Mifepristone May Help Prevent Adrenal Insufficiency After Adrenalectomy, Rat Study Suggests

Mifepristone, a medicine that blocks glucocorticoid hormone effects, may be useful for preventing adrenal insufficiency in people with Cushing’s syndrome, following surgery to remove adrenal glands, a study using rats suggests.

The study, “Glucocorticoid Receptor Antagonist Administration Prevents Adrenal Gland Atrophy in an ACTH-Independent Cushing’s Syndrome Rat Model,” was published in the International Journal of Endocrinology.

Cushing’s syndrome is an umbrella term used to designate several disorders that have in common an excess of the hormone cortisol in the body.

Some forms of Cushing’s syndrome are caused by producing too much ACTH, a hormone made by the pituitary glands that is released into the bloodstream and stimulates adrenal glands to produce cortisol.

Other forms of the syndrome are ACTH-independent, caused by tumors (benign or malign) in the adrenal glands that secrete too much cortisol, for example.

For those cases, first-line treatment is surgery to remove the cortisol-secreting tumors from the adrenal glands; that is called an adrenalectomy. However, this procedure frequently results in adrenal insufficiency — the inability to produce enough adrenal hormones.

Most times, this happens due to wasting (atrophy) of the adrenal tissue remaining after surgery due to chronic inhibition of ACTH release caused by excess cortisol. As a consequence, adrenal glands stop working properly to produce enough of its hormones (e.g., adrenaline, aldosterone, and cortisol).

People may take a long time — or never — to recover from adrenal insufficiency, requiring lifelong steroid replacement therapy.

In this study, researchers tested if mifepristone (brand names Korlym, Mifeprex), a medication that blocks the effects of glucocorticoid hormones such as cortisol, could help preserve adrenal gland tissue and prevent adrenal insufficiency.

Mifepristone is approved by the U.S. Food and Drug Administration (FDA), under the brand Korlym, sold by Corcept, for controlling high blood sugar caused by Cushing’s syndrome, in patients who have type 2 diabetes or glucose intolerance and who have either failed or are not eligible for surgery.

The medicine also has been used to treat excess cortisol in some patients, significantly improving insulin resistance, blood pressure control, psychiatric symptoms, and quality of life.

Mifepristone is also approved, under the brand Mifeprex, in combination with misoprostol, to end an early pregnancy.

In this study, using a rat model of Cushing’s syndrome, the team tested a seven-day oral treatment with mifepristone prior to adrenal surgery.

In a dose-determining experiment, one of the regimens tested was effective for increasing blood ACTH levels, without reducing the blood pressure too much (lowering cortisol can make blood pressure drop).

Consistent with these observations, after surgery there were fewer wasting signs on the tissue structure and weight of remaining adrenal tissue.

The glands also raised expression of the cortisol-producing enzyme (corticosterone synthase CYP11B1), indicating that mifepristone prevented damage and helped maintain the residual adrenal tissue’s proper function.

“Therefore, our study suggests that preoperative GR [glucocorticoid receptor] antagonist administration may improve residual adrenal function and prevent postoperative adrenal insufficiency in ACTH-independent CS [Cushing’s syndrome],” researchers wrote.