Combining Cortisol Blockers May Lead to Better Control in Cushing’s

Yedida Y Bogachkov PhD avatar

by Yedida Y Bogachkov PhD |

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A combination of medications that inhibit steroidogenesis — the process by which the body produces steroid hormones, like cortisol, from cholesterol — can be used to treat people with Cushing’s syndrome, allowing for adequate control of their cortisol levels until surgery, a case report highlighted.

Such combinations may be especially helpful to patients whose cortisol levels are not well controlled using a single medication alone.

The study, “Synergistic cortisol suppression by ketoconazole–osilodrostat combination therapy,” was published in the journal Endocrinology, Diabetes and Metabolism: Case Reports.

Cushing’s syndrome is characterized by high levels of the stress hormone cortisol, which can raise a person’s risk of dying due to due to heart-related complications and infections.

Patients can be treated with steroidogenesis inhibitors to help normalize cortisol production, easing their comorbidities or co-existing conditions. Most often, studies report a single blocker being used, leading to a roughly 50% reduction in cortisol production.

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“Steroidogenesis inhibitors can be combined to better control hypercortisolism [high cortisol levels],” the researchers wrote.

A team of researchers in France described a Cushing’s patient who was successfully treated with a combination of ketoconazole and Isturisa (osilodrostat).

Ketoconazole, sold as Nizoral among other brand names, inhibits several enzymes involved in steroid production within the adrenal glands, which are located above the kidneys that produce and release cortisol. Isturisa blocks an enzyme called 11-beta-hydroxylase that is also involved in cortisol production.

The patient, a 53-year-old man, was diagnosed with adrenocorticotrophic hormone (ACTH)-independent Cushing’s syndrome — meaning that excessive cortisol production was not being driven by an excess of ACTH, the hormone that normally stimulates cortisol production in the adrenal glands.

At diagnosis, the patient was found to have high blood pressure, low blood potassium levels, type 2 diabetes (diabetes mellitus), easy bruising, purple stretch marks on his abdomen, and “major” fluid retention in his lower limbs, all potential complications of Cushing’s.

Measures of his blood cortisol levels varied between 541–716 nanomoles per liter (nmol/L) over the course of a day. His ACTH levels were suppressed (mean of 1 picogram per milliliter or pg/mL).

His morning blood cortisol level was 1,000 nmol/L after taking a tablet of dexamethasone the previous night. Dexamethasone is often used to test whether patients have Cushing’s syndrome. In those without Cushing’s, cortisol levels will be lower as dexamethasone suppresses ACTH production, preventing cortisol production.

A CT scan of the patient’s adrenal glands found a 70 millimeter mass on his left adrenal gland and a 45 millimeter mass on the right gland. Given the ongoing COVID-19 pandemic, clinicians preferred trying steroidogenesis inhibitors as an alternative to immediate surgery.

Ketoconazole was started, with dose increases of up to 1,000 mg/day. The man’s cortisol control remained poor and there was a three-fold increase in liver enzymes.

Clinicians then chose to replace ketoconazole with Isturisa. But Isturisa at a dose of 30 mg/day was also ineffective at normalizing his cortisol levels and caused a slight increase in blood pressure.

A combination of the two medications was then attempted: Isturisa at a dose of 30 mg/day and ketoconazole at 600 mg/day, the “last maximal tolerated dose as monotherapy of each drug,” the team wrote. This combo was found to control his cortisol levels and restore their natural daily fluctuations without side effects.

A rapid improvement was seen in the patient’s high blood pressure, potassium levels, and diabetes control. Fluid retention was no longer evident in his legs.

“The occurrence of side effects should not lead to immediately switch[ing] to another drug, but rather to decrease the dose and add another cortisol-lowering drug,” the researchers recommended.

After additional scans, clinicians decided on surgery to remove the larger mass on patient’s left adrenal gland. Following surgery, his serum cortisol level dropped to 50 nmol/L. The patient was then given hydrocortisone at a dose of 30 mg/day, with a stepwise decrease to 10 mg/day over the course of three months.

Genetic testing of the removed mass revealed the presence of a deletion in the ARMC5 gene, which has been implicated in certain adrenal tumors.

“We report for the first time a case of [Cushing’s syndrome], in the context of [adrenal masses] successfully treated with a well-tolerated combination of ketoconazole and osilodrostat,” the researchers wrote.

“This strategy could be considered for any patient with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic,” they concluded.