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Diagnosing Cushing syndrome

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Who should be screened for Cushing syndrome?

If you have signs and symptoms of excess cortisol, your doctor may screen you for Cushing syndrome (hypercortisolism).

Knowing when to look for Cushing syndrome may be challenging. Many signs and symptoms of the condition are common and may be unrelated to excess cortisol. To avoid unnecessary testing in healthy people, there are criteria for screening. See below for the criteria that determine when screening is recommended versus when it is suggested.

Screening is recommended in

  • People with multiple signs and symptoms of classic, overt Cushing syndrome

  • All people with adrenal nodules

  • People with pituitary nodules who also show other signs of Cushing syndrome

Screening is suggested in people with

  • Poorly controlled diabetes and who are younger than age 50

  • Poorly controlled high blood pressure and who are younger than age 50

  • Bone fragility and fractures or low bone mineral density

Cushing syndrome is a spectrum

Faces of Hypercortisolism ImageFaces of Hypercortisolism Image

Patients in the above photos were diagnosed with hypercortisolism/Cushing syndrome. Some photographs from: Cushing H. Clinical manifestations of disordered function. In: The Pituitary Body and Its Disorders: Clinical States Produced by Disorders of the Hypophysis Cerebri. Philadelphia, PA: JB Lippincott Company; 1912. All other photographs used with permission.

How is Cushing syndrome diagnosed?

Cushing syndrome is a complex disease, and diagnosis may often be difficult. Tests used to measure cortisol levels have varying sensitivity levels and detect excess levels of cortisol using different methods. Also, cortisol levels naturally rise and fall throughout the day and night based on the sleep-wake cycle. This fluctuation in cortisol may make it challenging to determine whether cortisol levels are higher than they should be.

Because of this, your doctor may repeat steps to make a diagnosis, such as using multiple tests or giving the same test at different times.

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STEP 1 Cushing Syndrome is suspected
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If your doctor suspects you may have Cushing syndrome, the first step is to rule out other potential diagnoses:

  • Rule out external source of excess cortisol, such as medications that act like cortisol in the body (exogenous hypercortisolism)

  • In people with a nodule in the adrenal glands:

    • Rule out adrenal nodules that release other types of hormones besides cortisol

    • Rule out cancerous growths/malignancy

STEP 2Cortisol levels are measured
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Next, your doctor will recommend 1 or more screening tests to measure your cortisol levels. Because cortisol levels may fluctuate throughout the day and night, often more than 1 test is needed to confirm or rule out a diagnosis of Cushing syndrome.

STEP 3Source of excess cortisol is determined
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Hormone levels may point to the source of excess cortisol

Cortisol levels in the body are controlled by a feedback loop of hormones known as the hypothalamus–pituitary–adrenal (HPA) axis. Disruption to these hormones may result in the body making too much cortisol. Looking at certain hormone levels may help your doctor identify the source of excess cortisol in your body.

  • Low adrenocorticotrophic hormone (ACTH) typically points to a cortisol-producing nodule in the adrenal glands (adrenal hypercortisolism)
  • High ACTH, or ACTH levels that do not rise and fall in a normal pattern, may point to an ACTH-producing nodule in the pituitary (Cushing disease) or an ectopic nodule in a part of the body other than the pituitary or adrenal glands (ectopic hypercortisolism)
Follow-up laboratory tests to confirm the source

In people with suspected adrenal Cushing syndrome (low ACTH):

  • Dehydroepiandrosterone Sulfate (DHEA-S) levels
    A blood test that measures levels of a hormone produced by the adrenal glands. DHEA-S levels are typically lower than normal in people with adrenal Cushing syndrome
  • Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the adrenal gland
    Imaging of the adrenal glands, located just above the kidneys

In people with suspected Cushing disease (pituitary hypercortisolism) or ectopic Cushing syndrome (high ACTH):

  • Inferior petrosal sinus sampling (IPSS)
    A procedure that samples the veins draining the pituitary gland to measure ACTH levels
  • Corticotropin-releasing hormone (CRH) stimulation test
    An injection of a synthetic form of CRH, the hormone that signals the pituitary gland to produce ACTH. The test measures your body's response to CRH signaling
  • Pituitary magnetic resonance imaging (MRI)
    Imaging of the pituitary gland, located at the base of the brain
  • Octreotide scan
    An injection of a synthetic hormone that binds to ACTH-releasing nodules. The synthetic hormone is radio-labeled, so areas in the body where it is highly concentrated show up on the scan
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Tests to measure cortisol levels

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1-mg overnight dexamethasone suppression test

Tests the body's response to an external source of cortisol (glucocorticoid medication); also called DST, dex test, or low-dose DST

What is being tested?

  • 2-step test that measures your body's response to dexamethasone

  • Dexamethasone is a corticosteroid (kawr-tuh-koh-ster-oid) medication

  • Typically your body reduces the production of cortisol when you are exposed to medications that function like cortisol in the body, such as corticosteroids

  • How your body responds to dexamethasone may reveal whether cortisol is being produced appropriately

What if your doctor recommends a DST?

Understand what you can expect when taking the DST.

Download Test Overview

How is the sample collected?

DST Step 1:

  • You will take a 1-mg dexamethasone tablet the night (around 11 pm) before you come in to have your blood drawn

DST Step 2:

  • The following morning (around 8–9 am), a healthcare provider will draw your blood

  • A lab will use your blood sample to measure your cortisol levels

What do the results mean?

  • There may be a problem with how your body produces cortisol if your cortisol levels do not go down after taking dexamethasone the night before

  • Your healthcare provider will need to interpret your results to determine the appropriate next steps

What can affect the results?

  • Please inform your doctor about any medications you are taking

  • Some medications may affect the accuracy of your results

  • The timing of the test may also affect your results

Next: Late-night salivary cortisol
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Late-night salivary cortisol (LNSC)

Measures cortisol in the saliva when cortisol should be at its lowest level

What is being tested?

  • Detects changes in cortisol levels in response to the sleep-wake cycle.

  • Cortisol levels should be lower when you go to sleep than when you wake up

  • Cortisol levels are typically lowest in the evening (11 PM–1 AM) and highest around 9 AM

  • Saliva collected in the late evening should contain a relatively low amount of cortisol

How is the sample collected?

  • Requires a sample of saliva that you collect yourself

  • You will take home a collection device and receive instructions for how to take your saliva sample

  • The timing of the test is very important

  • You should collect the sample within the time frame your doctor tells you

  • Taking the test too early or too late may affect its accuracy

What do the results mean?

  • If your cortisol levels do not go down at night, it may mean your body is producing cortisol when it shouldn't be

  • Your healthcare provider will review your results

  • Follow-up testing may help determine the potential source of cortisol overproduction.

What can affect the results?

  • Taking the sample at a time when you don't normally go to sleep may affect your results

  • Feeling stressed during the sample collection may also affect your results. Cortisol is released in response to stress, so stress may cause higher levels than you would normally have at night

  • If your gums are bleeding or any blood gets into the sample, this may cause an inaccurate result

Next: Urinary free cortisol
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Urinary free cortisol (UFC)

Measures cortisol levels in the urine over a 24-hour period

What is being tested?

  • 24-hour test

  • Measures cortisol levels in urine over the course of a day

  • If excess cortisol is being produced, a higher-than-normal level of cortisol may be detected in your urine

How is the sample collected?

  • Requires you to collect your urine over the course of a 24-hour period

  • You will be given a container to take home

  • Begin collecting urine the second time you use the bathroom and each time thereafter

  • Also collect your urine the first time you use the bathroom the next morning

  • Store the container in the refrigerator until you can bring it back to your doctor

What do the results mean?

  • By looking at the cortisol levels in your urine over a 24-hour period, your doctor can see whether your body is producing too much cortisol

What can affect the results?

  • Drinking too much fluid may affect the accuracy of the test

  • People with kidney problems may also have inaccurate results

  • Certain coexisting medical conditions (such as poorly controlled type 2 diabetes, polycystic ovarian syndrome, pregnancy, or alcoholism) may result in a false-positive test

  • This test may also not be able to detect less severe levels of excess cortisol. It is not recommended for screening people with adrenal adenomas

If your test results confirm you have excess cortisol, your options for treatment may depend on a number of factors.
Know your Options