Multimodal Approach Promises Best Outcomes for Cushing's Disease

To achieve long-term remission, clinicians should anticipate the need for additional treatment following surgery for Cushing's disease in 25% of patients.

Written by Adam Marcus

With Moisés Mercado, MD, PhD, and Tamara Wexler, MD

Treating patients with Cushing’s disease that does not respond well to initial therapy likely requires the use of more than one approach,1 according to authors of a retrospective study published in Endocrine Practice.  

Most Patients Require Follow-up Treatment for Prolonged Remission

Although more than 80% of patients in the single-center analysis went into remission immediately after surgery, only about three-fourths of them remained in remission for a prolonged period.1 Nearly 40% of patients who underwent surgery received a second- or even a third-line therapy to bring their levels of cortisol under control,1 reported senior author Moisés Mercado, MD, PhD, of the Hospital de Especialidades in Mexico City, Mexico.  

The authors found that more patients responded quickly to repeat surgery for removal of a pituitary or adrenal tumor, but radiation therapy provided longer remissions.1

“We believe our results highlight the need for a multimodal approach in patients with [Cushing’s disease] and this approach would help clinicians to decide which treatment alternative is best suited for the individual patient,” Dr. Mercado told EndocrineWeb.

Managing Pituitary Adenomas in Cushing’s Disease

Cushing’s syndrome affects between 2 to 3 people per million in the United States each year,2 according to the National Institutes of Health. Most cases of the condition result from the use of medications, particularly glucocorticoids to treat other ailments, including autoimmune disorders.

A smaller fraction of cases originate from tumors of the pituitary or adrenal glands, or rarer still, tumors involving other organs such as the lungs or pancreas.2

The latest study focused on Cushing’s disease, the form of Cushing’s syndrome linked to pituitary adenomas. These benign tumors are implicated in 70% of Cushing’s cases in adults, and more than 90% in children when medications are not the cause. 

Although surgery to remove pituitary adenomas, as well as adrenal tumors that cause Cushing’s, generally are successful, they do not always eliminate the disease either immediately or permanently. Untreated Cushing’s disease has a 5-year mortality rate of 50%.

Are the Findings Applicable to US Population?

The researchers in Mexico reviewed the long-term outcomes of 82 people who had undergone surgical removal of tumors for Cushing’s disease between 1991 and 2014.1 Of the patients, 77 were female; the average age was 34 years; and median follow-up was 6.3 years, according to the investigators.

Dr. Mercado said that although treatment options in the United States were not identical to those in Mexico, the results were still relevant to clinicians in this country.

“Although in Mexico the only available pharmacological agents for Cushing's disease are ketoconazole and cabergoline [whereas mifepristone, pasireotide, and mitotane are available for treatment in the U.S. and Europe], ours is a comprehensive review of therapeutic alternatives for persistent and recurrent Cushing’s disease including adrenalectomy, pituitary surgical reintervention and [radiation therapy],” Dr. Mercado told EndocrineWeb. “Thus, our results are applicable to any other tertiary care center where these patients receive care,”

The FDA has not approved ketoconazole for the treatment of Cushing’s syndrome, yet it is the most widely-prescribed drug for the condition.   

To assess remission in their study,  findings were based on urinary free cortisol rather than modern immunoassays that are known to be more sensitive, which might have affected their results, stated the authors.

"This study offered a look into the outcomes of all pituitary Cushing’s patients who received full care at a single referral center between 1991-2014, reporting the results (cure, persistent Cushing’s relapse) based on hospital record review," said Tamara Wexler, MD, PhD, an endocrinologist and former director of the Pituitary Center at NYU Langone Medical Center in New York, New York, "Also worth noting in considering the findings, the 84 patients were young and predominantly female (mean age 34, 92% female."

"Certainly, the use of a single site makes it more difficult to generalize findings but offers good quality control in that there was a single diagnostic protocol used for all patients, and surgeries were performed by one of 2 surgeons, albeit 3 different radiotherapy modalities were used," Dr. Wexler said. 

Also, the medications used for the medical therapy arm were limited by what was available during 1991-2014 in Mexico: ketoconazole, with second-line use of CBG in 5 patients, which proved ineffective, she told EndocrineWeb. 

Notable observations, according to Dr. Wexler,  were that fact that Nelson’s syndrome was seen in approximately half of patients who underwent bilateral adrenalectomy (BA), but without any clinical effects; adrenal crisis requiring hospitalization was seen in a similar percentage of post-BA patients, and an association was noted between longer remission and older age. 

In sum, Dr. Wexler told EndocrineWeb, this paper offers some insights into outcomes at a single referral center, based on retrospective chart reviews, but it is difficult to generalize the findings which may be site-specific since treatment decisions are often based not only on patient characteristics and preference but on the available resources, which may be more limited in Mexico City, where experienced pituitary surgeons or access to radiotherapy may not be available.


  1. Espinosa-de-los-Monteros AL, Sosa-Eroza E, Espinosa E, Mendoza C, Arreola V, Mercado M. Long-term outcome of the different treatment alternatives for recurrent and persistent Cushing’s disease. Endocr Pract. Online ahead of press March 23, 2017. Available at:
  2. Eunice Kennedy Shriver National Institute of Child Health and Human Development.    Cushing Syndrome: Condition Information. Available at: Accessed May 1, 2017.

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