December 8, 2008

Looking for Signs — Detecting Evidence of Cushing’s Syndrome and Cushing’s Disease
By Kim M. Norton
For The Record
Vol. 20 No. 25 P. 24

One of the first and most striking aspects of patients with Cushing’s syndrome is how rapidly their bodies change and how quickly their symptoms appear. Hypertension, diabetes, high cholesterol, and obesity garner headlines both for their prevalence and for their relationships to diet and activity level. However, when these medical issues surface suddenly, there could be another underlying cause besides poor diet and lack of exercise: the pituitary.

A pea-sized gland at the base of the brain, the pituitary is considered the body’s master gland because of its ability to control hormone production and send signals to the thyroid, adrenal glands, and the ovaries or testes. The hormones produced by the pituitary affect functions such as metabolism, blood pressure, reproduction, growth, and lactation. If a patient experiences dramatic shifts in hormone-dependent conditions such as the development of diabetes, rapid weight gain, and mood swings, it is imperative for physicians to consider the pituitary.

Cushing’s syndrome occurs when excessive amounts of cortisol are produced due to a noncancerous tumor on the pituitary or adrenal gland. In rare cases, a cancerous tumor elsewhere in the body may also lead to Cushing’s syndrome. Too much cortisol can wreak havoc on the body, causing everything from rapid weight gain in the face and the upper back (also called moon face and buffalo hump, respectively) to disproportionate hair growth, fatigue, and depression. Excessive cortisol production also contributes to increased hypertension and the presentation of diabetes in a short period of time, explains Pejman Cohan, MD, a neuroendocrine specialist and an assistant professor of medicine at the UCLA School of Medicine.

The cause of Cushing’s syndrome is a pituitary adenoma (a noncancerous pituitary tumor found in more than 70% of patients), which is referred to as Cushing’s disease. Most adrenocorticotropic hormone (ACTH) adenomas are microadenomas. Cushing’s disease is relatively uncommon, affecting 10 to 15 out of every 1 million people each year and most commonly adults aged 20 to 50. Women account for more than 70% of cases. Given that Cushing’s disease causes so many problems commonly affecting the general population, it is possible for patients with Cushing’s disease to go undiagnosed for years.
 
The Cushing’s Patient
Diagnosing Cushing’s is not easy. Instead of relying on one test to make a diagnosis, physicians must administer multiple ones and repeat them over time to confirm their suspicions, says Cohan. Ask Cushing’s patients about their road to diagnosis and chances are you will hear tales filled with endless tests and doctor visits. Sharmyn McGraw is one such patient.

At the age of 31, McGraw was a size 2, in good physical condition, ate a balanced diet, and even used a personal trainer on occasion. Then, she rapidly started to gain weight. “At one point, I realized I had gained 11 pounds in four days, 85 pounds in six months, and 100 pounds in a year,” she says. Weight gain was just the beginning.
 
When McGraw turned to the medical community, she was met with the mantra, “There is nothing wrong with you. Try dieting and exercise.” After seven years without a diagnosis, she eventually used the Internet to determine that what she had sounded like Cushing’s syndrome.

McGraw connected with experts formerly at the UCLA Medical Center, and her diagnosis was confirmed. She had a tumor removed from her pituitary and subsequently regained the life she once enjoyed.

Going seven years without a definitive diagnosis may seem extreme, but the fact is this condition often flies under the radar. “Cushing’s is a diagnosis that doctors typically do not think about. They are taught in school that they may never see a case of Cushing’s, so they often do not entertain the diagnosis,” says Daniel F. Kelly, MD, director of the Brain Tumor Center at John Wayne Cancer Institute at Saint John’s Health Center in Santa Monica, Calif.

To determine whether symptoms are evidence of Cushing’s, there first needs to be a thorough patient workup that includes an in-depth discussion of the patient’s medical history. “If there is no family history of diabetes and the patient has had a steady weight for a long period of time or a relatively rapid onset of weight and new diabetes, these are red flags,” says Kelly, the pituitary neurosurgeon who operated on McGraw. Realistically, if a patient has Cushing’s, it can take months to years to get a definitive diagnosis, he says. If the patient’s medical history raises the prospect of Cushing’s, then hormonal testing takes place.

Searching for Answers
“The key to diagnosing Cushing’s and diagnosing it early is increased awareness of the symptoms and consideration of the diagnosis,” says Cohan.

Nothing about Cushing’s is considered guesswork, but timing is everything when it comes to monitoring and evaluating the pituitary for irregularities. An endocrinologist should always supervise the evaluation of a suspected case of Cushing’s. However, opinions differ as to which tests are best suited for nailing down a diagnosis. “No one test is 100% accurate. Some tests may even be misleading,” says Cohan, who adds that it’s important to remember that not all patients may have clear-cut abnormalities indicated by their blood cortisol tests.

Cohan, who recognizes that there are no set-in-stone guidelines for deciding on which hormonal tests to administer when considering Cushing’s, offers the following recommendations:

• 24-hour urine test for cortisol: “This is generally the best test to start with because it provides a daily average of cortisol levels and eliminates possible fluctuations in blood levels that commonly occur during the day.”

• Dexamethasone suppression test: In this test, the patient is given the synthetic steroid dexamethasone. In normal individuals, dexamethasone would temporarily suppress cortisol production. In contrast, patients with Cushing’s fail to suppress it.
 
• Late-night salivary cortisol test: In a typical person, cortisol levels decrease in the evening. However, the cortisol levels of patients with Cushing’s will remain high. This test does have limitations, though, especially when administered to patients who work nights.

Once the hormonal testing results have confirmed an imbalance, the work shifts to detecting the source of the cortisol overproduction. If lab workups suggest a pituitary source, then an MRI is performed to confirm the diagnosis, says Cohan.

“MRI is an effective tool in detecting the tumor, but imaging is never to be used to make a diagnosis of Cushing’s. The hormonal workup must be the first step in considering Cushing’s,” says Kelly. In cases where the MRI comes back clean but lab results strongly suggest Cushing’s, petrosal sinus sampling (a test to determine the source of the ACTH) should be performed to distinguish between ectopic ACTH production (usually due to a cancerous tumor) and pituitary ACTH production, he adds. The procedure can also be used in those patients with normal MRIs to help determine which side of the pituitary the adenoma is located. According to the Pituitary Network Association, petrosal sinus sampling should never be performed before the diagnosis of Cushing’s syndrome has been established.

Treatment
Once Cushing’s disease has been confirmed through hormonal testing and imaging, the best course of action is surgically removing the tumor. Endonasal transsphenoidal surgery (through a nostril) and removal of the adenoma is considered the first-line treatment option and the only way to achieve long-term remission, according to Kelly. “For the surgery to be a success, every last cell of the tumor must be removed or the patient will not go into remission,” says Kelly. Long-term remission or cure rates are 80% to 85% for microadenomas of less than 1 centimeter and adenomas contained within the sella but only around 50% to 65% for macroadenomas of greater than 1 centimeter and adenomas with suprasellar or cavernous sinus invasion, according to Kelly and Cohan.

If the entire tumor is removed, the changes are typically dramatic. “The patient should begin losing weight, hypertension and diabetes should disappear or improve, and the patient will psychologically begin to feel better,” says Kelly. To complement the surgery, the patient is placed on steroid replacement therapy for six to 12 months to help regulate ACTH production. “The pituitary tumor causes ACTH to go into a state of dormancy, and, following surgery, the steroid therapy helps reestablish the connections for proper ACTH production,” says Kelly.

Recurrence Rate
Following successful surgery to remove the tumor, patients are followed for the rest of their lives to monitor their hormone levels. Currently, there is a 5% to 10% recurrence rate for postsurgery patients. “Usually, patients are aware of any change in their bodies, and they know when their Cushing’s is back,” says Kelly, who monitors his patients with a 24-hour urine test for a cortisol baseline every six months for five years. “If the baseline is stable for five years, then we test the patient once a year,” he adds.

By keeping in close contact with patients, much of the anxiety related to the condition is eliminated. “These patients are monitored closely and should there be a recurrence, we act accordingly. In some patients, a repeat endonasal operation to remove recurrent tumor is performed; in others, radiosurgery (focused radiation therapy) and/or bilateral adrenalectomy (removal of the adrenal glands) is indicated,” says Kelly.

Physician Education
McGraw cannot say enough about the value of educating physicians on Cushing’s and its signs and symptoms. “I should not have had to turn to the Internet for answers; my doctors should have done more, considered more,” she says. Now in remission, under the direction of Kelly, she heads up the country’s largest pituitary patient support group at the Brain Tumor Center and speaks about her experiences to help others struggling to find a diagnosis.

“Cushing’s is curable, and, without proper physician education, some of these patients either go undiagnosed or become severely disabled,” McGraw says.
Adds Kelly, “Given that most pituitary hormonal disorders are readily treatable, healthcare professionals should have a low threshold to investigate for such disorders in patients with complaints or symptoms that may be hormonal in origin.”

— Kim M. Norton is a New Jersey-based freelance writer specializing in healthcare related topics for various trade and consumer publications. She can be contacted at kim_norton1@hotmail.com.