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One in a Million

The signs began about two years ago. Weight gain and fatigue were followed by growing body hair.

“I also had acne for the first time in my life, so I knew something wasn’t right,” says Veronica Guzman.

The medical answers to what might be causing her strange symptoms, however, were not to come quickly.

“I had several providers tell me my symptoms of weight gain and being tired were just things that happen to women my age,” recalls the 40-year-old from Houston.

Guzman underwent months of testing after a blood test revealed high levels of cortisol. Finally, last August as a patient at Baylor College of Medicine, Houston, Texas, a second MRI detected a tumor on her pituitary gland and confirmed a diagnosis of Cushing’s disease.

Guzman is one of an estimated one to three cases per million people to be newly diagnosed with the rare condition each year. It affects women five times more than men, and pituitary tumors cause 70% of Cushing’s disease cases (excluding those caused by corticosteroid use), reports the National Institutes of Health. A tumor or excess growth of the pituitary gland causes the excess secretion of the stress hormone cortisol. Typical symptoms include upper body obesity, a rounded full face, thin skin that bruises easily, acne or skin infections, depression, weakened bones, excess body hair growth and menstrual irregularities in women, and impotence in men.

A Challenging Diagnosis

The difficulty of treating Cushing’s disease begins with its diagnosis. Because its symptoms are often mistaken for those of more common medical conditions, physicians don’t often pinpoint the disease when patients first present with problems.

“Because of the high prevalence of obesity, diabetes, hypertension, depression, and polycystic ovarian syndrome, many patients with Cushing’s are treated for the immediate problem without screening for Cushing’s, thus resulting in a delay in diagnosis,” explains Mary Lee Vance, MD, from the University of Virginia, Charlottesville.

“The diagnosis and treatment of Cushing’s disease is the most difficult of all pituitary disorders,” Vance adds. “Diagnosis often requires multiple tests to con- firm consistent overproduction of cortisol, and this may take time, often several months.”

To add to the challenges, no single lab test is perfect in determining a definitive excess of cortisol. The Endocrine Society’s Clinical Guidelines for the Diagnosis of Cushing’s Syndrome recommends that patients with multiple symptoms be given one initial test with high accuracy: either the 24-hour urinary free cortisol test, late-night salivary cortisol, 1 mg overnight or 2 mg 48-h dexamethasone suppression test. If a patient has an abnormal result, a second test should be administered — either one of the above or a serum midnight cortisol or dexamethasonecorticotropin-releasing hormone test.

Other difficulties in diagnosis arise because the pituitary tumor that causes the disease can be too small to be found on MRI scans. The tumor can also become “inactive” so that it releases less cortisol at certain times.

Tackling Treatment

After a confirmed diagnosis, treating Cushing’s disease most often begins with the delicate transsphenoidal procedure to remove the pituitary tumor.

“The first treatment is surgery by an experienced pituitary neurosurgeon,” says Vance. “Outcomes of surgery are directly dependent upon the expertise of the neurosurgeon. In the best series reported by expert pituitary neurosurgeons, about 90% of patients have a successful outcome from removal of the pituitary tumor.”

If surgery does fail or a patient is not a suitable surgical candidate, radiation is another possibility.

A recent review in the January issue of Endocrine also suggests a medication, pasireotide diaspartate (Signifor) approved by the Food and Drug Administration in December 2012, that offers a quality option for non-surgical patients.

“Pasireotide, as the first medical therapy approved for Cushing’s disease, represents the most significant recent advancement in the medical management of the disease,” says lead reviewer Annamarie Colao, MD, PhD, from Università Federico II di Napoli in Naples, Italy.

“Acting at the pituitary level and targeting the cause of Cushing’s disease, pasireotide seems to be the ideal medical approach for management of this rare but severe disorder,” she adds. “It has shown a good efficacy profile, accompanied by shrinkage of tumor volume and improvements in clinical symptoms.”

Research has shown that pasireotide treatment is successful in up to 25% of patients. The drug, however, may potentially induce hypocortisolism, so patients need to be monitored and instructed on how to manage its signs, including weakness, fatigue, anorexia, and nausea, says Colao.

Susan L. Samson, MD, PhD, medical director of The Pituitary Center at Baylor and Guzman’s treating physician, says endocrinologists’ armamentarium of treatments for Cushing’s disease has indeed been expanded with the introduction of pasireotide as well as the use of mifepristone.

“Both of these medications can lead to improvements in the symptoms and physical effects of high cortisol including glucose levels, blood pressure, weight, and waist circumference,” says Samson.

“Before the availability of these medications, we have all struggled, as endocrinologists, to provide some relief for our patients,” she continues. “Many times we have only been able to combat the secondary effects of cortisol, such as trying to optimize blood pressure and diabetes control. Given the far-ranging effects of cortisol in the body, it seems now that it’s not quite enough to focus on the adverse effects of cortisol, when we have new medications that can help us by fighting the disease at the source.”

Facing Risks Despite Treatment

In the March issue of the Journal of Clinical Endocrinology & Metabolism, researchers reported that even after successful treatment, Cushing’s disease patients face increased risk of dying or developing cardiovascular disease.

The study examined the charts of 346 patients who underwent transsphenoidal surgery by a single surgeon between 1980 and 2011. Patients had a mean age of 40 and were followed, on average, for six years.

Of the 346 patients, the most prevalent comorbidities included hypertension (72%), diabetes (27%), and depression (22%). Patients were exposed to excess cortisol for an average of 40 months.

And while previous studies have shown that Cushing’s patients are at greater risk of developing and dying from cardiovascular disease than the average person, the researchers examined whether the risk could be eliminated or reduced when the disease is controlled. They found these risk factors remained well after patients were exposed to excess cortisol.

The study reported that people who were exposed to excess cortisol longer, endured longer duration of symptoms before diagnosis and remission, and who were older when diagnosed were linked with an increased risk of death. For patients who achieved remission, depression was found to increase the risk of death and cardiovascular disease.

“Cushing’s is rare but carries an extremely high morbidity and mortality risk, especially for untreated patients but even, to a lesser extent, for patients who achieve remission,” says study author Eliza B. Geer, MD, medical director of the Mount Sinai Pituitary Center, New York, NY. “It is critical that these patients receive endocrine and surgical care from physicians with significant experience treating Cushing’s.”

Geer’s study concludes that for patients to benefit from improved care, endocrinologists should provide long-term follow-up and management of persistent comorbidities.

“I tell my patients that I want to follow them ‘forever,’ because I’m very interested in knowing how they do over time, but also because, unfortunately, Cushing’s disease patients can develop recurrences very late, even 20 or more years after previous remission,” says Geer.

She adds that long-term monitoring should focus on several key factors:

• Endocrine status confirming Cushing’s disease remission;
• Metabolic outcomes, including weight, insulin resistance, blood pressure, lipid profile, and bone mineral density;
• Neuropsychiatric health, including depression, anxiety, memory, and concentration;
• Overall quality of life, focusing on aspects such as sleep and energy.

“Knowledge of, and experience treating this disease is needed to thoroughly educate and advise patients on appropriate care and follow up,” Geer adds.

As for Veronica Guzman, after successful surgical removal of her tumor in November, she says she feels like a different person.

“I don’t think I realized what type of burden it had on me, prior until now,” she says. “Even my temperament was not so fantastic before the surgery. But it all seemed to go away afterwards. It is truly remarkable.”

— Fauntleroy is a freelance writer based in Carmel, Ind., and
a regular contributor to Endocrine News. She wrote about
the health disparities of diabetes in the March issue.

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