Cushing’s disease diagnosis

Last updated Aug. 9, 2023, by Marisa Wexler, MS
Fact-checked by Patricia Silva, PhD

Diagnosing Cushing’s disease, which is marked by excess cortisol in the body, is a multistep process that involves tests to detect hormonal changes that are characteristic of the rare disorder, as well as other examinations to pinpoint the cause of these changes.

The cause of Cushing’s disease is a tumor in the brain’s pituitary gland. Such tumors cause the pituitary to secrete abnormally high amounts of the signaling molecule adrenocorticotropic hormone (ACTH). In turn, high ACTH levels prompt the adrenal glands, located above the kidneys, to produce excessive amounts of the stress hormone cortisol. High cortisol levels — a condition referred to as hypercortisolism — are ultimately what causes the symptoms of Cushing’s disease to develop.

Cushing’s disease is a specific form of Cushing’s syndrome, which is a broader term that encompasses disorders linked to high cortisol levels, regardless of the underlying cause. A key part of diagnosing Cushing’s disease is differentiating it from other forms of Cushing’s syndrome.

Identifying Cushing’s disease

The first step in diagnosing Cushing’s disease is recognizing the signs and symptoms of the disorder. These commonly include:

• weight gain
• a buildup of fat around the abdomen, face, and the back of the neck
• fatigue
• stretch marks
• skin changes such as acne, easy bruising, and poor wound healing
• balding of the hair on the head, or unusually dark, thick body hair
• changes in mood and memory
• decreased sex drive
• high blood pressure and irregularities in blood sugar.

These symptoms usually develop quite gradually over time, and any one person with Cushing’s usually won’t experience all of them.

Moreover, any of the symptoms associated with the disease also are seen in other conditions; as such, it is often challenging for physicians to recognize Cushing’s.

To accurately identify the disease, clinicians will generally look in detail at a patient’s medical history. This can help to identify changes over time, such as weight gain, that may be signs of Cushing’s disease.

It also is important to assess in detail a patient’s history of medications, given that certain drugs — particularly corticosteroids, a class of therapies used to manage inflammation — can cause Cushing’s-like symptoms.

Diagnostic tests

Once Cushing’s disease is suspected, the key first step toward establishing a diagnosis is to check whether the person’s cortisol levels are abnormally high, indicative of hypercortisolism. This can be done through assessments of urine, saliva, and/or blood.

For all of these Cushing’s disease tests, an important consideration is that cortisol levels normally fluctuate throughout the day. As such, these tests can have specific timing requirements to ensure accuracy.

Urine test

Cortisol levels may be measured in urine, sometimes referred to as 24-hour urinary-free cortisol testing. For this type of test, a patient’s urine is collected over the course of one day (24 hours). Depending on the specific technique used, usually a cortisol level higher than 50 to 100 micrograms in an adult may indicate Cushing’s disease in a urine test.

Saliva test

Cortisol levels also can be measured in saliva, known as a salivary cortisol measurement. In this test for Cushing’s disease, a person’s saliva is collected late at night, usually between 11 p.m. and midnight, because cortisol levels are typically low at that time. Specific diagnostic cutoffs indicating Cushing’s vary depending on the laboratory techniques used to measure cortisol levels.

As cortisol is naturally produced when a person is feeling stressed, it is sometimes necessary for a patient to stay in the hospital for about two days so as to reduce the likelihood of false positive results due to stress.

Blood test

Cushing’s disease blood tests also may be used to measure levels of cortisol. Like saliva tests, these assessments usually are done late at night when cortisol levels are normally low. They also may require a brief hospital stay to avoid false-positives. A cortisol level higher than 50 nanomoles per liter (nmol/L) typically indicates possible Cushing’s, though cutoffs may vary across different laboratories and analysis techniques.

Blood tests also can be used to measure levels of ACTH. Normally, when cortisol levels are high, production of ACTH decreases due to regulatory mechanisms within the body. As such, finding high cortisol levels accompanied by normal or high levels of ACTH can be indicative of Cushing’s disease, where excess ACTH drives cortisol production.

By contrast, if cortisol levels are high but ACTH levels are low, the underlying cause of high cortisol levels is unlikely to be excessive ACTH production.

Dexamethasone tests

Dexamethasone is a corticosteroid — a type of medication that works by mimicking the activity of cortisol in the body. Normally, when a person is given a corticosteroid like dexamethasone, it triggers regulatory mechanisms in the body that result in a decrease in cortisol levels. But in Cushing’s disease, these regulatory mechanisms are dysfunctional, so the body continues to produce high cortisol levels even after dexamethasone is given.

There are two versions of the dexamethasone test: a low-dose and high-dose version. The low-dose version is used to test for excessive cortisol production, whereas the high-dose version is more useful for determining the cause of high cortisol levels.

For the low-dose dexamethasone test, a patient is either given one dose of 1 mg of the corticosteroid late at night, or 0.5 mg doses at six-hour intervals over the course of two days. In either setup, cortisol levels are then measured in blood several hours later. A cortisol level below 1.8 micrograms/dL (or 50 nmol/L) is considered normal, while higher cortisol levels are indicative of Cushing’s.

Certain medications — most notably estrogen-based birth control pills — can cause false results on dexamethasone tests. As such, these therapies should either be stopped a few weeks before the test is performed, or other diagnostic tests should be used to determine the levels of cortisol in the body for patients taking them.

Diagnosing the cause of Cushing’s disease

Detecting high levels of cortisol can help to confirm the presence of Cushing’s syndrome. But it is not enough to confirm the diagnosis of Cushing’s disease, in which excess cortisol is specifically caused by a tumor in the pituitary gland that secretes ACTH. Accurate identification of the underlying cause is key to guiding decisions about Cushing’s disease treatment and also predicting the disorder’s prognosis.

To definitively establish the diagnosis, it is necessary to perform additional tests to confirm whether or not there is an ACTH-secreting pituitary tumor. Typically the first step in this process is a blood test to detect high ACTH levels, followed by other tests to pinpoint the source of ACTH.

Corticotropin-releasing hormone stimulation test

Corticotropin-releasing hormone (CRH) is a signaling molecule that prompts the pituitary gland to release more ACTH, and, in turn, increase cortisol production. In people with Cushing’s disease, which by definition is caused by a pituitary tumor, administering CRH will lead to an increase in cortisol levels. However, in people with high cortisol levels due to nonpituitary problems, CRH will not increase cortisol levels.

The CRH test is sometimes combined with the low-dose dexamethasone test, which can be particularly helpful for distinguishing Cushing’s disease from pseudo-Cushing’s syndrome, a condition where cortisol levels are unusually high but not due to a tumor. Pseudo-Cushing’s, which doesn’t cause long-term health problems like Cushing’s disease, sometimes develops in people with mental health problems like anxiety or depression, as well as individuals with poorly managed diabetes or who are very obese.

Imaging tests

Imaging tests, most commonly magnetic resonance imaging or MRI scans, can be used to look for a disease-driving tumor in the pituitary gland. These tests are not usually done to diagnose Cushing’s disease itself, because many people have small, benign growths on the pituitary that look like a disease-driving tumor on imaging but don’t actually cause health problems.

Instead, imaging of the pituitary is usually used to try to identify the disease-causing tumor once the diagnosis of Cushing’s disease is already established. This can be especially helpful in guiding plans for surgery to remove the tumor. However, given that pituitary tumors that cause Cushing’s disease are usually very small, people with the disease may not have a visible pituitary tumor on MRI, computerized tomography (CT) scans, or other imaging techniques.

Imaging tests also may be useful for identifying tumors in other parts of the body, especially in the adrenal glands, that can cause Cushing’s syndrome.

High-dose dexamethasone suppression test

The high-dose dexamethasone suppression test is similar to the low-dose version, but as its name suggests, it uses a higher dose of the corticosteroid — typically 2 mg given every six hours for two days, or 8 mg taken once.

The high dose of dexamethasone usually will lead to a reduction in cortisol levels in people with an ACTH-producing tumor in the pituitary gland, but not in those with an ACTH-producing tumor in other parts of the body. As such, this test can help to distinguish people with Cushing’s disease from those with other forms of endogenous Cushing’s syndrome driven by tumors.

Petrosal sinus sampling

Petrosal sinus sampling is an invasive test that measures levels of ACTH in the inferior petrosal sinuses, the veins that drain blood and other fluids from the pituitary gland. In Cushing’s disease, where this gland is producing excessive ACTH, levels of this molecule will be higher in these sinuses than in the rest of the body.

This type of testing is about 94% accurate in identifying Cushing’s disease and it is considered the gold standard for diagnosing the condition. However, because it’s an invasive procedure, petrosal sinus sampling is often not performed if other, less invasive tests have already confirmed the diagnosis.

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