CONTEMPORARY ENDOCRINOLOGY

Series Editor:P. Michael Conn, PhDOregon Health & Science UniversityBeaverton, OR

For other titles published in this series, go towww.springer.com/series/7680

MARCELLO D. BRONsTEINEditor

Cushing’s SyndromePathophysiology, Diagnosis and Treatment

First Edition

EditorMarcello D. BronsteinDivision of Endocrinology and MetabolismHospital das ClínicasUniversity of Sao Paulo Medical SchoolSao PauloBrazilmdbronstein@uol.com.br

ISBN 978-1-60327-448-7 e-ISBN 978-1-60327-449-4DOI 10.1007/978-1-60327-449-4Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2010937016

© Springer Science+Business Media, LLC 2011All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.

Printed on acid-free paper

Humana Press is part of Springer Science+Business Media (www.springer.com)

v

Preface

I usually say to my residents that when I was a resident myself, I was much more confident at diagnosing and treating Cushing’s syndrome than I am today! This statement aims at pointing out that the deeper you go in dealing with clinical, laboratorial, and image aspects of the differential diagnosis of the many etiologies of the syndrome, as well as the various treatment modalities, the more you will encounter cases that are exceptions to the rules, leading to diagnosis and treatment pitfalls. However, notwithstanding that, only insights provided by experts will help physicians dealing with Cushing’s syndrome to provide better care to their patients, avoiding the above-mentioned pitfalls.

This medical text, which Humana Press kindly invited me to edit, was initially intended to be a handbook on Cushing’s syndrome, giving insights on the various aspects of its diagnosis and treat-ment to trainee endocrinologists, internists, pediatricians, neurosurgeons, and urologists. Pursuing that task, I invited basic and clinical researchers with great experience in their respective areas, and I was gratified by their agreement to cooperate with the book. However, their chapters were so com-prehensive and profound that I ended up with a true textbook on Cushing’s syndrome, from the bench to bedside, encompassing molecular, physiological, clinical, and therapeutic aspects of all the many causes of hypercortisolism. As many chapters overlapped on some issues, duplication was inevitable. Nevertheless, I tried to keep the originality of each manuscript as much as possible, also aiming to stress important data for the reader by repeating the arguments under different perspectives.

I am indebted to Humana Press for the opportunity to edit a book with so distinguished a team of collaborators, and extremely grateful to all the colleagues who gave their outstanding knowledge and their time to enrich this work.

Sao Paulo, SP Marcello D. Bronstein

vii

Contents

Preface ........................................................................................................................................................... v

Contributors .................................................................................................................................................. ix

1 Physiology and Pathophysiology of the HPA Axis ............................................................................... 1Margaret Castro, Lucila Leico Elias, Paula Conde Lamparelli Elias,

and Ayrton Custodio Moreira

2 Etiologies of Cushing’s Syndrome........................................................................................................ 21John Newell-Price

3 Pathogenesis of Corticotropic Tumors .................................................................................................. 31Anat Ben-Shlomo, Ning-Ai Liu, and Shlomo Melmed

4 Pathogenesis of Adrenocortical Tumors ............................................................................................... 41Madson Q. Almeida, Emilia M. Pinto, and Ana Claudia Latronico

5 Clinical Features of Cushing’s Syndrome ............................................................................................. 53Oscar D. Bruno

6 Laboratorial Diagnosis of Cushing’s Syndrome: Differential Diagnosis with Pseudo Cushing’s Conditions as Obesity, Alcoholism and Depression ................................ 65

Martina De Martin, Francesca Pecori Giraldi, and Francesco Cavagnini

7 Laboratorial Diagnosis of Cushing’s Syndrome: Differential Diagnosis Among the Different Causes of ACTH-Dependent and ACTH-Independent Cushing’s Syndrome ............... 79

Antonio M. Lerário and Marcello D. Bronstein

8 Imaging for the Differential Diagnosis of Cushing’s Syndrome: MRI, CT, and Isotopic Scanning ................................................................................................................... 91

Wouter W. de Herder and Richard A. Feelders

9 Inferior Petrosal Sampling for the Differential Diagnosis of ACTH-Dependent Cushing’s Syndrome ................................................................................... 105

Bradley R. Javorsky, MD and James W. Findling, MD

10 The Surgical Management of Cushing’s Disease ................................................................................. 121Ian F. Dunn and Edward R. Laws, Jr

11 Adrenal-Directed Treatment Options for Cushing’s Disease ............................................................... 131William F. Young Jr. and Geoffrey B. Thompson

12 Radiation Therapy and Stereotactic Radiosurgery for Cushing’s Disease ........................................... 139Jay Jagannathan, Edward R. Laws, and Jason P. Sheehan

13 Medical Management of Cushing’s Syndrome ..................................................................................... 151Cuong Dang and Peter J. Trainer

viii Contents

14 ACTH-Dependent Cushing Syndrome: Clinical and Diagnostic Aspects, and Treatment Approaches for Ectopic Cushing’s Syndrome ...................................................... 163

Krystallenia I. Alexandraki, Andrea M. Isidori, and Ashley B. Grossman

15 Revisiting the Nelson’s Syndrome: Corticotroph Tumor Progression After Bilateral Adrenalectomy in Cushing’s Disease ............................................................................. 177

Guillaume Assie, Laurence Guignat, Jérôme Bertherat, and Xavier Bertagna

16 ACTH-Independent Cushing’s Syndrome: Adrenocortical Tumors ..................................................... 189Maria Candida Barisson Villares Fragoso, Sorahia Domenice,

Ana Claudia Latronico, and Berenice Bilharinho Mendonca

17 ACTH-Independent Cushing’s Syndrome: Bilateral Macronodular Hyperplasia ................................ 209Isabelle Bourdeau, Antoine Lampron, Tânia Longo Mazzuco, and André Lacroix

18 ACTH-Independent Cushing’s Syndrome: Primary Pigmented Nodular Adrenal Disease in the Context of Carney’s Complex ................................................................................ 225

Constantine Stratakis

19 Glucocorticoid Resistance .................................................................................................................... 235Elisabeth F. C. van Rossum and Steven W. J. Lamberts

20 Post-operative Replacement and Assessment of HPA Axis Recovery in Cushing’s Syndrome ................................................................................................. 249

Sibylle Kohler, Niki Karavitaki, and John A. H. Wass

21 Special Aspects of Cushing’s Syndrome: Pregnancy ........................................................................... 259Dima Abdelmannan and David C. Aron

22 Special Aspects of Cushing’s Syndrome: Childhood ........................................................................... 273Martin O. Savage, Farhad Afshar, Nicholas P. Plowman,

Renuka P. Dias, Ashley B. Grossman, and Helen L. Storr

23 Special Aspects of Cushing’s Syndrome: Cyclic Cushing’s Syndrome ............................................... 283Nora Albiger and Franco Mantero

Index ....................................................................................................................................................... 295

ix

Contributors

Dima Abdelmannan, md ●  Division of Clinical and Molecular Endocrinology, Department of Medicine, Case Western Reserve, University School of Medicine and VA Health Services Research & Development, Center for Quality Improvement Research, Louis Stokes Cleveland VAMC, Cleveland, OH, USA

Farhad Afshar, md ●  Department of Endocrinology, Barts and the London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London, UK

Nora Albiger, PhD ● Division of Endocrinology, School of Medicine, University of Padua, via Ospedale 105, 35128 Padua, Italy

Krystallenia I. Alexandraki, md/PhD/msc/msc ●  Department of Endocrinology, St. Bartholomew’s Hospital, London, UK

Madson Q. Almeida, md ●  Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular LIM-42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

David C. Aron, md/ms ●  Division of Clinical and Molecular Endocrinology, Department of Medicine, Case Western Reserve University, School of Medicine and VA Health Services Research & Deve lopment, Center for Quality Improvement Research, Louis Stokes Cleveland VAMC, Cleveland, OH, USA

Guillaume Assie ●  Service des Maladies Endocriniennes et Métaboliques, Centre de Référence des Maladies Rares de la Surrénale, INSERM U-567, Institut Cochin, Hôpital Cochin, Faculté de Médecine Paris Descartes, Université Paris 5, Paris, France

Anat Ben-Shlomo, md ●  Cedars-Sinai Medical Center, Pituitary center Los Angeles, CA, USAXavier Bertagna, md ●  Service des Maladies Endocriniennes et Métaboliques, Centre de

Référence des Maladies Rares de la Surrénale, INSERM U-567, Institut Cochin, Hôpital Cochin, Faculté de Médecine Paris Descartes, Université Paris 5, Paris, France

Jérôme Bertherat ●  Service des Maladies Endocriniennes et Métaboliques, Centre de Référence des Maladies Rares de la Surrénale, INSERM U-567, Institut Cochin, Hôpital Cochin, Faculté de Médecine Paris Descartes, Université Paris 5, 27, rue Fg St Jacques 75014, Paris, France

Isabelle Bourdeau, md ●  Division of Endocrinology, Department of Medicine, Centre hospitalier de l’Université de Montréal (CHUM), Montréal, Canada

Marcello D. Bronstein, md ●  Division of Endocrinology and Metabolism, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brasil

Oscar D. Bruno, md ●  Consultant Professor of Medicine, Hospital de Clínicas, University of Buenos Aires, Buenos Aires, Argentina

Margaret Castro, md ●  Professor of Endocrinology, Department of Internal Medicine, University of Sao Paulo at Ribeirao Preto, São Paulo, Brasil

Francesco Cavagnini, md ●  Chair of Endocrinology, Ospedale San Luca, Istituto Auxologico Italiano IRCCS, Università di Milano, Via Spagnoletto 3, Milano 20149, Milan, Italy

Martina De Martin, md ●  Chair of Endocrinology, Ospedale San Luca, Istituto Auxologico Italiano IRCCS, Università di Milano, Milan, Italy

Renuka P. Dias, md ●  Department of Endocrinology, Barts and the London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London, UK

x Contributors

Sorahia Domenice, md ●  Laboratório de Hormônios e Genética, Faculdade de Medicina da Universidade de São Paulo, Unidade de Endocrinologia do Desenvolvimento da, Hospital das Clínicas, Molecular LIM/42, São Paulo, Brasil

Ian F. Dunn, md ●  Clinical Instructor in Surgery, Neurosurgery Department, Brigham & Women’s Hospital, Boston, MA 02115, USA

Lucila Leico Kagohara Elias, md/PhD ●  Associated Professor of Physiology, Department of Physiology, University of São Paulo at Ribeirao Preto, São Paulo, Brasil

Paula Conde Lamparelli Elias, md ●  Assistant Physician of Endocrinology, Department of Internal Medicine, University of Sao Paulo at Ribeirao Preto, São Paulo, Brasil

Richard A. Feelders, md ●  Department of Internal Medicine, Sector of Endocrinology, Erasmus MC, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands

James W. Findling, md ●  Professor of Clinical Medicine, Director of Community Endocrine Services, Department of Medicine, Endocrinology Center, Medical College of Wisconsin, Menomonee Falls, WI, USA

Maria Candida Barisson Villares Fragoso, md ●  Laboratório de Hormônios e Genética Molecular LIM/42, Unidade de Endocrinologia do Desenvolvimento da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

Francesca Pecori Giraldi, md ●  Chair of Endocrinology, Ospedale San Luca, Istituto Auxologico Italiano, Università di Milano, Milan, Italy

Ashley B. Grossman, md/ba/bsc/frcp/fmedsci ●  Department of Endocrinology, Barts and the London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London, UK

Laurence Guignat ●  Service des Maladies Endocriniennes et Métaboliques, Faculté de Médecine Centre de Référence des Maladies Rares de la Surrénale, INSERM U-567, Institut Cochin, Hôpital Cochin, Paris Descartes, Université Paris 5, Paris, France

Wouter W. de Herder, md/PhD ●  Department of Internal Medicine, Sector of Endocrinology, Erasmus MC, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands

Andrea M. Isidori, md ●  Department of Endocrinology, St. Bartholomew’s Hospital, London, UKJay Jagannathan, md ●  Department of Neurological Surgery, University of Virginia Health

Sciences Center, Charlottesville, VA, USABradley R. Javorsky, md ●  Assistant Professor of Medicine, Department of Medicine, Endocrinology

Center, Medical College of Wisconsin, Building A, Suite 203, Menomonee Falls, WI 53051, USANiki Karavitaki, md ●  Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology

and Metabolism, Churchill Hospital, Oxford, 0X37LJ, UKSibylle Kohler, md ●  Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology

and Metabolism, Churchill Hospital, Oxford, 0X37LJ, UKAndré Lacroix, md ●  Professor of Medicine, Division of Endocrinology, Department of Medicine,

Centre hospitalier de l’Université de Montréal (CHUM), Montréal, CanadaSteven W.J. Lamberts md/PhD ●  Erasmus MC University Medical Center, Department of

Internal Medicine, ’s-Gravendijkwal 230, 3015 CE Rotterdam, The NetherlandsAntoine Lampron, md ●  Division of Endocrinology, Department of Medicine, Centre hospitalier

de l’Université de Montréal (CHUM), Montréal, CanadaAna Claudia Latronico ●  Associate Professor of Medicine, Unidade de Endocrinologia do

Desenvolvimento e Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas, da Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Enéas de carvelho Aguiar, 155, 2 andar Bloco 6, São Paulo, Brasil

xiContributors

Edward R. Laws, Jr, md ●  Department of Neurological Surgery, Brigham & Women’s Hospital, Boston, MA, USA

Antonio M. Lerário, md ●  Division of Endocrinology and Metabolism, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brasil

Ning-Ai Liu, md ●  Cedars-Sinai Medical Center, 8700 Beverly Blvd., Room 2015 Pituitary center, Los Angeles, CA, USA

Franco Mantero, md ●  Division of Endocrinology, School of Medicine, University of Padua, via Ospedale 105, 35128 Padua, Italy

Tânia Longo Mazzuco, md ●  Division of Endocrinology, Department of Medicine, Centre hospitalier de l’Université de Montréal (CHUM), Montréal, Canada

Shlomo Melmed, md ●  Cedars-Sinai Medical Center, 8700 Beverly Blvd., Room 2015 Pituitary center, Los Angeles, CA, USA

Berenice Bilharinho Mendonca, md ●  Unidade de Endocrinologia do Desenvolvimento da Faculdade de Medicina Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas, da Universidade de São Paulo, São Paulo, Brasil

Ayrton Custodio Moreira, md/PhD ●  Professor of Endocrinology, Department of Internal Medicine, University of São Paulo at Ribeirao Preto, São Paulo, Brasil

John Newell-Price ma/PhD/frcp ●  Reader and Consultant Endocrinologist, Academic Unit of Diabetes and Endocrinology, Royal Hallamshire Hospital, Room 0U142, Floor O, University of Sheffield, Sheffield, UK

Emilia M. Pinto, md ●  Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular LIM-42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

Nicholas P. Plowman, md ●  Department of Endocrinology, Barts and the London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London, UK

Elisabeth F.C. van Rossum, md/PhD ●  Erasmus MC University Medical Center, Department of Internal Medicine, ’s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands

Martin O. Savage, md ●  Department of Endocrinology, Barts and the London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London, UK

Jason P. Sheehan, md/PhD ●  Assistant Professor of Neurological Surgery and Radiation Oncol-ogy, Department of Neurological Surgery, University of Virginia Health Sciences Center, Charlottesville, VA, USA

Helen L. Storr, md ●  Department of Endocrinology, Barts and the London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London, UK

Constantine Stratakis, md/d(med)sci ●  Section on Endocrinology, Genetics (SEGEN), Program on Developmental Endocrinology & Genetics (PDEGEN), National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD, USA

Geoffrey B. Thompson, md ●  Division of Gastroenterologic and General Surgery, Mayo Clinic, Rochester, MN, USA

Peter J. Trainer, md/frcp ●  Professor, Department of Endocrinology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK

John A.H. Wass, md ●  Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, OX3 7LJ, UK

William F. Young, Jr., md/msc ●  Divisions of Endocrinology, Diabetes, Metabolism, Nutrition and Internal Medicine, Mayo Clinic, Rochester, MN, USA