title: Continuous subcutaneous hydrocortisone infusion therapy in Addison's disease: a randomized, placebo-controlled clinical trial.
abstract: BACKGROUND
  Patients with Addison's disease (AD) report impaired subjective health status (SHS). Since cortisol exhibits a robust circadian cycle that entrains other biological clocks, impaired SHS may be due to the noncircadian cortisol profile achieved with conventional glucocorticoid replacement. Continuous subcutaneous hydrocortisone infusion (CSHI) reproduces a circadian cortisol profile, but its effects on SHS have not been objectively evaluated.
  
  
  OBJECTIVE
  The aim of this study was to determine the effect of CSHI on SHS in AD.
  
  
  METHODS
  This was a multicentre, double-blind, placebo-controlled trial of CSHI vs oral glucocorticoid therapy. Participants received in random order 4 weeks of: CSHI and oral placebo, and subcutaneous placebo and oral hydrocortisone, separated by a 2-week washout period. SHS was assessed using the Short-Form 36 (SF-36), General Health Questionnaire (GHQ-28), Fatigue Scale (FS), Gastrointestinal Symptom Rating Scale (GSRS); and Addison's Quality of Life Questionnaire (AddiQoL). Participants were asked their (blinded) treatment preference. Twenty-four hour urine free cortisol (UFC) and diurnal salivary cortisol collections compared cortisol exposure during each treatment.
  
  
  RESULTS
  Ten participants completed the study. Baseline SHS scores (mean ± SE) were consistent with mild impairment: SF-36 physical component summary 48.4 (± 2.4), mental component summary 53.3 (± 3.0); GHQ-28 18.1 (± 3.3); GSRS 3.7 (± 1.6), and AddiQoL 94.7 (± 3.7). FS was similar to other AD cohorts 13.5 (± 1.0) (P = 0.82). UFC between treatments was not different (P = 0.87). The salivary cortisol at 0800 h was higher during CSHI (P = 0.03), but not at any other time points measured. There was no difference between the treatments in the SHS assessments. Five participants preferred CSHI, four oral hydrocortisone, and one was uncertain.
  
  
  CONCLUSIONS
  Biochemical measurements indicate similar cortisol exposure during each treatment period, although a more circadian pattern was evident during CSHI. CSHI does not improve SHS in AD with good baseline SHS. This casts some doubt on the potential benefit of circadian cortisol delivery on SHS in AD.
authors.affiliation: Endocrine and Metabolic Unit (L.G., M.A.N., T.R.J.T., D.J.T.), Royal Adelaide Hospital, Adelaide 5000, Australia; School of Medicine (L.G., M.A.N., D.J.T.), University of Adelaide 5000, Australia; Diabetes Centre (J.v.d.B.), Royal Adelaide Hospital, Adelaide 5000, Australia; Department of Chemical Pathology (W.A.R.), SA Pathology, Adelaide 5000, Australia; Department of Endocrinology and Diabetes (D.E.H.), Sir Charles Gairdner Hospital, Perth 6009, Australia; School of Medicine and Pharmacology (D.E.H.), University of Western Australia, Perth 6009, Australia; Department of Diabetes and Endocrinology (J.S., W.J.I.), Princess Alexandra Hospital, Brisbane 4102, Australia; and School of Medicine (W.J.I.), University of Queensland, Brisbane 4072, Australia.
authors.forename: Lucia
authors.initials: L
authors.lastname: Gagliardi
authors.forename: Marni A
authors.initials: MA
authors.lastname: Nenke
authors.forename: Tilenka R J
authors.initials: TR
authors.lastname: Thynne
authors.forename: Jenny
authors.initials: J
authors.lastname: von der Borch
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Rankin
authors.forename: David E
authors.initials: DE
authors.lastname: Henley
authors.forename: Jane
authors.initials: J
authors.lastname: Sorbello
authors.forename: Warrick J
authors.initials: WJ
authors.lastname: Inder
authors.forename: David J
authors.initials: DJ
authors.lastname: Torpy
mesh_terms: D000224:Addison Disease / Q000188:drug therapy*; D000328:Adult; D002940:Circadian Rhythm; D004311:Double-Blind Method; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use*; D006304:Health Status; D020249:Hormone Replacement Therapy; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage / Q000627:therapeutic use*; D055104:Infusions, Subcutaneous; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D016896:Treatment Outcome
chemical_list: D005938:Glucocorticoids; D006854:Hydrocortisone