Mifepristone Improves Octreotide Efficacy in Resistant Ectopic Cushing's Syndrome.

Andreas G Moraitis,Richard J Auchus

doi:10.1155/2016/8453801

Abstract

A 30-year-old Caucasian man presented with severe Cushing's syndrome (CS) resulting from ectopic adrenocorticotropin syndrome (EAS) from a metastatic pancreatic neuroendocrine tumor. The patient remained hypercortisolemic despite treatment with steroidogenesis inhibitors, chemotherapy, and octreotide long-acting release (LAR) and was enrolled in a 24-week, phase 3 clinical trial of mifepristone for inoperable hypercortisolemia. After mifepristone was added to ongoing octreotide LAR treatment, EAS symptoms essentially resolved. Cortisol decreased dramatically, despite mifepristone's competitive glucocorticoid receptor antagonist effects. The clinical and biochemical effects reversed upon mifepristone discontinuation despite the continued use of octreotide LAR therapy. Substantial improvement in octreotide LAR efficacy with mifepristone use was noted in this patient with ectopic CS, consistent with upregulation of somatostatin receptors previously downregulated by hypercortisolemia.

Highlights

Chronic hypercortisolemia resulting from ectopic adrenocorticotropin hormone secretion (EAS) accounts for approximately 10% of all adrenocorticotropin- (ACTH-) dependent Cushing’s syndrome (CS) [1, 2]
After 12 months in the extension phase, substantial increases in ACTH (3738 pg/mL (822.4 pmol/L)), serum cortisol (135.2 mcg/dL (3732 nmol/L)), and urinary-free cortisol (UFC) (10716.5 mcg/24 hours (29577.5 nmol/24 hours)) were observed. This case describes a patient with pancreatic neuroendocrine tumors (NETs) associated with EAS, in whom treatment with the somatostatin analog octreotide became much more effective in controlling cortisol and ACTH after the addition of glucocorticoid receptor (GR) antagonist therapy with mifepristone
Using murine corticotrope tumor cells, van der Hoek et al demonstrated a dexamethasone-dependent inhibitory effect of octreotide treatment targeting SST2 that was not found with analogs that targeted primarily SST5 [15]

Summary

Introduction

Chronic hypercortisolemia resulting from ectopic adrenocorticotropin hormone secretion (EAS) (nonpituitary) accounts for approximately 10% of all adrenocorticotropin- (ACTH-) dependent Cushing’s syndrome (CS) [1, 2]. At the time of enrollment, the patient had overtly cushingoid features, including moon facies, plethora, and enlarged dorsocervical and supraclavicular fat pads; purple striae; bruising; edema; and proximal muscle weakness that was so severe that he was unable to rise from a chair without use of his hands He had ongoing diabetes, depression, and hypertension associated with hypokalemia. In addition to clinical improvement, a dramatic decrease in cortisol and ACTH was noted during therapy with mifepristone and octreotide LAR (Figure 1, Table 1). After 2 weeks, his UFC and ACTH increased to 4716 mcg/24 hours (13016 nmol/24 hours) and 652 pg/mL (143.4 pmol/L), respectively (Figure 1, Table 1). After 12 months in the extension phase, substantial increases in ACTH (3738 pg/mL (822.4 pmol/L)), serum cortisol (135.2 mcg/dL (3732 nmol/L)), and UFC (10716.5 mcg/24 hours (29577.5 nmol/24 hours)) were observed

Discussion

Disclosure

Findings

Conflict of Interests