How are cortisol levels evaluated and treated?

Evaluation and Treatment of Cortisol Levels

For suspected hypercortisolism (Cushing's syndrome), screen with late-night salivary cortisol (LNSC) or 1 mg overnight dexamethasone suppression test (DST), while for suspected adrenal insufficiency, measure morning cortisol with ACTH and confirm with cosyntropin stimulation testing if needed. 1, 2

Evaluation of Hypercortisolism (High Cortisol)

Screening Tests

• Perform at least 2-3 late-night salivary cortisol (LNSC) measurements at usual bedtime (not necessarily midnight), as cortisol nadir is tightly entrained to sleep onset; values >3.6 nmol/L suggest Cushing's syndrome with 92% sensitivity 1, 3

• Administer 1 mg dexamethasone orally at 11 PM and measure serum cortisol at 8 AM the following morning; cortisol <1.8 μg/dL (50 nmol/L) excludes Cushing's syndrome, while values >5 μg/dL (138 nmol/L) strongly suggest autonomous cortisol production 1, 2

• Collect 24-hour urine free cortisol (UFC) on 2-3 separate occasions to account for day-to-day variability of up to 50%; this test is independent of cortisol-binding globulin changes but less reliable in renal impairment (CrCl <60 mL/min) 1

Confirmatory Testing

• Measure plasma ACTH level to distinguish ACTH-dependent (pituitary or ectopic) from ACTH-independent (adrenal) causes of hypercortisolism 2, 4

• Obtain adrenal CT imaging to characterize any adrenal mass; Hounsfield units <10 on non-contrast CT suggest benign adenoma 2

• Screen for pheochromocytoma with plasma or 24-hour urinary metanephrines if Hounsfield units ≥10 before any intervention 2

Important Caveats

• False-positive DST results occur with medications that induce CYP3A4 (phenobarbital, carbamazepine, St. John's wort), rapid dexamethasone absorption, or elevated cortisol-binding globulin from oral estrogens or pregnancy 1

• LNSC should not be performed in night-shift workers due to disrupted circadian rhythm 1

• Multiple sequential LNSC measurements are particularly useful for detecting cyclic Cushing's syndrome, where patients exhibit weeks to months of normal cortisol interspersed with hypercortisolism episodes 1

Evaluation of Adrenal Insufficiency (Low Cortisol)

Initial Assessment

• Measure morning (8 AM) serum cortisol and plasma ACTH simultaneously in patients with unexplained collapse, hypotension, vomiting, diarrhea, hyperpigmentation, hyponatremia, hyperkalaemia, or hypoglycemia 1

• Cortisol <250 nmol/L with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency; cortisol <400 nmol/L with elevated ACTH raises strong suspicion 1

• Low ACTH with low cortisol indicates secondary (central) adrenal insufficiency from pituitary or hypothalamic dysfunction 1

Confirmatory Testing

• Perform cosyntropin (ACTH) stimulation test when basal cortisol is equivocal (between 250-500 nmol/L): administer 0.25 mg tetracosactide IM or IV and measure cortisol at 30-60 minutes; peak cortisol <500 nmol/L confirms adrenal insufficiency 1, 5

• For diagnostic testing with metyrapone, administer 30 mg/kg (maximum 3 grams) at midnight with food, then measure 11-deoxycortisol and ACTH at 7:30-8:00 AM; 11-deoxycortisol >70 mcg/L indicates intact HPA axis 6

Critical Pitfalls to Avoid

• Never delay treatment for diagnostic testing in suspected acute adrenal crisis; give IV hydrocortisone 100 mg or dexamethasone 4 mg immediately 1

• Morning cortisol is unreliable in patients currently taking corticosteroids; hydrocortisone must be held for 24 hours and other steroids longer before assessing endogenous function 1

• ACTH stimulation testing can give false-negative results early in hypophysitis as adrenal reserve declines slowly after pituitary stimulation is lost 1

• Patients on corticosteroids for other immune-related adverse events can develop isolated central adrenal insufficiency with low ACTH; test for HPA axis recovery after 3 months of maintenance therapy 1

Treatment of Hypercortisolism

Surgical Management (First-Line)

• Transsphenoidal surgery is first-line treatment for pituitary Cushing's disease 4

• Surgical removal of ectopic ACTH-producing tumors when resectable, or bilateral laparoscopic adrenalectomy for unresectable primary tumors 4

Medical Management

• Ketoconazole 400-1200 mg/day for medical management of hypercortisolism when surgery is not feasible or as bridge to surgery 4

• Mitotane for adrenal carcinoma 4

• Octreotide for ectopic Cushing syndrome if tumor is Octreoscan-positive 4

Treatment of Adrenal Insufficiency

Primary Adrenal Insufficiency

• Hydrocortisone 15-25 mg daily in divided doses (10-20 mg in morning, 5-10 mg in early afternoon); use lowest dose compatible with well-being 1, 4

• Fludrocortisone 50-200 µg daily as single morning dose for mineralocorticoid replacement; adjust based on volume status, sodium level, and plasma renin activity 1, 4

• Children require hydrocortisone 6-10 mg/m² body surface area daily 1

Secondary Adrenal Insufficiency

• Hydrocortisone 15-20 mg daily in divided doses (no fludrocortisone needed as mineralocorticoid function is preserved) 4

Acute Adrenal Crisis Management

• Immediate IV hydrocortisone 100 mg plus at least 2 liters normal saline for volume resuscitation 1

• Taper stress-dose corticosteroids to maintenance over 7-14 days after stabilization 1

• For hypophysitis with severe symptoms: prednisone 1-2 mg/kg daily tapered over at least 1-2 weeks to physiologic maintenance 1

Stress Dosing and Special Situations

• Double or triple maintenance glucocorticoid dose during illness or physical stress 4

• Hydrocortisone 50-100 mg IV every 6-8 hours for initial stress dosing in hospitalized patients 1

• Always start corticosteroids several days before thyroid hormone when treating multiple pituitary hormone deficiencies to prevent precipitating adrenal crisis 1

Essential Patient Education

• All patients must wear medical alert bracelet/necklace identifying adrenal insufficiency 1, 4

• Provide emergency injectable hydrocortisone with instructions for self-administration 1

• Educate on stress dosing protocols and when to seek emergency care for impending adrenal crisis 1, 4

• Endocrine consultation before surgery for stress-dose planning 1

Monitoring

• Follow clinical symptoms and electrolytes regularly for dose adjustment 4

• Retest HPA axis recovery at 3 months in patients with isolated central adrenal insufficiency after corticosteroid treatment for other conditions 1

• For functioning tumors causing hypercortisolism: follow-up imaging and biomarkers every 3-6 months 4