Harrison’s Endocrinology 4th Edition J.

Larry Jameson
Visit to download the full and correct content document:
https://ebookmass.com/product/harrisons-endocrinology-4th-edition-j-larry-jameson/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...

Harrison. Principios de Medicina Interna 20th Edition

Jameson J. Larry [Enarm]

https://ebookmass.com/product/harrison-principios-de-medicina-
interna-20th-edition-jameson-j-larry-enarm/

Juvenile Delinquency: Theory, Practice, and Law 13th

Edition Larry J. Siegel

https://ebookmass.com/product/juvenile-delinquency-theory-
practice-and-law-13th-edition-larry-j-siegel/

Criminology in Canada Theories, Patterns, and

Typologies (Eighth Edition) Larry J. Siegel

https://ebookmass.com/product/criminology-in-canada-theories-
patterns-and-typologies-eighth-edition-larry-j-siegel/

An Artful Corpse Helen A. Harrison [Harrison

https://ebookmass.com/product/an-artful-corpse-helen-a-harrison-
harrison/
Cornea 4th Edition Mark J Mannis

https://ebookmass.com/product/cornea-4th-edition-mark-j-mannis/

System Dynamics 4th Edition William J. Palm

https://ebookmass.com/product/system-dynamics-4th-edition-
william-j-palm/

Coal Geology 3rd Edition Larry Thomas

https://ebookmass.com/product/coal-geology-3rd-edition-larry-
thomas/

Endocrinology of Aging 1st Edition Emiliano Corpas

https://ebookmass.com/product/endocrinology-of-aging-1st-edition-
emiliano-corpas/

Guiding Cassandra (Surrender Book 12) Becca Jameson

https://ebookmass.com/product/guiding-cassandra-surrender-
book-12-becca-jameson/
 4th Edition

’
HARRISON S
TM

ENDO CRINO LO GY
 Derived from Harrison’s Principles of Internal Medicine, 19th Edition
Editors
DENNISL. KASPER, md
William Ellery Channing Pro essor o Medicine, Pro essor o
Microbiology and Immunobiology, Department o Microbiology
and Immunobiology, Harvard Medical School; Division o
In ectious Diseases, Brigham and Women’s Hospital
Boston, Massachusetts
STEPHENL. HAUSER, md
Robert A. Fishman Distinguished Pro essor and Chairman,
Department o Neurology, University o Cali ornia, San Francisco
San Francisco, Cali ornia
J. LARRYJAMESON, md, phd
Robert G. Dunlop Pro essor o Medicine;
Dean, Perelman School o Medicine at the University o Pennsylvania;
Executive Vice-President, University o Pennsylvania or the
Health System, Philadelphia, Pennsylvania
ANTHONYS. FAUCI, md
Chie , Laboratory o Immunoregulation; Director, National
Institute o Allergy and In ectious Diseases, National Institutes o
Health, Bethesda, Maryland
DANL. LONGO, md
Pro essor o Medicine, Harvard Medical School; Senior Physician,
Brigham and Women’s Hospital; Deputy Editor, New England
Journal o Medicine, Boston, Massachusetts
JOSEPHLOSCALZO, md, phd
Hersey Pro essor o the T eory and Practice o Medicine, Harvard
Medical School; Chairman, Department o Medicine, and
Physician-in-Chie , Brigham and Women’s Hospital,
Boston, Massachusetts
 4th Edition

’
HARRISON S
TM

ENDO CRINO LO GY

EDITOR
J. Larry Jameson, MD, PhD
Robert G. Dunlop Pro essor o Medicine;
Dean, Perelman School o Medicine at the University o Pennsylvania;
Executive Vice-President, University o Pennsylvania or the
Health System, Philadelphia, Pennsylvania

CONTENTS

New York Chicago San Francisco Athens London Madrid Mexico City
Milan New Delhi Singapore Sydney oronto
Copyright © 2017 by McGraw-Hill Education. All rights reserved. Except as permitted under the United States Copyright Act of 1976,
no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system,
without the prior written permission of the publisher.

ISBN: 978-1-25-983573-5

MHID: 1-25-983573-1.

The material in this eBook also appears in the print version of this title: ISBN: 978-1-25-983572-8,
MHID: 1-25-983572-3.

eBook conversion by codeMantra

Version 1.0

All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked
name, we use names in an editorial fashion only, and to the bene t of the trademark owner, with no intention of infringement of the
trademark. Where such designations appear in this book, they have been printed with initial caps.

McGraw-Hill Education eBooks are available at special quantity discounts to use as premiums and sales promotions or for use in corpo-
rate training programs. To contact a representative, please visit the Contact Us page at www.mhprofessional.com.

Dr. Fauci’s work as an editor and author was performed outside the scope of his employment as a U.S. government employee. This work
represents his personal and professional views and not necessarily those of the U.S. government.

TERMS OF USE

This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in and to the work. Use of this work is subject
to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may
not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate,
sell, publish or sublicense the work or any part of it without McGraw-Hill Education’s prior consent. You may use the work for your
own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if
you fail to comply with these terms.

THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE NO GUARANTEES OR WAR-
RANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING
THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR
OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED
TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill Education
and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its opera-
tion will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any
inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill Education has no
responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill Education and/
or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or
inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply
to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.
 CONTENTS

Contributors vii 12 esticular Cancer 186

Robert J. Motzer, Darren R. Feldman,
Pre ace ix George J. Bosl
13 Disorders o the Female
SECTION I
Reproductive System 192
INTRODUCTION TO ENDOCRINOLOGY Janet E. Hall
1 Approach to the Patient with 14 In ertility and Contraception 202
Endocrine Disorders 2 Janet E. Hall
J. Larry Jameson
15 Menstrual Disorders and Pelvic Pain 209
2 Mechanisms o Hormone Action 8 Janet E. Hall
J. Larry Jameson
16 Menopause and Postmenopausal
Hormone T erapy 215
SECTION II
JoAnn E. Manson, Shari S. Bassuk
PITUITARY, THYROID, AND ADRENAL
DISORDERS 17 Hirsutism 226
David A. Ehrmann
3 Anterior Pituitary: Physiology o Pituitary
Hormones 18 18 Gynecologic Malignancies 232
Shlomo Melmed, J. Larry Jameson Michael V. Seiden

4 Hypopituitarism 25 19 Sexual Dys unction 241

Shlomo Melmed, J. Larry Jameson Kevin . McVary

5 Anterior Pituitary umor Syndromes 35

Shlomo Melmed, J. Larry Jameson SECTION IV
DIABETES MELLITUS, OBESITY, LIPOPROTEIN
6 Disorders o the Neurohypophysis 55 METABOLISM
Gary L. Robertson
20 Biology o Obesity 252
7 Disorders o the T yroid Gland 68 Je rey S. Flier, Elef heria Maratos-Flier
J. Larry Jameson, Susan J. Mandel,
Anthony P. Weetman 21 Evaluation and Management o Obesity 262
Robert F. Kushner
8 Disorders o the Adrenal Cortex 107
Wiebke Arlt 22 T e Metabolic Syndrome 272
Robert H. Eckel
9 Pheochromocytoma 136
Hartmut P. H. Neumann 23 Diabetes Mellitus: Diagnosis, Classif cation, and
Pathophysiology 280
Alvin C. Powers
SECTION III
REPRODUCTIVE ENDOCRINOLOGY 24 Diabetes Mellitus: Management and T erapies 293
Alvin C. Powers
10 Disorders o Sex Development 146
John C. Achermann, J. Larry Jameson 25 Diabetes Mellitus: Complications 317
Alvin C. Powers
11 Disorders o the estes and Male Reproductive
System 159 26 Hypoglycemia 329
Shalender Bhasin, J. Larry Jameson Philip E. Cryer, Stephen N. Davis

v
 vi Contents

27 Disorders o Lipoprotein Metabolism 339 33 Hypercalcemia and Hypocalcemia 442

Daniel J. Rader, Helen H. Hobbs Sundeep Khosla
34 Disorders o the Parathyroid Gland
SECTION V and Calcium Homeostasis 446
DISORDERS AFFECTING MULTIPLE John . Potts, Jr., Harald Jüppner
ENDOCRINE SYSTEMS
35 Osteoporosis 480
28 Endocrine umors o the Gastrointestinal ract Robert Lindsay, Felicia Cosman
and Pancreas 362
Robert . Jensen 36 Paget’s Disease and Other Dysplasias o Bone 503
Murray J. Favus, amara J. Vokes
29 Multiple Endocrine Neoplasia 390
Appendix
Rajesh V. T akker
Laboratory Values o Clinical Importance . . . . . 515
30 Autoimmune Polyendocrine Syndromes 405 Alexander Kratz, Michael A. Pesce,
Peter A. Gottlieb Robert C. Basner, Andrew J. Einstein

31 Paraneoplastic Syndromes: Endocrinologic/ Review and Sel -Assessment . . . . . . . . . . . . . . . . . . . . 533

Hematologic 413 Charles M. Wiener, Cynthia D. Brown,
J. Larry Jameson, Dan L. Longo Brian Houston
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
SECTION VI
DISORDERS OF BONE AND CALCIUM
METABOLISM
32 Bone and Mineral Metabolism in Health
and Disease 424
F. Richard Bringhurst, Marie B. Demay,
Stephen M. Krane, Henry M. Kronenberg
 CONTRIBUTORS
Numbers in brackets re er to the chapter(s) written or co-written by the contributor.
John C Achermann, MD, PhD, MB
Wellcome rust Senior Research Fellow in Clinical Science,
University College London; Pro essor o Paediatric Endocrinology,
UCL Institute o Child Health, University College London, London,
United Kingdom [10]
Wiebke Arlt, MD, DSc, FRCP, FMedSci
Pro essor o Medicine, Centre or Endocrinology, Diabetes and
Metabolism, School o Clinical and Experimental Medicine,
University o Birmingham; Consultant Endocrinologist, University
Hospital Birmingham, Birmingham, United Kingdom [8]
Robert C Basner, MD
Pro essor o Clinical Medicine, Division o Pulmonary, Allergy, and
Critical Care Medicine, Columbia University College o Physicians
and Surgeons, New York, New York [Appendix]
Shari S Bassuk, ScD
Epidemiologist, Division o Preventive Medicine, Brigham and
Women’s Hospital, Boston, Massachusetts [16]
Shalender Bhasin, MBBS
Pro essor o Medicine, Harvard Medical School; Director, Research
Program in Men’s Health: Aging and Metabolism; Director, Boston
Claude D. Pepper Older Americans Independence Center; Site
Director, Harvard Catalyst Clinical Research Center at BWH,
Brigham and Women’s Hospital, Boston, Massachusetts [11]
George J Bosl, MD
Pro essor o Medicine, Weill Cornell Medical College; Chair,
Department o Medicine; Patrick M. Byrne Chair in Clinical
Oncology, Memorial Sloan-Kettering Cancer Center, New York,
New York [12]
F Richard Bringhurst, MD
Associate Pro essor o Medicine, Harvard Medical School;
Physician, Massachusetts General Hospital, Boston,
Massachusetts [32]
Cynthia D Brown, MD
Associate Pro essor o Clinical Medicine, Division o Pulmonary,
Critical Care, Sleep and Occupational Medicine, Indiana University,
Indianapolis, Indiana [Review and Sel -Assessment]
Felicia Cosman, MD
Pro essor o Medicine, Columbia University College o Physicians
and Surgeons, New York, New York [35]
Philip E Cryer, MD
Pro essor o Medicine Emeritus, Washington University in St.
Louis; Physician, Barnes-Jewish Hospital, St. Louis, Missouri [26]
Stephen N Davis, MBBS, FRCP
T eodore E. Woodward Pro essor and Chairman o the Department
o Medicine, University o Maryland School o Medicine; Physician-
in-Chie , University o Maryland Medical Center, Baltimore,
Maryland [26]
vii
Marie B Demay, MD
Pro essor o Medicine, Harvard Medical School; Physician,
Massachusetts General Hospital, Boston, Massachusetts [32]
Robert H Eckel, MD
Pro essor o Medicine, Division o Endocrinology, Metabolism
and Diabetes, Division o Cardiology; Pro essor o Physiology
and Biophysics, Charles A. Boettcher, II Chair in Atherosclerosis,
University o Colorado School o Medicine, Anschutz Medical
Campus, Director Lipid Clinic, University o Colorado Hospital,
Aurora, Colorado [22]
David A Ehrmann, MD
Pro essor, Department o Medicine, Section o Endocrinology,
Diabetes, and Metabolism, T e University o Chicago Pritzker
School o Medicine, Chicago, Illinois [17]
Andrew J Einstein, MD, PhD
Victoria and Esther Aboodi Assistant Pro essor o Medicine;
Director, Cardiac C Research; Co-Director, Cardiac C and
MRI, Department o Medicine, Cardiology Division, Department
o Radiology, Columbia University College o Physicians and
Surgeons, New York-Presbyterian Hospital, New York, New York
[Appendix]
Murray J Favus, MD
Pro essor o Medicine, Department o Medicine, Section o
Endocrinology, Diabetes and Metabolism, Director Bone
Program, University o Chicago Pritzker School o Medicine,
Chicago, Illinois [36]
Darren R Feldman, MD
Associate Pro essor in Medicine, Weill Cornell Medical Center;
Assistant Attending, Genitourinary Oncology Service, Memorial
Sloan-Kettering Cancer Center, New York, New York [12]
Je rey S Flier, MD
Caroline Shields Walker Pro essor o Medicine and Dean, Harvard
Medical School, Boston, Massachusetts [20]
Peter A Gottlieb, MD
Pro essor o Pediatrics and Medicine, Barbara Davis Center,
University o Colorado School o Medicine, Aurora, Colorado [30]
Janet E Hall, MD, MSc
Pro essor o Medicine, Harvard Medical School and Associate
Chie , Reproductive Endocrine Unit, Massachusetts General
Hospital, Boston, Massachusetts [13–15]
Helen H Hobbs, MD
Pro essor, Internal Medicine and Molecular Genetics, University o
exas Southwestern Medical Center; Investigator, Howard Hughes
Medical Institute, Dallas, exas [27]
Brian Houston, MD
Division o Cardiology, Department o Medicine, Johns Hopkins
Hospital, Baltimore, Maryland [Review and Sel -Assessment]
 viii Contributors
J Larry Jameson
Robert G. Dunlop Pro essor o Medicine;
Dean, Perelman School o Medicine at the University o Pennsylvania;
Executive Vice-President, University o Pennsylvania or the
Health System, Philadelphia, Pennsylvania [1–5, 7, 10, 11, 31]
Robert Jensen, MD
Chie , Cell Biology Section, National Institutes o Diabetes, Diges-
tive and Kidney Diseases, National Institutes o Health, Bethesda,
Maryland [28]
Harald Jüppner, MD
Pro essor o Pediatrics, Endocrine Unit and Pediatric Nephrology
Unit, Massachusetts General Hospital, Boston, Massachusetts [34]
Sundeep Khosla, MD
Pro essor o Medicine and Physiology, College o Medicine, Mayo
Clinic, Rochester, Minnesota [33]
Stephen M Krane, MD
Persis, Cyrus and Marlow B. Harrison Distinguished Pro essor
o Medicine, Harvard Medical School; Massachusetts General
Hospital, Boston, Massachusetts [32]
Alexander Kratz, MD, MPH, PhD
Associate Pro essor o Clinical Pathology and Cell
Biology, Columbia University College o Physicians and Surgeons;
Director, Core Laboratory, Columbia University Medical
Center and the New York Presbyterian Hospital; Director, the Allen
Hospital Laboratory, New York, New York [Appendix]
Henry M Kronenberg, MD
Pro essor o Medicine, Harvard Medical School; Chie , Endocrine
Unit, Massachusetts General Hospital, Boston, Massachusetts [32]
Robert F Kushner, MD, MS
Pro essor o Medicine, Northwestern University Feinberg School o
Medicine, Chicago, Illinois [21]
Robert Lindsay, MD, PhD
Chie , Internal Medicine; Pro essor o Clinical Medicine, Helen
Hayes Hospital, West Haverstraw, New York [35]
Dan L Longo, MD
Pro essor o Medicine, Harvard Medical School; Senior Physician,
Brigham and Women’s Hospital; Deputy Editor, New England
Journal o Medicine, Boston, Massachusetts [31]
Susan J Mandel, MD, MPH
Pro essor o Medicine; Associate Chie , Division o Endocrinology,
Diabetes and Metabolism, Perelman School o Medicine, University
o Pennsylvania, Philadelphia, Pennsylvania [7]
JoAnn E Manson, MD, DrPH
Pro essor o Medicine and the Elizabeth Fay Brigham Pro essor
o Women’s Health, Harvard Medical School; Chie , Division o
Preventive Medicine, Brigham and Women’s Hospital, Boston,
Massachusetts [16]
Elef heria Maratos-Flier, MD
Pro essor o Medicine, Harvard Medical School; Division o
Endocrinology, Beth Israel Deaconess Medical Center, Boston,
Massachusetts [20]
Kevin McVary, MD, FACS
Pro essor and Chairman, Division o Urology, Southern Illinois
University School o Medicine, Spring eld, Illinois [19]
Shlomo Melmed, MD
Senior Vice President and Dean o the Medical Faculty,
Cedars-Sinai Medical Center, Los Angeles, Cali ornia [3–5]
Robert J Motzer, MD
Pro essor o Medicine, Joan and San ord Weill College o Medicine
o Cornell University D. Attending Physician, Genitourinary
Oncology Service, Memorial Sloan-Kettering Cancer Center, New
York, New York [12]
Hartmut P H Neumann, MD
Universitaet Freiburg, Medizinische Universitaetsklinik, Freiburg
im Breisgau, Germany [9]
Michael A Pesce, PhD
Pro essor Emeritus o Pathology and Cell Biology, Columbia
University College o Physicians and Surgeons; Director,
Biochemical Genetics Laboratory, Columbia University Medical
Center, New York Presbyterian Hospital, New York, New York
[Appendix]
John Potts, Jr , MD
Jackson Distinguished Pro essor o Clinical Medicine, Harvard
Medical School; Physician-in-Chie and Director o Research
Emeritus, Massachusetts General Hospital, Boston, Massachusetts [34]
Alvin C Powers, MD
Joe C. Davis Chair in Biomedical Science; Pro essor o Medicine,
Molecular Physiology and Biophysics; Director, Vanderbilt
Diabetes Center; Chie , Division o Diabetes, Endocrinology, and
Metabolism, Vanderbilt University School o Medicine, Nashville,
ennessee [23–25]
Daniel J Rader, MD
Seymour Gray Pro essor o Molecular Medicine; Chair, Department
o Genetics; Chie , Division o ranslational Medicine and Human
Genetics, Department o Medicine, Perelman School o Medicine at
the University o Pennsylvania, Philadelphia, Pennsylvania [27]
Gary L Robertson, MD
Emeritus Pro essor o Medicine, Northwestern University School o
Medicine, Chicago, Illinois [6]
Michael V Seiden, MD, PhD
Chie Medical O cer, McKesson Specialty Health, T e Woodlands,
exas [18]
Rajesh V T akker, MD, FMedSci, FR
May Pro essor o Medicine, Academic Endocrine Unit, University
o Ox ord; O.C.D.E.M., Churchill Hospital, Headington, Ox ord,
United Kingdom [29]
amara J Vokes, MD
Pro essor, Department o Medicine, Section o Endocrinology,
University o Chicago, Chicago, Illinois [36]
Anthony P Weetman, MD, DSc
University o She eld, School o Medicine She eld, She eld,
United Kingdom [7]
Charles M Wiener, MD
Vice President o Academic A airs, Johns Hopkins Medicine Interna-
tional, Pro essor o Medicine and Physiology, Johns Hopkins School o
Medicine, Baltimore, Maryland [Review and Sel -Assessment]
 PREFACE
Harrison’s Principles o Internal Medicine has been a
respected source o medical in ormation or students,
residents, internists, amily physicians, and other health
care providers or many decades. T is book, Harrison’s
Endocrinology, now in its ourth edition, is a compila-
tion o chapters related to the specialty o endocrinol-
ogy, a eld that includes some o the most commonly
encountered diseases such as diabetes mellitus, obesity,
thyroid disorders, and metabolic bone disease.
Our readers consistently note the practical value o
the specialty sections o Harrison’s. Speci cally, these
sections include a rigorous explanation o pathophysiol-
ogy as a background or di erential diagnosis and patient
management. Our goal was to bring this in ormation to
readers in a more compact and usable orm. Because
the topic is more ocused, it is possible to improve the
presentation o the material by enlarging the text and
the tables and providing clearly illustrated gures that
elucidate challenging concepts. We have also included a
Review and Sel -Assessment section that includes ques-
tions and answers to provoke re ection and to provide
additional teaching points.
T e clinical mani estations o endocrine disorders
can usually be explained by considering the physiologic
role o hormones, which are either de cient or exces-
sive. T us, a thorough understanding o hormone action
and principles o hormone eedback arms the clini-
cian with a logical diagnostic approach and a concep-
tual ramework or treating patients. T e rst chapter
o the book, Approach to the Patient with Endocrine
Disorders, provides this type o “systems” overview.
Using numerous examples o translational research, this
introduction links genetics, cell biology, and physiology
with pathophysiology and treatment. T e integration
o pathophysiology with clinical management is a hall-
mark o Harrison’s, and can be ound throughout each
o the subsequent disease-oriented chapters. T e book is
divided into six main sections that re ect the physiologic
roots o endocrinology: (I) Introduction to Endocrinol-
ogy; (II) Pituitary, T yroid, and Adrenal Disorders; (III)
ix
Reproductive Endocrinology; (IV) Diabetes Mellitus,
Obesity, Lipoprotein Metabolism; (V) Disorders A ect-
ing Multiple Endocrine Systems; and (VI) Disorders o
Bone and Calcium Metabolism.
While Harrison’s Endocrinology is classic in its organi-
zation, readers will sense the impact o scienti c advances
as they explore the individual chapters in each section.
In addition to the dramatic discoveries emanating rom
genetics and molecular biology, the introduction o
an unprecedented number o new drugs, particularly
or the management o diabetes, hypogonadism, and
osteoporosis, is trans orming the eld o endocrinology.
Numerous recent clinical studies involving common
diseases like diabetes, obesity, hypothyroidism, hypo-
gonadism, and osteoporosis provide power ul evidence
or medical decision making and treatment. T ese rapid
changes in endocrinology are exciting or new students
o medicine and underscore the need or practicing phy-
sicians to continuously update their knowledge base and
clinical skills.
Our access to in ormation through web-based jour-
nals and databases is remarkably e cient, but also
daunting, creating a need or books that synthesize con-
cepts and highlight important acts. T e preparation o
these chapters is there ore a special craf that requires
distillation o core in ormation rom the ever-expanding
knowledge base. T e editors are indebted to our authors,
a group o internationally recognized authorities who
are masters at providing a comprehensive overview
while being able to distill a topic into a concise and inter-
esting chapter. We are also indebted to our colleagues at
McGraw-Hill. Jim Shanahan is a tireless champion or
Harrison’s, and these books were impeccably produced
by Kim Davis.
We hope you nd this book use ul in your e ort to
achieve continuous learning on behal o your patients.
J. Larry Jameson, MD, PhD
 NOTICE
Medicine is an ever-changing science. As new research and clinical expe-
rience broaden our knowledge, changes in treatment and drug therapy are
required. T e authors and the publisher o this work have checked with
sources believed to be reliable in their e orts to provide in ormation that is
complete and generally in accord with the standards accepted at the time o
publication. However, in view o the possibility o human error or changes in
medical sciences, neither the authors nor the publisher nor any other party
who has been involved in the preparation or publication o this work war-
rants that the in ormation contained herein is in every respect accurate or
complete, and they disclaim all responsibility or any errors or omissions or
or the results obtained rom use o the in ormation contained in this work.
Readers are encouraged to con rm the in ormation contained herein with
other sources. For example and in particular, readers are advised to check the
product in ormation sheet included in the package o each drug they plan to
administer to be certain that the in ormation contained in this work is accu-
rate and that changes have not been made in the recommended dose or in the
contraindications or administration. T is recommendation is o particular
importance in connection with new or in requently used drugs.

Review and sel -assessment questions and answers were taken rom Wiener CM,
Brown CD, Houston B (eds). Harrison’s Sel -Assessment and Board Review, 19th ed.
New York, McGraw-Hill, 2017, ISBN 978-1-259-64288-3 .

T e global icons call greater attention to key epidemiologic and clinical di erences in the practice o medicine
throughout the world.

T e genetic icons identi y a clinical issue with an explicit genetic relationship.

 SECTION I

INTRODUCTION TO
ENDOCRINOLOGY
 CH AP TER 1
APPROACH TO THE PATIENT WITH
ENDOCRINE DISORDERS
J. La rry Ja m e so n
T e management o endocrine disorders requires
a broad understanding o intermediary metabo-
lism, reproductive physiology, bone metabolism, and
growth. Accordingly, the practice o endocrinology
is intimately linked to a conceptual ramework or
understanding hormone secretion, hormone action,
and principles o eedback control (Chap. 2). T e
endocrine system is evaluated primarily by measuring
hormone concentrations, arming the clinician with
valuable diagnostic in ormation. Most disorders o the
endocrine system are amenable to e ective treatment
once the correct diagnosis is determined. Endocrine
de ciency disorders are treated with physiologic hor-
mone replacement; hormone excess conditions, which
usually are caused by benign glandular adenomas, are
managed by removing tumors surgically or reducing
hormone levels medically.
SCO P E O F ENDO CRINO LO GY
T e specialty o endocrinology encompasses the study
o glands and the hormones they produce. T e term
endocrine was coined by Starling to contrast the actions
o hormones secreted internally (endocrine) with those
secreted externally (exocrine) or into a lumen, such as
the gastrointestinal tract. T e term hormone, derived
rom a Greek phrase meaning “to set in motion,” aptly
describes the dynamic actions o hormones as they
elicit cellular responses and regulate physiologic pro-
cesses through eedback mechanisms.
Unlike many other specialties in medicine, it is not
possible to de ne endocrinology strictly along anatomic
lines. T e classic endocrine glands—pituitary, thyroid,
parathyroid, pancreatic islets, adrenals, and gonads—
communicate broadly with other organs through the
nervous system, hormones, cytokines, and growth
2
actors. In addition to its traditional synaptic unctions,
the brain produces a vast array o peptide hormones,
and this has led to the discipline o neuroendocrinol-
ogy. T rough the production o hypothalamic releas-
ing actors, the central nervous system (CNS) exerts
a major regulatory in uence over pituitary hormone
secretion (Chap. 3). T e peripheral nervous system
stimulates the adrenal medulla. T e immune and endo-
crine systems are also intimately intertwined. T e adre-
nal hormone cortisol is a power ul immunosuppressant.
Cytokines and interleukins (ILs) have pro ound e ects
on the unctions o the pituitary, adrenal, thyroid, and
gonads. Common endocrine diseases such as autoim-
mune thyroid disease and type 1 diabetes mellitus are
caused by dysregulation o immune surveillance and
tolerance. Less common diseases such as polyglandular
ailure, Addison’s disease, and lymphocytic hypophysitis
also have an immunologic basis.
T e interdigitation o endocrinology with physi-
ologic processes in other specialties sometimes blurs
the role o hormones. For example, hormones play
an important role in maintenance o blood pressure,
intravascular volume, and peripheral resistance in the
cardiovascular system. Vasoactive substances such as
catecholamines, angiotensin II, endothelin, and nitric
oxide are involved in dynamic changes o vascular tone
in addition to their multiple roles in other tissues. T e
heart is the principal source o atrial natriuretic pep-
tide, which acts in classic endocrine ashion to induce
natriuresis at a distant target organ (the kidney). Eryth-
ropoietin, a traditional circulating hormone, is made
in the kidney and stimulates erythropoiesis in bone
marrow. T e kidney is also integrally involved in the
renin-angiotensin axis (Chap. 8) and is a primary target
o several hormones, including parathyroid hormone
(P H), mineralocorticoids, and vasopressin. T e gas-
trointestinal tract produces a surprising number o
peptide hormones, such as cholecystokinin, ghrelin, hormones, are used in numerous physiologic processes, 3
gastrin, secretin, and vasoactive intestinal peptide, including vision, smell, and neurotransmission.
among many others. Carcinoid and islet tumors can
secrete excessive amounts o these hormones, lead-

C
H
ing to speci c clinical syndromes (Chap. 28). Many o

A
PATHO LO GIC MECHANISMS O F

P
T
these gastrointestinal hormones are also produced in

E
ENDO CRINE DISEASE

R
the CNS, where their unctions are poorly understood.

1
Adipose tissue produces leptin, which acts centrally to Endocrine diseases can be divided into three major
control appetite, along with adiponectin, resistin, and types o conditions: (1) hormone excess, (2) hormone
other hormones that regulate metabolism. As hormones

A
de ciency, and (3) hormone resistance (Table 1-1).

p
p
such as inhibin, ghrelin, and leptin are discovered, they

r
o
a
become integrated into the science and practice o med-

c
h
icine on the basis o their unctional roles rather than

t
o
CAUSES OF HORMONE EXCESS

t
their tissues o origin.

h
e
P
Characterization o hormone receptors requently Syndromes o hormone excess can be caused by neo-

a
t
i
reveals unexpected relationships to actors in nonen- plastic growth o endocrine cells, autoimmune dis-

e
n
t
docrine disciplines. T e growth hormone (GH) and orders, and excess hormone administration. Benign

w
i
t
leptin receptors, or example, are members o the cyto- endocrine tumors, including parathyroid, pituitary,

h
E
n
kine receptor amily. T e G protein–coupled receptors and adrenal adenomas, o en retain the capacity to pro-

d
o
(GPCRs), which mediate the actions o many peptide duce hormones, perhaps re ecting the act that these

c
r
i
n
e
D
i
s
o
r
d
TABLE 1 -1

e
r
s
CAUSES OF ENDOCRINE DYSFUNCTION
TYPE OF ENDOCRINE DISORDER EXAMPLES

Hyp e r fu n ct io n
Neoplastic
Benign Pituitary adenomas, hyperparathyroidism, autonomous thyroid or adrenal nodules,
pheochromocytoma
Malignant Adrenal cancer, medullary thyroid cancer, carcinoid
Ectopic Ectopic ACTH, SIADH secretion
Multiple endocrine neoplasia (MEN) MEN 1, MEN 2
Autoimmune Graves’disease
Iatrogenic Cushing’s syndrome, hypoglycemia
In ectious/in ammatory Subacute thyroiditis
Activating receptor mutations LH, TSH, Ca 2+, PTH receptors, Gsα
Hyp o fu n ct io n
Autoimmune Hashimoto’s thyroiditis, type 1 diabetes mellitus, Addison’s disease, polyglandular ailure
Iatrogenic Radiation-induced hypopituitarism, hypothyroidism, surgical
In ectious/in ammatory Adrenal insuf ciency, hypothalamic sarcoidosis
Hormone mutations GH, LHβ, FSHβ, vasopressin
Enzyme de ects 21-Hydroxylase de ciency
Developmental de ects Kallmann syndrome, Turner’s syndrome, transcription actors
Nutritional/vitamin de ciency Vitamin D de ciency, iodine de ciency
Hemorrhage/in arction Sheehan’s syndrome, adrenal insuf ciency
Ho rm o n e Re sist a n ce
Receptor mutations
Membrane GH, vasopressin, LH, FSH, ACTH, GnRH, GHRH, PTH, leptin, Ca 2+
Nuclear AR, TR, VDR, ER, GR, PPARγ
Signaling pathway mutations Albright’s hereditary osteodystrophy
Postreceptor Type 2 diabetes mellitus, leptin resistance

Ab brevia tio n s: ACTH, adrenocorticotropic hormone; AR, androgen receptor; ER, estrogen receptor; FSH, ollicle-stimulating hormone; GHRH, growth
hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; GR, glucocorticoid receptor; LH, luteinizing hormone; PPAR, peroxisome proli er-
ator activated receptor; PTH, parathyroid hormone; SIADH, syndrome o inappropriate antidiuretic hormone; TR, thyroid hormone receptor; TSH, thyroid-
stimulating hormone; VDR, vitamin D receptor.
4 tumors are relatively well di erentiated. Many endo- In autoimmune Graves’ disease, antibody interac-
crine tumors exhibit subtle de ects in their “set points” tions with the thyroid-stimulating hormone ( SH)
or eedback regulation. For example, in Cushing’s dis- receptor mimic SH action, leading to hormone over-
ease, impaired eedback inhibition o adrenocortico- production (Chap. 7). Analogous to the e ects o acti-
S
E
tropic hormone (AC H) secretion is associated with vating mutations o the SH receptor, these stimulating
C
T
I
autonomous unction. However, the tumor cells are not autoantibodies induce con ormational changes that
O
N
completely resistant to eedback, as evidenced by AC H release the receptor rom a constrained state, thereby
I
suppression by higher doses o dexamethasone (e.g., triggering receptor coupling to G proteins.
high-dose dexamethasone test) (Chap. 8). Similar set
point de ects are also typical o parathyroid adenomas
I
n
t
r
and autonomously unctioning thyroid nodules. CAUSES OF HORMONE DEFICIENCY
o
d
u
T e molecular basis o some endocrine tumors, such
c
Most examples o hormone de ciency states can be
t
i
o
as the multiple endocrine neoplasia (MEN) syndromes
n
attributed to glandular destruction caused by autoim-
t
(MEN 1, 2A, 2B), have provided important insights
o
munity, surgery, in ection, in ammation, in arction,
E
n
into tumorigenesis (Chap. 29). MEN 1 is characterized
d
hemorrhage, or tumor in ltration ( able 1-1). Auto-
o
primarily by the triad o parathyroid, pancreatic islet,
c
r
immune damage to the thyroid gland (Hashimoto’s
i
n
and pituitary tumors. MEN 2 predisposes to medullary
o
thyroiditis) and pancreatic islet β cells (type 1 diabe-
l
o
thyroid carcinoma, pheochromocytoma, and hyper-
g
tes mellitus) is a prevalent cause o endocrine disease.
y
parathyroidism. T e MEN1 gene, located on chromo-
Mutations in a number o hormones, hormone recep-
some 11q13, encodes a putative tumor-suppressor gene,
tors, transcription actors, enzymes, and channels can
menin. Analogous to the paradigm rst described or
also lead to hormone de ciencies.
retinoblastoma, the a ected individual inherits a mutant
copy o the MEN1 gene, and tumorigenesis ensues a er a
somatic “second hit” leads to loss o unction o the nor-
HORMONE RESISTANCE
mal MEN1 gene (through deletion or point mutations).
In contrast to inactivation o a tumor-suppressor Most severe hormone resistance syndromes are due to
gene, as occurs in MEN 1 and most other inherited can- inherited de ects in membrane receptors, nuclear recep-
cer syndromes, MEN 2 is caused by activating muta- tors, or the pathways that transduce receptor signals.
tions in a single allele. In this case, activating mutations T ese disorders are characterized by de ective hormone
o the RET protooncogene, which encodes a receptor action despite the presence o increased hormone levels.
tyrosine kinase, leads to thyroid C cell hyperplasia in In complete androgen resistance, or example, muta-
childhood be ore the development o medullary thyroid tions in the androgen receptor result in a emale phe-
carcinoma. Elucidation o this pathogenic mechanism notypic appearance in genetic (XY) males, even though
has allowed early genetic screening or RET mutations LH and testosterone levels are increased (Chap. 29). In
in individuals at risk or MEN 2, permitting identi- addition to these relatively rare genetic disorders, more
cation o those who may bene t rom prophylactic common acquired orms o unctional hormone resis-
thyroidectomy and biochemical screening or pheo- tance include insulin resistance in type 2 diabetes mel-
chromocytoma and hyperparathyroidism. litus, leptin resistance in obesity, and GH resistance in
Mutations that activate hormone receptor signal- catabolic states. T e pathogenesis o unctional resis-
ing have been identi ed in several GPCRs. For example, tance involves receptor downregulation and postrecep-
activating mutations o the luteinizing hormone (LH) tor desensitization o signaling pathways; unctional
receptor cause a dominantly transmitted orm o male- orms o resistance are generally reversible.
limited precocious puberty, re ecting premature stimula-
tion o testosterone synthesis in Leydig cells (Chap. 11).
CLINICAL EVALUATION OF ENDOCRINE
Activating mutations in these GPCRs are located pre-
DISORDERS
dominantly in the transmembrane domains and induce
receptor coupling to Gsα even in the absence o hormone. Because most glands are relatively inaccessible, the physi-
Consequently, adenylate cyclase is activated, and cyclic cal examination usually ocuses on the mani estations o
adenosine monophosphate (AMP) levels increase in a hormone excess or de ciency as well as direct examina-
manner that mimics hormone action. A similar phenom- tion o palpable glands, such as the thyroid and gonads.
enon results rom activating mutations in Gsα. When For these reasons, it is important to evaluate patients in
these mutations occur early in development, they cause the context o their presenting symptoms, review o sys-
McCune-Albright syndrome. When they occur only in tems, amily and social history, and exposure to medica-
somatotropes, the activating Gsα mutations cause GH- tions that may a ect the endocrine system. Astute clinical
secreting tumors and acromegaly (Chap. 5). skills are required to detect subtle symptoms and signs
suggestive o underlying endocrine disease. For example,
a patient with Cushing’s syndrome may mani est speci c
ndings, such as central at redistribution, striae, and
proximal muscle weakness, in addition to eatures seen
commonly in the general population, such as obesity,
plethora, hypertension, and glucose intolerance. Simi-
larly, the insidious onset o hypothyroidism—with men-
tal slowing, atigue, dry skin, and other eatures—can be
dif cult to distinguish rom similar, nonspeci c ndings
in the general population. Clinical judgment that is based
on knowledge o disease prevalence and pathophysiology
is required to decide when to embark on more extensive
evaluation o these disorders. Laboratory testing plays an
essential role in endocrinology by allowing quantitative
assessment o hormone levels and dynamics. Radiologic
imaging tests such as computed tomography (C ) scan,
magnetic resonance imaging (MRI), thyroid scan, and
ultrasound are also used or the diagnosis o endocrine
disorders. However, these tests generally are employed
only a er a hormonal abnormality has been established
by biochemical testing.
HORMONE MEASUREMENTS AND
ENDOCRINE TESTING
Immunoassays are the most important diagnostic tool
in endocrinology, as they allow sensitive, speci c, and
quantitative determination o steady-state and dynamic
changes in hormone concentrations. Immunoassays use
antibodies to detect speci c hormones. For many peptide
hormones, these measurements are now con gured to
use two di erent antibodies to increase binding af nity
and speci city. T ere are many variations o these assays;
a common ormat involves using one antibody to cap-
ture the antigen (hormone) onto an immobilized sur ace
and a second antibody, coupled to a chemiluminescent
(immunochemiluminescent assay [ICMA]) or radioac-
tive (immunoradiometric assay [IRMA]) signal, to detect
the antigen. T ese assays are sensitive enough to detect
plasma hormone concentrations in the picomolar to
nanomolar range, and they can readily distinguish struc-
turally related proteins, such as P H rom P H-related
peptide (P HrP). A variety o other techniques are used
to measure speci c hormones, including mass spectros-
copy, various orms o chromatography, and enzymatic
methods; bioassays are now rarely used.
Most hormone measurements are based on plasma or
serum samples. However, urinary hormone determina-
tions remain use ul or the evaluation o some conditions.
Urinary collections over 24 h provide an integrated assess-
ment o the production o a hormone or metabolite, many
o which vary during the day. It is important to assure com-
plete collections o 24-h urine samples; simultaneous mea-
surement o creatinine provides an internal control or the
adequacy o collection and can be used to normalize some
hormone measurements. A 24-h urine ree cortisol mea- 5
surement largely re ects the amount o unbound cortisol,
thus providing a reasonable index o biologically available
hormone. Other commonly used urine determinations
C
H
include 17-hydroxycorticosteroids, 17-ketosteroids, vanillyl-
A
P
T
mandelic acid, metanephrine, catecholamines, 5-hydroxyin-
E
R
doleacetic acid, and calcium.
1
T e value o quantitative hormone measurements lies
in their correct interpretation in a clinical context. T e
normal range or most hormones is relatively broad,
A
p
p
o en varying by a actor o two- to ten old. T e normal
r
o
a
ranges or many hormones are sex- and age-speci c.
c
h
T us, using the correct normative database is an essential
t
o
t
part o interpreting hormone tests. T e pulsatile nature o
h
e
P
hormones and actors that can a ect their secretion, such
a
t
i
as sleep, meals, and medications, must also be consid-
e
n
t
ered. Cortisol values increase ve old between midnight
w
i
t
and dawn; reproductive hormone levels vary dramati-
h
E
n
cally during the emale menstrual cycle.
d
o
For many endocrine systems, much in ormation
c
r
i
n
can be gained rom basal hormone testing, particularly
e
D
when di erent components o an endocrine axis are
i
s
o
r
assessed simultaneously. For example, low testoster-
d
e
r
one and elevated LH levels suggest a primary gonadal
s
problem, whereas a hypothalamic-pituitary disorder is
likely i both LH and testosterone are low. Because SH
is a sensitive indicator o thyroid unction, it is gener-
ally recommended as a rst-line test or thyroid disor-
ders. An elevated SH level is almost always the result
o primary hypothyroidism, whereas a low SH is most
o en caused by thyrotoxicosis. T ese predictions can be
con rmed by determining the ree thyroxine level. In
the less common circumstance when ree thyroxine and
SH are both low, it is important to consider second-
ary hypopituitarism caused by hypothalamic-pituitary
disease. Elevated calcium and P H levels suggest
hyperparathyroidism, whereas P H is suppressed in
hypercalcemia caused by malignancy or granulomatous
diseases. A suppressed AC H in the setting o hyper-
cortisolemia, or increased urine ree cortisol, is seen
with hyper unctioning adrenal adenomas.
It is not uncommon, however, or baseline hormone
levels associated with pathologic endocrine conditions
to overlap with the normal range. In this circumstance,
dynamic testing is use ul to separate the two groups ur-
ther. T ere are a multitude o dynamic endocrine tests,
but all are based on principles o eedback regulation, and
most responses can be rationalized based on principles
that govern the regulation o endocrine axes. Suppres-
sion tests are used in the setting o suspected endocrine
hyper unction. An example is the dexamethasone sup-
pression test used to evaluate Cushing’s syndrome
(Chaps. 5 and 8). Stimulation tests generally are used
to assess endocrine hypo unction. T e AC H stimula-
tion test, or example, is used to assess the adrenal gland
6 TABLE 1 -2
EXAMPLES OF PREVALENT ENDOCRINE AND METABOLIC DISORDERS IN THE ADULT
APPROX.
PREVALENCE IN
S
E
DISORDER ADULTS a SCREENING/TESTING RECOMMENDATIONS b CHAPTER(S)
C
T
I
O
Obesity 34% BMI ≥30 Calculate BMI Ch a p . 21
N
68% BMI ≥25 Measure waist circum erence
I
Exclude secondary causes
Consider comorbid complications
Type 2 diabetes mellitus >7% Beginning at age 45, screen every 3 years, or earlier in high-risk groups: Ch a p . 23
I
n
Fasting plasma glucose (FPG) >126 mg/dL
t
r
o
Random plasma glucose >200 mg/dL
d
u
An elevated HbA1c
c
t
i
Consider comorbid complications
o
n
t
Hyperlipidemia 20–25% Cholesterol screening at least every 5 years; more o ten in high-risk Ch a p . 27
o
E
groups
n
d
Lipoprotein analysis (LDL, HDL) or increased cholesterol, CAD, diabetes
o
c
Consider secondary causes
r
i
n
o
Metabolic syndrome 35% Measure waist circum erence, FPG, BP, lipids Ch a p . 22
l
o
g
Hypothyroidism 5–10%, women TSH; con rm with ree T4 Ch a p . 7
y
0.5–2%, men Screen women a ter age 35 and every 5 years therea ter
Graves’disease 1–3%, women TSH, ree T4 Ch a p . 7
0.1%, men
Thyroid nodules and 2–5% palpable Physical examination o thyroid Ch a p . 7
neoplasia >25% by ultrasound Fine-needle aspiration biopsy
Osteoporosis 5–10%, women Bone mineral density measurements in women >65 years or in post- Ch a p . 35
2–5%, men menopausal women or men at risk
Exclude secondary causes
Hyperparathyroidism 0.1–0.5%, women Serum calcium Ch a p . 34
> men PTH, i calcium is elevated
Assess comorbid conditions
In ertility 10%, couples Investigate both members o couple Ch a p s. 11,
Semen analysis in male 13
Assess ovulatory cycles in emale
Speci c tests as indicated
Polycystic ovarian 5–10%, women Free testosterone, DHEAS Ch a p . 13
syndrome Consider comorbid conditions
Hirsutism 5–10% Free testosterone, DHEAS Ch a p . 17
Exclude secondary causes
Additional tests as indicated
Menopause Median age, 51 FSH Ch a p . 16
Hyperprolactinemia 15% in women with PRL level Ch a p . 5
amenorrhea or MRI, i not medication-related
galactorrhea
Erectile dys unction 10–25% Care ul history, PRL, testosterone Ch a p . 19
Consider secondary causes (e.g., diabetes)
Hypogonadism, male 1–2% Testosterone, LH Ch a p . 11
Gynecomastia 15% O ten, no tests are indicated Ch a p . 11
Consider Kline elter’s syndrome
Consider medications, hypogonadism, liver disease
Kline elter’s syndrome 0.2%, men Karyotype Ch a p . 10
Testosterone
Vitamin D de ciency 10% Measure serum 25-OH vitamin D Ch a p . 32
Consider secondary causes
Turner’s syndrome 0.03%, women Karyotype Ch a p . 10
Consider comorbid conditions

a
The prevalence o most disorders varies among ethnic groups and with aging. Data based primarily on U.S. population.
b
See individual chapters or additional in ormation on evaluation and treatment. Early testing is indicated in patients with signs and symptoms o disease
and in those at increased risk.
Abb revia tio ns: BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; DHEAS, dehydroepiandrosterone; FSH, ollicle-stimulating hor-
mone; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LH, luteinizing hormone; MRI, magnetic resonance imaging; PRL, prolactin; PTH, para-
thyroid hormone; TSH, thyroid-stimulating hormone.
response in patients with suspected adrenal insuf ciency. SCREENING AND ASSESSMENT OF 7
Other stimulation tests use hypothalamic-releasing ac- COMMON ENDOCRINE DISORDERS
tors such as corticotropin-releasing hormone (CRH)
Many endocrine disorders are prevalent in the adult
and growth hormone–releasing hormone (GHRH) to

C
population (Table 1-2) and can be diagnosed and man-

H
evaluate pituitary hormone reserve (Chap. 5). Insulin-

A
aged by general internists, amily practitioners, or other

P
T
induced hypoglycemia also evokes pituitary AC H and

E
primary health care providers. T e high prevalence and

R
GH responses. Stimulation tests based on reduction or

1
clinical impact o certain endocrine diseases justi es
inhibition o endogenous hormones are now used in re-
vigilance or eatures o these disorders during routine
quently. Examples include metyrapone inhibition o
physical examinations; laboratory screening is indicated
cortisol synthesis and clomiphene inhibition o estrogen

A
p
in selected high-risk populations.

p
eedback.

r
o
a
c
h
t
o
t
h
e
P
a
t
i
e
n
t
w
i
t
h
E
n
d
o
c
r
i
n
e
D
i
s
o
r
d
e
r
s
 CH AP TER 2
MECHANISMS OF HORMONE ACTION
J. La rry Ja m e so n
CLASSES O F HO RMO NES
Hormones can be divided into ve major types: (1)
amino acid derivatives such as dopamine, catechol-
amine, and thyroid hormone; (2) small neuropeptides
such as gonadotropin-releasing hormone (GnRH), thy-
rotropin-releasing hormone ( RH), somatostatin, and
vasopressin; (3) large proteins such as insulin, luteiniz-
ing hormone (LH), and parathyroid hormone (P H);
(4) steroid hormones such as cortisol and estrogen that
are synthesized rom cholesterol-based precursors;
and (5) vitamin derivatives such as retinoids (vitamin
A) and vitamin D. A variety o peptide growth factors,
most o which act locally, share actions with hormones.
As a rule, amino acid derivatives and peptide hormones
interact with cell-sur ace membrane receptors. Steroids,
thyroid hormones, vitamin D, and retinoids are lipid-
soluble and interact with intracellular nuclear receptors,
although many also interact with membrane receptors
or intracellular signaling proteins as well.
HORMONE AND RECEPTOR FAMILIES
Hormones and receptors can be grouped into amilies,
re ecting structural similarities and evolutionary ori-
gins (Table 2-1). T e evolution o these amilies gener-
ates diverse but highly selective pathways o hormone
action. Recognition o these relationships has proven
use ul or extrapolating in ormation gleaned rom one
hormone or receptor to other amily members.
T e glycoprotein hormone amily, consisting o thy-
roid-stimulating hormone ( SH), ollicle-stimulating
hormone (FSH), LH, and human chorionic gonado-
tropin (hCG), illustrates many eatures o related hor-
mones. T e glycoprotein hormones are heterodimers
that share the α subunit in common; the β subunits are
distinct and con er speci c biologic actions. T e over-
all three-dimensional architecture o the β subunits is
similar, re ecting the locations o conserved disul de
8
bonds that restrain protein con ormation. T e cloning
o the β-subunit genes rom multiple species suggests
that this amily arose rom a common ancestral gene,
probably by gene duplication and subsequent diver-
gence to evolve new biologic unctions.
As hormone amilies enlarge and diverge, their
receptors must co-evolve to derive new biologic unc-
tions. Related G protein–coupled receptors (GPCRs),
or example, have evolved or each o the glycoprotein
hormones. T ese receptors are structurally similar, and
each is coupled predominantly to the Gsα signaling
pathway. However, there is minimal overlap o hormone
binding. For example, SH binds with high speci city
to the SH receptor but interacts minimally with the
LH or FSH receptors. Nonetheless, there can be subtle
physiologic consequences o hormone cross-reactivity
with other receptors. Very high levels o hCG during
pregnancy stimulate the SH receptor and increase
thyroid hormone levels, resulting in a compensatory
decrease in SH.
Insulin and insulin-like growth actor I (IGF-I) and
IGF-II have structural similarities that are most appar-
ent when precursor orms o the proteins are compared.
In contrast to the high degree o speci city seen with
the glycoprotein hormones, there is moderate cross-talk
among the members o the insulin/IGF amily. High
concentrations o an IGF-II precursor produced by cer-
tain tumors (e.g., sarcomas) can cause hypoglycemia,
partly because o binding to insulin and IGF-I receptors
(Chap. 34). High concentrations o insulin also bind to
the IGF-I receptor, perhaps accounting or some o the
clinical mani estations seen in conditions with chronic
hyperinsulinemia.
Another important example o receptor cross-talk
is seen with P H and parathyroid hormone–related
peptide (P HrP) (Chap. 34). P H is produced by the
parathyroid glands, whereas P HrP is expressed at high
levels during development and by a variety o tumors
(Chap. 31). T ese hormones have amino acid sequence
TABLE 2 -1 receptor, retinoic acid receptor, peroxisome proli erator 9
EXAMPLES OF MEMBRANE RECEPTOR FAMILIES AND activated receptor) that bind thyroid hormone, vitamin
SIGNALING PATHWAYS D, retinoic acid, or lipid derivatives. Certain unctional
domains in nuclear receptors, such as the zinc nger

C
SIGNALING

H
DNA-binding domains, are highly conserved. However,

A
RECEPTORS EFFECTORS PATHWAYS

P
T
selective amino acid di erences within this domain

E
G Pro t e in –Co u p le d Se ve n -Tra n sm e m b ra n e Re ce p t o r

R
(GPCR) con er DNA sequence speci city. T e hormone-binding

2
β-Adrenergic, LH, GSα, adenylate Stimulation o domains are more variable, providing great diversity
FSH, TSH cyclase cyclic AMP pro- in the array o small molecules that bind to di erent
nuclear receptors. With ew exceptions, hormone bind-

M
duction, protein

e
c
kinase A ing is highly speci c or a single type o nuclear recep-

h
a
Ca2+ channels

n
Glucagon, PTH, Calmodulin, tor. One exception involves the glucocorticoid and

i
s
m
PTHrP, ACTH, Ca 2+-dependent mineralocorticoid receptors. Because the mineralo-

s
MSH, GHRH, CRH kinases

o
corticoid receptor also binds glucocorticoids with high

f
H
α-Adrenergic, Giα Inhibition o cyclic
a nity, an enzyme (11β-hydroxysteroid dehydroge-

o
r
somatostatin AMP production

m
nase) in renal tubular cells inactivates glucocorticoids,

o
Activation o K+,

n
allowing selective responses to mineralocorticoids such

e
Ca2+ channels

A
c
TRH, GnRH Gq , G11 Phospholipase C, as aldosterone. However, when very high glucocorticoid

t
i
o
concentrations occur, as in Cushing’s syndrome, the

n
diacyl-glycerol,
IP3, protein glucocorticoid degradation pathway becomes saturated,
kinase C, voltage- allowing excessive cortisol levels to exert mineralocor-
dependent Ca 2+
channels
ticoid e ects (sodium retention, potassium wasting).
T is phenomenon is particularly pronounced in ecto-
Re ce p t o r Tyro sin e Kin a se
pic adrenocorticotropic hormone (AC H) syndromes
Insulin, IGF-I Tyrosine kinases, MAP kinases, PI (Chap. 8). Another example o relaxed nuclear recep-
IRS 3-kinase; AKT tor speci city involves the estrogen receptor, which can
EGF, NGF Tyrosine kinases, Ra , MAP kinases,
ras RSK
bind an array o compounds, some o which have little
apparent structural similarity to the high-a nity ligand
Cyto kin e Re ce p to r–Lin ke d Kin a se
estradiol. T is eature o the estrogen receptor makes
GH, PRL JAK, tyrosine STAT, MAP kinase, it susceptible to activation by “environmental estro-
kinases PI 3-kinase, IRS-1 gens” such as resveratrol, octylphenol, and many other
Se rin e Kin a se aromatic hydrocarbons. However, this lack o speci c-
Activin, TGF-β, MIS Serine kinase Smads ity provides an opportunity to synthesize a remarkable
series o clinically use ul antagonists (e.g., tamoxi en)
Abb revia tio ns: IP3, inositol triphosphate; IRS, insulin receptor substrates; and selective estrogen response modulators (SERMs)
MAP, mitogen-activated protein; MSH, melanocyte-stimulating hormone; such as raloxi ene. T ese compounds generate dis-
NGF, nerve growth actor; PI, phosphatidylinositol; RSK, ribosomal S6
kinase; TGF-β, trans orming growth actor β. For all other abbreviations,
tinct con ormations that alter receptor interactions
see text. Note that most receptors interact with multiple ef ectors and with components o the transcription machinery (see
activate networks o signaling pathways. below), thereby con erring their unique actions.
similarity, particularly in their amino-terminal regions.
Both hormones bind to a single P H receptor that
HORMONE SYNTHESIS AND PROCESSING
is expressed in bone and kidney. Hypercalcemia and
hypophosphatemia there ore may result rom excessive T e synthesis o peptide hormones and their receptors
production o either hormone, making it di cult to occurs through a classic pathway o gene expression:
distinguish hyperparathyroidism rom hypercalcemia transcription → mRNA → protein → posttranslational
o malignancy solely on the basis o serum chemistries. protein processing → intracellular sorting, ollowed by
However, sensitive and speci c assays or P H and membrane integration or secretion.
P HrP now allow these disorders to be distinguished Many hormones are embedded within larger precur-
more readily. sor polypeptides that are proteolytically processed to
Based on their speci cities or DNA binding sites, yield the biologically active hormone. Examples include
the nuclear receptor amily can be subdivided into proopiomelanocortin (POMC) → AC H; progluca-
type 1 receptors (glucocorticoid receptor, mineralo- gon →glucagon; proinsulin →insulin; and pro-P H →
corticoid receptor, androgen receptor, estrogen recep- P H, among others. In many cases, such as POMC and
tor, progesterone receptor) that bind steroids and type proglucagon, these precursors generate multiple bio-
2 receptors (thyroid hormone receptor, vitamin D logically active peptides. It is provocative that hormone
Another random document with
no related content on Scribd:
 Hilgard’s method, 436
Methods of Official Agricultural Chemists, 434
Müller’s method 438–440
soda-lime method, 445
nature in soils, 430–434
order of oxidation, 465
organic, in soils, 459–461
oxidized, estimation in soils, 459–570
soda-lime method, 441–444
in presence of nitrates, 444
Nitrous acid, development in soils, 461
estimation, by coloration of a ferrous salt, 567
colorimetric comparison, 559
potassium ferrocyanid, 567
classification of methods, 496–498
iodometric method, 564–567
ferment, isolation, 471, 477
Nöbel’s apparatus, 207
Nöllner, nitrate deposits, 16
Norwacki and Borchardt, auger for soil sampling, 83

O
Odoriferous matters, determination, 98
in soils, 97
Official Agricultural Chemists, latest methods, 454–456
method for reduction of nitric acid, 532, 533
of analysis of soil extract, 353–356
soil solution, 349
Organic matter, estimation, 314
influence on absorption, 124
total, 315
Origin of soils, 43
Orth, classification, 185
Osborne, Berlin-Schöne method, 224
method, comparison with Schloesing’s, 241
of silt analysis, 196
-Schöne method, 219
comparisons, 223
Oxygen, 3
absorption, 286
estimation of organic, 324

P
Packard, separation of silt particles, 273
Pasturel, estimation of humus, 336
Peligot, preliminary treatment of samples, 91
Percolation, measurement, 161
soils in situ, 164
Petermann, determination of water absorption, 138
method for phosphoric acid, 409
preliminary treatment of samples, 92
Petrographic examination of silt particles, 266
microscope, 256
Pfaundler, specific heat method, 104–110
Phenylsulfuric acid, reagent for nitric acid, 554
Phosphoric acid, Carnot’s method, 403
estimation, 354, 362, 403–406, 409–416
French method, 406–409
Halle method, 404, 405
in muck soils, 415
method of Goss, 416–418
Hilgard, 413
Petermann’s method, 409
Russian method, 412
separation from iron and alumina, 414
Phosphorus, 6
 microchemical examination, 266
state of existence in soils, 411
Piccini method for nitric acid, 558
nitrous acid, 567
Pillitz and Zalomanoff, method of determining soil absorption, 125
Pissis, nitrate deposits, 16
Polarized light, examination, 261
Porosity, 131
determination, 133
Potash, condition in soils, 367
estimation, 355, 358, 361, 365, 368, 370–372, 375–378, 381, 382
international method, 381
Italian method, 377
method of German experiment stations, 375
Tatlock and Dyer, 382
Russian method, 376
salts, deposits, 20
Smith’s method, 378–381
soluble in cold dilute acid, 370
concentrated acids, 368
Potassium, 18
microchemical examination, 263
Pratt, bowlder phosphates, 9

Q
Qualities of soils, 52, 53

R
Rain water, method of collecting, 569
preparation for analysis, 569
Raulin, method of estimating humus, 334
potash, 375
Reaction of a soil, 303
Refractive index, determination, 259
Rideal, method for nitric acid, 553
Rocks, aeolian, 38
aqueous, 32
chemical composition, 30
color, 31
composition, 43
decay, 43–52
eruptive, 41–42
kinds, 32
metamorphic, 39
microscopical structure, 28
minerals, 24–26
sedimentary, 35
types, 28
Rohrbach’s solution, 271
Rowland, fall of particles in liquid, 180

S
Sachsse and Becker, method for iron, 401–403
Salts, preparation for absorption, 130
Samples for moisture, 74
permeability, 74
staple crops, 75
preparation, 454
for elutriation, 229
Sampling, general directions, 66
method of Caldwell, 71
German experiment stations, 69
Grandeau, 77
Hilgard, 67
Lawes, 80
Official Agricultural Chemists, 79
 French Commission, 69, 80
Peligot, 72
Richards, 69
Royal Agricultural Society, 76
Wahnschaffe, 72, 81
Whitney, 68, 73
Wolff, 81
Sandstone, 35
Schaeffer and Deventer, method for nitrous acid, 567
Schloesing method, comparison with Beaker, 241
DeKonick’s modification, 514–516
for nitric acid, 500
French modification, 500–505
of collecting soil gases, 291
silt analysis, 200
Schmidt’s process, 516
Schulze-Tiemann modification, 510–514
Spiegel’s modification, 509
Warington’s modification, 505–508
Schmidt’s method for nitric acid, 539
Schöne’s elutriator, 212
Schulze-Tiemann method, 510–514
Sea-weeds, analysis, 13
Sedimentary rocks, classification, 35
Sediments, separation of fine, 233
weighing, 235
Seeding, method employed, 475
Selective absorption of soils, 122
Separation of silt particles, 272
Shaler, phosphatic limestones, 12
Sieve analysis, classification, 185
German experiment stations, 183
 separation, 182
Sievert’s method for nitric acid, 536
Sifting with water, 183
Silica, 4
direct estimation, 424
estimation, 356, 361, 365
Silt analyses, value, 279
analysis, Belgian method, 204
classification of results, 235, 236
interpretation, 251
Italian method, 195, 206
method of Hilgard, 225
Osborne, 196
Schöne, 212–220
methods, 185
Moore’s modification, 192
Schloesing’s method, 200
statement of results, 194
subsidence of soil particles, 186–188
Wolff’s method, 192
classes, illustrations, 258
particles, color and transparency, 278
examination, with polarized light, 261
forms and dimensions, 257
microchemical examination, 262–266
petrographic examination, 266
separation by specific gravity, 268–277
staining, 261
percentage in soils, 249
separates, microscopic examination, 256
Mineralogical examination, 254–278
Siphon silt cylinder, 190
Soda, estimation, 355, 358, 361, 365, 374, 384
Sodium, 22
amalgam process, 537–539
microchemical examination, 263
Soil absorption, importance, 124
method of determining, 125
analyses, special methods, 367–428
definition, 1
extracts, method of preparing, 158
gases, 149, 150
heat, sources, 102
ingredients, distribution, 247
moisture, 132
particles, number, 251–253
standard sizes, 181
surface area, 253
samples, air drying, 88
preliminary examination, 87–93
treatment in laboratory, 87
sampling, general principles, 65
solutions, analyses, 352–367
temperatures, method of determining, 111
thermometry, 111–116
Soils, absorptive power, 117–131
and subsoils, 62, 63
as a mass, 95
carbon dioxid, 293
chemical elements, 2
classification; according to deposition, 52
cohesion and adhesion, 116, 117
color, 95
compact, 90
composition, relation to gases, 282
conductivity for heat, 115
deficient in carbonates, 340
digestion with solvents, 343–352
estimation of carbonates, 337
loose, 89
mechanical analysis, 171–179
method of estimating absorption of heat, 115
nitrifying power, 467
origin, 1, 43
 preliminary treatment, 87–93
qualities, 52–53
reaction, 303
selective absorption, 122
specific gravity, 98
determination, 99
unusual constituents, 591–593
volume, 100
weight of one hectare, 102
Solar heat, absorption, 103
Specific gravity, 30
of soils, 98–110
apparent, 101
determination of apparent, 101
heat of soils, 102
determination, 104–110
variations, 110
Spencer, photomicrographs, 259
Squanto, manurial value of fish, 14
Staining organisms, method, 487
silt particles, 261
Stassfurt potash salts, 20
Sterilization, 489
by heat, 490
high pressure steam, 492
Sterilized soil, nitrification, 487, 488
Sterilizing apparatus, 490, 493
oven, 491
Stockbridge, composition of humus, 61
soil moisture, 132
Strontium, microchemical examination, 265
Stutzer’s method for nitric acid, 537
Subcultures, method, 479
Subsidence, physical explanation, 180
Sulfanilic acid, preparation, 562
reagent for nitrous acid, 560
Sulfur, 51
state of existence in soils, 419
Sulfuric acid, estimation, 355, 358, 361
French method, 419
Italian method, 422
method of Berthelot and André, 419
Von Bemmelén, 420–422
Wolff, 422
Surface area, influence on absorption, 123
particles, effect of potential, 172
tension, influence, 174
method of estimating, 157
of fertilizers, 156

T
Thenard, humic acid, 62
Thermometry, general principles of soil, 111
Thermostats, 494
Thoulet’s solution, 268

U
Ulmic acid, 61
Ulsch’s method for nitric acid, 539

V
Von Bemmelén, determination of water, 310
method of humus estimation, 332
Vegetable life, action, 48
 soils, 58–60
Volatile matter, estimation, 455

W
Wahnschaffe, preliminary treatment of samples, 91
Warington, absorption of potash and ammonia, 120
and Peake, oxidation of carbon, 316
experiments in nitrification, 468–470, 485–488
indigo method, 528–531
Schloesing method, 505–508
Water absorption by soils, determination, 136–143
capacity of soils, effect of pressure, 143
determination at 110°, 306
general conclusions, 313
estimation after air drying, 305
in water-free atmosphere, 149
in fresh samples, 304
soils, determination, 303–314
movement, causes, 155
in soils, 151–169
methods, 151
relative flow, 159
residual amount, dried at 110°, 308
solvent, action, 47
for soils, 343
special examination, 576–583
total solid matter, 576
Way, absorptive power of soils, 118, 120
Weight of soil, 102
Welitschowsky, measurement of percolation, 161–163
Wheeler and Hartwell, analysis of sea-weeds, 13
Whitney and Marvin, method of determining soil temperatures, 112–
115
causes of water movement, 155
 determination of interstitial space, 134
effect of potential, 172
influence of surface area on absorption, 123
measurement of percolation, 163
relative flow of water, 159
surface tension of fertilizers, 156
theory of subsidence, 180
Williams, machine for mineral sections, 267
-Warington method for nitric acid, 540, 541
Winogradsky, experiments in nitrification, 471–483
Wolff and Wahnschaffe, method of determination of water
absorption, 136
determination of coefficient of evaporation, 148
method for silt analysis, 192
preliminary treatment of soil samples, 88
Wollny, determination of water absorption, 142
occurrence of carbon dioxid, 282
Wülfing’s apparatus, 277
Wyatt, phosphate deposits, 8

X
Xylic acid, 62

Z
Zinc, estimation, 592
 TRANSCRIBER’S NOTES
1. Silently corrected palpable typographical errors;
retained non-standard spellings and dialect.
2. Corrected the items listed on p. viii.
3. Reindexed chapter footnotes using numbers and table
footnotes using letters.
*** END OF THE PROJECT GUTENBERG EBOOK PRINCIPLES
AND PRACTICE OF AGRICULTURAL ANALYSIS. VOLUME 1 (OF
3), SOILS ***

Updated editions will replace the previous one—the old editions

will be renamed.

Creating the works from print editions not protected by U.S.

copyright law means that no one owns a United States copyright
in these works, so the Foundation (and you!) can copy and
distribute it in the United States without permission and without
paying copyright royalties. Special rules, set forth in the General
Terms of Use part of this license, apply to copying and
distributing Project Gutenberg™ electronic works to protect the
PROJECT GUTENBERG™ concept and trademark. Project
Gutenberg is a registered trademark, and may not be used if
you charge for an eBook, except by following the terms of the
trademark license, including paying royalties for use of the
Project Gutenberg trademark. If you do not charge anything for
copies of this eBook, complying with the trademark license is
very easy. You may use this eBook for nearly any purpose such
as creation of derivative works, reports, performances and
research. Project Gutenberg eBooks may be modified and
printed and given away—you may do practically ANYTHING in
the United States with eBooks not protected by U.S. copyright
law. Redistribution is subject to the trademark license, especially
commercial redistribution.

START: FULL LICENSE

THE FULL PROJECT GUTENBERG LICENSE
 PLEASE READ THIS BEFORE YOU DISTRIBUTE OR USE THIS WORK

To protect the Project Gutenberg™ mission of promoting the

free distribution of electronic works, by using or distributing this
work (or any other work associated in any way with the phrase
“Project Gutenberg”), you agree to comply with all the terms of
the Full Project Gutenberg™ License available with this file or
online at www.gutenberg.org/license.

Section 1. General Terms of Use and

Redistributing Project Gutenberg™
electronic works
1.A. By reading or using any part of this Project Gutenberg™
electronic work, you indicate that you have read, understand,
agree to and accept all the terms of this license and intellectual
property (trademark/copyright) agreement. If you do not agree to
abide by all the terms of this agreement, you must cease using
and return or destroy all copies of Project Gutenberg™
electronic works in your possession. If you paid a fee for
obtaining a copy of or access to a Project Gutenberg™
electronic work and you do not agree to be bound by the terms
of this agreement, you may obtain a refund from the person or
entity to whom you paid the fee as set forth in paragraph 1.E.8.

1.B. “Project Gutenberg” is a registered trademark. It may only

be used on or associated in any way with an electronic work by
people who agree to be bound by the terms of this agreement.
There are a few things that you can do with most Project
Gutenberg™ electronic works even without complying with the
full terms of this agreement. See paragraph 1.C below. There
are a lot of things you can do with Project Gutenberg™
electronic works if you follow the terms of this agreement and
help preserve free future access to Project Gutenberg™
electronic works. See paragraph 1.E below.
1.C. The Project Gutenberg Literary Archive Foundation (“the
Foundation” or PGLAF), owns a compilation copyright in the
collection of Project Gutenberg™ electronic works. Nearly all the
individual works in the collection are in the public domain in the
United States. If an individual work is unprotected by copyright
law in the United States and you are located in the United
States, we do not claim a right to prevent you from copying,
distributing, performing, displaying or creating derivative works
based on the work as long as all references to Project
Gutenberg are removed. Of course, we hope that you will
support the Project Gutenberg™ mission of promoting free
access to electronic works by freely sharing Project
Gutenberg™ works in compliance with the terms of this
agreement for keeping the Project Gutenberg™ name
associated with the work. You can easily comply with the terms
of this agreement by keeping this work in the same format with
its attached full Project Gutenberg™ License when you share it
without charge with others.

1.D. The copyright laws of the place where you are located also
govern what you can do with this work. Copyright laws in most
countries are in a constant state of change. If you are outside
the United States, check the laws of your country in addition to
the terms of this agreement before downloading, copying,
displaying, performing, distributing or creating derivative works
based on this work or any other Project Gutenberg™ work. The
Foundation makes no representations concerning the copyright
status of any work in any country other than the United States.

1.E. Unless you have removed all references to Project

Gutenberg:

1.E.1. The following sentence, with active links to, or other

immediate access to, the full Project Gutenberg™ License must
appear prominently whenever any copy of a Project
Gutenberg™ work (any work on which the phrase “Project
Gutenberg” appears, or with which the phrase “Project
Gutenberg” is associated) is accessed, displayed, performed,
viewed, copied or distributed:

This eBook is for the use of anyone anywhere in the United

States and most other parts of the world at no cost and with
almost no restrictions whatsoever. You may copy it, give it
away or re-use it under the terms of the Project Gutenberg
License included with this eBook or online at
www.gutenberg.org. If you are not located in the United
States, you will have to check the laws of the country where
you are located before using this eBook.

1.E.2. If an individual Project Gutenberg™ electronic work is

derived from texts not protected by U.S. copyright law (does not
contain a notice indicating that it is posted with permission of the
copyright holder), the work can be copied and distributed to
anyone in the United States without paying any fees or charges.
If you are redistributing or providing access to a work with the
phrase “Project Gutenberg” associated with or appearing on the
work, you must comply either with the requirements of
paragraphs 1.E.1 through 1.E.7 or obtain permission for the use
of the work and the Project Gutenberg™ trademark as set forth
in paragraphs 1.E.8 or 1.E.9.

1.E.3. If an individual Project Gutenberg™ electronic work is

posted with the permission of the copyright holder, your use and
distribution must comply with both paragraphs 1.E.1 through
1.E.7 and any additional terms imposed by the copyright holder.
Additional terms will be linked to the Project Gutenberg™
License for all works posted with the permission of the copyright
holder found at the beginning of this work.

1.E.4. Do not unlink or detach or remove the full Project

Gutenberg™ License terms from this work, or any files
containing a part of this work or any other work associated with
Project Gutenberg™.
 1.E.5. Do not copy, display, perform, distribute or redistribute
this electronic work, or any part of this electronic work, without
prominently displaying the sentence set forth in paragraph 1.E.1
with active links or immediate access to the full terms of the
Project Gutenberg™ License.

1.E.6. You may convert to and distribute this work in any binary,
compressed, marked up, nonproprietary or proprietary form,
including any word processing or hypertext form. However, if
you provide access to or distribute copies of a Project
Gutenberg™ work in a format other than “Plain Vanilla ASCII” or
other format used in the official version posted on the official
Project Gutenberg™ website (www.gutenberg.org), you must, at
no additional cost, fee or expense to the user, provide a copy, a
means of exporting a copy, or a means of obtaining a copy upon
request, of the work in its original “Plain Vanilla ASCII” or other
form. Any alternate format must include the full Project
Gutenberg™ License as specified in paragraph 1.E.1.

1.E.7. Do not charge a fee for access to, viewing, displaying,

performing, copying or distributing any Project Gutenberg™
works unless you comply with paragraph 1.E.8 or 1.E.9.

1.E.8. You may charge a reasonable fee for copies of or

providing access to or distributing Project Gutenberg™
electronic works provided that:

• You pay a royalty fee of 20% of the gross profits you derive from
the use of Project Gutenberg™ works calculated using the
method you already use to calculate your applicable taxes. The
fee is owed to the owner of the Project Gutenberg™ trademark,
but he has agreed to donate royalties under this paragraph to
the Project Gutenberg Literary Archive Foundation. Royalty
payments must be paid within 60 days following each date on
which you prepare (or are legally required to prepare) your
periodic tax returns. Royalty payments should be clearly marked
as such and sent to the Project Gutenberg Literary Archive
Foundation at the address specified in Section 4, “Information
 about donations to the Project Gutenberg Literary Archive
Foundation.”

• You provide a full refund of any money paid by a user who

notifies you in writing (or by e-mail) within 30 days of receipt that
s/he does not agree to the terms of the full Project Gutenberg™
License. You must require such a user to return or destroy all
copies of the works possessed in a physical medium and
discontinue all use of and all access to other copies of Project
Gutenberg™ works.

• You provide, in accordance with paragraph 1.F.3, a full refund of

any money paid for a work or a replacement copy, if a defect in
the electronic work is discovered and reported to you within 90
days of receipt of the work.

• You comply with all other terms of this agreement for free
distribution of Project Gutenberg™ works.

1.E.9. If you wish to charge a fee or distribute a Project

Gutenberg™ electronic work or group of works on different
terms than are set forth in this agreement, you must obtain
permission in writing from the Project Gutenberg Literary
Archive Foundation, the manager of the Project Gutenberg™
trademark. Contact the Foundation as set forth in Section 3
below.

1.F.

1.F.1. Project Gutenberg volunteers and employees expend

considerable effort to identify, do copyright research on,
transcribe and proofread works not protected by U.S. copyright
law in creating the Project Gutenberg™ collection. Despite
these efforts, Project Gutenberg™ electronic works, and the
medium on which they may be stored, may contain “Defects,”
such as, but not limited to, incomplete, inaccurate or corrupt
data, transcription errors, a copyright or other intellectual
property infringement, a defective or damaged disk or other
medium, a computer virus, or computer codes that damage or
cannot be read by your equipment.

1.F.2. LIMITED WARRANTY, DISCLAIMER OF DAMAGES -

Except for the “Right of Replacement or Refund” described in
paragraph 1.F.3, the Project Gutenberg Literary Archive
Foundation, the owner of the Project Gutenberg™ trademark,
and any other party distributing a Project Gutenberg™ electronic
work under this agreement, disclaim all liability to you for
damages, costs and expenses, including legal fees. YOU
AGREE THAT YOU HAVE NO REMEDIES FOR NEGLIGENCE,
STRICT LIABILITY, BREACH OF WARRANTY OR BREACH
OF CONTRACT EXCEPT THOSE PROVIDED IN PARAGRAPH
1.F.3. YOU AGREE THAT THE FOUNDATION, THE
TRADEMARK OWNER, AND ANY DISTRIBUTOR UNDER
THIS AGREEMENT WILL NOT BE LIABLE TO YOU FOR
ACTUAL, DIRECT, INDIRECT, CONSEQUENTIAL, PUNITIVE
OR INCIDENTAL DAMAGES EVEN IF YOU GIVE NOTICE OF
THE POSSIBILITY OF SUCH DAMAGE.

1.F.3. LIMITED RIGHT OF REPLACEMENT OR REFUND - If

you discover a defect in this electronic work within 90 days of
receiving it, you can receive a refund of the money (if any) you
paid for it by sending a written explanation to the person you
received the work from. If you received the work on a physical
medium, you must return the medium with your written
explanation. The person or entity that provided you with the
defective work may elect to provide a replacement copy in lieu
of a refund. If you received the work electronically, the person or
entity providing it to you may choose to give you a second
opportunity to receive the work electronically in lieu of a refund.
If the second copy is also defective, you may demand a refund
in writing without further opportunities to fix the problem.

1.F.4. Except for the limited right of replacement or refund set

forth in paragraph 1.F.3, this work is provided to you ‘AS-IS’,
WITH NO OTHER WARRANTIES OF ANY KIND, EXPRESS