Endocrinology Basic and Clinical Principles - part 1 ppsx

RICARDO AZZIZ,MD,MPH,MBA • Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA RACHEL L.. HEANEY,MD,PhD • Division of Endocrino

E NDOCRINOLOGY

Cedars Sinai Medical Center

and UCLA School of Medicine

P M ICHAEL C ONN , P h D

Oregon Health & Science University

Beaverton, OR

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Library of Congress Cataloging-in-Publication Data

Endocrinology : basic and clinical principles / edited by Shlomo Melmed, P Michael Conn.— 2nd ed.

p cm.

Includes bibliographical references and index.

ISBN 1-58829-427-7 (alk paper) eISBN 1-59259-829-3

1 Endocrinology 2 Hormones 3 Endocrine glands—Diseases I Melmed, Shlomo II Conn, P Michael.

QP187.E555 2005

612.4—dc22 2004018638

Endocrinology: Basic and Clinical Principles,

Sec-ond Edition aims to provide a comprehensive

knowl-edge base for the applied and clinical science of

endocrinology The challenge in its presentation was

to produce a volume that was timely, provided

integra-tion of basic science with physiologic and clinical

prin-ciples, and yet was limited to 500 pages This length

makes the volume suitable as a text; and the timeliness

we have striven for allows the book to serve as an

off-the-shelf reference Our goal was achieved largely

through the selection of authors who are both expert

writers and teachers Tables and illustrative matter

were used optimally to present information in a

con-cise and comparative format

Endocrinology: Basic and Clinical Principles,

Sec-ond Edition will be useful to physicians and scientists as

well as to students who wish to have a high-quality,

P REFACE

current reference to the general field of endocrinology.The use of an outline system and a comprehensive indexwill allow readers to locate promptly topics of particu-lar interest Key references are provided throughout forindividuals requiring more in-depth information Thevolume covers the comprehensive spectrum of currentknowledge of hormone production and action, evenincluding nonmammalian systems and plants, coveragerarely included in similar volumes

The editors wish to express appreciation to our tinguished chapter authors for their efforts, as well asdiligently meeting publication deadlines and to the staff

dis-at Humana Press for their cooperdis-ation and useful gestions

sug-Shlomo Melmed

P Michael Conn

Preface viiContributors ixValue Added eBook xi

1 Introduction to Endocrinology 3

P Michael Conn

2 Receptors: Molecular Mediators of Hormone Action 9

Derek Henley, Jonathan Lindzey, and Kenneth S Korach

5 Plasma Membrane Receptors for Steroid Hormones

in Cell Signaling and Nuclear Function 67

Richard J Pietras and Clara M Szego

6 Growth Factors 85

Derek LeRoith and William L Lowe Jr.

7 Prostaglandins and Leukotrienes: Locally Acting Agents 93

John A McCracken

8 The Neuroendocrine–Immune Interface 113

Michael S Harbuz and Stafford L Lightman

9 Insect Hormones 127

Lawrence I Gilbert

10 Phytohormones and Signal Transduction Pathways in Plants 137

William Teale, Ivan Paponov, Olaf Tietz, and Klaus Palme

11 Comparative Endocrinology 149

Fredrick Stormshak

vii

C ONTENTS

Part IV Hypothalamic–Pituitary

12 Hypothalamic Hormones:

GnRH, TRH, GHRH, SRIF, CRH, and Dopamine 173 Constantine A Stratakis and George P Chrousos

13 Anterior Pituitary Hormones 197

Ilan Shimon and Shlomo Melmed

14 Posterior Pituitary Hormones 211

Daniel G Bichet

15 Endocrine Disease: Value for Understanding Hormonal Actions 233

Anthony P Heaney and Glenn D Braunstein

16 The Pineal Hormone (Melatonin) 255

Irina V Zhdanova and Richard J Wurtman

19 Oncogenes and Tumor Suppressor Genes in Tumorigenesis

of the Endocrine System 301

Anthony P Heaney and Shlomo Melmed

20 Insulin Secretion and Action 311

Run Yu, Hongxiang Hui, and Shlomo Melmed

21 Cardiovascular Hormones 321

Willis K Samson and Meghan M Taylor

22 Adrenal Medulla (Catecholamines and Peptides) 337

William J Raum

23 Hormones of the Kidney 353

Masashi Mukoyama and Kazuwa Nakao

24 Reproduction and Fertility 367

Neena B Schwartz

25 Endocrinology of Fat, Metabolism, and Appetite 375

Rachel L Batterham and Michael A Cowley

26 Endocrinology of the Ovary 391

Denis Magoffin, Ashim Kumar, Bulent Yildiz, and Ricardo Azziz

RICARDO AZZIZ,MD,MPH,MBA • Department of

Obstetrics and Gynecology, Cedars-Sinai Medical

Center, UCLA School of Medicine, Los Angeles, CA

RACHEL L BATTERHAM,MBBS,PhD • University College

London, London, UK

DANIEL G BICHET,MD • Clinical Research Unit and

Nephrology Service, Hospital du Sacre-Coeur de

Montreal, Montreal, Canada

GLENN D BRAUNSTEIN,MD • Department of Medicine,

Cedars-Sinai Medical Center, UCLA School

of Medicine, Los Angeles, CA

GREGORY A BRENT,MD • Departments of Medicine

and Physiology, UCLA School of Medicine,

Los Angeles, CA

GEORGE P CHROUSOS,PhD • National Institute of Child

Health & Human Development, National Institutes

of Health, Bethesda, MD

P MICHAEL CONN,PhD • Oregon National Primate

Research Center, Oregon Health and Science

University, Beaverton, OR

MICHAEL A COWLEY,PhD • Oregon National Primate

Research Center, Oregon Health and Science

University, Beaverton, OR

LAWRENCE I GILBERT,PhD • Department of Biology,

University of North Carolina, Chapel Hill, NC

MICHAEL S HARBUZ,PhD • Department of Medicine,

Henry Wellcome Laboratories for Integrated

Neuroscience and Endocrinology, University

of Bristol, Bristol, UK

ANTHONY P HEANEY,MD,PhD • Division of

Endocrinology and Metabolism, Cedars-Sinai

Medical Center, UCLA School of Medicine, Los

Angeles, CA

GEOFFREY N HENDY,PhD • Department of Medicine,

Royal Victoria Hospital, McGill University,

Montreal, Canada

DEREK V HENLEY,PhD • Laboratory of Reproductive

and Developmental Toxicology, National Institute

of Environmental Health Sciences, National

Institutes of Health, Research Triangle Park, NC

AMIYA SINHA HIKIM,PhD • Division of Endocrinology,

Department of Medicine, Harbor-UCLA Medical

Center and Education and Research Institute,

UCLA School of Medicine, Torrance, CA

C ONTRIBUTORS

HONGXIANG HUI,MD,PhD • Division of Endocrinology,

Cedars-Sinai Medical Center, UCLA School

of Medicine, Los Angeles, CA

TAKAHIKO KOGAI,MD,PhD • Division of Endocrinology

and Diabetes, VA Greater Los Angeles Healthcare System, UCLA School of Medicine,

Los Angeles, CA

KENNETH S KORACH,PhD • Laboratory of Reproductive

and Developmental Toxicology, National Institute

of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC

ASHIM KUMAR,MD • Department of Obstetrics and

Gynecology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA

STEVEN W J LAMBERTS,MD,PhD • Department

of Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

DEREK LEROITH,MD,PhD • Diabetes Branch, National

Institutes of Health, Bethesda, MA

STAFFORD L LIGHTMAN,PhD • Department of Medicine,

Henry Wellcome Laboratories for Integrated Neuroscience and Endocrinology, University

of Bristol, Bristol, UK

JONATHAN LINDZEY,PhD • Department of Natural

Sciences, Clayton College and State University, Morrow, GA

WILLIAM L LOWE JR.,MD • Department of Medicine,

Northwestern University Medical School, Chicago, IL

DENIS MAGOFFIN,PhD • Department of Obstetrics and

Gynecology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA

KELLY E MAYO,PhD • Department of Biochemistry,

Molecular Biology, and Cell Biology, Center for Reproductive Science, Northwestern University, Evanston, IL

JOHN A MCCRACKEN,PhD • University of Connecticut,

Storrs, CT

SHLOMO MELMED,MD • Division of Endocrinology and

Metabolism, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA

MASASHI MUKOYAMA,MD,PhD • Department of Medicine

and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan

KAZUWA NAKAO,MD,PhD • Department of Medicine

and Clinical Science, Kyoto University Graduate School

of Medicine, Kyoto, Japan

KLAUS PALME,PhD • Institute for Biology,

Albert-Ludwigs-Universität Freiburg, Freiburg,

Germany

IVAN PAPONOV,PhD • Institute for Biology,

Albert-Ludwigs-Universität Freiburg, Freiburg,

Germany

RICHARD J PIETRAS,MD,PhD • Department

of Medicine, Division of Hematology-Oncology,

Jonsson Comprehensive Cancer Center, UCLA

School of Medicine, Los Angeles, CA

WILLIAM J RAUM,MD,PhD • Departments of Medicine

and Surgery, Louisiana State University Medical

Center, New Orleans, LA

WILLIS K SAMSON,PhD • Department of

Pharmacologic and Physiologic Science, St.

Louis University School of Medicine, St Louis,

MO

NEENA B SCHWARTZ,PhD • Department of

Neuro-biology and Physiology, Northwestern University,

Evanston, IL

ILAN SHIMON,MD • Institute of Endocrinology, Sheba

Medical Center, Tel-Hashomer, Israel

ELIOT R SPINDEL,MD,PhD • Oregon National Primate

Research Center, Oregon Health and Science

University, Beaverton, OR

FREDRICK STORMSHAK,PhD • Departments of

Biochemistry/Biophysics and Animal Sciences,

Oregon State University, Corvalis, OR

CONSTANTINE A STRATAKIS,PhD,DSc • National

Institutes of Health, Bethesda, MD

RONALD S SWERDLOFF,MD • Division of Endocrinology,

Department of Medicine, Harbor-UCLA Medical Center and Education and Research Institute, UCLA School of Medicine, Torrance, CA

CLARA M SZEGO,PhD • Department of Molecular,

Cellular, and Developmental Biology, Molecular Biology Institute, University of California, Los Angeles, CA

MEGHAN M TAYLOR,PhD • Department of

Pharma-cologic and Physiologic Science, St Louis University School of Medicine, St Louis, MO

WILLIAM TEALE,PhD • Institute for Biology,

Albert-Ludwigs-Universität Freiburg, Freiburg, Germany

OLAF TIETZ,PhD • Institute for Biology, Universität Freiburg, Freiburg, Germany

Albert-Ludwigs-CHRISTINA WANG,MD • Division of Endocrinology,

Department of Medicine, General Clinical Research Center, Harbor-UCLA Medical Center and Education and Research Institute, UCLA School of Medicine, Torrance, CA

RICHARD J WURTMAN,MD • Department of Brain

and Cognitive Sciences, Clinical Research Center, Massachusetts Institute of Technology,

Cambridge, MA

BULENT YILDIZ,MD • Interdepartmental Clinical

Pharma-cology Center, UCLA School of Medicine, Los Angeles, CA

RUN YU,MD,PhD • Division of Endocrinology,

Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA

IRINA V ZHDANOVA,MD,PhD • Department of Anatomy

and Neurobiology, Boston University School

of Medicine, Boston, MA

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xi

Chapter 1 / Short Chapter Title 1

I NTRODUCTION

P ART

I

2 Part I / Introduction

Chapter 1 / Short Chapter Title 3

3

From: Endocrinology: Basic and Clinical Principles, Second Edition

(S Melmed and P M Conn, eds.) © Humana Press Inc., Totowa, NJ

HORMONE-DERIVED DRUGS

ENDOCRINOLOGY AS A LEAD SCIENCE

responses in another animal are referred to as

phero-mones.

Sometimes the word hormone is used as a reference

to substances in plants (phytohormones) or in brates that have open “circulatory” systems very dif-ferent from those found in vertebrates On otheroccasions, growth factors are (appropriately) calledhormones, because they mediate signaling betweencells In recent years, the word has become a catchall todescribe substances released by one cell that provoke aresponse in another cell even when the messenger sub-stance does not enter the general circulation The sci-ence of endocrinology has broad coverage indeed

inverte-3 HORMONES CONVEY INFORMATION THAT REGULATES CELL PROCESSES

Characteristically, hormones transmit informationabout the status of one organ to another, regulating cor-rective actions to maintain homeostasis For example,elevated glucose in the blood signals the pancreas torelease insulin Insulin travels through the circulation,signaling target cells in liver and fat cells to increasetheir permeability to glucose; conversely, processedsugar is stored in cells as blood levels drop

1 INTRODUCTION

The earliest bacterial fossils date back about 3

bil-lion years That was a simpler time! Communications

between cells were more modest than those required to

maintain a multicellular organism and were probably

focused on the ability to signal the presence of

benefi-cial substances (food) or deleterious substances

(tox-ins) in the local environment

2 DEFINITIONS

Substances that provide the chemical basis for

com-munication between cells are called hormones This

word, coined by Bayliss and Starling, was originally

used to describe the products of ductless glands

released into the general circulation in order to respond

to changes in homeostasis Hormone has taken on a

broader usage in recent years Sometimes hormones

are released into portal (closed) circulatory systems

and have local actions The word paracrine is used to

describe the release of locally acting substances This

word also describes local hormone action as the

diffu-sion of gastric juice acts on neighboring cells

Hor-monal substances released by an animal that influence

4 Part I / Introduction

To be effective, hormones should not be degraded

too quickly (i.e., before arrival at the target site) If

degradation is too slow, on the other hand, the

infor-mation conveyed will be obsolete and may evoke an

inappropriate response Accordingly, it is not

surpris-ing that different hormones have varysurpris-ing half-lives in

the circulation, depending, in part, on the distance that

the signal must travel and the nature of the information

to be conveyed

Concentrations of hormones are sensed by

recep-tors, usually proteins, located on the surface (i.e.,

plasma membrane) or inside target cells Receptors

bind their respective hormone ligands with high

affin-ity and specificaffin-ity For example, although estrogen and

testosterone are chemically similar, receptors must

dis-tinguish between them because they mediate very

dif-ferent cellular responses indeed When hormone

receptors are situated on the surface of target cells and

the response involves intracellular changes (e.g.,

evok-ing secretione), transduction of the hormonal message

must occur Such transduction molecules are termed

second messengers of hormone action.

It is a general truth that the chemical structures of

hormones do not change markedly during evolution;

instead, nature identifies and conserves molecules that

already have information value and develops systems

that preserve and utilize that information Steroids,

thy-roid hormones, and peptides are present in some species

that do not utilize them for the same endocrine purpose

as do mammals

4 IDENTIFYING HORMONES

The effects of ablation of endocrine organs have

been documented back to the time of Aristotle (384–

322BC), who described changes in secondary sex

char-acteristics and loss of reproductive capacity associated

with castration in men Much insight into the role of

endocrine substances has come from disease states,

surgical errors, and animal experimentation in which

damage to endocrine organs is correlated with

particu-lar phenotypic changes in the organism

Ancient medical procedures prevalent in many

cul-tures were based on the premise that administration of

extracts from healthy organs aids in the recovery of

dis-eased organs This practice may be viewed as a

prede-cessor to hormone replacement therapy Restoration of

function by supplements derived from healthy

endo-crine organs administered to animals with endoendo-crine

ablations has formed the basis of discovering active

principles of the endocrine system

In the mid-1800s, Berthold showed that the effects of

castration in avians could be reversed by placing a testis

in the body cavity Since the transplant was ectopic and

not innervated, he concluded that the testes released asubstance that controlled secondary sex characteristics

A few years later, Claude Bernard, providing dence to support a model of homeostasis, showed thatthe liver could release sugar to the blood From the mid-1850s to the twentieth century, endocrinology grew at adramatic pace Assays became more sensitive and spe-cific; biosynthetic and genetic engineering techniquesnow allow synthesis of biologically active and highlypurified hormones

evi-5 HORMONE-DERIVED DRUGS

The identification of new hormonal activities oftenfollows a similar pattern The observation is made thatdamage to a particular gland is associated with loss of acertain function Efforts are then focused on isolatingthe active principle from the gland The active principle

is then administered to restore the function to the animalpatient who has ablated glandular function The devel-opment of drugs is usually directed toward preparingpurified fractions that can be used in replacementtherapy The hormone itself and, ultimately, chemicalanalogs can now readily be synthesized Analogs can bedesigned to possess desirable properties, such as pro-longed circulation half-lives, chemical stability, or spe-cific receptor or tissue targeting The availability ofpurified fractions or synthetic hormone preparationsoften spawns studies designed to understand the cellularand molecular basis of hormone action This informa-tion is then used to design even more useful drugs thatrecognize the target cell receptor with higher specificityand affinity; antagonists can also be prepared that blockthe receptor or its signaling The science of endocrinol-ogy is poised to take advantage of our understanding ofintricate second-messenger systems, sensitive and pre-cise assay systems (radioimmunoassays, bioassays,radioligand assays), and advances in structural and func-tional molecular biology As the tools of endocrinologyhave become more precise, we have discovered that eventhe brain, heart, and lung possess substantial endocrinefunctions

6 ENDOCRINOLOGY

AS A LEAD SCIENCE

Endocrinology continues to be a lead science ManyNobel Prizes have recognized the contributions of endo-crinologists The first cloned gene products to reach theclinical pharmaceutical market were endocrine sub-stances Many advances in our understanding of cellulartransduction systems, receptor binding, and physiologicregulation are derivatives of the studies conducted inendocrine laboratories Why is this so? A likely answer

Chapter 1 / Short Chapter Title 5

is found by understanding that endocrinologists study

the actions of specific chemicals that cause cells to

undergo specific and (usually) easily quantifiable and

regulated responses These are very simple, basic, and

well-defined processes Accordingly, clear and

inter-pretable experiments can be designed at a complexity

ranging from molecular to physiologic This is part ofthe general appeal and high level of achievement of thisscience—and much of the reason that those who callthemselves endocrinologists have made a major contri-bution to our understanding of regulatory biologic pro-

cesses.

Chapter 2 / Receptors 7

H ORMONE S ECRETION AND A CTION

P ART

II

8 Part II / Hormone Secretion and Action

Chapter 2 / Receptors 9

9

From: Endocrinology: Basic and Clinical Principles, Second Edition

(S Melmed and P M Conn, eds.) © Humana Press Inc., Totowa, NJ

GENERAL ASPECTS OF RECEPTOR ACTION

CELL-SURFACE RECEPTORS

INTRACELLULAR RECEPTORS

RECEPTORS, HEALTH,AND DISEASE

CONCLUSION

1 INTRODUCTION

The appropriate proliferation and differentiation of

cells during development and the maintenance of

cellu-lar homeostasis in the adult require a continuous flow of

information to the cell This is provided either by

diffus-ible signaling molecules or by direct cell–cell and cell–

matrix interactions All cells utilize a wide variety of

signaling molecules and signal transduction systems to

communicate with one another, but within the

verte-brate endocrine system, it is the secreted hormones that

are classically associated with cellular signaling

Hor-mones are chemical messengers produced from the

en-docrine glands that act either locally or at a distance to

regulate the activity of a target cell As discussed in

detail elsewhere within this volume, prominent groups

of hormonal agents include peptide hormones; steroid,

retinoid, and thyroid hormones; growth factors;

cyto-kines; pheromones; and neurotransmitters or

neuro-modulators

Endocrine signaling molecules exert their effects by

interacting with specific receptor proteins that are

gen-erally coupled to one or more intracellular effector

sys-tems The presence of an appropriate receptor thereforedefines the population of target cells for a given hor-mone and provides a molecular mechanism by whichthe hormone elicits its biologic actions These hormonereceptor proteins are the focus of this chapter Section 2considers general concepts of receptor action, includingreceptor structure, interaction with the hormone ligand,activation of cellular effector systems, and receptorregulation Sections 3 and 4 then examine the majorfamilies of hormone receptors, grouped with respect

to their structures and signaling properties, in greaterdetail, using specific examples that illustrate the generalfeatures of each family Finally, Section 5 discussessome of the endocrinopathies that result from knownalterations in hormone receptor structure or function

2 GENERAL ASPECTS

OF RECEPTOR ACTION 2.1 Receptors as Mediators