At a Glance

Why get tested?

To help diagnose primary adrenal insufficiency (Addison disease) and to detect conditions affecting the pituitary gland (secondary adrenal insufficiency)

When to get tested?

When your cortisol level is low and/or your healthcare provider suspects that your adrenal glands are not producing enough of the hormone cortisol or that the pituitary gland is not producing enough adrenocorticotropic hormone (ACTH)

Sample required?

An initial blood sample is collected and then a small amount of a synthetic fragment of ACTH is injected into a muscle (IM) or into a vein (intravenously). Additional blood samples are taken 30 minutes and/or 60 minutes after the intravenous injection.

Test Preparation Needed?

Follow directions given to you by your health care practitioner. In some cases, you may be instructed to refrain from taking certain medications on the day of testing.

What is being tested?

Although the ACTH stimulation test name sounds as though it would measure adrenocorticotropic hormone (ACTH), it is actually a procedure used to evaluate cortisol production and to help diagnose adrenal insufficiency.

Cortisol is a hormone produced by two small glands that sit atop the kidneys called the adrenal glands. Cortisol plays a role in the metabolism of proteins, lipids, and carbohydrates. It affects blood glucose levels, helps maintain blood pressure, and helps regulate the immune system. Normally, the level of cortisol in the blood rises and falls in a consistent pattern throughout the day (called diurnal variation), peaking shortly after waking, then declining gradually to its lowest level at bedtime.

Production of cortisol by the adrenal glands is regulated by a negative feedback system involving the hypothalamus in the brain and the pituitary gland, a small organ located below the brain. Normally, in a healthy person:

  • When the cortisol level falls, the hypothalamus responds by releasing corticotropin-releasing hormone (CRH).
  • CRH signals the pituitary gland to produce ACTH.
  • ACTH then signals the adrenal glands to produce and release cortisol.
  • As the cortisol level rises, the hypothalamus decreases CRH production, the pituitary reduces ACTH production, and the adrenal glands decrease cortisol production.

In order for appropriate amounts of cortisol to be made, the hypothalamus, the pituitary, and the adrenal glands must be functioning and communicating with each other properly.

Decreased cortisol levels may be seen with:

  • Underactive or damaged adrenal glands (adrenal insufficiency) that limit cortisol production; this is referred to as primary adrenal insufficiency and is also known as Addison disease.
  • An underactive pituitary gland or a pituitary gland tumor that inhibits ACTH production; this is known as secondary adrenal insufficiency.
  • Treatment utilizing glucocorticoids, such as dexamethasone and prednisone.

If you have a cortisol test done and the result is low, your healthcare practitioner may do an ACTH stimulation test to help confirm the findings and to help determine its cause.

The most common ACTH stimulation test is the short or rapid test. For this test:

  • Your blood is drawn for an initial, baseline level (pre-stimulation).
  • You are given an injection of a manufactured fragment of ACTH (cosyntropin or tetracosactide). The manufactured fragment may be injected into a muscle or vein. When the manufactured ACTH fragment is administered, it acts like the body’s own ACTH and stimulates the adrenal glands to produce cortisol.
  • Your blood is drawn again after a specified amount of time (30 minutes and/or 60 minutes).
  • The cortisol level is measured in both the first (baseline) and subsequent samples.

The 2016 guidelines from the Endocrine Society consider this the best test to establish a diagnosis of primary adrenal insufficiency.

Common Questions

How is the test used?

The ACTH stimulation test may be used to investigate a low cortisol test result. It may be used to help diagnose primary adrenal insufficiency (Addison disease) if your health care practitioner suspects that your adrenal glands may not be producing enough cortisol. The test may also be done to help determine whether a condition affecting the pituitary gland is causing low cortisol levels (secondary adrenal insufficiency).

This test is used to determine whether your adrenal glands are capable of responding to ACTH and whether this is a typical response.

The Endocrine Society recommends using tests for ACTH, aldosterone (also produced by the adrenal glands) and renin (a hormone that controls aldosterone production) as part of the evaluation for primary adrenal insufficiency.

When is it ordered?

The ACTH stimulation test may be ordered when you have a low result on a cortisol test and a combination of signs and symptoms that suggest low cortisol or adrenal insufficiency, such as:

  • Weight loss
  • Muscle weakness
  • Fatigue
  • Low blood pressure
  • Abdominal pain
  • Dark patches of skin (this occurs in Addison disease but not secondary adrenal insufficiency)
  • Low blood sugar (hypoglycemia, especially in children)

What does the test result mean?

If your adrenal glands are functioning normally, then your cortisol level will rise in response to the ACTH you are given. (The cortisol level in the second sample drawn should be elevated above a certain level and to a certain degree when compared to the baseline sample.) This result rules out primary adrenal insufficiency (Addison disease).

If your adrenal glands are damaged or not functioning properly, then your cortisol level will not increase after you are given ACTH. You may be diagnosed with adrenal insufficiency. Additional testing may be necessary to identify the cause.

The ACTH stimulation test is not a definitive test for adrenal insufficiency due to pituitary damage. If injury to the pituitary occurred only in the previous few weeks, a falsely normal response to ACTH injection may be observed. A repeat ACTH stimulation test 6 to 8 weeks later might then reveal secondary adrenal insufficiency. Other tests may also be considered.

Rarely, there is a problem with the hypothalamus and the production of corticotropin-releasing hormone (CRH). The ACTH stimulation test does not distinguish this problem from other causes of adrenal insufficiency.

I have been taking prednisone (glucocorticoid medication) for some time. Why would suddenly stopping it cause signs and symptoms of adrenal insufficiency?

Glucocorticoids such as prednisone, hydrocortisone, dexamethasone, etc. are prescribed for a variety of conditions. These medications can suppress cortisol production by the adrenal glands. If you need to stop taking them, your healthcare practitioner will usually taper off your dose so that your adrenal gland cortisol production has time to restart and you avoid “withdrawal” adrenal insufficiency symptoms. In some people who have taken glucocorticoids chronically (especially at high dose) for various medical conditions (other than Addison disease), it may take up to one year for the body to resume normal cortisol production after the glucocorticoids are stopped.

What are the causes of primary adrenal insufficiency?

The most common cause of primary adrenal insufficiency in adults in the U.S. is an autoimmune disorder where the body’s immune system attacks the adrenal glands. The most common cause of primary adrenal insufficiency in children in the U.S. is a congenital disease called congenital adrenal hyperplasia (CAH). Other causes in any age group include damage from bleeding into the adrenal glands and infections such as tuberculosis or HIV infection.

Why is my health care provider testing me for 21-hydroxylase autoantibodies and/or adrenal cytoplasmic autoantibodies?

Tests for these autoantibodies can help determine the cause of primary adrenal insufficiency. The most common cause of primary adrenal insufficiency in adults (about 75%) is an autoimmune process in which an inappropriate immune response destroys tissues within the adrenal glands. 21-hydroxylase autoantibodies and/or adrenal cytoplasmic autoantibodies are markers of this autoimmune process.

What is an adrenal crisis?

Sometimes, decreased cortisol production combined with a stressor can cause an adrenal crisis that can be life-threatening and requires immediate medical attention. Signs and symptoms of a crisis may include:

  • Sudden onset of severe pain in the lower back, abdomen, or legs
  • Vomiting and diarrhea, resulting in dehydration
  • Low blood pressure (hypotension)
  • Loss of consciousness
  • Low blood glucose

Adrenal crisis is the most common cause of death in patients with adrenal insufficiency.

Is there anything else I should know?

Once your health care practitioner has identified a problem associated with the adrenal glands, pituitary gland, or other cause, other testing such as CT (computerized tomography) or MRI (magnetic resonance imaging) scans may be performed to locate the source of the problem and to evaluate the extent of any damage to the glands. For more details about these imaging scans, see RadiologyInfo.org.

Since the ACTH stimulation test involves giving an injection of manufactured ACTH, the test can interfere with subsequent tests that measure ACTH levels. Therefore, ACTH testing is not recommended for several hours following an ACTH stimulation test.

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