title: Mifepristone reduces insulin resistance in patient volunteers with adrenal incidentalomas that secrete low levels of cortisol: a pilot study.
abstract: BACKGROUND
  Incidental adrenal masses are commonly detected during imaging for other pathologies. 10% of the elderly population has an 'adrenal incidentaloma', up to 20% of these show low-grade autonomous cortisol secretion and 60% of patients with autonomous cortisol secretion have insulin resistance. Cortisol excess is known to cause insulin resistance, an independent cardiovascular risk marker, however in patients with adrenal incidentalomas it is unknown whether their insulin resistance is secondary to the excess cortisol and therefore potentially reversible. In a proof of concept study we examined the short-term effects of glucocorticoid receptor (GR) antagonism in patients with an adrenal incidentaloma to determine whether their insulin resistance was reversible.
  
  
  RESULTS
  In a prospective open-label pilot study, six individuals with adrenal incidentalomas and autonomous cortisol secretion were treated with mifepristone (a GR antagonist) 200 mg twice daily and studied for 4 weeks on a Clinical Research Facility. Insulin resistance at four weeks was assessed by insulin resistance indices, lnHOMA-IR and lnMatsuda, and AUC insulin during a 2-hour glucose tolerance test. Biochemical evidence of GR blockade was shown in all individuals and across the group there was a significant reduction in insulin resistance: lnHOMA-IR (1.0vs0.6; p = 0.03), lnHOMA-%beta (4.8vs4.3; p = 0.03) and lnMatsuda (1.2vs1.6; p = 0.03). Five out of six individuals showed a reduction in insulin AUC >7237 pmol/l.min, and in two patients this showed a clinically significant cardiovascular benefit (as defined by the Helsinki heart study).
  
  
  CONCLUSIONS
  Short-term GR antagonism is sufficient to reduce insulin resistance in some individuals with adrenal incidentalomas and mild cortisol excess. Further assessment is required to assess if the responses may be used to stratify therapy as adrenal incidentalomas may be a common remediable cause of increased cardiovascular risk.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00721201.
authors.affiliation: Academic Unit of Diabetes, Endocrinology and Reproduction, Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Miguel
authors.initials: M
authors.lastname: Debono
authors.forename: Rita
authors.initials: R
authors.lastname: Chadarevian
authors.forename: Richard
authors.initials: R
authors.lastname: Eastell
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ross
authors.forename: John
authors.initials: J
authors.lastname: Newell-Price
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D015735:Mifepristone / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D010865:Pilot Projects; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D012449:Safety
chemical_list: D014408:Biomarkers, Tumor; D015735:Mifepristone; D006854:Hydrocortisone