Limited Efficacy of Mifepristone Due to Poor Tolerance: A Clinical Challenge in Managing Cortisol Excess

Abstract

A 53-year male with incidental bilateral adrenal masses along with symptoms of proximal muscle weakness, anxiety, and depression. Past medical history of uric acid nephrolithiasis, hypertension, hyperlipidemia, type 2 diabetes mellitus, anxiety, and depression. A right adrenal mass of 2.8cm and a left adrenal mass of 1.5cm both of <10 HU on non-enhancing CT. Hormonal activity workup was ordered which showed cortisol levels of 4.7mcg/dL on 1mg ONDST suggestive of autonomous cortisol excess and workup for primary hyperaldosteronism was negative. On follow up CT adrenal masses remained stable, but the patient underwent the annual hormonal workup for incidentaloma with 1mg ONDST and found with cortisol 4.5mcg/dL, eventually repeated with 2-day LDDST which showed no suppression of cortisol with levels at 4.5 mcg/dL confirming the diagnosis of autonomous cortisol excess. ACTH found to be suppressed at 3.1pg/dL (7.2–63.3 pg/dL) which helped confirm the diagnosis of non-ACTH dependent autonomous cortisol excess. Referred to surgery evaluation due to complications associated with cortisol excess as osteoporosis and uncontrolled hyperglycemia however surgical intervention was deferred until the source of cortisol excess could be identified within the bilateral adrenal masses and it was recommended to continue with medical therapy.As the cortisol excess source cannot be identified by localizing procedures and despite adequate medical therapy and stable adrenal masses on imaging, patient persisted with uncontrolled DM/hypertension and worsening BMD in the spine and hip with surgery not being an option. The patient was started on glucocorticoid receptor antagonist mifepristone in which upon reevaluation weakness and fatigue were noticeable along with hypokalemia of 3.1mmol/L after 2 weeks of therapy that was eventually replaced but 2 weeks later the patient discontinued therapy as he could not tolerate side effects related to adrenal insufficiency associated with mifepristone, such as weakness, fatigue, and dependence of potassium supplementation due to hypokalemia.This effect is physiologically important, because cortisol binds as avidly as aldosterone to the mineralocorticoid receptor, and the plasma cortisol concentration is approximately 100-fold higher than the plasma aldosterone concentration and it can lead to hypokalemia by the mechanism of apparent mineralocorticoid excess. Also, as mifepristone blocks cortisol action, the levels of ACTH and cortisol increase so high that hormonal measurement cannot be used to judge either therapeutic efficacy or adrenal insufficiency, we must go based on signs and symptoms.