Mifepristone: A Step Forward in the Medical Treatment of Cushing’s Syndrome

Emerging treatment provides significant improvement

By Laurence Kennedy, MD, FRCP (Lond and Edin)

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Endogenous Cushing’s syndrome is a horrible condition. A lot of people do not realize that left untreated, the prognosis for this condition is worse than most cancers.

Because successful surgical treatment inevitably causes temporary adrenal insufficiency, it was all but impossible to treat Cushing’s syndrome in the days before synthetic steroids were available. Now, in the hands of an experienced pituitary surgeon, Cushing’s disease can be cured in more than 80 percent of patients with a pituitary microadenoma, though significantly fewer when there is a macroadenoma.

Bilateral adrenalectomy remains the “ultimate weapon” for continuing hypercortisolemia in Cushing’s disease. Adrenal surgery will cure most cases of primary adrenal Cushing’s, with the exception of adrenocortical cancer.

Nevertheless, there remains a significant minority of patients for whom a successful medical treatment would be welcome, if not essential.

Most medications guided by clinical use

Because Cushing’s syndrome is relatively uncommon, no drug has been tested in a randomized, placebo-controlled trial. One orphan drug, pasireotide, was tested at different doses in a randomized study without placebo controls.

All other drugs currently prescribed, with varying degrees of success in reducing hypercortisolemia, have been accepted through the simple expediency of prudent clinical use. For all of these drugs, the success — or lack of it — can be assessed by measuring, in one form or another (serum, urine, saliva), the cortisol level.

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Mifepristone: An emerging potential treatment option

Mifepristone, originally used as a progesterone receptor antagonist, is at higher doses a glucocorticoid rather than mineralocorticoid receptor antagonist; its affinity for the receptors exceeds that of cortisol by 18-fold.

As such, improvement in the clinical features of Cushing’s syndrome brought about by mifepristone treatment are accompanied by a rise in serum, urine and salivary cortisol and ACTH levels in patients with Cushing disease — with either no change or a rise in cortisol in patients with primary adrenal Cushing’s syndrome. Therefore, cortisol levels cannot be used to assess the drug’s efficacy in Cushing’s syndrome.

However, using hyperglycemia as a surrogate for the effect of hypercortisolemia, it has been demonstrated that mifepristone leads to a significant biochemical improvement in patients with either diabetes or some degree of hyperglycemia. Perhaps of even more significance is that 87 percent of patients experienced improvements in the signs and symptoms of Cushing’s syndrome and in their well-being.

Author experience: Promising patient feedback

These impressive statistics on their own may not make mifepristone appear any better than competing medications. However, in my clinical experience — and I have used most of the competitor drugs in 40 years of treating Cushing’s syndrome — mifepristone is the first drug that has patients coming back saying they notice a real improvement in how they feel, as opposed to tests just showing a significant biochemical improvement.

That is important.

Where vigilance is needed

Lack of a direct measure of adrenocortical function understandably causes concern about diagnosing adrenal insufficiency in the event of overtreatment. Also, the risk of hypokalemia from stimulation of mineralocorticoid receptors by the heightened cortisol levels—and other potential adverse effects,  including endometrial thickening in females — are potentially worrisome to physicians who do not see too many patients with Cushing’s syndrome. In fact, severe or acute adrenal insufficiency is actually quite uncommon.

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Hypokalemia, on the other hand, is common and predictable based on the mode of action, so it should be anticipated, with appropriate monitoring and treatment with potassium supplements and/or spironolactone.

A drug to watch

In time, it’s quite possible that mifepristone will come to be accepted as an option in Cushing’s syndrome patients without obvious hyperglycemia, simply relying on clinical response. This is not so different from drug use in many clinical areas.

This is a drug to watch!

Dr. Kennedy (kennedl4@ccf.org; 216.445.8645) is Chairman of Cleveland Clinic’s Department of Endocrinology, Diabetes and Metabolism.