Selective Estrogen Receptor Modulators: Research and Clinical Applications

369 Pages·2002·9.156 MB·English

by  Stefan Nilsson PhD, Jan-Åke Gustafsson MD, PhD (auth.), Andrea Manni MD, Michael F. Verderame PhD (eds.)

SELECTIVE ESTROGEN RECEPTOR MODULATORS
CONTEMPORARY ENDOCRINOLOGY
P. Michael Conn,
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SELECTIVE ESTROGEN
RECEPTOR MODULATORS
Research and Clinical Applications
Edited by
ANDREA MANNI, MD
F.
MICHAEL VERDERAME, PhD
Division ofE ndocrinology, Diabetes, and Metabolism
Pennsylvania State University College ofM edicine
Milton S. Hershey Medical Center
Hershey, PA
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Library of Congress Cataloging-in-Publication Data
Selective estrogen receptor modulators : research and clinic al applications / edited by Andrea Manni, Michael F.
Verderame.
p. ; cm. -- (Contemporary endocrinology)
Includes bibliographical references and index.
ISBN 978-1-4684-9665-9 ISBN 978-1-59259-157-2 (eBook)
DOI 10.1007/978-1-59259-157-2
1. Selective estrogen receptor modulators. 2. Menopause--Hormone therapy. 1. Manni, Andrea. II.
Verderame, Michael, 1957-III. Contemporary endocrinology (Totowa, N.J.)
[DNLM: 1. Selective Estrogen Receptor Modulators. 2. Estrogen Replacement Therapy--methods. 3.
Postmenopause--drug effects. 4. Receptors, Estrogen--physiology. WP 522 S464 2002]
RG186.S442002
618.1 '75--dc21
2001026442
PREFACE
The sharp decline in ovarian steroidogenesis occurring at the time of the menopause
results in immediate adverse events that impair quality of life. These can include vaso
motor instability and urogenital atrophy, as well as more long-term sequelae such as
increased morbidity and mortality from cardiovascular disease and osteoporotic
fractures. Hormone replacement therapy (HRT) with estrogen and progesterone (in the
presence of an intact uterus) is clearly effective in alleviating symptoms of hot flashes and
urogenital atrophy. Case control and cohort studies have also indicated that HRT reduces
the risks of cardiovascular disease and osteoporotic fractures. However, results from
the Heart and EstrogenlProgestin Replacement Study (HERS), which failed to demonstrate
a benefit in cardiovascular mortality in women with established heart disease, emphasize
the difficulty in drawing conclusions from epidemiological data. Despite its proven or
implied benefits, HRT is associated with a variety of significant drawbacks that
include increased risks of breast cancer, uterine cancer, deep vein thrombosis, gall
bladder disease, and breast enlargement/tenderness. Because of these disadvantages,
HRT is restricted to a relatively small fraction of postmenopausal women, and long-term
compliance with treatment is estimated to be only 15-40%.
Agents that retain the benefits of estrogens but at the same time avoid the risks are
urgently needed to provide postmenopausal women with an optimal form of HRT.
Selective Estrogen Receptor Modulators (SERMs) are a class of drugs with mixed estrogen
agonistic/antagonistic activity that holds promise in fulfilling this need. Tamoxifen, the
first and most studied of these compounds, has been in clinical practice for over 20 years
in the treatment of women with hormone-responsive breast cancer. As a result of its
antiestrogenic action in the breast, tamoxifen may, indeed, be effective as a chemo
preventive agent for hormone-responsive breast cancer, while its partial estrogen agonistic
effects on the skeletal system and on serum lipoproteins may offer protection from
osteoporosis and cardiovascular disease. Although demonstration of these clinical
benefits is still preliminary or lacking (e.g., reduction in heart disease risk), such mixed
agonistic/antagonistic properties of tamoxifen provide proof of principle for the feasi
bility of developing new SERMs with an improved pharmacologic and therapeutic
activity profile. A possible improvement in this regard may have been the introduction
of raloxifene, which, in contrast to tamoxifen, has minimal estrogen-like activity in the
uterus. As a result, its use has not been associated with an increased risk of endometrial
cancer.
Over the last several years, our knowledge of the basic cellular mechanisms governing
estrogen action has grown exponentially. The simple model of estradiol binding to
its cognate receptors (ER) followed by binding of the complexed receptor to estrogen
responsive elements of target genes has significantly expanded to include multiple addi
tional interactive components. Several chapters in the Basic Studies section address in
detail the cellular mechanisms of action of estrogens and SERMS, focusing on important
aspects such as distinct ligand-dependent conformational changes in the ER that playa
v
vi Preface
critical role in the recruitment of coactivators and corepressors and the bidirectional
crosstalk between estrogen receptor and growth-factor signaling. Differences in
tissue distribution and function ofER-a and -~ are also reviewed and discussed. Under
standing of these basic mechanisms is critical for the design of new SERMs with
improved tissue-specific estrogen agonistic/antagonistic activity resulting in maximal
health benefits and minimal risks. The chapters in the Basic Studies section will provide
a comprehensive updated review of the preclinical studies with currently available
SERMs focusing on their effects on critical target organs such as the cardiovascular
system and the brain.
The Clinical Studies section will compare and contrast the influence of estrogens and
currently available SERMs (primarily tamoxifen and raloxifene) on the major clinical
endpoints, such as incidences of breast cancer, cardiovascular disease, osteoporosis, and
cognitive impairment. Based on our current state of knowledge, a tentative approach to
menopause-related health issues will be provided both for normal women as well as for
women with a previous diagnosis of localized breast cancer. We believe that
Selective Estrogen Receptor Modulators: Research and Clinical Applications will be of
interest to basic scientists in endocrinology, tumor biology, and pharmacology, as well
as a wide range of clinicians, including endocrinologists, medical oncologists, gynecol
ogists, and family practitioners. We wish to thank the many contributors, who are distin
guished leading experts in their fields and without whose major efforts this book would
not have been possible.
Andrea Manni, MD
Michael F. Verderame, PhD
CONTENTS
Preface ................................................................................................... v
Contributors ......................................................................................... ix
BASIC STUDIES
I Molecular Mechanisms of Estrogen Receptor Function
1 Structure and Function of the Estrogen Receptor
Stefan Nilsson, PHD and Jan-like Gustafsson, MD, PHD ....................... 3
2 Ligand-Induced Conformational Changes
in Estrogen Receptors-a and -~
Elizabeth A. Allegretto, PHD •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 19
3 Expression and Function of Estrogen Receptors-a and -~
Jonathan Lindzey, PHD •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 29
4 SERM Modulation of Gene Expression:
Role of Coactivators and Corepressors
Paul Webb, PHD ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 57
5 Crosstalk Between Estrogen Receptors
and Growth Factor Signaling
Douglas Yee, MD and Carol A. Lange, PHD •••••••••••••••••••••••••••••••••••••••• 77
II Tissue-Specific Effects of Estrogens and SERMs
6 Direct Estrogen Effects on the Cardiovascular System
Munish K. Goyal, MD and Suzanne Oparil, MD ................................ 99
7 Estrogens and the Brain: Implications for the Treatment
of Postmenopausal Women
Bruce S. McEwen, PHD, Phyllis M. Wise, PHD,
and Stanley Birge, MD ................................................................. 121
III Preclinical Studies
8 Insights into the Molecular Mechanism of SERMs
Through New Laboratory Models
Csaba Gajdos, MD, James Zap/, PHD,
and V. Craig Jordan, PHD, DSc .................................................................................... 147
9 Third- and Fourth-Generation SERMs
Fernand Labrie, MD, PHD, Claude Labrie, MD, PHD,
Alain Belanger, PHD, and Jacques Simard, PHD .......................... 167
VlI
viii Contents
CLINICAL STUDIES
IV Organ Specific Effects of Estrogens and SERMs
10 SERMs' Effect on the Neuroendocrine System
and the Reproductive Organs
Nanette F. Santoro, MD, and Peter Kovacs, MD .............................. 191
11 Epidemiology of Cardiovascular Disease in Women:
Role of Estrogens
Jacques E. Rossouw, MD .................................................................. 207
12 SERMs Effects on Cardiovascular Risk Factors and Disease
Richard R. wve, MD ......................................................................... 223
13 Estrogen and the Skeleton
Michael Kleerekoper, MD, FACE and Ashish Verma, MD ................. 237
14 Effects of SERMs on Bone in Clinical Studies
Aurelie Fontana, MD, and Pierre D. Delmas, MD, PHD .................... 245
15 Estrogens and SERMs: Clinical Aspects of Cognition
with Aging and Neurodegenerative Disorders
Alan J. Lerner, MD ............................................................................ 255
V SERMs and Endocrine Dependent Tumors
16 SERMs and Breast Cancer Prevention
Jenny Chang, MD and C. Kent Osborne, MD ................................... 267
17 SERMs in Postmenopausal Women's Health
Jan L. Shifren, MD, and Leo Plouffe, Jr., MD, CM ........................... 279
VI Roles of Estrogens and SERMs
in Postmenopausal Hormone Replacement Therapy
18 Menopause Therapy: An Individualized Approach
Nananda F. Col, MD, FACP, MPP, MPH, Michele G. Cyr, MD, FACP
and Anne W. Moulton, MD, FACP ................................................. 299
19 Alternatives to Estrogen for Treatment of Menopause
Richard J. Santen, MD and JoAnn V. Pinkerton, MD ..................... 313
20 Phytoestrogens in the Context of SERMs
Susan R. Davis, MB, BS, PHD, FRACP ................................................... 345
Index .................................................................................................. 365
CONTRIBUTORS
ELIZABETH A. ALLEGRETTO, PHD • Experimental Station, Dupont Pharmaceuticals
Company, Wilmington, DE
ALAIN BELANGER, PHD • Oncology and Molecular Endocrinology Research Center,
Quebec City, Quebec, Canada
STANLEY BIRGE, MD • Department of Geriatrics, Washington University School
of Medicine, St. Louis, MO
JENNY CHANG, MD • Breast Center, Baylor College of Medicine, Houston, TX
NANANDA F. COL, MD, FACP, MPP, MPH • Department of Medicine, Harvard University
Medical School and Brigham and Women's Hospital, Boston, MA
MICHELE G. CYR, MD, FACp· Department of Medicine, Brown University School
of Medicine, Providence, RI
SUSAN R. DAVIS, MB, BS, PHD, FRACp· The Jean Hailes Research Unit, Victoria, Australia
PIERRE D. DELMAS, MD, PHD • Claude Bernard University of Lyon, Hospital Herriot,
Lyon, France
AURELIE FONTANA, MD • Claude Bernard University of Lyon, Hospital Herriot, Lyon,
France
CSABA GAJDOS, MD • Robert H. Lurie Comprehensive Cancer Center, Northwestern
University Medical School, Chicago, IL
MUNISH K. GOYAL, PHD· University of Alabama at Birmingham, Birmingham, AL
JAN-AKE GUSTAFSSON, MD, PHD • Department of Medical Nutrition, Karolinska
Institute; Novum-Huddinge University Hospital, Huddinge, Sweden
V. CRAIG JORDAN, PHD, DSc· Robert H. Lurie Comprehensive Cancer Center,
Northwestern University Medical School, Chicago, IL
MICHAEL KLEEREKOPER, MD, FACE· Division of Endocrinology, Wayne State
University, Detroit, MI
PETER KOVACS, MD· Division of Reproductive Endocrinology, Department
of Obstetrics/Gynecology and Women's Health, Albert Einstein College
of Medicine, Bronx, NY
CLAUDE LABRIE, MD, PHD • Oncology and Molecular Endocrinology Research Center,
Quebec City, Quebec, Canada
FERNAND LABRIE, MD, PHD • Oncology and Molecular Endocrinology Research Center,
Quebec City, Quebec, Canada
CAROL A. LANGE, PHD • University of Minnesota Cancer Center, Minneapolis, MN
ALAN J. LERNER, MD • Department of Neurology, Case Western Reserve University;
Alzheimer Center, Cleveland, OH
JONATHAN LINDZEY, PHD • Department of Biology, University of South Florida,
Tampa, FL
RICHARD R. LOVE, MD· Department of Medicine, University of Wisconsin,
Madison, WI
ix
x Contributors
BRUCE S. McEwEN, PHD • Laboratory of Neuroendocrinology, Rockefeller
University, New York, NY
ANNE W. MOULTON, MD, FACP • Department of Medicine, Brown University School
of Medicine, Providence, RI
STEFAN NILSSON, PHD • KaroBio AB, Novum, Huddinge, Sweden
SUZANNE OPARIL, MD • University of Alabama at Birmingham, Birmingham, AL
C. KENT OSBORNE, MD • Breast Center, Baylor College of Medicine, Houston, TX
JOANN PINKERTON, MD • Midlife Health Center, University of Virginia Health
Science Center, Charlottesville, VA
LEO PLOUFFE, JR., MD, CM • Lilly Research Laboratory, Eli Lilly Company,
Indianapolis, IN
JACQUES E. Rossouw, MD· Women's Health Initiative, National Heart, Lung, and
Blood Institute, Bethesda, MD
RICHARD J. SANTEN, MD • Division of Endocrinology, University of Virginia Health
Science Center, Charlottesville, VA
NANETTE F. SANTORO, MD • Director, Division of Reproductive Endocrinology,
Department of Obstetrics/Gynecology and Women's Health, Albert Einstein
College of Medicine, Bronx, NY
JAN L. SHIFREN, MD • Vincent OB/GYN Service, Massachusetts General Hospital;
Harvard University Medical School, Boston, MA
JACQUES SIMARD, PHD • Oncology and Molecular Endocrinology Research Center,
Quebec City, Quebec, Canada
ASHISH VERMA, MD • Division of Endocrinology, Wayne State University, Detroit,
MI
PAUL WEBB, PHD • Metabolic Research Unit, University of California
at San Francisco, San Francisco, CA
PHYLLIS M. WISE, PHD • Department of Physiology, University of Kentucky School
of Medicine, Lexington, KY
DOUGLAS YEE, MD • University of Minnesota Cancer Center, Minneapolis, MN
JAMES ZAPF, PHD • Maxie Pharmaceutical, San Diego, CA