Retinoic Acid for Cushing’s Disease

Retinoic acid is a compound that results from the metabolism of vitamin A, and is being investigated as a potential treatment for Cushing’s disease.

How does retinoic acid work?

Cushing’s disease symptoms occur due to hypercortisolism, or prolonged abnormally high levels of the hormone cortisol, which is caused by a tumor in the pituitary gland. This tumor stimulates the excessive production of adrenocorticotropic hormone (ACTH). In turn, ACTH triggers the production and release of cortisol from the adrenal glands.

Researchers think that retinoic acid plays a role in both lowering cortisol levels and potentially reducing the size of the tumor. It can inhibit the action of AP-1 and Nur77, two proteins that are important for the production and release of ACTH from the pituitary gland. By blocking these proteins, retinoic acid may be able to reduce the levels of ACTH. This, in turn, could lower cortisol levels.

A preclinical study in dogs with Cushing’s disease compared the effect of retinoic acid to Nizoral (ketoconazole, a medication that reduces ACTH production). The results, which appeared in the journal Endocrinology, showed that retinoic acid led to a significant reduction in cortisol levels, compared to Nizoral. Also, the pituitary tumor was significantly smaller by the end of a 180-day treatment period.

Retinoic acid in clinical trials for Cushing’s

Researchers have assessed retinoic acid in a number of small-scale clinical trials in Cushing’s disease patients.

A small proof-of-concept clinical trial tested the safety of daily doses of retinoic acid, ranging from 10 to 80 mg for six to 12 months in seven Cushing’s disease patients. The trial also measured changes in participants’ ACTH and cortisol levels. Five of the seven patients showed a reduction in cortisol levels, with two patients achieving normal levels of cortisol during the treatment, according to results published in the Journal of Clinical Endocrinology and Metabolism. Patients tolerated the treatment well, with only mild side effects.

A prospective open-label clinical trial in Brazil assessed the safety and efficacy of a synthetic retinoic acid called isotretinoin in 16 Cushing’s disease patients who still had hypercortisolism despite surgery to remove their pituitary tumors. Patients received 60 to 80 mg of isotretinoin daily for six to 12 months. Researchers evaluated the adverse effects of the treatment and changes in cortisol levels. Of the 16 patients who took part in the trial, four achieved normal cortisol levels, with a reduction of up to 52% in the remaining patients. Mild side effects due to isotretinoin treatment were found in seven patients. These results were published in the International Journal of Endocrinology. 

The findings from these proof-of-concept clinical trials suggest that retinoic acid could be an effective and safe treatment for Cushing’s disease. However, larger clinical trials are necessary to fully assess the potential of retinoic acid to treat Cushing’s disease.


Last updated: April 27, 2020


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