title: Acute effect of increasing glucocorticoid replacement dose on cardiovascular risk and insulin sensitivity in patients with adrenocorticotrophin deficiency.
abstract: BACKGROUND
  Higher hydrocortisone doses are associated with increased overall and cardiovascular mortality in ACTH-deficient patients. The mechanisms underlying this association have not been fully defined.
  
  
  OBJECTIVE
  The aim of the study was to determine whether increasing hydrocortisone (or equivalent) to 30 mg/d in ACTH-deficient patients increased cardiovascular risk and whether a reduction in insulin sensitivity and attenuation of insulin's hemodynamic effects was responsible for this effect.
  
  
  METHODS
  We conducted an open interventional study between 2011 and 2013.
  
  
  METHODS
  The study was performed in the Endocrine Research Unit, Repatriation General Hospital, Adelaide, Australia.
  
  
  METHODS
  Seventeen ACTH-deficient subjects taking hydrocortisone (≤20 mg/d) for at least 6 months were studied.
  
  
  METHODS
  Subjects were studied before and after a 7-day increase in hydrocortisone to 30 mg/d.
  
  
  METHODS
  The primary outcome was the change in pulse wave velocity, both fasting and after a 75-g oral glucose load.
  
  
  RESULTS
  Fasting and post-glucose load pulse wave velocities were not significantly different on the higher glucocorticoid dose. Fasting augmentation index (24.9 ± 2.7 vs 22.6 ± 2.6%; P = .04) and reactive hyperemia index (2.3 ± 0.2 vs 2.0 ± 0.2; P = 0.04) were lower on the higher glucocorticoid dose, with no significant difference in the post-glucose load changes in these variables. There were no significant changes in insulin sensitivity or secretion on the higher glucocorticoid dose.
  
  
  CONCLUSIONS
  Endothelial dysfunction may contribute to the increased cardiovascular mortality associated with higher glucocorticoid doses. This may be a direct glucocorticoid effect, not mediated by insulin resistance. ACTH-deficient patients should thus be prescribed the lowest safe glucocorticoid replacement dose.
authors.affiliation: Faculty of Health Sciences (C.J.P., C.H.T., M.G.B.), Flinders University, Adelaide SA 5042, Australia; Southern Adelaide Diabetes and Endocrine Services (C.J.P., B.L.M., M.G.B.), Repatriation General Hospital, Adelaide 5041, Australia; and Discipline of Medicine (C.H.T.), University of Adelaide, Adelaide SA 5005, Australia.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Petersons
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Mangelsdorf
authors.forename: Campbell H
authors.initials: CH
authors.lastname: Thompson
authors.forename: Morton G
authors.initials: MG
authors.lastname: Burt
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000172:deficiency; D000328:Adult; D000368:Aged; D050260:Carbohydrate Metabolism / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000401:mortality; D002319:Cardiovascular System / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000009:adverse effects*; D020249:Hormone Replacement Therapy / Q000009:adverse effects*; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000009:adverse effects*; D007018:Hypopituitarism / Q000188:drug therapy* / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D063177:Pulse Wave Analysis; D012307:Risk Factors
chemical_list: D005938:Glucocorticoids; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone