title: Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline.
abstract: OBJECTIVE
  This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency.
  
  
  METHODS
  The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review.
  
  
  METHODS
  This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recommendations and the quality of evidence.
  
  
  METHODS
  The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies identified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine Society's Clinical Guidelines Subcommittee and Clinical Affairs Core Committee, members responding to a web posting, and the Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments.
  
  
  CONCLUSIONS
  We recommend diagnostic tests for the exclusion of primary adrenal insufficiency in all patients with indicative clinical symptoms or signs. In particular, we suggest a low diagnostic (and therapeutic) threshold in acutely ill patients, as well as in patients with predisposing factors. This is also recommended for pregnant women with unexplained persistent nausea, fatigue, and hypotension. We recommend a short corticotropin test (250 μg) as the "gold standard" diagnostic tool to establish the diagnosis. If a short corticotropin test is not possible in the first instance, we recommend an initial screening procedure comprising the measurement of morning plasma ACTH and cortisol levels. Diagnosis of the underlying cause should include a validated assay of autoantibodies against 21-hydroxylase. In autoantibody-negative individuals, other causes should be sought. We recommend once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15-25 mg/d) or cortisone acetate replacement (20-35 mg/d) applied in two to three daily doses in adults. In children, hydrocortisone (∼8 mg/m(2)/d) is recommended. Patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticosteroids and associated autoimmune diseases, particularly autoimmune thyroid disease.
authors.affiliation: Medizinische Klinik und Poliklinik III (S.R.B., A.B.), Universitätsklinikum Dresden, 01307 Dresden, Germany; Department of Endocrinology and Diabetes (S.R.B.), King's College London, London WC2R 2LS, United Kingdom; Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Heart Failure Center (B.A.), University of Würzburg, 97080 Würzburg, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Endokrinologikum Ruhr (A.B.), 44866 Bochum, Germany; Department of Pathology and Molecular Medicine (A.D.-W.), McMaster University, Hamilton, ON L8S 4L8, Canada; Hamilton Regional Laboratory Medicine Program (A.D.-W.), Hamilton, ON L8N 4A6, Canada; Department of Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology, and Diabetes, and Cancer Center, University of Michigan, Ann Arbor, Michigan 48109; Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital (E.S.H.), 5021 Bergen, Norway; National Institutes of Health Clinical Center (D.P.M.), Bethesda, Maryland 20814; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.A.S.), National Institutes of Health, Bethesda, Maryland 20892; and Endocrine and Metabolic Unit (D.J.T.), Royal Adelaide Hospital, University of Adelaide, Adelaide SA 5000, Australia.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: Medizinische Klinik und Poliklinik III (S.R.B., A.B.), Universitätsklinikum Dresden, 01307 Dresden, Germany; Department of Endocrinology and Diabetes (S.R.B.), King's College London, London WC2R 2LS, United Kingdom; Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Heart Failure Center (B.A.), University of Würzburg, 97080 Würzburg, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Endokrinologikum Ruhr (A.B.), 44866 Bochum, Germany; Department of Pathology and Molecular Medicine (A.D.-W.), McMaster University, Hamilton, ON L8S 4L8, Canada; Hamilton Regional Laboratory Medicine Program (A.D.-W.), Hamilton, ON L8N 4A6, Canada; Department of Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology, and Diabetes, and Cancer Center, University of Michigan, Ann Arbor, Michigan 48109; Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital (E.S.H.), 5021 Bergen, Norway; National Institutes of Health Clinical Center (D.P.M.), Bethesda, Maryland 20814; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.A.S.), National Institutes of Health, Bethesda, Maryland 20892; and Endocrine and Metabolic Unit (D.J.T.), Royal Adelaide Hospital, University of Adelaide, Adelaide SA 5000, Australia.
authors.forename: Bruno
authors.initials: B
authors.lastname: Allolio
authors.affiliation: Medizinische Klinik und Poliklinik III (S.R.B., A.B.), Universitätsklinikum Dresden, 01307 Dresden, Germany; Department of Endocrinology and Diabetes (S.R.B.), King's College London, London WC2R 2LS, United Kingdom; Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Heart Failure Center (B.A.), University of Würzburg, 97080 Würzburg, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Endokrinologikum Ruhr (A.B.), 44866 Bochum, Germany; Department of Pathology and Molecular Medicine (A.D.-W.), McMaster University, Hamilton, ON L8S 4L8, Canada; Hamilton Regional Laboratory Medicine Program (A.D.-W.), Hamilton, ON L8N 4A6, Canada; Department of Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology, and Diabetes, and Cancer Center, University of Michigan, Ann Arbor, Michigan 48109; Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital (E.S.H.), 5021 Bergen, Norway; National Institutes of Health Clinical Center (D.P.M.), Bethesda, Maryland 20814; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.A.S.), National Institutes of Health, Bethesda, Maryland 20892; and Endocrine and Metabolic Unit (D.J.T.), Royal Adelaide Hospital, University of Adelaide, Adelaide SA 5000, Australia.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
authors.affiliation: Medizinische Klinik und Poliklinik III (S.R.B., A.B.), Universitätsklinikum Dresden, 01307 Dresden, Germany; Department of Endocrinology and Diabetes (S.R.B.), King's College London, London WC2R 2LS, United Kingdom; Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Heart Failure Center (B.A.), University of Würzburg, 97080 Würzburg, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Endokrinologikum Ruhr (A.B.), 44866 Bochum, Germany; Department of Pathology and Molecular Medicine (A.D.-W.), McMaster University, Hamilton, ON L8S 4L8, Canada; Hamilton Regional Laboratory Medicine Program (A.D.-W.), Hamilton, ON L8N 4A6, Canada; Department of Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology, and Diabetes, and Cancer Center, University of Michigan, Ann Arbor, Michigan 48109; Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital (E.S.H.), 5021 Bergen, Norway; National Institutes of Health Clinical Center (D.P.M.), Bethesda, Maryland 20814; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.A.S.), National Institutes of Health, Bethesda, Maryland 20892; and Endocrine and Metabolic Unit (D.J.T.), Royal Adelaide Hospital, University of Adelaide, Adelaide SA 5000, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Barthel
authors.affiliation: Medizinische Klinik und Poliklinik III (S.R.B., A.B.), Universitätsklinikum Dresden, 01307 Dresden, Germany; Department of Endocrinology and Diabetes (S.R.B.), King's College London, London WC2R 2LS, United Kingdom; Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Heart Failure Center (B.A.), University of Würzburg, 97080 Würzburg, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Endokrinologikum Ruhr (A.B.), 44866 Bochum, Germany; Department of Pathology and Molecular Medicine (A.D.-W.), McMaster University, Hamilton, ON L8S 4L8, Canada; Hamilton Regional Laboratory Medicine Program (A.D.-W.), Hamilton, ON L8N 4A6, Canada; Department of Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology, and Diabetes, and Cancer Center, University of Michigan, Ann Arbor, Michigan 48109; Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital (E.S.H.), 5021 Bergen, Norway; National Institutes of Health Clinical Center (D.P.M.), Bethesda, Maryland 20814; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.A.S.), National Institutes of Health, Bethesda, Maryland 20892; and Endocrine and Metabolic Unit (D.J.T.), Royal Adelaide Hospital, University of Adelaide, Adelaide SA 5000, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Don-Wauchope
authors.affiliation: Medizinische Klinik und Poliklinik III (S.R.B., A.B.), Universitätsklinikum Dresden, 01307 Dresden, Germany; Department of Endocrinology and Diabetes (S.R.B.), King's College London, London WC2R 2LS, United Kingdom; Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Heart Failure Center (B.A.), University of Würzburg, 97080 Würzburg, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Endokrinologikum Ruhr (A.B.), 44866 Bochum, Germany; Department of Pathology and Molecular Medicine (A.D.-W.), McMaster University, Hamilton, ON L8S 4L8, Canada; Hamilton Regional Laboratory Medicine Program (A.D.-W.), Hamilton, ON L8N 4A6, Canada; Department of Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology, and Diabetes, and Cancer Center, University of Michigan, Ann Arbor, Michigan 48109; Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital (E.S.H.), 5021 Bergen, Norway; National Institutes of Health Clinical Center (D.P.M.), Bethesda, Maryland 20814; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.A.S.), National Institutes of Health, Bethesda, Maryland 20892; and Endocrine and Metabolic Unit (D.J.T.), Royal Adelaide Hospital, University of Adelaide, Adelaide SA 5000, Australia.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hammer
authors.affiliation: Medizinische Klinik und Poliklinik III (S.R.B., A.B.), Universitätsklinikum Dresden, 01307 Dresden, Germany; Department of Endocrinology and Diabetes (S.R.B.), King's College London, London WC2R 2LS, United Kingdom; Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Heart Failure Center (B.A.), University of Würzburg, 97080 Würzburg, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Endokrinologikum Ruhr (A.B.), 44866 Bochum, Germany; Department of Pathology and Molecular Medicine (A.D.-W.), McMaster University, Hamilton, ON L8S 4L8, Canada; Hamilton Regional Laboratory Medicine Program (A.D.-W.), Hamilton, ON L8N 4A6, Canada; Department of Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology, and Diabetes, and Cancer Center, University of Michigan, Ann Arbor, Michigan 48109; Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital (E.S.H.), 5021 Bergen, Norway; National Institutes of Health Clinical Center (D.P.M.), Bethesda, Maryland 20814; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.A.S.), National Institutes of Health, Bethesda, Maryland 20892; and Endocrine and Metabolic Unit (D.J.T.), Royal Adelaide Hospital, University of Adelaide, Adelaide SA 5000, Australia.
authors.forename: Eystein S
authors.initials: ES
authors.lastname: Husebye
authors.affiliation: Medizinische Klinik und Poliklinik III (S.R.B., A.B.), Universitätsklinikum Dresden, 01307 Dresden, Germany; Department of Endocrinology and Diabetes (S.R.B.), King's College London, London WC2R 2LS, United Kingdom; Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Heart Failure Center (B.A.), University of Würzburg, 97080 Würzburg, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Endokrinologikum Ruhr (A.B.), 44866 Bochum, Germany; Department of Pathology and Molecular Medicine (A.D.-W.), McMaster University, Hamilton, ON L8S 4L8, Canada; Hamilton Regional Laboratory Medicine Program (A.D.-W.), Hamilton, ON L8N 4A6, Canada; Department of Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology, and Diabetes, and Cancer Center, University of Michigan, Ann Arbor, Michigan 48109; Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital (E.S.H.), 5021 Bergen, Norway; National Institutes of Health Clinical Center (D.P.M.), Bethesda, Maryland 20814; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.A.S.), National Institutes of Health, Bethesda, Maryland 20892; and Endocrine and Metabolic Unit (D.J.T.), Royal Adelaide Hospital, University of Adelaide, Adelaide SA 5000, Australia.
authors.forename: Deborah P
authors.initials: DP
authors.lastname: Merke
authors.affiliation: Medizinische Klinik und Poliklinik III (S.R.B., A.B.), Universitätsklinikum Dresden, 01307 Dresden, Germany; Department of Endocrinology and Diabetes (S.R.B.), King's College London, London WC2R 2LS, United Kingdom; Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Heart Failure Center (B.A.), University of Würzburg, 97080 Würzburg, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Endokrinologikum Ruhr (A.B.), 44866 Bochum, Germany; Department of Pathology and Molecular Medicine (A.D.-W.), McMaster University, Hamilton, ON L8S 4L8, Canada; Hamilton Regional Laboratory Medicine Program (A.D.-W.), Hamilton, ON L8N 4A6, Canada; Department of Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology, and Diabetes, and Cancer Center, University of Michigan, Ann Arbor, Michigan 48109; Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital (E.S.H.), 5021 Bergen, Norway; National Institutes of Health Clinical Center (D.P.M.), Bethesda, Maryland 20814; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.A.S.), National Institutes of Health, Bethesda, Maryland 20892; and Endocrine and Metabolic Unit (D.J.T.), Royal Adelaide Hospital, University of Adelaide, Adelaide SA 5000, Australia.
authors.forename: M Hassan
authors.initials: MH
authors.lastname: Murad
authors.affiliation: Medizinische Klinik und Poliklinik III (S.R.B., A.B.), Universitätsklinikum Dresden, 01307 Dresden, Germany; Department of Endocrinology and Diabetes (S.R.B.), King's College London, London WC2R 2LS, United Kingdom; Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Heart Failure Center (B.A.), University of Würzburg, 97080 Würzburg, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Endokrinologikum Ruhr (A.B.), 44866 Bochum, Germany; Department of Pathology and Molecular Medicine (A.D.-W.), McMaster University, Hamilton, ON L8S 4L8, Canada; Hamilton Regional Laboratory Medicine Program (A.D.-W.), Hamilton, ON L8N 4A6, Canada; Department of Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology, and Diabetes, and Cancer Center, University of Michigan, Ann Arbor, Michigan 48109; Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital (E.S.H.), 5021 Bergen, Norway; National Institutes of Health Clinical Center (D.P.M.), Bethesda, Maryland 20814; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.A.S.), National Institutes of Health, Bethesda, Maryland 20892; and Endocrine and Metabolic Unit (D.J.T.), Royal Adelaide Hospital, University of Adelaide, Adelaide SA 5000, Australia.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.affiliation: Medizinische Klinik und Poliklinik III (S.R.B., A.B.), Universitätsklinikum Dresden, 01307 Dresden, Germany; Department of Endocrinology and Diabetes (S.R.B.), King's College London, London WC2R 2LS, United Kingdom; Department of Internal Medicine I (B.A.), Endocrine and Diabetes Unit, University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Heart Failure Center (B.A.), University of Würzburg, 97080 Würzburg, Germany; Centre for Endocrinology, Diabetes, and Metabolism (W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Endokrinologikum Ruhr (A.B.), 44866 Bochum, Germany; Department of Pathology and Molecular Medicine (A.D.-W.), McMaster University, Hamilton, ON L8S 4L8, Canada; Hamilton Regional Laboratory Medicine Program (A.D.-W.), Hamilton, ON L8N 4A6, Canada; Department of Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology, and Diabetes, and Cancer Center, University of Michigan, Ann Arbor, Michigan 48109; Department of Clinical Science, University of Bergen, and Department of Medicine, Haukeland University Hospital (E.S.H.), 5021 Bergen, Norway; National Institutes of Health Clinical Center (D.P.M.), Bethesda, Maryland 20814; Mayo Clinic, Division of Preventive Medicine (M.H.M.), Rochester, Minnesota 55905; Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.A.S.), National Institutes of Health, Bethesda, Maryland 20892; and Endocrine and Metabolic Unit (D.J.T.), Royal Adelaide Hospital, University of Adelaide, Adelaide SA 5000, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Torpy
mesh_terms: D000309:Adrenal Insufficiency / Q000175:diagnosis* / Q000628:therapy*; D019317:Evidence-Based Medicine; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods; D006801:Humans; D011247:Pregnancy; D012955:Societies, Medical