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Finding Your Way Through Complicated Cushing's Syndrome

Cushing's syndrome is a rare, but complex disorder affecting many aspects of the body. It may be caused by certain medications you are taking, or from a tumor that alters the production of cortisol, a hormone associated with stress. If left untreated, it can lead to a host of problems including osteoporosis, high blood pressure and muscle loss. Finding the cause of your Cushing's syndrome is the key to finding the proper treatment.

How does a doctor determine the source of the disease? Dr. Elena Plummer, MD, a member of the American Association of Clinical Endocrinologists (AACE) and the Endocrine Society outlines the potential causes of this syndrome and what treatment options are available to help.

What is Cushing's syndrome?
Cushing's syndrome develops from excess cortisol, a steroid, that's either ingested exogenously, from the outside, or produced endogenously, within the body. Cushing's syndrome is an umbrella name for all the conditions including high cortisol level and its manifestations.

It is a very rare problem. There are anywhere from 5 to 25 cases per million per year. It is more common in females than in males and is generally a disease of women between 20 and 45 years of age.

What is the function of cortisol in a healthy person?
There is no one main function of cortisol and researchers have found that just about any part of the body is regulated by cortisol. It's a hormone that regulates many activities; glucose metabolism, the immune system, the metabolism of calcium and bone metabolism. And too much (Cushing's syndrome) or too little (Addison's disease), is detrimental. Addison's disease causes the opposite effects of Cushing's syndrome: blood pressure is too low, electrolytes are abnormal, potassium is high, patients lose weight and are very fatigued.

What controls cortisol production?
There is a small gland in the middle of the brain called the pituitary gland that makes several stimulating hormones that go on to regulate the production other hormones. For example, there's a hormone called thyroid-stimulating hormone (TSH) in the pituitary that goes and tells your thyroid how much to work. The same thing happens with the adrenal gland. There is a hormone in the pituitary called adrenocorticotropic-stimulating hormone (ACTH) that stimulates cortisol production in the adrenal gland. So in a healthy person there is generally a small amount of ACTH, causing the production of a small amount of cortisol.

If you're under a large amount of physical stress, your body produces more cortisol to counteract this and stimulate the immune system, regulate blood pressure and initiate bone building where needed. First, the pituitary gland produces more ACTH, then the adrenals respond by making a lot of cortisol. When the stress is over, the high amount of cortisol feeds back on the pituitary, and shuts off the production of the stimulating hormone, ACTH. In fact, any time you have too much cortisol, whether it's physiologic or not, your pituitary should shut off the production until it is at a lower level in the body. But in Cushing's disease, there is a problem where the body is making uncontrolled amounts of ACTH and the adrenals keep on responding.

What causes high cortisol levels in the body?
There are two major categories of problems that cause high cortisol. The first is when your own body produces too much cortisol. Second, when a person is given medications that contain steroids, like cortisone, prednisone or hydrocortisone to control inflammation caused by other diseases, such as rheumatoid arthritis, asthma and some allergies, he or she may develop the exact same syndrome that you may have if your own body starts making too much cortisol.

About 70 to 80 percent of all Cushing's syndrome patients are actually ACTH-dependent, which means that the excess cortisol production is caused by the overproduction of the stimulating hormone, ACTH, in the pituitary gland; this may be caused by a pituitary tumor.

Cushing's can also develop if your adrenals produce too much cortisol. This is the second-most common cause of excess cortisol production. Your adrenals may produce too much cortisol as a result of a small tumor on the adrenal gland. In these patients, the amount of ACTH will be low, but the cortisol will be increased.

What are the symptoms of Cushing's syndrome?
One of the main symptoms is weight gain in the abdomen. An additional place where a patient usually gains weight is in the face, called "moon facies," where the face gets rounded and very red. There is also a redistribution of the fat in the back of the neck, what doctors call a "buffalo hump," and also over the clavicles, the bones just below the front of the neck. Also, patients often get large, wide, purple stretch marks across the abdomen. Stretch marks are usually associated with pregnancy or fast weight gain, but in Cushing's syndrome they're much wider and very deeply colored.

It's also very common to have thinning of the muscles in the legs and arms; it will be difficult for patients to get up from a chair, climb stairs, comb hair. Other things that are also common are high blood pressure, abnormal glucose metabolism and even diabetes.

There are some psychological and psychiatric changes that are also possible, such as depression, anxiety, anger problems and psychosis.

How does a doctor determine the source of high cortisol levels?
The first question: "Is this patient taking any medications that have steroids?" Any topical creams or ointments, health-food preparations, shots that are given for joint pain or arthritis, inhalers and even nasal preparations may contain cortisol-simulating glucocorticoids; they act like cortisol. After that is ruled out, a 24-hour urine cortisol test can look at the endogenous production of cortisol. We collect all the urine over 24 hours and analyze it for cortisol levels.

There are other ways to do it, too. There are some blood tests. There is also a new salivary test that seems promising and much easier to perform for patients.
If we find that the patient does indeed have endogenous Cushing's syndrome, then the next question to answer is, "Where is it coming from?"

We then concentrate on finding if the cortisol production is ACTH-dependent. If it is ACTH-independent, the cortisol comes from the adrenal gland. So imaging of the adrenal gland is done. If it's ACTH-dependent, it most likely comes from the pituitary gland, but there is also a small category of tumors that are actually located elsewhere in the body that make hormones like ACTH. Those are usually carcinoid tumors in the lungs, sometimes found in smokers, but there are some unusual cancers that can also make ACTH. You try to localize the source of ACTH with different imaging tests.

If a tumor is found to be the cause of excess cortisol, how is Cushing's syndrome treated?
Any time a tumor is found, surgery is the first choice of treatment. Most of the pituitary tumors that cause Cushing's are very small tumors in the pituitary gland, a pea-sized gland behind the eyes in the middle of the brain. Because they're so aggressive, they actually make enough hormone for patients to be diagnosed before it becomes a large tumor. In this case, the best treatment is surgery to remove the tumor. The procedure is only done in highly specialized centers by highly trained neurosurgeons. If the tumor is found in the adrenal gland, it is removed laparoscopically, [through the use of cameras and instruments inserted into the body through small holes in the skin] which is certainly much less invasive than general surgery.

Patients who are not surgical candidates and those that do not have a successful surgery can receive several medications that can be used to turn off cortisol production. But these are second-line therapies because the medications have side effects and would have to be used lifelong.

What advice do you have for people to avoid Cushing's syndrome?
Basically, anybody is susceptible to effects of excess cortisol. Physicians generally are very cautious about prescribing certain medications, especially for chronic use, because of the knowledge of all the detrimental effects.