Table 5.
Adrenal hormone abnormality | Indication for testing | First-line testing | Second-line or confirmatory testing | Other considerations and remarks |
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Cortisol excess | Anyone with adrenal mass, regardless of symptoms | 1-mg DST. Abnormal result: serum cortisol >1.8 mcg/dL. The ESE-ENSAT guidelines on adrenal incidentalomas define MACS as “possible” when 1-mg DST serum cortisol is 1.8-5.0 mcg/dL and “confirmed” when 1-mg DST serum cortisol is >5.0 mcg/dL. Possible causes of false-positive results: • Oral estrogens (e.g., OCP) • CYP3A4 inducers. • Exogenous glucocorticoids (assay interference). • Uncontrolled hyperglycemia. • Alcoholism. • Psychiatric disorders. • Morbid obesity. • Pregnancy. • Chronic active hepatitis. • Kidney failure • Older age • Dementia |
• ACTH. • DHEAS. • 24-h urine free cortisol (if Cushing syndrome is suspected). • Salivary cortisol (if Cushing syndrome is suspected). • In selected cases: repeat 1-mg DST; perform 8-mg DST; 2-day, low-dose DST (Liddle test); CRH test. |
• ACTH-independent cortisol excess must be confirmed before considering adrenal surgery. • Patients with adrenal hypercortisolism have abnormal DST, low ACTH, and DHEA-S. • 24h urine free cortisol is usually normal in MACS. • The accuracy of salivary cortisol in MACS is low. |
Aldosterone excess | Anyone with hypertension, with or without spontaneous hypokalemia | Morning aldosterone + renin (DRCorPRA). Abnormal result: aldosterone >10 ng/dL and suppressed renin (DRC or PRA). Possible causes of false-positive results:a • Beta-blockers. • α-methyldopa • NSAIDs. • Oral estrogens (renin measured as DRC). • Testing during the luteal phase (women of reproductive age). • Impaired renal function with hyperkalemia. Possible causes of false-negative results:a • Mineralocorticoid receptor antagonists. • Diuretics. • Dihydropyridine calcium channel blockers. • Inhibitors. • Angiotensin II receptor blockers. • SSRIs. • SGLT2-inhibitors. |
Unnecessary if positive first-line test and spontaneous hypokalemia. Otherwise: salt loading test, saline infusion test, captopril challenge, or fludrocortisone test. |
• Patients with confirmed primary aldosteronism will need subtype evaluation with imaging and adrenal vein sampling. • Imaging finding of adrenal mass is accurate only in 60% of cases in subtype determination. • Cortisol co-secretion is highly prevalent in primary aldosteronism (abnormal 1-mg DST is found in up to 22% of patients).b |
Catecholamine excess | Anyone with indeterminate adrenal mass (HU ≥ 10), with or without symptoms | Plasma or 24-h urine metanephrines. Abnormal result: usually >2× upper limit of normal. Possible causes of false-positive results: • Collection of plasma metanephrines under not controlled conditions. • Medications: tricyclic antidepressants; psychoactive agents; prochlorperazine; L-dopa; adrenergic receptor agonists; phenoxybenzamine. |
• Usually not needed unless false-positive results are suspected.d • Urinary or plasma dopamine or plasma methoxy tyramine is a possible add-on test to detect tumors with dopamine hypersecretion (increased risk of malignancy). |
• 24-h urine fractionated metanephrines have excellent sensitivity and specificity. • Plasma fractionated metanephrines have excellent sensitivity but suboptimal specificity if not collected appropriately. Fasting collection after 30 min in the supine position and the use of age-adjusted upper limits of normal increase specificity. |
• Physical stress or illness: significant illness requiring hospitalization; congestive heart failure; panic attacks; subarachnoid bleeding; obstructive sleep apnea. • Withdrawal from alcohol, clonidine, and other drugs. Possible causes of false-negative results: small pheochromocytomas (especially with maximum diameter < 2 cm).c |
• In patients with suspected pheochromocytoma, extra-adrenal disease and associated genetic predisposition need to be considered (Table 4). |
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Suspected steroid precursor, androgen, or estrogen excess | Anyone suspected to have adrenocortical carcinoma, with or without symptoms | DHEA-S, progesterone, 17-OH-progesterone, 17-OH-pregnenolone, 11-deoxycortisol, androstenedione, testosterone (women), estradiol (men, postmenopausal women). If available, consider urine multisteroid profiling. |
• Avoid adrenal biopsy. • Open adrenalectomy is usually recommended. • Experienced adrenal surgeon is key! |
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Anyone with bilateral adenomas or myelolipomas should be evaluated for congenital adrenal hyperplasia | Early-morning 17-OH-progesterone (to be collected during the early follicular phase in menstruating females). | ACTH stimulation test for cortisol and 17-OH-progesterone. | Consider genetic testing. | |
Adrenal insufficiency | Anyone with indeterminate bilateral masses likely to be adrenal metastases or bilateral infiltration of other causes | Morning ACTH and cortisol. If electrolyte abnormalities, test for aldosterone deficiency (paired aldosterone and renin). |
Potential need for additional dynamic testing such as ACTH stimulation. |
aWe advise against routine washout from potential interfering medications when assessing a patient with a newly diagnosed adrenal mass. The main issue with interfering medications is false-negative results for mild or optimally treated primary aldosteronism cases (mostly from a nonsuppressed renin). Case detection testing can be done even in patients treated with mineralocorticoid receptor antagonists because patients with hypertension are usually treated with doses lower than those required to fully block the mineralocorticoid receptor. A suppressed renin in this scenario (especially if hypokalemia is present) makes the diagnosis of primary aldosteronism very likely. If retesting is required, this should be carried out in the morning, 2 to 4 h after waking up. If it is safe to do so, interfering medications should be stopped for 2 to 4 weeks before testing. Alternative treatments that do not interfere with the test are verapamil, doxazosin, prazosin, terazosin, hydralazine, and moxonidine.
bCortisol co-secretion is not only relevant from a cardiometabolic risk perspective; it may also affect the performance of adrenal vein sampling, the risk of developing adrenal insufficiency after unilateral adrenalectomy, and the rate of clinical success after surgery.
cSmaller catecholamine-secreting tumors may have negative metanephrine test results. This is relevant for smaller incidentalomas with HU > 10 and especially for patients with known genetic disorders associated with pheochromocytoma who undergo routine surveillance imaging for other manifestations of their disease. In such cases, it is therefore appropriate to retest patients if the initial test was negative and the adrenal mass increases in size and/or the patient develops symptoms of catecholamine excess during follow-up.
dTricyclic antidepressants and other psychoactive agents should be tapered down and discontinued at least 2 wk before retesting. Selective serotonin reuptake inhibitors should not significantly affect the screening tests.
Abbreviations: CRH, corticotropin releasing hormone; CYP3A4, cytochrome P450 3A4; DHEA-S, dehydroepiandrosterone sulfate; DRC, direct renin concentration; DST, dexamethasone suppression test; MACS, mild autonomous cortisol secretion; NSAIDs, nonsteroidal anti-inflammatory drugs; OCP, oral contraceptive pill; PRA, plasma renin activity; SGLT2, sodium-glucose co-transporter-2.