Use of Mifepristone for Prevention of Adrenal Insufficiency Following Resection of Cortisol-Secreting Adrenal Adenoma Harleen Kaur Dehal, M.B.B.S., Shruti Bhandari, M.D., Esther Irina Krug, M.D. Sinai Hospital of Baltimore, Baltimore, Maryland

INTRODUCTION About 9%  of unilateral adrenal adenomas are functional, resulting in Cushing’s syndrome (CS) due to cortisol (C) excess. Depending on the amount of glucocorticoids (GC) secreted by the tumor, the clinical spectrum ranges from altered diurnal cortisol rhythm to atrophy of contralateral adrenal with lasting adrenal insufficiency (AI) after unilateral adrenalectomy. Patients with suppressed plasma ACTH generally have AI after surgery and  need GC replacement until recovery of the hypothalamic–pituitary–adrenal (HPA) axis ( 6–18 months after surgery). Mifepristone (Mif), a GC and progesterone-receptor antagonist, was recently approved in the US for control of hyperglycemia due to hypercortisolism in patients with CS.   Mifepristone binds to human GC receptors with an affinity 3 to 4 times higher than that of dexamethasone and about 18 times higher than that of cortisol. Mif affects central actions of cortisol (negative feedback on CRH/ACTH secretion) as well as its peripheral actions. Due to its rapid onset of action and a long half-life, Mif has the potential to allow preoperative restoration of HPA axis and reversal of cortical atrophy (in the contralateral gland) in functional unilateral adrenal adenomas.  

Case Presentation A 56 year old postmenopausal woman, with history of hirsutism, adult acne, obesity, oligomenorrhea, and male pattern balding, presented with worsening hyperandrogenism (HA), plethora and labile hypertension. The patient was eventually diagnosed with Cushing’s, secondary to a functional right adrenal adenoma.

MRI of the abdomen revealed 2.5 x 3.1 x 2.6 cm right adrenal mass.

Pre Adrenalectomy In preparation for right adrenalectomy, the patient was started on Mifepristone, 300 mg PO every other day in an effort to re-establish the normal HPA axis and prevent post-operative adrenal insufficiency. We monitored ACTH level every 10-14 days to assure that ACTH level remained in target range (low normal). Mif was stopped 48 hours preoperatively to prevent persistent inhibition of GC receptors in early post-operative period.

This chart shows the ACTH variation pre treatment (Pre Rx), on mifepristone (On Rx) and post surgery (Post Sx). This also emphasizes our hypothesis that ACTH can safely be used to guide therapy with Mifepristone in ACTH independent Cushings, without precipitating adrenal crisis.

POst surgery The patient continued to do well post surgery, with no evidence of adrenal crisis. No GC supplementation required. ACTH level post op: 20.3 pg/mL and Cortisol: 19 ug/dL

WHat makes this case different? This case suggests efficacy and safety of Mif in restoration of HPA axis in patients with CS due to unilateral adrenal adenoma in preparation for adrenalectomy. Serial ACTH measurements appear to reliably guide Mif dosing and help prevent AI due to excessive GC receptor blockade.

Dicsussion Due to it’s mechanism of action, Mif has the potential to alter the treatment algorithm of patients with CS caused by unilateral adrenal adenoma. In these cases, the glucocorticoid antagonist action of the drug appears to result in reversal of HPA axis suppression as manifested by gradual normalization of ACTH. Normalized ACTH levels stimulate restoration of steroidogenesis in contralateral adrenal gland. Treatment with Mif of 10-12 weeks duration preoperatively with target ACTH in low- to mid- normal range appears to be sufficient to restore function in contralateral adrenal gland and prevent post-operative adrenal insufficiency. We monitored ACTH level every 10-14 days to assure that ACTH level remained in target range. We stopped Mif 48 hours preoperatively (Half life of Mif: 36-48 hours) to prevent persistent inhibition of GC receptors in early post- operative period. As a result, our patient required no GC replacement postoperatively, nor did she show any evidence of AI. Although, more studies are needed to study the efficacy and the long term results of Mif treatment preoperatively in patients with CS due to unilateral adrenal adenoma, it appears that Mif administration has the potential to reduce the preoperative morbidity and to prevent postoperative adrenal insufficiency and ablating the need for long term exogenous GC therapy.

Thank you.