Version July 2025
ALGORITHM —
(algorithm 1 and algorithm 2 and algorithm 3)
IMMEDIATE ACTION —
Rapidly identify and begin immediate treatment (intravenous saline and glucocorticoids) of patients with suspected adrenal crisis (algorithm 1 and table 1 and table 2):
●Dehydration, hypotension, or shock
●Nausea and vomiting
●Unexplained hypoglycemia
●Unexplained fever
●Hyperkalemia and/or hyponatremia
●Confusion or coma
If possible, obtain repeat serum cortisol and adrenocorticotrophic hormone (ACTH) before giving glucocorticoids; schedule an ACTH stimulation test. (See 'Initial evaluation' below.)
The treatment of patients who present in possible adrenal crisis should not be delayed while awaiting the results of diagnostic testing. An ACTH stimulation test can be performed to confirm the diagnosis of adrenal insufficiency after initiation of glucocorticoid treatment, if supraphysiologic doses of glucocorticoids have not been given for more than a few days. Withhold glucocorticoids on the morning of the test and resume after the test is completed while awaiting results. (See "Treatment of adrenal insufficiency in adults", section on 'Adrenal crisis'.)
INITIAL EVALUATION —
Patients with suspected chronic adrenal insufficiency (table 3) not requiring immediate action require a timely evaluation to confirm the presence and cause of adrenal insufficiency (algorithm 2 and algorithm 3):
●Suspected central adrenal insufficiency – Risk factors that increase the suspicion for central adrenal insufficiency include previous exposure to exogenous glucocorticoids via any route (particularly injections for pain), chronic opioid use, high-dose progestins with glucocorticoid activity (eg, megestrol acetate used to treat selected patients with cancer), history of cranial irradiation therapy, head trauma, or pituitary surgery.
●Suspected primary adrenal insufficiency – Risk factors for primary adrenal insufficiency include HIV infection, malignancy, anticoagulation, neurologic abnormalities or family history consistent with adrenoleukodystrophy, and personal or familial history of polyglandular autoimmune disease.
Confirm diagnosis of adrenal insufficiency — The clinical diagnosis of chronic adrenal insufficiency is often more difficult than that of acute adrenal insufficiency. Signs and symptoms that are relatively specific for chronic primary adrenal insufficiency include hyperkalemia, skin hyperpigmentation, postural hypotension, and salt craving. Nonspecific findings in both chronic primary and central adrenal insufficiency include hyponatremia, fatigue, weakness, joint pain, decreased appetite, and weight loss. Hypoglycemia and hypercalcemia are not common.
Measurements of serum cortisol are extremely useful for the assessment of suspected chronic adrenal insufficiency if measured at the time of day when it should be high. For people who sleep at night, the peak cortisol levels occur early in the morning, and measurement between 6 and 9 AM is ideal. (See "Diagnosis of adrenal insufficiency in adults", section on 'Suspected chronic adrenal insufficiency'.)
It is necessary to know the type of cortisol assay used to interpret the results (see "Diagnosis of adrenal insufficiency in adults", section on 'Influence of cortisol assay technique').
●Early morning cortisol – Measure repeat serum cortisol and plasma ACTH in the early morning (6:00 to 9:00 AM or within three hours of waking). For night shift workers, the "morning" serum cortisol should be obtained when the individual wakes up (algorithm 2).
The lower the serum cortisol concentration, the more certain is the diagnosis of adrenal insufficiency. However, caution should be taken in interpreting the cortisol results in patients with decreases in corticosteroid-binding globulin (CBG) or albumin, as may occur with cirrhosis or nephrotic syndrome. Some individuals have low levels of CBG on a genetic basis. In these settings, decreased cortisol levels may lead to an incorrect diagnosis of adrenal insufficiency.
Conversely, patients with increased CBG values, such as pregnant individuals or those taking oral estrogens (eg, oral contraceptives, especially at a dose of 30 mcg or higher), may have apparently normal cortisol values, so that the diagnosis of adrenal insufficiency may be missed. (See "Diagnosis of adrenal insufficiency in adults", section on 'Abnormal CBG'.)
•Cortisol ≤3 mcg/dL – A low early morning serum cortisol concentration (≤3 mcg/dL [80 nmol/L]) in the absence of CBG deficiency or exogenous synthetic glucocorticoids is consistent with adrenal insufficiency. When multiple symptoms correlate with the low cortisol value, ACTH stimulation testing typically is not needed to confirm the diagnosis. However, if symptoms do not correlate with biochemical findings, perform an ACTH stimulation test. (See 'Determine the cause' below.)
•Cortisol >3 mcg/dL but <18 mcg/dL – If the morning serum cortisol concentration is >3 mcg/dL (>80 nmol/L) but <18 mcg/dL (<500 nmol/L) using an older cortisol assay, perform a standard ACTH stimulation test. With cortisol assays that use more specific monoclonal antibodies, the upper threshold to exclude adrenal insufficiency is 13 to 14 mcg/dL (360 to 390 nmol/L) instead of 18 mcg/dL (ie, perform ACTH stimulation test if cortisol is >3 mcg/dL but <13 to 14 mcg/dL).
•Cortisol ≥18 mcg/dL – An early morning serum cortisol concentration ≥18 mcg/dL (≥500 nmol/L) in the absence of CBG excess excludes primary adrenal insufficiency and most patients with central adrenal insufficiency. When cortisol is measured using an immunoassay with a more specific monoclonal antibody to cortisol or using liquid chromatography/tandem mass spectrometry (LC-MS/MS), the morning cortisol threshold to exclude adrenal insufficiency is approximately 25 to 30 percent lower (eg, 13 to 14 mcg/dL instead of 18 mcg/dL [360 to 390 nmol/L instead of 500 nmol/L]).
●ACTH stimulation test – The standard high-dose (250 mcg) ACTH stimulation tests can be performed at any time of day. However, if baseline ACTH is being obtained with stimulation test, the test must be performed in the morning, between 6 and 9 AM.
•Measure basal cortisol
•Administer intravenous or intramuscular corticotrophin (cosyntropin) 250 mcg
•Measure serum cortisol 30 and 60 minutes after administration
Interpretation of the ACTH stimulation test is based on the peak cortisol value, which typically occurs 60 minutes after administration (but may occur at 30 minutes) (algorithm 2):
•<14 mcg/dL (390 nmol/L) – Adrenal insufficiency likely.
•≥14 to <18 mcg/dL (390 to 500 nmol/L) – The interpretation of the cortisol result depends on the type of assay that is used to measure it (table 4) and the clinical likelihood of adrenal insufficiency in an individual patient. If the assay type is unknown or diagnosis is uncertain, a dehydroepiandrosterone sulfate (DHEAS) level may be useful. A normal DHEAS (using an age- and sex-specific reference range) makes adrenal insufficiency unlikely. (See "Diagnosis of adrenal insufficiency in adults", section on 'Interpretation of results' and "Diagnosis of adrenal insufficiency in adults", section on 'DHEAS'.)
•≥18 mcg/dL (500 nmol/L) – Adrenal insufficiency is generally excluded, regardless of assay used to measure cortisol.
All patients with suspected new ACTH deficiency within two weeks of a recent event (eg, recent pituitary surgery) should be referred to an endocrinologist for testing as a normal ACTH stimulation test does not exclude new-onset secondary adrenal insufficiency. (See "Diagnosis of adrenal insufficiency in adults", section on 'Recent ACTH deficiency'.)
Determine the cause — Although the cortisol response to ACTH stimulation is used to make the diagnosis of adrenal insufficiency, the paired basal ACTH and cortisol values are used to establish the level of the defect (algorithm 3) (see "Determining the etiology of adrenal insufficiency in adults", section on 'Establish the level of defect'):
●ACTH high with low cortisol – In patients with confirmed cortisol deficiency, an increased plasma ACTH above the upper limit of the reference range is consistent with primary adrenal insufficiency. Depending on the clinical presentation, additional testing to determine the cause may include:
•Renin and aldosterone to determine the presence of mineralocorticoid deficiency.
•Adrenal enzyme antibodies against side chain cleavage or 21-hydroxylase to identify autoimmune adrenalitis (the most common cause of primary adrenal insufficiency in resource-abundant countries).
•Very long chain fatty acids in males, particularly in those with a personal or family history of neurologic abnormalities consistent with adrenomyeloneuropathy.
•Computed tomography (CT) imaging, if the etiology is uncertain, to identify infectious diseases (eg, tuberculosis), hemorrhage, or metastases.
●ACTH low or inappropriately normal with low cortisol – If both the serum cortisol and plasma ACTH concentrations are low (or plasma ACTH inappropriately normal), the patient has central adrenal insufficiency. Prolonged administration of supraphysiologic doses of synthetic glucocorticoids is, by far, the most common cause of central adrenal insufficiency. If the cause remains unexplained, additional testing to determine the cause may include:
•Assessment of other pituitary hormones (eg, thyroid-stimulating hormone, free thyroxine, luteinizing hormone, follicle-stimulating hormone, prolactin, insulin-like growth factor 1 [IGF-1], estradiol [females], testosterone [males]).
•Magnetic resonance imaging (MRI) of pituitary and hypothalamus if etiology uncertain.
●Indeterminate – Patients with confirmed cortisol deficiency who have an ACTH level in the upper half of the reference range may have either primary or central adrenal insufficiency. Measurement of aldosterone and renin may help distinguish between the two possibilities. A low plasma aldosterone level with an elevated renin level is consistent with primary adrenal insufficiency. Plasma levels of renin and aldosterone are usually unaffected in central adrenal insufficiency. (See "Determining the etiology of adrenal insufficiency in adults", section on 'ACTH interpretation'.)
REFERENCE RANGE —
The serum cortisol concentration has circadian rhythmicity. In the nonpregnant adult, the normal reference range for cortisol is approximately 10 to 25 mcg/dL (275 to 690 nmol/L) in the early morning and 2 to 14 mcg/dL (55 to 386 nmol/L) at 4 PM.
The normal reference ranges can vary depending on the patient population and assay(s) used by the clinical laboratory. Interpretation of a specific abnormal test result should be based upon the reference range reported with that result.
CITATIONS —
The supporting references for this content are accessible in the linked topics.
DISCLOSURE —
The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
