When is cortisol testing recommended for patients with symptoms of hormonal imbalance, such as weight gain, fatigue, or changes in blood pressure, and what testing protocols are used?

When to Order Cortisol Testing for Hormonal Imbalance Symptoms

Order morning (8:00-9:00 AM) serum cortisol with simultaneous ACTH when patients present with unexplained fatigue, weight changes, hypotension, or electrolyte abnormalities (hyponatremia with or without hyperkalemia) to screen for adrenal insufficiency, which is a life-threatening condition that requires prompt diagnosis. 1

Primary Clinical Indications for Cortisol Testing

Symptoms Suggesting Adrenal Insufficiency

• Fatigue and weakness are the most common presenting symptoms, occurring in nearly all patients with adrenal insufficiency and warrant cortisol evaluation 1
• Weight loss, nausea, vomiting, and poor appetite are classic features that should trigger testing, as nausea occurs in 20-62% of adrenal insufficiency cases 1
• Orthostatic hypotension or unexplained hypotension requires immediate cortisol assessment, particularly if refractory to standard treatment 1
• Unexplained hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases and mandates cortisol testing to distinguish from SIADH 1
• Salt craving is a specific clinical clue for primary adrenal insufficiency 1

High-Risk Scenarios Requiring Urgent Testing

• 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 1
• Patients on immune checkpoint inhibitor therapy with new fatigue, weakness, or electrolyte abnormalities need evaluation for immune-related adrenal insufficiency 2
• Vasopressor-resistant hypotension in critically ill patients, particularly those with cirrhosis, warrants screening or empiric hydrocortisone treatment 1

Testing Protocol: Step-by-Step Approach

Initial Screening Test

• Draw morning cortisol and ACTH simultaneously at 8:00-9:00 AM from the same blood draw to capture the physiologic peak of cortisol secretion 2
• This timing provides optimal sensitivity and specificity for detecting both adrenal insufficiency and hypercortisolism 2
• ACTH is extremely labile and requires immediate processing on ice—coordinate with the laboratory before drawing 2

Interpretation of Morning Cortisol Results

• Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1
• Cortisol <275 nmol/L in morning samples identifies subnormal adrenal function with 96.2% sensitivity and requires confirmatory testing 3
• Cortisol >500 nmol/L (>18 μg/dL) essentially excludes adrenal insufficiency 1
• Cortisol 250-500 nmol/L (9-18 μg/dL) requires ACTH stimulation testing for definitive diagnosis 1

Confirmatory Testing: ACTH Stimulation Test

When morning cortisol is indeterminate (250-500 nmol/L), proceed with cosyntropin stimulation test 1:

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 1
• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes adrenal insufficiency 1

Distinguishing Primary from Secondary Adrenal Insufficiency

• High ACTH with low cortisol indicates primary adrenal insufficiency (Addison's disease) 1
• Low or inappropriately normal ACTH with low cortisol indicates secondary (central) adrenal insufficiency 1
• Hyponatremia plus hyperkalemia suggests primary adrenal insufficiency, while hyponatremia without hyperkalemia suggests secondary adrenal insufficiency 1

Alternative Testing for Cushing's Syndrome

When symptoms suggest cortisol excess (weight gain, hypertension, proximal muscle weakness, easy bruising):

Screening Tests for Hypercortisolism

• Overnight 1-mg dexamethasone suppression test (DST) is the preferred screening test: give 1 mg dexamethasone at 11 PM, measure cortisol at 8 AM 2
  • Cortisol <50 nmol/L excludes hypercortisolism
  • Cortisol 51-138 nmol/L suggests possible autonomous cortisol secretion
  • Cortisol >138 nmol/L indicates cortisol hypersecretion 2
• Late-night salivary cortisol (LNSC) collected at bedtime (at least 2-3 samples) is highly specific for Cushing's syndrome 2
• 24-hour urinary free cortisol has lower sensitivity but is useful when DST or LNSC results are equivocal 2, 4

Critical Pitfalls to Avoid

Testing Errors

• Never interpret cortisol without knowing the collection time—the same value may be normal at 9 AM but pathologically elevated at midnight 2
• Do not test patients actively taking corticosteroids for adrenal insufficiency, as morning cortisol will be falsely low due to iatrogenic HPA suppression 1
• Wait at least 3 months after stopping corticosteroids before performing definitive HPA axis testing 1
• Avoid testing shift workers or patients with disrupted circadian rhythms using time-dependent tests like morning cortisol or late-night salivary cortisol 2

Clinical Errors

• Never delay treatment of suspected adrenal crisis for diagnostic testing—give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion if the patient is unstable 1
• Do not rely on electrolyte abnormalities alone—hyperkalemia is present in only ~50% of adrenal insufficiency cases, and its absence does not rule out the diagnosis 1
• If you must treat but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1

Special Populations

• Document medications affecting cortisol binding globulin (CBG)—oral estrogens, pregnancy, and chronic active hepatitis increase total cortisol and can lead to false interpretation 2
• Avoid strenuous exercise for 24-48 hours before testing, as physical stress significantly elevates cortisol 2
• When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before thyroid hormone to prevent precipitating adrenal crisis 1

Secondary Hypertension Screening

For patients with resistant hypertension (particularly with hypokalemia), consider screening for:

• Primary aldosteronism (occurs in 5-10% of hypertensive patients, 20% with resistant hypertension) using aldosterone-to-renin ratio 4
• Cushing's syndrome using 24-hour urinary free cortisol or dexamethasone suppression test 4
• These conditions cause greater target organ damage than primary hypertension, with significantly increased risk of heart failure, stroke, and atrial fibrillation 4