- 1 How Is Cushing's Syndrome Diagnosed?
- 1.1 24-hour urinary free cortisol test (UFC)
- 1.2 CRH Stimulation Test
- 1.3 Dexamethasone-CRH Test
- 1.4 Dexamethasone Suppression Test
- 1.5 Direct Visualization of the Endocrine Glands (Radiologic Imaging)
- 1.6 LDDST
- 1.7 Midnight plasma cortisol and late-night salivary cortisol measurements
- 1.8 Saliva Testing
- 1.9 Petrosal Sinus Sampling
- 1.10 What is a bilateral inferior petrosal sinus sample (IPSS) test?
- 2 What tests are used to diagnose Cushing's disease?
- 3 Do you have to go to the hospital for these tests?
- 4 Drugs that may interfere with testing
How Is Cushing's Syndrome Diagnosed?
Diagnosis is based on a review of the patient's medical history, physical examination and laboratory tests. Often x-ray exams of the adrenal or pituitary glands are useful for locating tumors. These tests help to determine if excess levels of cortisol are present and why.
No single lab test is perfect, and usually, several are needed. The three most common tests used to diagnose Cushing's syndrome are the 24-hour urinary free cortisol test, the measurement of midnight plasma cortisol or late-night salivary cortisol, and the low-dose dexamethasone suppression test (LDDST). Another test, the dexamethasone-corticotropin-releasing hormone (dexamethasone-CRH) test, may be needed to distinguish Cushing's syndrome from other causes of excess cortisol.
24-hour urinary free cortisol test (UFC)
In this test, a person's urine is collected several times over a 24-hour period and tested for corticosteroid hormones. This is the most specific diagnostic test. The patient's urine is collected over a 24-hour period and tested for the amount of cortisol. Levels higher than 50-100 micrograms a day for an adult suggest Cushing's syndrome. The normal upper limit varies in different laboratories, depending on which measurement technique is used.
Once Cushing's syndrome has been diagnosed, other tests are used to find the exact location of the abnormality that leads to excess cortisol production. The choice of test depends, in part, on the preference of the endocrinologist or the center where the test is performed.
CRH Stimulation Test
This test helps to distinguish between patients with pituitary adenomas and those with ectopic ACTH syndrome or cortisol-secreting adrenal tumors. Patients are given an injection of CRH, the corticotropin-releasing hormone which causes the pituitary to secrete ACTH. Patients with pituitary adenomas usually experience a rise in blood levels of ACTH and cortisol. This response is rarely seen in patients with ectopic ACTH syndrome and practically never in patients with cortisol-secreting adrenal tumors.
A CRH stimulation test involves giving an intravenous injection of CRH. First, a blood test is performed to check ACTH and serum cortisol levels. Then, the CRH injection is given. After that, blood tests are repeated several times to recheck ACTH and serum cortisol levels. If these levels are higher, this helps to confirm that there is a pituitary tumor (Cushing's disease)
Some individuals have high cortisol levels, but do not develop the progressive effects of Cushing's syndrome, such as muscle weakness, fractures and thinning of the skin. These individuals may have Pseudo Cushing's syndrome, which was originally described in people who were depressed or drank excess alcohol, but is now known to be more common. Pseudo Cushing's does not have the same long-term effects on health as Cushing's syndrome and does not require treatment directed at the endocrine glands. Although observation over months to years will distinguish Pseudo Cushing's from Cushing's, the dexamethasone-CRH test was developed to distinguish between the conditions rapidly, so that Cushing's patients can receive prompt treatment. This test combines the dexamethasone suppression and the CRH stimulation tests. Elevations of cortisol during this test suggest Cushing's syndrome.
Some patients may have sustained high cortisol levels without the effects of Cushing's syndrome. These high cortisol levels may be compensating for the body's resistance to cortisol's effects. This rare syndrome of cortisol resistance is a genetic condition that causes hypertension and chronic androgen excess.
Sometimes other conditions may be associated with many of the symptoms of Cushing's syndrome. These include polycystic ovarian syndrome (PCOS), which may cause menstrual disturbances, weight gain from adolescence, excess hair growth and sometimes impaired insulin action and diabetes. Commonly, weight gain, high blood pressure and abnormal levels of cholesterol and triglycerides in the blood are associated with resistance to insulin action and diabetes; this has been described as the "Metabolic Syndrome-X." Patients with these disorders do not have abnormally elevated cortisol levels.
Dexamethasone Suppression Test
This test helps to distinguish patients with excess production of ACTH due to pituitary adenomas from those with ectopic ACTH-producing tumors. Patients are given dexamethasone, a synthetic glucocorticoid, by mouth every 6 hours for 4 days. For the first 2 days, low doses of dexamethasone are given, and for the last 2 days, higher doses are given. Twenty-four hour urine collections are made before dexamethasone is administered and on each day of the test. Since cortisol and other glucocorticoids signal the pituitary to lower secretion of ACTH, the normal response after taking dexamethasone is a drop in blood and urine cortisol levels. Different responses of cortisol to dexamethasone are obtained depending on whether the cause of Cushing's syndrome is a pituitary adenoma or an ectopic ACTH-producing tumor.
The dexamethasone suppression test can produce false-positive results in patients with depression, alcohol abuse, high estrogen levels, acute illness, and stress. Conversely, drugs such as phenytoin and phenobarbital may cause false-negative results in response to dexamethasone suppression. For this reason, patients are usually advised by their physicians to stop taking these drugs at least one week before the test.
Direct Visualization of the Endocrine Glands (Radiologic Imaging)
Imaging tests reveal the size and shape of the pituitary and adrenal glands and help determine if a tumor is present. The most common are the CT (computerized tomography) scan and MRI (magnetic resonance imaging). A CT scan produces a series of x-ray pictures giving a cross-sectional image of a body part. MRI also produces images of the internal organs of the body but without exposing the patient to ionizing radiation.
Imaging procedures are used to find a tumor after a diagnosis has been established. Imaging is not used to make the diagnosis of Cushing's syndrome because benign tumors, sometimes called "incidentalomas", are commonly found in the pituitary and adrenal glands. These tumors do not produce hormones detrimental to health and are not removed unless blood tests show they are a cause of symptoms or they are unusually large. Conversely, pituitary tumors are not detected by imaging in almost 50 percent of patients who ultimately require pituitary surgery for Cushing's syndrome.
Computerized tomography scan (Also called a CT or CAT scan) - a diagnostic imaging procedure that uses a combination of x-rays and computer technology to produce cross-sectional images (often called slices), both horizontally and vertically, of the body
Magnetic resonance imaging (MRI) - a diagnostic procedure that uses a combination of large magnets, radiofrequencies and a computer to produce detailed images of organs and structures within the body
A diagnostic test which uses invisible electromagnetic energy beams to produce images of internal tissues, bones and organs onto film
MSS (Magnetic Stereotaxis System)
This new system uses magnets and advanced computer imaging, allowing surgeons to precisely direct a flexible catheter along a curved path within the brain or other parts of the body.
The Magnetic Stereotaxis System (MSS), developed by a team of American neurosurgeons, is touted as a safer, less invasive and more effective way to biopsy brain tumors. Other applications may include diagnosing and treating cardiovascular conditions, such as coronary artery disease, cardiac arrhythmia and aneurysms.
For more information about MSS, see The Magnetic Stereotaxis System (MSS)
In this test, a person is given a low dose of dexamethasone, a synthetic glucocorticoid, by mouth every six hours for two days. Urine is collected before dexamethasone is administered and several times on each day of the test. A modified LDDST uses a onetime overnight dose.
Cortisol and other glucocorticoids signal the pituitary to release less adrenocorticotropic hormone (ACTH). So, the normal response after taking dexamethasone is a drop in blood and urine cortisol levels. If cortisol levels do not drop, Cushing's syndrome is suspected.
Midnight plasma cortisol and late-night salivary cortisol measurements
The midnight plasma cortisol test measures cortisol concentrations in blood. Cortisol production is normally suppressed at night, but in Cushing's syndrome, this suppression doesn't occur. The test generally requires a 48-hour hospital stay to avoid falsely elevated cortisol levels due to stress.
The patient only has to chew a cotton tube for 2-3 minutes and place it in the plastic tube. Late-evening salivary cortisol is not intended to replace the current standard screening test - measurement of a 24 hr urine free cortisol. However, the salivary cortisol test can be extremely useful for patients suspected of having intermittent Cushing's syndrome.
Cushing's syndrome - endogenous hypercortisolism - is characterized by a loss of circadian rhythmicity. In normal patients, cortisol levels peak in the early morning hours and decrease to substantially lower levels at night. Rather than the normal decrease in late evening cortisol, patients with Cushing's syndrome of any cause fail to decrease cortisol secretion in the late evening. Therefore, the measurement of elevated late evening cortisol is helpful in the diagnosis of Cushing's syndrome. Obtaining a late night, unstressed plasma cortisol is virtually impossible in most clinical practices. Salivary cortisol is in equilibrium with the free, biologically active portion of cortisol in the plasma. Therefore, if one obtains a saliva sample in patients at bedtime in their homes under unstressed conditions, one can make the diagnosis of endogenous hypercortisolism.
A simple way to sample saliva is by using a Salivette. This device consists of a cotton tube and plastic tubes. The patient only has to chew the cotton tube for 2-3 minutes and place it in the plastic tube. The tube is then transported to our lab for analysis.
Late-evening salivary cortisol is not intended to replace the current standard screening test - measurement of a 24 hr urine free cortisol. However, the salivary cortisol test can be extremely useful for patients suspected of having intermittent Cushing's syndrome. Due to the convenience of sample collection, the patient can sample saliva several evenings in a row. In fact, our clinical endocrinologists routinely order 2-3 consecutive late-evening salivary cortisol samples.
- More on Salivary Cortisol from NIH
- On the Message Boards - Salivary Testing
- Patient Question: Does anyone know how to use this test? I have the saliva kit!!! four tubes... lab said there was instructions inside. yes! there is but, no time to do it. Is it a four day or three a day? Geesh! Does it have to be taken to the lab one day at a time so It is handled properly? Anyone? Thanks, Cherlyn
- Patient Answers
- do salivaries at 11 pm. Putting the cotton in your mouth and chewing it until it is saturated. put back in tube and put in freezer. Make sure to mark date on tubes. Turn them in all at the same time.
- Agree with the above. The only difference is I was told to collect mine at midnight, but I would guess this would depend on the endocrinologist and what they wanted. I wasn't given any cotton to chew on though, just had to collect salivary specimen in sterile container and freeze. So I guess it depends on what kit you are given as well. Good luck.
- We were told to only chew for one minute.
- I did mine at 11pm, chewed nasty cotton until it was soaked through which took about a minute, dropped it into the tube, but was never told to freeze it, I just turned it in as is.
- Mine are at 11 pm as well. Told to refrigerate but I believe that is just so it's not smelly. I don't think anything happens if it weren't to be kept cold. It doesn't "break down".
- Patient Answers
Petrosal Sinus Sampling
This test is not always required, but in many cases, it is the best way to separate pituitary from ectopic causes of Cushing's syndrome. Patients who are suspected of having a pituitary tumor resulting in Cushing's syndrome may be referred for inferior petrosal sinus sampling if findings on MRI examination of the pituitary did not reveal a tumor or are inconclusive.
This test relies on the fact that if the source of your high ACTH is the pituitary gland blood levels taken from very near the gland will be higher than the blood level in an arm vein. Pituitary gland tumors are often tiny and can't be seen even with the most modern scanners. This test will help your endocrinologist to know with almost 100% certainty whether the pituitary gland is the source or if a search is needed elsewhere (for example in the lungs or abdomen). This guides treatment, for example the recommendation for Pituitary surgery.
Samples of blood are drawn from the petrosal sinuses, veins which drain the pituitary, by introducing catheters through a vein in the upper thigh/groin region, with local anesthesia and mild sedation. X-rays are used to confirm the correct position of the catheters. Often CRH, the hormone which causes the pituitary to secrete ACTH, is given during this test to improve diagnostic accuracy. Levels of ACTH in the petrosal sinuses are measured and compared with ACTH levels in a forearm vein. ACTH levels higher in the petrosal sinuses than in the forearm vein indicate the presence of a pituitary adenoma; similar levels suggest ectopic ACTH syndrome.
What is a bilateral inferior petrosal sinus sample (IPSS) test?
In this test, catheters are threaded from the groin area up to near the pituitary gland to get a better view where a suspected tumor may be. It is important to lie very still after the test so that the insertion points can heal properly.
What tests are used to diagnose Cushing's disease?
Once you have been diagnosed with Cushing's syndrome, your doctor will perform tests to determine if you have Cushing's disease. The doctor uses a blood test to measure ACTH levels, an MRI and/or CT scan, and other tests to find out if Cushing's syndrome is caused by a pituitary tumor that is producing too much ACTH (Cushing's disease), or a tumor in another part of the body that is producing too much ACTH or cortisol.
Do you have to go to the hospital for these tests?
Not usually. Samples of urine and saliva can be gathered at home and are then tested in a lab. For the blood test, one or more doses of dexamethasone are taken at home, then a blood sample is taken a few hours later at the doctor's office.