Impact of mifepristone, a glucocorticoid/progesterone antagonist, on HDL cholesterol, HDL particle concentration, and HDL function.

Abstract

Mifepristone is a glucocorticoid and progestin antagonist under investigation for the treatment of Cushing's syndrome. Mifepristone decreases high-density lipoprotein (HDL) cholesterol (HDL-C) levels in treated patients, but the clinical significance of this is unclear because recent studies suggest that functional properties of HDL predict cardiovascular disease status better than does HDL-C concentration. The aim of the study was to characterize the impact of mifepristone administration on HDL particle concentration and function. We conducted a double-blind, randomized, placebo-controlled trial at a single-site, clinical research center. Thirty healthy postmenopausal female volunteers participated in the study. Individuals were randomized to receive daily oral mifepristone (600 mg) or placebo for 6 wk. We measured HDL-C, serum HDL particle concentration, and HDL-mediated cholesterol efflux by treatment group. As expected, ACTH, cortisol, estradiol, and testosterone levels increased in the mifepristone group. Mifepristone treatment decreased HDL-C and HDL particle concentration by 26 and 25%, respectively, but did not alter pre-β HDL concentration. In contrast, the serum HDL-mediated cholesterol efflux decreased with mifepristone treatment by only 12%, resulting in an effective increase of the efflux capacity per HDL particle. No changes were observed in cholesterol ester transfer protein or lecithin:cholesterol acyltransferase activity. Treatment with mifepristone reduced HDL-C, HDL particle concentration, and serum HDL cholesterol efflux in postmenopausal women. However, on a per particle basis, the efflux capacity of serum HDL increased. These observations support the concept that a decrease in HDL-C may not represent proportional impairment of HDL function.