For the majority of individuals with Cushing’s syndrome (CS), surgery directed at the pituitary or adrenal glands is the first and most important treatment; however, many patients do not have a sustained remission after surgery. As a result, treatment options other than surgery are needed for many patients with CS. Until recently, the use of medications to treat CS has been limited. Prior to 2012, there were no medications approved by the United States Food and Drug Administration (FDA) for the treatment of CS. Since 2012, two medications, mifepristone and pasireotide, have been FDA approved for the treatment of CS.

In addition to the FDA approved medications, a number of drugs originally designed for the treatment of other conditions have been used to treat CS. The most common of these medications block the adrenal glands production of cortisol. This group includes ketoconazole, mitotane, and metyrapone.

Ketoconazole, an antibiotic used in the treatment of fungal infections, has been the most commonly used medication in this group. About 50-75% of the individuals with CS who are treated with ketoconazole have their cortisol levels normalized. However, its effectiveness may be limited by side effects including liver damage. The FDA has recently issued a warning regarding the use of ketoconazole as it can cause liver injury, which may result in the need for liver transplantation or death.  The affect on the liver can occur at any dose of ketoconazole, and the liver injury may be irreversible even after stopping the drug. The FDA has recommended weekly blood testing to monitor liver function for the duration of treatment with ketoconazole.

Mitotane, a medication primarily used in patients with adrenal gland cancer, is also be used to lower cortisol levels. Like ketoconazole, mitotane blocks production of cortisol, but in higher doses it may also cause destruction of adrenal cells. Studies show it is effective in >80% of patients, but nearly as many patients have side effects that can be significant. Many patients may have gastrointestinal problems and some develop problems with confusion and impaired mental function while taking mitotane.

Metyrapone is an agent that is available in the United States only on special request from the manufacturer. There are no good published studies on metyrapone’s effectiveness in CS. Additionally, more than 1 in 5 individuals have side effects such as increased facial hair growth in women, swelling, low potassium levels, and dizziness.

In patients with CS caused by pituitary disease, there are two additional medications that can be used. Cabergoline is a medication mainly used for the treatment of prolactin secreting pituitary tumors, but it has been shown to normalize cortisol levels in 20-40% of patients with CS. Unfortunately, the effects of cabergoline tend to wear off over time and cortisol levels rise despite continued treatment.

The other medication in this group is pasireotide. Pasireotide is one of two FDA approved medications for the treatment of CS. It is given twice daily as an injection under the skin. Although it lowers cortisol in the majority of treated patients, pasireotide normalizes cortisol levels in about 25% of patients. The major side effect of pasireotide is increased blood sugars. Forty percent of patients had increased blood sugars and nearly 1 in 5 develop diabetes.

A final medication used for the therapy of CS is mifepristone. Its approval in early 2012 made it the first FDA approved medication for the treatment of CS. Mifepristone works differently than the other medications as it blocks the action of cortisol in the body, rather than decreasing the amount of cortisol that is made. Sixty percent of patients treated with mifepristone have achieved improvement in blood sugars and 80-90% have improvement of physical features of CS. Like all medications for the treatment of CS, mifepristone can have significant side effects. Nausea, headaches, and low potassium levels occurred in nearly half of the patients taking mifepristone. Women taking this drug may also have vaginal bleeding, and mifepristone should never be taken for the treatment of CS in women during pregnancy.

The last few years have been an exciting time in the medical treatment of CS. The availability of FDA approved medications and a renewed interest in developing new medications is likely to produce further treatment options for patients affected by CS in the years to come.

Author: Dr. Ty Carroll, MD (Winter, 2013)
Editor’s Note: Dr. Ty Carroll is Assistant Professor of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin where he is an associate with Dr. James Findling.