The first test for adrenal insufficiency is a simple morning blood draw measuring cortisol, typically taken between 8 and 9 AM when levels naturally peak. A cortisol level above 15 mcg/dL generally rules out adrenal insufficiency, while a level below 3 mcg/dL strongly suggests it. Values that fall in between require follow-up with a stimulation test to get a definitive answer.
Morning Cortisol: The Starting Point
Cortisol follows a predictable daily rhythm, peaking in the early morning and dropping through the evening. That peak is what makes an 8 to 9 AM blood draw so useful as a screening tool. If your adrenal glands can produce a strong cortisol surge at their natural high point, they’re likely functioning well. If they can’t even reach a normal level at their best moment, that’s a red flag.
Interpreting the number is straightforward at the extremes. A morning cortisol below 3 mcg/dL is highly suspicious for adrenal insufficiency. A level above 15 mcg/dL makes the diagnosis unlikely. The gray zone between those two values, which is where many patients land, means the blood test alone isn’t enough and a stimulation test is the next step.
Several medications can throw off cortisol results. Estrogen-containing birth control pills and hormone therapy raise the levels of a protein that binds cortisol in the blood, which can make cortisol look artificially normal even when the adrenals are failing. Synthetic steroids like prednisone or hydrocortisone, anti-seizure drugs, and androgens can also interfere. Your doctor will likely ask you to temporarily stop certain medications before testing.
The ACTH Stimulation Test
When morning cortisol is inconclusive, the gold standard follow-up is the ACTH stimulation test, sometimes called the cosyntropin test. This measures how your adrenal glands respond when they’re told to produce cortisol on demand.
The procedure is simple and takes about an hour. A baseline blood sample is drawn, then you receive an injection of synthetic ACTH (the hormone that signals the adrenals to make cortisol). Blood is drawn again at 30 minutes and 60 minutes. In a healthy person, cortisol rises sharply after the injection. A peak cortisol level that stays below 18 mcg/dL after stimulation is considered diagnostic for adrenal insufficiency.
This test is especially reliable for primary adrenal insufficiency, where the adrenal glands themselves are damaged. It can sometimes miss early or mild secondary adrenal insufficiency (caused by pituitary problems), because the adrenal glands may still respond to a large dose of synthetic ACTH even when they haven’t been getting enough natural signaling from the pituitary for weeks or months.
Telling Primary From Secondary Causes
Once adrenal insufficiency is confirmed, the next question is why. Primary adrenal insufficiency (Addison’s disease) means the adrenal glands themselves are failing. Secondary adrenal insufficiency means the pituitary gland isn’t sending enough ACTH to stimulate the adrenals. The distinction matters because the causes, treatment, and associated conditions are different.
A plasma ACTH level drawn alongside morning cortisol is the key to sorting this out. In primary adrenal insufficiency, ACTH is high or elevated because the pituitary is working overtime trying to get the damaged adrenals to respond. Typical levels in primary disease run around 250 pg/mL, sometimes much higher. In secondary adrenal insufficiency, ACTH is low or undetectable, often below 10 pg/mL, because the pituitary itself is the problem. Normal ACTH ranges top out around 46 pg/mL, so a level above that points toward a primary adrenal problem with about 75% sensitivity and 85% specificity.
Routine Blood Work That Offers Clues
Basic lab panels can raise suspicion before specialized hormone tests are even ordered. The most common findings in primary adrenal insufficiency are low sodium (hyponatremia), high potassium (hyperkalemia), and low blood sugar (hypoglycemia). This pattern occurs because damaged adrenal glands stop producing aldosterone, the hormone that regulates sodium and potassium balance, alongside cortisol.
Anemia is also common. These findings are nonspecific on their own, meaning they can show up in many conditions, but the combination of low sodium with high potassium in someone experiencing fatigue, weight loss, or darkening skin should prompt cortisol testing. In secondary adrenal insufficiency, potassium is typically normal because aldosterone production is preserved. That’s another useful clue for distinguishing the two types.
The Insulin Tolerance Test
For suspected secondary adrenal insufficiency, particularly when the ACTH stimulation test is borderline, the insulin tolerance test is considered the most accurate option. It works by inducing a brief episode of low blood sugar through an insulin injection. Low blood sugar is a powerful stress signal that should trigger the entire hormonal chain: the hypothalamus signals the pituitary, which releases ACTH, which tells the adrenals to produce cortisol. If cortisol fails to rise adequately, it confirms a problem somewhere in that chain.
This test has significant restrictions. It’s not appropriate for people over 60, anyone with heart disease or epilepsy, those with very low baseline cortisol (below about 3.6 mcg/dL), or anyone with untreated thyroid problems, which can blunt the cortisol response. It also requires close medical supervision because of the intentional drop in blood sugar. For these reasons, it’s reserved for cases where the ACTH stimulation test doesn’t give a clear answer.
CRH Stimulation Test
When secondary adrenal insufficiency is confirmed, doctors sometimes need to determine whether the problem originates in the pituitary gland or the hypothalamus (the brain region that controls the pituitary). The CRH stimulation test helps here. CRH is the hormone the hypothalamus uses to signal the pituitary.
After an injection of CRH, two patterns emerge. If the pituitary gland itself is damaged, ACTH levels stay low and respond poorly. If the hypothalamus is the problem but the pituitary is intact, ACTH shows a delayed but exaggerated rise because the pituitary has been starved of its usual CRH signal and over-responds when it finally receives one. This distinction can guide the search for underlying causes, such as pituitary tumors versus damage from prolonged steroid use.
Salivary Cortisol as a Screening Option
Salivary cortisol testing is well established for diagnosing Cushing’s syndrome (cortisol excess) and is gaining traction as a screening tool for adrenal insufficiency. An early morning salivary cortisol above 5.9 nmol/L can help rule out adrenal insufficiency without requiring a stimulation test. The appeal is convenience: you collect saliva at home rather than needing a morning blood draw at a lab.
Research suggests salivary testing could reduce the number of patients who need to undergo ACTH stimulation tests by filtering out those whose cortisol levels are clearly adequate. It’s not yet a standalone diagnostic tool, but it may serve as a useful intermediate step between a borderline blood cortisol and committing to a stimulation test.
Acute Crisis: Testing Under Pressure
If adrenal crisis is suspected, meaning severe low blood pressure, confusion, or shock, there’s no time for the standard testing sequence. A single cortisol level below 18 mcg/dL in someone who is acutely ill and hypotensive is enough to support the diagnosis. In critical illness, cortisol should be high as part of the body’s stress response. A level that would be “normal” in a healthy person is inappropriately low in someone who is severely stressed, and treatment typically begins before confirmatory testing is complete.