Ketoconazole May Be Better Choice for Cushing’s Syndrome Patients When Surgery Is Not Available

Note: This story was updated Aug. 6, 2020, to note that ketoconazole is approved to treat Cushing’s in Europe and is used off-label for the same indication in the U.S.

In cases where surgery is temporarily unavailable for Cushing’s syndrome patients due to the COVID-19 pandemic, a group of researchers suggest that treatment with ketoconazole should be considered as the next-best choice, because it may carry a lower risk of viral infection over other therapies.

But, the researchers add, patients on other cortisol-lowering medications should not stop their current treatment and switch to ketoconazole if their disease is under control.

Their suggestions were published in a letter to the editor, titled “Consideration on TMPRSS2 and the risk of COVID-19 infection in Cushing’s syndrome,” in the journal Endocrine.

Ketoconazole, sold as Nizoral among other brand names, is an anti-fungal medication that works to lower cortisol levels, as well as the production of male sex hormones. In the U.S. it has been used off-label to treat Cushing’s, while in Europe it has been approved — under the brand name Ketoconazole HRA by HRA Pharma — for this indication.

Cushing’s syndrome results from the excessive production of the hormone cortisol by the adrenal glands, which sit on top of the kidneys. In most cases, this is triggered by the excessive production of the adrenocorticotropic hormone (ACTH) as a consequence of a tumor in the pituitary gland or elsewhere in the body.

High cortisol levels also decrease the proliferation of immune B-cells and hamper the response of other types of immune cells responsible for protecting the body from external threats, increasing patients’ susceptibility to infections.

“Given the high mortality of untreated [Cushing’s syndrome], a rapid surgical approach to the cause of the hormonal excess is the first-tier option. In the current pandemic scenario, access to surgical procedure have been necessarily restrained, as most of our affords have been shifted to handle COVID-19 patients,” the researchers wrote.

As a result, many patients will now have to rely on cortisol-lowering medications that are normally adopted as a second-line of treatment when surgery fails, until the situation stabilizes and they are able to undergo surgery.

Medications that block the production of steroid-based hormones, such as ketoconazole and Metopirone (metyrapone), are viable options in these instances. In addition to being easy to administer and having a rapid effect on the body, these medications also lower the production of androgens (male sex hormones), which are thought to contribute to the higher prevalence and worse prognosis of COVID-19 in men.

According to the authors, this sex-related difference may be caused by the presence of an enzyme called transmembrane protease serine 2 (TMPRSS2), whose activity is controlled by androgens, in the lining of the lungs. When overly active, this enzyme has been shown to promote viral spread and infection.

“Since [Cushing’s syndrome] is a condition frequently associated with androgen excess in female, it is a fair assumption to speculate that these patients might have higher expression of TMPRSS2 and consequently an increased risk of COVID-19 infection,” the researchers wrote.

Based on these observations, the authors argue that Cushing’s patients who must manage their disease with pharmacological therapies during the pandemic should be treated with ketoconazole as a first choice due to its cortisol-lowering and anti-androgen properties, as well as the possibility that it may carry a lower risk of contracting COVID-19 in these patients than other therapies.

“Surgery remains the only curative option and should be performed as soon as clinical activity returns to normal. Further studies are still required to verify this hypothesis and confirm the role of anti-androgen therapy in COVID-19 prevention,” they concluded.