Tests to diagnose Cushing’s syndrome and its cause

Tests to diagnose Cushing’s syndrome

There are 3 types of tests that are generally used to find out if a person has endogenous Cushing’s syndrome. These tests measure the amount of cortisol in samples of urine, blood, or saliva to determine how much cortisol is circulating in the body. If the tests show that the level of cortisol is too high, it means a person has Cushing’s syndrome.¹

Following are brief descriptions of these tests. However, complete information about these tests, along with instructions for patients, should be obtained from a doctor.

Urine-free cortisol (UFC) test^1,2

What it measures:

• Cortisol in urine

Why it’s used:

• Almost all people with Cushing’s syndrome have high urine cortisol levels
• The UFC test only measures the type of cortisol that causes Cushing’s syndrome, which is called “circulating, free cortisol.” It does not measure “bound” cortisol, which increases in the blood from taking certain medicines such as estrogen, but does not cause Cushing’s syndrome

How it’s done:

• Urine samples are collected at every opportunity throughout a 24-hour period. The samples are then given to a lab for testing

Special instructions:

• During the 24-hour testing period, don’t drink a lot of fluids or use glucorticoid medicines or products, such as hemorrhoid or skin creams that contain steroids

Late-night salivary cortisol test^1,3

What it measures:

• Cortisol in saliva

Why it’s used:

• Normally, the amount of cortisol in saliva is lowest late at night. However, Cushing’s syndrome will cause there to be more cortisol than normal in saliva at this time

How it’s done:

• A saliva sample is obtained between 11 pm and midnight on 2 different nights. These are then given to a lab for testing

Special instructions:

• Don’t eat licorice, smoke cigarettes, or chew tobacco on the days when samples are obtained
• Avoid situations that create extreme stress or excitement
• If bedtime is usually well past midnight, obtain samples at bedtime

Dexamethasone suppression test (DST)^1,3

What it measures:

• Cortisol in blood

Why it’s used:

• Normally, low doses of dexamethasone will reduce cortisol levels. However, if a person has Cushing’s syndrome, these doses will not have an effect on cortisol levels

Overnight DST (short test)

How it’s done

• A 1-mg dose of dexamethasone is taken between 11 pm and midnight
• A blood sample is taken at the doctor’s office between 8 am and 9 am the next morning

Special instructions:

• Don’t drink or eat anything for at least 10 hours preceding the blood test

48-hour DST (long test)

How it’s done

• A 0.5-mg dose of dexamethasone is taken every 6 hours for 48 hours
• A blood sample is taken at the doctor’s office 6 hours following the last dose

Special instructions:

• Be sure to take dexamethasone every 6 hours as instructed ²

(Note: The longer DST is considered more accurate in determining whether high cortisol levels are caused by Cushing’s syndrome or some other condition.¹)

How to determine the most appropriate test(s)

In certain cases, experts recommend specific types of tests based on a person’s medical history. Some of these recommendations are included below.

Special recommendations for
Cushing’s syndrome diagnostic testing¹

For people who …	UFC test	Late-night salivary cortisol	DST
Are pregnant	Yes	*	No
Are taking medicine for seizures (for example, phenobarbital, phenytoin, or carbamazepine)	Yes	Yes	No
Have kidney failure	No	*	Yes (1 mg overnight)
Have an adrenal mass	No	Yes	Yes (1 mg overnight)

UFC=urine free cortisol; DST=dexamethasone suppression test.
*=No recommendation stated.

All people who are going to be tested for Cushing’s syndrome should provide their doctors with complete medical histories, including any conditions they have and medicines they are taking. This can help the doctor determine the most appropriate test for them.

If the test is positive for Cushing’s syndrome …
… the next step is additional testing to confirm the diagnosis and then test to diagnose the cause of Cushing’s syndrome to determine how to treat it.¹

If the test is not positive for Cushing’s syndrome …
… signs and symptoms should be closely watched. If they get worse, retesting should be done in about 6 months.¹

Tests to diagnose the cause of Cushing’s syndrome

ACTH measurement
To diagnose the cause of Cushing’s syndrome, the doctor first needs to perform blood tests to measure the level of adrenocorticotropic hormone (ACTH) in the body. This gives doctors important information about where to look for the tumor that is causing Cushing’s syndrome.^4,5

If blood tests show that ACTH levels are high …
… this means that Cushing’s syndrome is caused by a tumor that is producing excess ACTH. Excess ACTH causes the adrenal glands to produce too much cortisol Click here for more information.

In the majority of cases, excess ACTH comes from a benign tumor in the pituitary gland. This is referred to as Cushing’s disease. However, excess ACTH can sometimes be produced by another type of tumor. This is referred to as ectopic Cushing’s syndrome.^4,5

If blood tests show that ACTH levels are low …
… this means that Cushing’s syndrome is caused by an adrenal gland tumor that produces excess cortisol.^4,5

Imaging tests

Based on the results of the ACTH measurement, the doctor will usually order one of the following imaging tests to locate the tumor, as well as additional tests if needed:

An MRI* scan of the pituitary gland if ACTH is high

or

A CT* or MRI scan of the adrenal gland if ACTH levels are low4

*MRI=magnetic resonance imaging; CT=computerized tomography.

Corticotropin-releasing hormone (CRH) stimulation test

There are several other tests that can be used to help diagnose the cause of Cushing’s syndrome. One of these is a CRH stimulation test. The CRH test can be used if either the ACTH measurement or the pituitary MRI is inconclusive.⁴

First, a blood test is performed to check ACTH and cortisol levels. Then, a CRH intravenous injection is given. After that, blood tests are repeated several times to recheck ACTH and cortisol levels. If these levels are higher, this helps to confirm that there is a pituitary tumor.^2,5


Adapted from Neiman and Ilias.⁴
*MRI=magnetic resonance imaging; CT=computerized tomography.

Other testing

If a pituitary tumor is suspected but not found on MRI, it may be because either the tumor is too small to see, or it is not a pituitary tumor, but instead an ACTH-producing tumor in another part of the body. Additional imaging and/or other tests are then needed to determine the cause of Cushing’s syndrome.²

A test called the inferior petrosal sinus sampling (IPSS) test can be used to determine whether an ACTH-producing tumor is in the pituitary gland or elsewhere.⁵

Once the cause of Cushing’s syndrome is found, the doctor will then decide the most appropriate treatment.

Next, find out why Cushing’s syndrome is often misdiagnosed.

References: 1. Nieman LK, Biller BMK, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93:1526-1540. 2. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006;367:1605-1617. 3. The Hormone Foundation’s patient guide to the diagnosis of Cushing’s syndrome. The Hormone Foundation. http://www.hormone.org/resources/patient_guides/upload/mgmt-cushings-syndrome-070609.pdf Accessed August 4, 2009. 4. Nieman LK, Ilias I. Evaluation and treatment of Cushing’s syndrome. Am J Med. 2005;118:1340-1346. 5. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2003;88:5593-5602.