Retinoic acid, a substance formed from the metabolism of vitamin A, is being investigated as a potential treatment for Cushing’s disease by multiple researchers worldwide.

How retinoic acid works

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

Retinoic acid is believed to play multiple roles 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 involved in the production and release of ACTH from the pituitary gland. By blocking these proteins, retinoic acid can reduce the levels of ACTH, which in turn lowers cortisol levels.

Retinoic acid in clinical trials

A preclinical trial carried out in dogs with Cushing’s disease compared the effect of retinoic acid to Nizoral (ketoconazole). The results, published in the scientific journal Endocrinology, demonstrated that retinoic acid achieved a significant reduction in cortisol levels compared to Nizoral. Also, the size of the pituitary tumor was significantly reduced by the end of a 180-day treatment period.

Retinoic acid has been assessed in a number of small-scale clinical trials in Cushing’s disease patients.

A small proof-of-concept clinical trial, published in the Journal of Clinical Endocrinology and Metabolism, was carried out in seven Cushing’s disease patients. It tested the safety of daily doses of retinoic acid ranging from 10 to 80 mg for six to 12 months, as well as measuring changes in ACTH and cortisol levels. Five of the seven patients had a reduction in cortisol levels, with two patients achieving normal levels of cortisol during the treatment. Retinoic acid treatment appeared well tolerated among the patients, with only mild side effects reported.

A prospective open-label clinical trial in Brazil, published in the International Journal of Endocrinology, assessed the safety and efficacy of a synthetic retinoic acid called isotretinoin. The trial assessed the effects of isotretinoin in 16 Cushing’s disease patients who still had hypercortisolism following surgery to remove the pituitary tumor. Patients received 60 to 80 mg of isotretinoin daily for six to 12 months and were evaluated for 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. A reduction of up to 52 percent was seen in the remaining patients. Mild side effects due to isotretinoin treatment were observed in seven patients.

Another clinical trial, currently being carried out in Italy (EudraCT: 2008-006379-65), aims to test another synthetic retinoic acid called tretinoin in 10 Cushing’s disease patients.

The results from these proof-of-concept clinical trials suggest that retinoic acid could be an effective and safe treatment for Cushing’s disease, but larger randomized, placebo-controlled, double-blind clinical trials are required to fully assess the potential of retinoic acid in Cushing’s disease patients.


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