When is cortisol testing recommended for adults with symptoms suggestive of cortisol imbalance, such as weight gain, hypertension, glucose intolerance, or signs of adrenal insufficiency, like fatigue, hypotension, or electrolyte imbalances, particularly those with a history of pituitary or adrenal disorders?

Cortisol Testing in Adults with Suspected Cortisol Imbalance

When to Test for Hypercortisolism (Cushing's Syndrome)

All patients with adrenal incidentalomas should be screened for autonomous cortisol secretion using the 1 mg dexamethasone suppression test (DST), regardless of symptoms. 1

Clinical Features Warranting Hypercortisolism Screening

Test for Cushing's syndrome when patients present with: 1

• Physical examination findings: Central obesity, supraclavicular fat accumulation, dorsocervical fat pad ("buffalo hump"), facial plethora, purple striae >1 cm wide, thinned skin, easy bruising/ecchymoses, proximal muscle weakness or wasting 1
• Metabolic complications: Severe hypertension, diabetes or glucose intolerance, fragility fractures 1
• Constitutional symptoms: Weight gain (particularly central), fatigue, depression, sleep disturbances 1
• Reproductive symptoms: Menstrual irregularities, virilization in females 1

Preferred Screening Test for Hypercortisolism

The 1 mg DST is the preferred screening test for identifying autonomous cortisol secretion. 1 Administer 1 mg dexamethasone at 11 PM and measure serum cortisol at 8 AM the following morning. 1

Interpretation: 1, 2

• <50 nmol/L (<1.8 μg/dL): Excludes cortisol hypersecretion
• 51-138 nmol/L (1.8-5 μg/dL): Possible autonomous cortisol secretion—obtain ancillary testing (24-hour urinary free cortisol, midnight salivary cortisol)
• >138 nmol/L (>5 μg/dL): Evidence of cortisol hypersecretion

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When to Test for Adrenal Insufficiency

High-Priority Clinical Scenarios Requiring Immediate Testing

Never delay treatment for diagnostic testing if adrenal crisis is suspected—immediately administer IV hydrocortisone 100 mg and 0.9% saline infusion at 1 L/hour. 3, 4, 5 Draw blood for cortisol and ACTH before treatment if possible, but do not delay therapy. 3, 4

Clinical Features Warranting Adrenal Insufficiency Testing

Test for adrenal insufficiency when patients present with: 3, 4, 5

• Cardiovascular: Unexplained hypotension, orthostatic hypotension, hypotension requiring vasopressors, unexplained collapse 3, 4
• Gastrointestinal: Nausea (20-62% of cases), vomiting, anorexia, weight loss (43-73% of cases), abdominal pain 3, 4, 5
• Constitutional: Fatigue (50-95% of cases), weakness, muscle pain/cramps 3, 4, 5
• Metabolic: Hyponatremia (present in 90% of cases), hypoglycemia (particularly in children), hyperkalemia (only ~50% of cases) 3, 4, 5
• Neurological: Altered mental status, confusion, loss of consciousness 4
• Dermatological: Hyperpigmentation (primary adrenal insufficiency only due to elevated ACTH) 3

Specific High-Risk Populations

Test for adrenal insufficiency in: 3, 4

• Patients taking ≥20 mg/day prednisone or equivalent for ≥3 weeks who develop unexplained hypotension 4
• Patients with pituitary or adrenal disorders 3
• Patients with hypo-osmolar hyponatremia before diagnosing SIADH (both conditions present identically) 4
• Patients with refractory hypotension despite vasopressor therapy 4

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Diagnostic Testing Algorithm for Adrenal Insufficiency

Step 1: Initial Morning Testing

Obtain paired early morning (8 AM) serum cortisol and plasma ACTH as the first-line diagnostic approach. 3, 4, 5 Also measure basic metabolic panel (sodium, potassium) and DHEAS. 5

Interpretation of Morning Cortisol: 3, 4, 2, 5

• <250 nmol/L (<9 μg/dL) with elevated ACTH: Diagnostic of primary adrenal insufficiency in acute illness 3, 4
• <275 nmol/L (<10 μg/dL): Concerning—proceed to ACTH stimulation testing 2
• 140-275 nmol/L (5-10 μg/dL) with low/normal ACTH: Suggestive of secondary adrenal insufficiency—proceed to ACTH stimulation testing 4, 5
• >550 nmol/L (>20 μg/dL): Excludes adrenal insufficiency 2

Step 2: Confirmatory ACTH Stimulation Test (Cosyntropin Test)

The cosyntropin stimulation test is mandatory when initial results are equivocal. 3, 4, 6, 5

Protocol: 3, 4, 6, 5

1. Administer 0.25 mg (250 mcg) cosyntropin IV or IM
2. Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration
3. Perform in the morning (preferred but not mandatory) 4

Interpretation: 3, 4, 2, 6, 5

• Peak cortisol <500 nmol/L (<18 μg/dL): Diagnostic of adrenal insufficiency
• Peak cortisol >550 nmol/L (>20 μg/dL): Normal—excludes adrenal insufficiency

Step 3: Distinguish Primary from Secondary Adrenal Insufficiency

Use ACTH levels to differentiate: 4, 5

• Primary adrenal insufficiency: Low cortisol + high ACTH + low DHEAS 4, 5
• Secondary adrenal insufficiency: Low cortisol + low/normal ACTH + low/normal DHEAS 4, 5

Step 4: Etiologic Workup

For primary adrenal insufficiency: 3, 4

• Measure 21-hydroxylase autoantibodies (autoimmunity accounts for ~85% of cases in Western populations) 3, 4
• If autoantibodies negative, obtain CT imaging of adrenals to evaluate for hemorrhage, tumor, tuberculosis, or structural abnormalities 3, 4

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Critical Pitfalls to Avoid

Testing Pitfalls

Do not rely on electrolyte abnormalities alone—hyperkalemia is present in only ~50% of adrenal insufficiency cases, and 10-20% of patients have normal electrolytes at presentation. 3, 4

Do not test cortisol in patients actively taking corticosteroids—exogenous steroids (including prednisone, prednisolone, inhaled fluticasone) suppress the HPA axis and cause iatrogenic secondary adrenal insufficiency, making morning cortisol levels unreliable. 4, 2 Wait until corticosteroids have been discontinued with adequate washout time (at least 24 hours for hydrocortisone, longer for other steroids). 4

If you must treat suspected adrenal crisis but still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone—dexamethasone does not interfere with cortisol assays. 4

Medication Interactions Affecting Test Results

Drugs that interfere with cortisol testing: 1, 4, 2

• CYP3A4 inducers (anticonvulsants, rifampin, barbiturates) accelerate dexamethasone metabolism, causing false-positive suppression tests 2
• Oral estrogens and pregnancy increase cortisol-binding globulin, falsely elevating total serum cortisol 2
• Grapefruit juice and liquorice decrease cortisol clearance 4

Stop drugs affecting pituitary or adrenocortical function before testing (consider at least 5 half-lives). 6

Treatment Pitfalls

Never attempt to discontinue hydrocortisone in patients with confirmed primary or secondary adrenal insufficiency from non-iatrogenic causes—these conditions are permanent and stopping replacement will precipitate life-threatening adrenal crisis. 4

When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before initiating thyroid hormone replacement—starting thyroid hormone first can precipitate adrenal crisis. 4

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Treatment Implications of Confirmed Adrenal Insufficiency

Confirmed adrenal insufficiency requires lifelong glucocorticoid replacement therapy: 3, 4, 5

• Glucocorticoid replacement: Hydrocortisone 15-25 mg daily in divided doses (e.g., 10 mg at 7 AM, 5 mg at 12 PM, 2.5-5 mg at 4 PM) or prednisone 3-5 mg daily 3, 4, 5
• Mineralocorticoid replacement (primary adrenal insufficiency only): Fludrocortisone 0.05-0.1 mg daily, adjusted based on blood pressure, salt cravings, and plasma renin activity 3, 4, 5

All patients must receive: 3, 4, 5

• Education on stress dosing (double or triple dose during illness, fever, or physical stress) 4, 5
• Medical alert bracelet indicating adrenal insufficiency 3, 4, 5
• Emergency injectable hydrocortisone 100 mg IM kit with self-injection training 3, 4, 5
• Annual screening for associated autoimmune conditions (thyroid function, diabetes, pernicious anemia, celiac disease) 4