Diagnosing adrenal insufficiency starts with a simple morning blood draw for cortisol, typically taken between 6 and 9 AM when levels naturally peak. A cortisol level below 5 mcg/dL strongly suggests the adrenal glands aren’t producing enough hormone, while a level above 13 mcg/dL generally rules it out. Values that fall between those two numbers require further testing, most commonly an ACTH stimulation test, to reach a definitive answer.
Why Morning Cortisol Comes First
Cortisol follows a predictable daily rhythm, peaking in the early morning hours and dropping to its lowest point around midnight. Drawing blood within three hours of waking captures cortisol at its highest, making it the most informative single measurement. A level at or below 1 mcg/dL is essentially diagnostic on its own, with 100% sensitivity for confirming adrenal insufficiency. As the value climbs from 1 to 5 mcg/dL, confidence in that diagnosis gradually decreases, dropping to about 72% sensitivity at the 5 mcg/dL mark.
On the other end, values above roughly 13 mcg/dL reliably indicate that the stress hormone system is functioning normally. The gray zone between 5 and 13 mcg/dL is where most diagnostic uncertainty lives, and that’s where stimulation testing becomes necessary.
When a doctor strongly suspects primary adrenal insufficiency based on symptoms like low blood pressure upon standing, darkened skin, salt cravings, and persistent fatigue, they’ll often order cortisol alongside ACTH, renin, and aldosterone in a single blood draw. This speeds up both the diagnosis and the process of figuring out exactly where the problem originates.
The ACTH Stimulation Test
This is the gold standard confirmatory test. A synthetic version of ACTH (the pituitary hormone that tells your adrenal glands to produce cortisol) is injected into a vein, and your cortisol is measured 30 and 60 minutes later. The test essentially asks your adrenal glands to work at full capacity and checks whether they can deliver.
A peak cortisol response of 18 mcg/dL or higher at either the 30 or 60 minute mark is considered normal and rules out adrenal insufficiency. Falling short of that threshold confirms the diagnosis. Both high-dose (250 mcg) and low-dose (1 mcg) versions of the test have been studied extensively, and meta-analyses have found similar diagnostic accuracy between the two.
The test takes about an hour, requires no special preparation beyond showing up in the morning, and carries minimal risk. It’s the go-to when your baseline cortisol falls in the inconclusive range or when clinical symptoms don’t match a borderline lab result.
Primary vs. Secondary: Where the Problem Is
Once adrenal insufficiency is confirmed, the next step is determining whether the adrenal glands themselves are failing (primary) or whether the pituitary gland in the brain isn’t sending the right signals (secondary). This distinction matters because the causes, treatments, and monitoring differ significantly.
The key to telling them apart is the ACTH level in the initial blood draw. In primary adrenal insufficiency, the pituitary detects low cortisol and compensates by flooding the bloodstream with ACTH. Median levels in primary AI patients run around 251 pg/mL, often far above the normal upper limit of 46 pg/mL. In secondary adrenal insufficiency, the pituitary is the problem, so ACTH levels stay low or normal, with a median around 9 pg/mL. An elevated ACTH correctly identifies primary AI about 75% of the time, and specificity improves substantially when combined with other clinical findings.
Aldosterone and renin levels add another layer of clarity. In primary AI, the adrenal glands can’t produce aldosterone either, leading to sodium loss, potassium buildup, and low blood volume. In secondary AI, aldosterone production is usually preserved because it’s regulated by a separate system (renin-angiotensin) rather than ACTH alone. So if aldosterone is low and renin is high, the problem is almost certainly at the adrenal gland level.
Distinguishing Pituitary From Hypothalamic Causes
Secondary adrenal insufficiency stems from the pituitary gland, while tertiary insufficiency originates one step higher, in the hypothalamus. The most common cause of tertiary AI is abrupt withdrawal from long-term steroid medications like prednisone, which suppresses the hypothalamus. A CRH stimulation test can help separate the two: synthetic CRH (the hormone the hypothalamus normally sends to the pituitary) is injected, and ACTH is measured afterward. If ACTH rises in response, the pituitary is healthy and the problem is hypothalamic. If ACTH stays flat, the pituitary itself is impaired.
The Insulin Tolerance Test
This test is considered the most rigorous way to evaluate the entire stress hormone axis from brain to adrenal gland, but it’s reserved for specific situations because it involves inducing controlled low blood sugar. It’s primarily used when secondary adrenal insufficiency is suspected and ACTH stimulation results are ambiguous, or when growth hormone deficiency also needs evaluation.
Insulin is injected to drop blood sugar below about 40 mg/dL, creating a stress response that should trigger a surge of cortisol. A cortisol level above 18 mcg/dL during the test rules out adrenal insufficiency. Because of the risks involved with intentional hypoglycemia, the test must be done under direct medical supervision with emergency supplies on hand. It’s not appropriate for people with seizure disorders or heart conditions.
Salivary Cortisol as a Screening Tool
Collecting saliva at home in the early morning is a newer approach that may spare some patients from needing the ACTH stimulation test. Research has found that a morning salivary cortisol above 5.9 nmol/L can reliably rule out adrenal insufficiency, while a level below 1.0 nmol/L strongly suggests it. In one study, using these cutoffs allowed about 34% of patients to receive a diagnosis without undergoing stimulation testing at all.
Salivary testing is painless, can be done at home, and avoids the need for a blood draw. It’s not yet a universal standard, but it’s gaining traction as a practical first step, particularly for patients who have difficulty getting to a clinic for early-morning blood work.
Imaging After a Confirmed Diagnosis
Blood tests confirm whether adrenal insufficiency exists and where the failure occurs, but imaging helps explain why. For primary AI, a CT scan of the adrenal glands can reveal the underlying cause. Tuberculosis and fungal infections like histoplasmosis typically show bilateral enlargement of the glands with a central area of tissue death and a bright outer rim on contrast-enhanced scans. Adrenal hemorrhage, which can cause sudden-onset insufficiency, appears as a round, dense mass (50 to 90 HU on CT) that gradually fades on follow-up imaging.
For secondary or tertiary AI, an MRI of the pituitary gland is the standard next step, looking for tumors, inflammation, or structural damage that could explain why ACTH production has dropped.
Recognizing Adrenal Crisis
Sometimes the first sign of adrenal insufficiency is a full-blown crisis, which is a medical emergency. The defining feature is a systolic blood pressure below 100 mmHg, or a drop of at least 20 mmHg from someone’s usual baseline. This is accompanied by severe nausea, vomiting, abdominal pain, and confusion that can progress to shock or coma.
Lab work during a crisis typically shows low sodium, high potassium (in primary AI), and low blood sugar. In this situation, treatment begins immediately based on clinical suspicion. A blood sample for cortisol and ACTH is drawn before treatment starts, but doctors don’t wait for results before acting. The diagnosis is confirmed retrospectively once the patient is stabilized.