectively excludes adrenal insufficiency 3
• <10 µg/dL (<275 nmol/L) in symptomatic patients requires ACTH stimulation testing 2, 3, 5
• Equivocal values (10-14 µg/dL) warrant ACTH stimulation test 2

ACTH stimulation test protocol: 2, 6

• Administer 0.25 mg cosyntropin (0.125 mg for children <2 years) IV or IM 2, 6
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes 2, 6
• Peak cortisol <500 nmol/L (<18 µg/dL) confirms primary adrenal insufficiency 2, 3

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Common Pitfalls and How to Avoid Them

Medications That Invalidate Testing

• Oral estrogens/contraceptives increase cortisol-binding globulin, falsely elevating total cortisol without true hypercortisolism 2, 3
• CYP3A4 inducers (phenytoin, rifampin, carbamazepine) accelerate dexamethasone metabolism, causing false-positive DST 2, 3
• Glucocorticoids and spironolactone must be stopped on the day of ACTH stimulation testing; long-acting glucocorticoids require longer washout 6

Pseudo-Cushing's States

Depression, alcoholism, severe obesity, and polycystic ovary syndrome can activate the HPA axis, causing mild hypercortisolism that mimics true Cushing's syndrome. 2 In these cases:

• Monitor for 3-6 months to see if symptoms resolve 2
• Treatment of the underlying condition often restores normal cortisol levels 2
• Consider Dex-CRH or desmopressin testing at an expert center if diagnostic uncertainty persists 2

Cyclic Cushing's Disease

In patients with unpredictable fluctuating cortisol levels, dynamic testing should be preceded by confirmatory LNSC, DST, or UFC to document active hypercortisolism. 2 Serial testing over weeks to months may be necessary to capture episodes of cortisol excess 2

Critical Care Setting

Do not use ACTH stimulation testing in critically ill patients with septic shock to decide on hydrocortisone treatment. 1 Random cortisol measurements in critical illness show marked hourly variability (coefficient of variation 8-30%) with no circadian rhythm, limiting the utility of single measurements 7

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When to Refer to Endocrinology

Refer when any screening test is abnormal, when results are equivocal despite high clinical suspicion, or when pseudo-Cushing's states require differentiation from true hypercortisolism. 2, 3 The Endocrine Society emphasizes that subsequent testing requires considerable expertise both clinically and in the laboratory, making referral essential for optimal patient outcomes 2