Ketoconazole may help keep cortisol levels under control in Cushing’s

Antifungal medicine effective after pituitary surgery for most patients

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A person weighs a choice between two medicines, with one poised above each hand.

An antifungal medication called ketoconazole may be safe and effective for treating Cushing’s disease when pituitary surgery to remove a disease-causing tumor has failed to lower cortisol levels in the body, according to a new meta-analysis study.

Researchers found that in nearly two-thirds of cases reported in the literature, ketoconazole helped cortisol reach normal levels while having no serious side effects.

The patients took ketoconazole — commonly used to treat athlete’s foot and yeast infections, among other fungal infections — for an average of 31 months, or just longer than 2.5 years.

“Ketoconazole can be considered a safe and efficacious option for Cushing’s disease treatment after pituitary surgery,” the researchers wrote.

The study, “Ketoconazole as second-line treatment for Cushing’s disease after transsphenoidal surgery: systematic review and meta-analysis,” was published in the journal Frontiers in Endocrinology.

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Ketoconazole helped cortisol reach normal levels post-surgery in Cushing’s

Cushing’s disease occurs when the body produces too much of a hormone called cortisol. Generally this happens because of a tumor in the brain’s pituitary gland that produces excessive amounts of another hormone called adrenocorticotropic hormone (ACTH). ACTH is known to promote cortisol production.

The first line of treatment for Cushing’s disease is a surgical procedure called transsphenoidal surgery, in which the pituitary tumor is removed through the nose.

While such surgery typically is successful, sometimes cortisol levels remain high after the procedure. In those cases, ketoconazole can be used as a second-line treatment. However, there is not much information about how safe and effective ketoconazole is for use in Cushing’s patients.

Ketoconazole, sold under the brand name Nizoral among others, is an anti-fungal agent that can help control cortisol levels even when surgery is not an option. It works by blocking several enzymes involved in the production of steroid hormones, including cortisol. Ketoconazole is approved to treat Cushing’s disease in Europe and used off-label for the same indication in the U.S.

Now, researchers in Brazil sought to learn more about the use of ketoconazole as a second-line treatment for Cushing’s. To that end, the team searched the literature for studies on how well ketoconazole or fluconazole, a medication from the same class, controlled cortisol levels in the body.

Initial research identified more than 800 articles on the subject. From there, the team identified 10 studies that included a total of 270 people with Cushing’s disease who had been treated with ketoconazole.

Such treatment was given for a mean of 31.4 months and a maximum of 45 months, or just shy of four years, after undergoing pituitary surgery. None of the studies involved fluconazole use.

In nearly two-thirds of the cases (63%), ketoconazole kept cortisol under control according to a 24-hour urinary free cortisol test. That test measures the levels of cortisol in the urine over a 24-hour period. One study instead looked at cortisol levels in the blood.

In some cases, ketoconazole lowered cortisol levels by more than 50%; however, the hormone did not reach normal levels according to the 24-hour urinary free cortisol test.

One of the most common side effects of ketoconazole was elevated levels of liver enzymes — a known side effect of the medication and a sign that the liver may be inflamed or damaged. Other side effects included diarrhea, abdominal pain, skin rash, enlarged breasts in men, and adrenal gland dysfunction.

However, “no serious adverse effects or treatment-related deaths were observed,” the researchers wrote.

The team also found that other factors, such as the final dosage of ketoconazole, how long it was taken, and the initial levels of cortisol in the urine, did not affect how well the medication worked to keep cortisol under control.

“Our meta-analysis showed that ketoconazole effectively controlled hypercortisolism in approximately 63% of [Cushing’s disease] patients when used … [for] patients without remission after [pituitary surgery],” the researchers concluded.