NATIONAL INSTITUTES 

National Heart, Lung, and Blood Institute

O f f i c e o f R e s e a rc h o n Wo m e n ’s H e a l t h

Giovanni Lorenzini Medical Science Founda

I NTERNATIONAL

P OSITION P APER

o n

W OMEN ’ S H EALTH

AND M ENOPAUSE :

A C OMPREHENSIVE

A PPROACH

NATIONAL HEART, LUNG, 

AND BLOOD INSTITUTE

OFFICE OF RESEARCH ON

WOMEN’S HEALTH

NATIONAL INSTITUTES OF HEALTH

AND

GIOVANNI LORENZINI MEDICAL

SCIENCE FOUNDATION

NIH PUBLICATION NO. 02-3284

JULY 2002
II

CHAIRS AND EDITORS

Chair and Editor

Nanette K. Wenger, M.D. 

Professor of Medicine (Cardiology)

Emory University School of Medicine

Atlanta, GA, U.S.A.

Cochair and Coeditor

Rodolfo Paoletti, M.D.

Professor of Pharmacology

Director, Department of Pharmacological Sciences

University of Milan

Milan, Italy 

Cochair and Coeditor

Claude J. M. Lenfant, M.D.

Director

National Heart, Lung, and Blood Institute

National Institutes of Health

Bethesda, MD, U.S.A.

Cochair and Coeditor

Vivian W. Pinn, M.D.

Associate Director for Research on 

Women’s Health

Director, Office of Research on Women’s Health

National Institutes of Health

Bethesda, MD, U.S.A.

PANEL MEMBERS

Elizabeth Barrett-Connor, M.D. 

Professor and Chief 

Division of Epidemiology

Department of Family and Preventive Medicine

University of California, San Diego School of

Medicine

La Jolla, CA, U.S.A.

Martin H. Birkhäuser, M.D. 

Professor

Division of Gynecological Endocrinology

Department of Obstetrics and Gynecology

University of Bern

Bern, Switzerland

Louise A. Brinton, Ph.D. 

Chief, Environmental Epidemiology Branch

National Cancer Institute

National Institutes of Health

Bethesda, MD, U.S.A.

Aila Collins, Ph.D.

Associate Professor

Psychology Section

Department of Clinical Neuroscience

Karolinska Institute

Stockholm, Sweden
III

Peter Collins, M.D. 

Reader and Honorary Consultant Cardiologist

Imperial College School of Medicine and Royal

Brompton Hospital

London, United Kingdom

Pier Giorgio Crosignani, M.D. 

Professor and Chairman

First Department of Obstetrics and Gynecology

University of Milan

Milan, Italy

Lorraine Dennerstein, A.O., M.B.B.S., Ph.D.,

D.P.M., F.R.A.N.Z.C.P.

Professor and Director

Office for Gender and Health

Department of Psychiatry

University of Melbourne

Royal Melbourne Hospital

Parkville, VIC, Australia

Bruce Ettinger, M.D.

Senior Investigator

Division of Research

Kaiser Permanente Medical Care Program

Oakland, CA, U.S.A.

Jan-Åke Gustafsson, M.D., Ph.D.

Professor and Chairman

Department of Medical Nutrition

Chairman, Department of Biosciences

Karolinska Institute 

Novum, Huddinge University Hospital

Huddinge, Sweden

Victor W. Henderson, M.D., M.S.

Professor

Departments of Geriatrics and Neurology

Donald W. Reynolds Center on Aging

Alzheimer’s Disease Center

University of Arkansas for Medical Sciences

Little Rock, AR, U.S.A.

Susan Hendrix, D.O.

Associate Professor

Division of Gynecology

Department of Obstetrics and Gynecology

Wayne State University School of Medicine

Hutzel Hospital

Detroit, MI, U.S.A.

Carlo La Vecchia, M.D.

Head, Laboratory of Epidemiology

Mario Negri Institute for Pharmacological

Research

Professor of Epidemiology

University of Milan

Milan, Italy

Robert Lindsay, M.D., Ph.D.

Chairman of Medicine

Helen Hayes Hospital

Professor of Clinical Medicine

College of Physicians and Surgeons

Columbia University

New York, NY, U.S.A.

Adriana Maggi, Ph.D.

Professor of Biotechnology and Pharmacology

Director, Molecular Pharmacology Laboratory

Department of Pharmacological Sciences

University of Milan

Milan, Italy

Joan A. McGowan, Ph.D.

Director, Musculoskeletal Diseases Branch

National Institute of Arthritis and Musculoskeletal

and Skin Diseases 

National Institutes of Health

Bethesda, MD, U.S.A.
IV

Susan M. Resnick, Ph.D.

Investigator

Cognition Section

Laboratory of Personality and Cognition

National Institute on Aging

National Institutes of Health

Baltimore, MD, U.S.A.

Jacques E. Rossouw, M.D.

Acting Director, Women’s Health Initiative

National Heart, Lung, and Blood Institute

National Institutes of Health

Bethesda, MD, U.S.A.

Sherry Sherman, Ph.D.

Director, Clinical Endocrinology and 

Osteoporosis Research

National Institute on Aging

National Institutes of Health

Bethesda, MD, U.S.A.

Anne McTiernan, M.D., Ph.D.

Associate Member

Public Health Sciences Division

Fred Hutchinson Cancer Research Center

Research Associate Professor

Department of Epidemiology

University of Washington Schools of Medicine and

Public Health and Community Medicine

Seattle, WA, U.S.A.

Maryann Redford, D.D.S., M.P.H. 

Director, Clinical Trials and Epidemiologic 

Studies Program

National Institute of Dental and Craniofacial

Research

National Institutes of Health

Bethesda, MD, U.S.A.

NONPANEL COAUTHORS

Janet R. Guthrie, Ph.D., M.Sc.

Research Fellow

Office for Gender and Health

Department of Psychiatry

Faculty of Medicine, Dentistry, and 

Health Sciences

The University of Melbourne

Parkville, VIC, Australia

Barbara E. K. Klein, M.D., M.P.H.

Professor of Ophthalmology and Visual Sciences

Ocular Epidemiology

University of Wisconsin-Madison

Madison, WI, U.S.A.

Stefan Nilsson, Dr. Med. Sci.

Associate Professor

Affiliated to Department of Medical Nutrition

Karolinska Institute

Novum, Huddinge University Hospital

Huddinge, Sweden

Nanette Santoro, M.D.

Division Director 

Division of Reproductive Endocrinology 

Department of Obstetrics, Gynecology, and

Women’s Health

Albert Einstein College of Medicine 

Bronx, NY, U.S.A.
WITH APPRECIATION FOR THE EXPERTISE OF THE FOLLOWING, WHO GRACIOUSLY REVIEWED AND

COMMENTED ON THE PRELIMINARY INDIVIDUAL CHAPTERS: 

Beth Alder, Ph.D.

Professor and Director of Research

Faculty of Health and Life Sciences

Napier University

Edinburgh, United Kingdom

Gloria A. Bachmann, M.D.

Professor 

Department of Obstetrics and Gynecology

Robert Wood Johnson Medical School

University of Medicine and Dentistry 

of New Jersey

New Brunswick, NJ, U.S.A.

Linda Cardozo, M.D.

Professor of Urogynecology

Department of Obstetrics and Gynecology

King’s College Hospital

London, United Kingdom

Sir Richard Doll

Emeritus Professor of Medicine

Clinical Trial Service Unit and Epidemiology 

Study Unit (CTSU)

University of Oxford

Harkness Laboratory

Oxford, United Kingdom

Timothy M. M. Farley, Ph.D.

Epidemiological Research

Special Programme of Research

Development and Research Training in Human

Reproduction

Department of Reproductive Health and Research

World Health Organization

Geneva, Switzerland

Marcha Flint, Ph.D.

Department of Anthropology

Montclair State University

Upper Montclair, NJ, U.S.A.

V

Silvia Franceschi, M.D.

Chief, Unit of Field and Intervention Studies

International Agency for Research on Cancer

Lyon Cedex, France

Ulysses J. Gaspard, M.D., Ph.D.

Professor and Chief

Service of Gynecology

University Center of Liege

Liege, Belgium

Anna Glasier, M.D., Ph.D.

Consultant and Director

Family Planning and Well Woman Services

Lothian Primary Care

Edinburgh, United Kingdom

Elina Hemminki, M.D., Ph.D.

Research Professor

National Research and Development Centre for

Welfare and Health, STAKES

Helsinki, Finland

Myra S. Hunter, Ph.D.

Department of Psychology

St. Thomas Hospital

London, United Kingdom

Won-Whe Kim, M.D.

Professor

Department of Obstetrics and Gynecology

Pusan National University School of Medicine

Pusan, Korea

Britt-Marie Landgren, M.D., Ph.D.

Professor

Department of Obstetrics and Gynecology

Huddinge University Hospital

Stockholm, Sweden
VI

Lenore Manderson, Ph.D.

Director and Professor

Key Centre for Women’s Health in Society

Faculty of Medicine, Dentistry, and 

Health Sciences

The University of Melbourne

Carlton, VIC, Australia

Olav Meirik, M.D., Ph.D.

Senior Research Associate

Chilean Institute of Reproductive Medicine

Providencia, Santiago, Chile

Daniel R. Mishell, Jr., M.D.

Lyle G. McNeile Professor and Chairman

Department of Obstetrics and Gynecology

Keck School of Medicine

University of Southern California

Los Angeles, CA, U.S.A.

Bert O’Malley, M.D.

Department of Molecular and Cellular Biology

Baylor College of Medicine

Houston, TX, U.S.A.

Bent Ottesen, M.D.

Department of Obstetrics and Gynecology

Hvidovre Hospital

University of Copenhagen

Copenhagen, Denmark

David Purdie, M.D. 

Centre for Metabolic Bone Disease

Hull Royal Infirmary

Hull, United Kingdom

Lawrence G. Raisz, M.D.

Program Director

General Clinical Research Center

University of Connecticut Health Center

Farmington, CT, U.S.A.

Henri Rochefort, M.D., Ph.D.

Hormones and Cancer Unit

INSERM U540

Montpellier, France

Giuseppe Rosano, M.D., Ph.D.

Institute of Cardiology

San Raffaele del Monte Tabor Hospital

Rome, Italy

Raymond Rosen, Ph.D.

Robert Wood Johnson Medical School

Department of Psychiatry

Piscataway, NJ, U.S.A.

Karin Schenck-Gustafsson, M.D., Ph.D.

Associate Professor, Department of Cardiology

Director, Women’s Health Center

Karolinska Institute

Stockholm, Sweden

Peter Schmidt, M.D.

National Institute of Mental Health

National Institutes of Health

Bethesda, MD, U.S.A.

Ethel Siris, M.D.

Madeline C. Stabile Professor of 

Clinical Medicine

Director of the Toni Stabile Osteoporosis Center

Columbia University

New York, NY, U.S.A.

Sven O. Skouby, M.D.

Professor, D.M.Sc.

Department of Obstetrics and Gynecology

Frederiksberg University Hospital

Copenhagen, Denmark

Leon Speroff, M.D.

Department of Obstetrics and Gynecology

Oregon Health Sciences University

Portland, OR, U.S.A.
VII

John C. Stevenson, M.B.B.S.

Endocrinology and Metabolic Medicine

Mint Wing, St. Mary’s Hospital

London, United Kingdom

David W. Sturdee, M.D.

Consultant, Obstetrician and Gynecologist

Department of Obstetrics and Gynecology

Solihull Hospital

Senior Clinical Lecturer

Birmingham University

West Midlands, United Kingdom

Cornelia Van Duijn, M.D.

Department of Epidemiology and Biostatistics

Erasmus University Medical School

Rotterdam, The Netherlands

Nancy F. Woods, Ph.D., R.N.

Dean, School of Nursing

University of Washington

Seattle, WA, U.S.A.

WITH APPRECIATION FOR THE EXPERTISE OF THE FOLLOWING, WHO GRACIOUSLY REVIEWED AND

COMMENTED ON THE PRELIMINARY COMPOSITE MANUSCRIPT:

Takeshi Aso, M.D., Ph.D.

Professor and Chairman

Comprehensive Reproductive Medicine

Department of Obstetrics and Gynecology

Graduate School, Tokyo Medical and 

Dental University

Tokyo, Japan

Giuseppe Benagiano, M.D.

Professor and Past Director

National Institute of Health

Rome, Italy

Henry Burger, M.D., Ph.D.

Professor, Prince Henry’s Institute of 

Medical Research

Monash Medical Center

Clayton, VIC, Australia

Desmond Julian, M.D.

Emeritus Professor, Department of Cardiology

Medical School University of Newcastle upon Tyne

London, United Kingdom

Peter Kenemans, M.D., Ph.D.

Professor and Chairman

Department of Obstetrics and Gynecology

Director Menopause Project “Ageing Women”

Vrije University Medical Centre

Amsterdam, The Netherlands

Luella Klein, M.D.

Charles Howard Candler Professor

Department of Gynecology and Obstetrics

Emory University School of Medicine

Director, Maternal and Infant Care Project

Grady Memorial Hospital

Atlanta, GA, U.S.A.

Rogerio A. Lobo, M.D.

Willard C. Rappleye Professor of Obstetrics and

Gynecology

Chairman of the Department

College of Physicians and Surgeons of 

Columbia University

Director, Sloane Hospital for Women

Columbia-Presbyterian Medical Center

New York, NY, U.S.A.
VIII

Michael Mendelsohn, M.D.

Director, Molecular Cardiac Research Institute

New England Medical Center

Professor of Medicine and Physiology

Tufts University School of Medicine

Boston, MA, U.S.A.

Henri Rozenbaum, M.D.

President

French Association for the Study of 

Menopause (AFEM)

Federation of European Menopause 

Societies (FEMS)

Paris, France

Goran Samsioe, M.D.

Professor

Department of Obstetrics and Gynecology

Lund University Hospital

President-Elect

European Menopause and Andropause Society

Lund, Sweden

Isaac Schiff, M.D.

Joe Vincent Meigs Professor of Gynecology,

Harvard Medical School

Chief of Vincent Memorial, Obstetrics and

Gynecology Service

The Women’s Care Division of the Massachusetts

General Hospital

Boston, MA, U.S.A.

Piero Sismondi, M.D., Ph.D.

Professor of Gynecologic Oncology

Director, Department of Obstetrics and

Gynecology

Umberto I Mauriziano Hospital

Institute for Cancer Research and Treatment

(I.R.C.C.)

Candiolo (Turin), Italy

Wulf H. Utian, M.D.

Chairman

The North American Menopause Society

Mayfield Heights, OH, U.S.A.

Nelson Watts, M.D.

Director, University of Cincinnati 

Osteoporosis Center

Cincinnati, OH, U.S.A.

SPECIAL ACKNOWLEDGMENT

Suzanne S. Hurd, Ph.D.

Scientific Director

Medical Communications Resources, Inc.

Gaithersburg, MD, U.S.A.

Ruth Johnsson Hegyeli, M.D.

Associate Director for International Programs

National Heart, Lung, and Blood Institute

National Institutes of Health

Bethesda, MD, U.S.A.
IX

OTHER ACKNOWLEDGMENTS

Silvia Belcredito

Scientific Editor

Department of Pharmacological Sciences

University of Milan

Milan, Italy

Cristina Bolsi

Giovanni Lorenzini Medical Science Foundation

Milan, Italy

Andrea Cignarella, Ph.D.

Department of Pharmacological Sciences

University of Milan

Milan, Italy

Anna Cozzi

Giovanni Lorenzini Medical Science Foundation

Milan, Italy

Emanuela Folco

Giovanni Lorenzini Medical Science Foundation

Milan, Italy

Ann S. Jackson

Giovanni Lorenzini Medical Science Foundation

Houston, TX, U.S.A.

Anna Miniotti

Giovanni Lorenzini Medical Science Foundation

Milan, Italy

Nancy Morris

Women’s Health Initiative

National Heart, Lung, and Blood Institute

National Institutes of Health

Bethesda, MD, U.S.A.

Nora Iris Rivera

Office of International Programs

National Heart, Lung, and Blood Institute

National Institutes of Health

Bethesda, MD, U.S.A.
X
XI

TABLE OF CONTENTS

Preface XIII

1 Executive Summary 1

2 The Menopause and Aging 23

3 Symptoms and the Menopause 43

4 Sociocultural Issues in Menopause 65

5 Physiological Role of Estrogen and Estrogen Receptors 77

6 The Pharmacologic Modulation of Estrogen Receptor Activity 103

7 Sexuality 121

8 Cardiovascular and Pulmonary Disease 141

9 Osteoporosis and Oral Bone Loss in Aging Women: Risks and Therapy 181

10 Gynecologic and Urinary Aspects of Menopause 203

11 Hormone Replacement Therapy, Related Therapies, and Cancer 223

12 Menopause and Disorders of Neurologic Function, Mental Health, and the Eye 251

13 Best Clinical Practices: A Comprehensive Approach 271

14 List of Abbreviations 295
XII
XIII

Women’s health and menopause is a rapidly

expanding field of medical practice and scientific

investigation. It is a field of great social importance and impact, nationally and globally, in 

developed as well as developing countries.

Menopause is a normal event in a woman’s life.

Some women view it as a positive and liberating

experience. Others think of it as a negative event.

Today, most women live long enough to become

postmenopausal. In the developed world, the percentage of women over 50 years of age has tripled

in the last 100 years. During this period, women’s

life expectancy in the United States has increased

from 50 to 81.7 years, meaning that more than one

third of life will be lived in postmenopause.

This “International Position Paper on Women’s

Health and Menopause: A Comprehensive

Approach” is based on extensive international

review and evaluation of the scientific evidence for

current clinical practices as presented in the published literature. The purpose of this international

and multidisciplinary monograph is to enhance the

composite health of menopausal and postmenopausal

women on a global basis, with consideration of

sociocultural concerns and economic issues.

The monograph represents the culmination of 7

years of cooperation between the National Heart,

Lung, and Blood Institute (NHLBI) and the

Giovanni Lorenzini Medical Science Foundation

(Milan, Italy and Houston, TX) in a public/private

partnership in the development and cosponsorship

of four international conferences on Women’s Health

and Menopause since the mid-1990s. The first three

conferences were held in Italy, and the most recent

one was held in May 2001 in Washington, DC. The

last two conferences were also cosponsored by the

Office of Research on Women’s Health (ORWH),

National Institutes of Health (NIH). These conferences have addressed not only cardiovascular disease, but also other health problems, such as cancer,

osteoporosis, and Alzheimer’s disease, as well as

the use and impact of hormone replacement therapy.

Menopause offers the primary care health provider

an opportunity to assess a woman’s health, her

concerns, and her needs for health promotion and

disease prevention measures worldwide. Given 

the multifactorial approaches needed for women 

during their middle and older years, the NHLBI,

the ORWH, and the Giovanni Lorenzini Medical

Science Foundation, in a cooperative venture

assembled an international panel of experts on

menopausal health.

The individual chapters of the International

Position Paper, prepared by panel members and

invited authors, evaluate published research studies

to establish relevant background information and

compile strategies for management. These were

reviewed by internationally acknowledged leaders

in their fields. The volume describes and references

relevant clinical information and provides 

evidence-based recommendations for best clinical

practices as well as recommendations for future

research. Importantly, the goal of this monograph

is that the materials be reproduced and translated

in individual countries for optimal global dissemination, which will be furthered by presentations at

topic-related scientific meetings.

PREFACE
XIV

On behalf of the NHLBI, I would like to thank

Nanette K. Wenger, M.D., chair of the Executive

Committee of the International Position Paper;

Rodolfo Paoletti, M.D., cochair; Vivian W. Pinn,

M.D., cochair; the panel members; the nonpanel

coauthors; and the experts who reviewed the preliminary versions of the individual chapters and of

the composite document for their valuable scientific contributions and dedication during this 4-year

effort to critically review and evaluate extensive

international databases on women’s health and

menopause. I hope that the readers will come away

with a sense of appreciation for what biomedical

research has accomplished in this important field

and anticipation of the many opportunities and

needs for future research.

Claude Lenfant, M.D.

Director, National Heart, Lung, and Blood Institute

and Cochair, Executive Committee of the

“International Position Paper on Women’s Health

and Menopause: A Comprehensive Approach.”

National Institutes of Health
1

Today, most women live long enough to become

menopausal. In the developed world, the percentage of women over 50 years of age has tripled in

the last 100 years. Mean female life expectancy

has increased from 50 to 81.7 years, meaning that

more than one-third of life will be lived in postmenopause. The absolute and relative numbers of

older people in both developed and developing

countries substantially increased during the 20th

century, and the mean age of the population of the

world will increase much faster in the next half

century. It is projected that there will be almost 

2 billion (1,970 million) older persons in 2050,

compared with 580 million in 1998; the majority

of these elderly are women. The quality of life of

older women in the aging population will depend

in large measure on the ability of societies to cope

with the economic, social, and medical challenges

of the postmenopausal years.

Menopause is not a disease, but rather a normal

physiologic event in a woman’s life. It can be associated, however, with health complaints, a decrease

in quality of life, and an increase in risk for illnesses,

such as osteoporosis

and coronary heart 

disease (CHD). Studies

of menopause are

numerous but largely

recent. Although many

clinically relevant 

questions remain unanswered, women seeking

advice about menopause currently have more options

and better interventions for healthy menopausal

years than ever before. Menopause is a time in a

woman’s life when the primary health care provider

should assess a woman’s health and her need for

health promotion and disease prevention measures.

Given the multifactorial approaches needed for

women during their middle and older years, the

National Heart, Lung, and Blood Institute

(NHLBI) and the Office of Research on Women’s

Health of the National Institutes of Health (NIH)

in Bethesda, MD and the Giovanni Lorenzini

Medical Science Foundation of Milan, Italy, and

Houston, TX, in a cooperative venture assembled

CHAPTER 1: EXECUTIVE SUMMARY

Nanette K. Wenger, M.D., Chair; Rodolfo Paoletti, M.D., Cochair; Claude J. M. Lenfant, M.D., Cochair; Vivian W. Pinn,

M.D., Cochair, Elizabeth Barrett-Connor, M.D.; Martin H. Birkhäuser, M.D.; Louise A. Brinton, Ph.D.; Aila Collins,

Ph.D.; Peter Collins, M.D.; PierGiorgio Crosignani, M.D.; Lorraine Dennerstein, A.O., M.B.B.S., Ph.D., D.P.M.,

F.R.A.N.Z.C.P.; Bruce Ettinger, M.D.; Jan-Åke Gustafsson, M.D., Ph.D.; Janet Guthrie, Ph.D., M.Sc.; Victor W. Henderson,

M.D., M.S.; Susan Hendrix, D.O.; Barbara E. K. Klein, M.D., M.P.H.; Carlo La Vecchia, M.D.; Robert Lindsay, M.D.,

Ph.D.; Adriana Maggi, Ph.D.; Joan A. McGowan, Ph.D.; Anne McTiernan, M.D., Ph.D.; Stefan Nilsson, Dr. Med. Sci.;

Maryann Redford, D.D.S., M.P.H.; Susan M. Resnick, Ph.D; Jacques E. Rossouw, M.D.; Nanette Santoro, M.D.; and Sheryl

S. Sherman, Ph.D.

1. INTRODUCTION

Menopause is a time in

a woman’s life when

the primary health care

provider should assess

a woman’s health and

her need for health

promotion and disease

prevention measures.
2

an international panel of experts on menopausal

and postmenopausal health. Through a collaboration that included a series of meetings from

November 1998 to July 2000, the Executive

Committee and Panel members evaluated published information to determine management

strategies that would constitute evidence-based

recommendations on menopause for best clinical

practice. Evidence statements and recommendations were categorized by a level of evidence ranging from A to D as shown in table 1–1 and indicated

within square brackets in the text. Additional participants in document development were referees and

reviewers, selected by the Executive Committee in

cooperation with the panel members. The resulting

multichapter monograph addresses a spectrum of

evidence to provide a multidisciplinary approach

to the enhancement of menopausal and postmenopausal health globally. Although the evidence

reviewed is disease specific, the monograph is

designed to enhance the composite health of

menopausal and postmenopausal women and is not

intended to medicalize menopause.

The terms “estrogen replacement therapy (ERT)” and 

“hormone replacement therapy

(HRT),” along with their 

initialisms ERT and HRT, are

well established; nevertheless,

the panel concurs with critics

who view replacement as 

suggesting that menopause is a

disease state and that hormonal

status should be restored to

that of the reproductive years.

In the absence of scientific consensus regarding a

more appropriate term, the panel has decided to

use the term HRT for the present monograph, since

HRT is now the most common in use by the medical

profession and familiar to the general public.

Possible benefits and risks of HRT are summarized

in table 1–2.

2. MENOPAUSE AND AGING

• Menopause is defined as the permanent cessation of menstruation resulting from the loss of

ovarian follicular activity. Natural menopause is

recognized to have occurred after 12 consecutive

months of amenorrhea for which there is no

other obvious pathologic or physiologic cause. At

present, it can be recognized only retrospectively.

• Endocrine changes will have begun years earlier.

Changes in serum concentrations of folliclestimulating hormone (FSH) and estradiol are

maximal in the year of the final menstrual 

period (FMP). FSH elevation, while a harbinger

of menopause, is a poor predictor of age at

menopause; the clinician cannot draw any 

conclusions about the timing of an individual

woman’s menopause on the basis of the 

presence or degree of FSH elevation.

• The endocrine changes of menopause do not

include any acute decrease in androgens. After

menopause, estrone, rather than the more potent

estradiol, is the major circulating estrogen. It is

produced primarily by peripheral aromatization

of androgens, so that fat cells become the major

source of endogenous estrogen after menopause.

• There is considerable individual and racial/

ethnic variation in age at natural menopause, in 

climacteric signs and symptoms, and in what

may be considered menopause-related sequelae.

• There is a lack of consensus as to whether changes

in health occurring during the climacteric or

presenting later in life are attributable to menopause and reduced ovarian function or to aging.

Menopause is

defined as the 

permanent cessation

of menstruation

resulting from the

loss of ovarian 

follicular activity.
3

Evidence Category 

A

B 

C 

D

TABLE 1–1

Evidence Categories

Sources of Evidence 

Randomized, controlled trials

(rich body of data) 

Randomized, controlled trials

(limited body of data)

Nonrandomized trials and/or

observational studies

Expert judgment

Definition

Evidence is from endpoints of well-defined RCTs 

(or trials that depart only minimally from randomization) that provide a consistent pattern of findings

in the population for which the recommendation is

made. Category A, therefore, requires substantial

numbers of studies involving substantial numbers 

of participants. 

Evidence is from endpoints of intervention studies

that include only a limited number of RCTs, post

hoc or subgroup analysis of RCTs or meta-analysis

of RCTs, controlled trials. In general, category B

pertains when few randomized trials exist, they 

are small in size, and the trial results are somewhat

inconsistent, or the trials were undertaken in a 

population that differs from the target population 

of the recommendation.

Evidence is from outcomes of uncontrolled or 

nonrandomized trials or from observational studies.

Expert judgment is based on the authors’ synthesis

of evidence from research described in the literature

that does not meet the above-listed criteria, taking

into consideration critical advice by other members

of the international panel of experts, external 

referees, and external reviewers. The category is

used only in cases in which the provision of some 

guidance was deemed valuable but an adequately

compelling clinical literature addressing the subject

of the recommendation was deemed insufficient to 

justify placement in one of the other categories 

(A through C).

Source: Adapted from the NIH. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. The Evidence

Report. Bethesda, MD, 1998; NIH publication no. 98–4083.
4

Possible Benefits

Hot flushes

Symptoms of 

vulvovaginal atrophy 

Decreased sexual 

function*

Urinary flow problems

Urinary tract infection

Osteoporosis 

Oral bone loss*

TABLE 1–2

Possible Benefits and Risks of Hormone Replacement Therapy, 

With Evidence Categories

Regimen

Estrogen Alone Estrogen Plus Progestin

Significant reductions [A] 

Improvements, with topical as well as

systemic administration [A/C]

Variable success; data inconclusive [B]

Alleviation in many cases of urgency,

urge incontinence, frequency [B], 

nocturia, and dysuria [D]; may worsen

genuine stress incontinence [A] 

Reduction in frequency, with local as

well as systemic administration [D]

Maintenance of bone density and favorable effects on markers of bone resorption [A]; marked reduction in risk for

vertebral fracture [B]; non-vertebral

fracture [C]

Possible benefit [C/D]

Same [A] 

Improvements with systemic preparation

(only available preparation) [A/C]

Estrogen and androgen: same [B] 

Same

Same [D]

Same

Same [C/D]

Note: Evidence categories are shown in square brackets. A = randomized clinical trials (rich body of data); B = randomized clinical trials (limited data); 

C = nonrandomized trials and observational epidemiologic studies; D = Panel expert judgment. (See also table 1–1.)

* Because clinical data are sparse or inconclusive, consideration of potential benefit would ordinarily be overridden by the extent to which benefits and

risks of HRT are well characterized for other organ systems or disorders.

† All findings belong to evidence category C, as they address side effects rather than interventions. This should not weaken the significance of the results.
5

TABLE 1–2 (continued)

Regimen

Estrogen Alone Estrogen Plus Progestin

Possible preservation of certain cognitive skills during the period immediately

after induced menopause [B] and during

the aging process [C]; possible reduction in risk for Alzheimer’s disease with

replacement therapy begun after

menopause [C], with no effect when

begun after the onset of dementia symptoms [B]; possible benefit in certain

sleep disorders occurring during the climacteric [C]; possible positive effect on

mood [B]

Little evidence of an effect on age-related maculopathy, cataract, and dry eye

[C]

Possible reduction in risk

Vaginal bleeding may occur [A]

Significant increase in breast tenderness

[A] 

Apparent increase in risk in the first 1 or

2 years of therapy [A]; no definitive evidence-based rationale to recommend for

prevention of disease

Conflicting results; no overall effect on

stroke risk [B] or possible increase in

risk and possible decrease in stroke

mortality [C]

Possible preservation of certain cognitive

skills during the aging process [C]; possible reduction in risk for Alzheimer’s disease with therapy begun after menopause

[C]; possible benefit in certain sleep disorders occurring during the climacteric [C];

possible positive effect on mood [C]

Same [C] 

Same, but less information available

May improve, remain the same, or worsen

depending on the specific formulation

(e.g., MPA versus norethindrone acetate),

dose, or schedule (sequential versus combined continuous) of the progestin [A]

Same or increased discomfort [A]

Same

Same

Possible Benefits

Neurologic function and

mental health*

Eye*

Colorectal cancer*†

Possible Risks

Period-like symptoms,

including vaginal 

bleeding

Mastalgia

CHD events

Stroke
• Estimates of the median age of menopause range

from 45 to 55 years worldwide. Understanding

of the factors that influence age at menopause is

limited. Familial or hereditary factors appear to be

the most predictive. Of other variables studied, the

most consistent relation is for cigarette smoking,

which advances menopause by 1 to 2 years. The

timing of menopause may substantially influence 

subsequent morbidity and mortality.

• Contraception is still needed during the

menopausal transition.

3. SYMPTOMS AND THE MENOPAUSE

• The climacteric* is sometimes but not always

associated with symptoms. There is debate as 

to whether the term “symptoms” should be used

when referring to events of the climacteric. 

The term is used here to refer to those bodily

perceptions presented as complaints by the 

individual woman. The presence of occasional

symptoms does not indicate their impact on the

woman and may not be clinically relevant or

indicative of treatment needs.

• Conflicting findings as to the causes of symptoms in midlife reflect some of the methodologic difficulties inherent in menopause research as

well as specific issues pertaining to the measurement of symptoms. General methodologic

issues relate to sample selection, validity of

6

TABLE 1–2 (continued)

Regimen

Estrogen Alone Estrogen Plus Progestin

Possible Risks

Increase in risk, perhaps fourfold

increase in RR initially, with a persistent twofold increase thereafter [A]

No appreciable risk association with

short-term (< 5 years’) use; moderate

excess risk with longer use for current

users but not for former users

Significant increase in risk

Possible increase in risk

Apparent increase in risk [B/C]

Possible increase in risk with CEEs [C]

Similar [A]

Possible higher risk compared with

unopposed estrogen

Not related to a major excess risk when

progestins are given for more than

10–14 days per cycle

No adequate information

Apparent increase in risk [B/C]

No data 

Venous thromboembolic

events in legs and lungs

Breast cancer*†

Endometrial cancer*†

Ovarian cancer*†

Gallbladder disease

Asthma
7

symptom measures, cultural factors, determination of menopausal phase, lack of systematic

hormonal level assessment, age at baseline and

length of followup, separation of the effects of

natural menopause transition from those of

induced menopause, and statistical and experimental design. A number of studies suggests

that symptom experience is likely to be worse

when women have undergone surgical

menopause. There is a risk that stereotypes will

become operative in menopause research when

subjects know the topic of the research.

• Individual women may view menopause as negative and troublesome or positive and liberating.

Importantly, the knowledge base on menopause

is narrow in that most studies have been carried

out on white women of northern European

ancestry; relatively little is known about the

range of climacteric experiences in women of

other racial/ethnic groups. Only studies of

women derived randomly from a general population provide findings that can be confidently

generalized to be the experience of most women

of that particular culture and geographic location.

• The following generalizations about climacteric

symptoms can be made.

• When symptom checklists are used,

middle-aged women are highly symptomatic.

• Age-related symptoms have to be differentiated

from those related to the menopausal phase.

• It is important to consider whether reported

symptoms reflect a change relative to a 

baseline level.

• Only vasomotor symptoms, vulvovaginal

atrophic symptoms, and breast tenderness

consistently vary with the phase of the 

climacteric and are significantly affected [A]

by the administration of hormones.

• Other symptoms, such as insomnia and

changes in mood, may be affected by the

presence of bothersome vasomotor symptoms.

• Symptoms are influenced by psychosocial

and lifestyle factors.

3.1 Vasomotor Symptoms

In North America and Europe, most women have

at least some menopausal hot flushes (also called

hot flashes). While menopausal hot flushes have

been described in a limited number of studies in a

variety of other cultures, the prevalence varies

widely. There is consensus about the marked temporal relation of vasomotor symptoms to the climacteric. They begin to increase in the menopausal

transition, peak 1 to 2 years after the FMP, and may

remain increased for several years. A number of

studies have shown a statistical relation between hot

flushes and night sweats, and

some show a relation between

those vasomotor symptoms and

insomnia. The mechanism of

menopausal flushing remains

unclear. Core body temperature

elevations precede the

menopausal hot flush and serve

as one trigger of the heat loss

phenomenon, but what is

responsible for the core temperature elevation is uncertain.

• Hormone replacement therapy. Estrogen

therapy is effective in reducing hot flushes [A].

The use of continuous or sequential progestins

with estrogen does not reduce the efficacy of

estrogen in the reduction of hot flushes.

• Other pharmacologic agents. Other agents

reported to be more effective than placebo in

decreasing hot flushes include megestrol

acetate, veralipride, opipramol, venlafaxine, 

sertraline, paroxetine, and tibolone [B].

The knowledge base

on menopause is

narrow in that most

studies have been

carried out on white

women of northern

European ancestry.

* Perimenopause comprises the period of time immediately before menopause (when the endocrinologic, biologic, and clinical features of approaching

menopause commence) and the first year after menopause. The climacteric incorporates perimenopause by extending for a longer, variable period of

time before and after it.
8

• Physical activity. Evidence is conflicting as to

whether increased physical activity affects

menopausal symptoms.

• Foods and beverages. Avoidance of hot beverages, foods containing nitrites or sulfites, spicy

foods, and alcohol may help limit hot flushes.

• Phytoestrogens. Although some evidence suggests that dietary supplementation with phytoestrogens yields improvements

in hot flushes, the issue

remains unclear because of

methodologic limitations of the

studies.

• Gamma-linolenic acid.

Gamma-linolenic acid provided in evening primrose oil, a popular alternative

therapy, appears to offer no benefit over placebo

in the treatment of vasomotor symptoms [B].

3.2 Vulvovaginal Atrophic Symptoms

Atrophic changes of the vulva, vagina, and lower

urinary tract are common causes of complaints

among menopausal women. Only vulvovaginal

atrophic changes can be clearly related to

menopause; findings as to whether disorders of

urinary tract atrophy are menopause or age related

are conflicting. (See also “Lower Genital and

Urinary Tract Atrophy” in “Gynecologic and

Urinary Aspects” below.) With estrogen loss, the

vagina shortens and narrows, and its walls become

thinner. Decreased production of lactic and acetic

acids alters the normal low vaginal pH, to create a

milieu that does not favor continued growth of the

normal flora. A decrease in estrogen-supported

lubrication causes vaginal dryness, which can lead

to vaginitis, vaginismus, and dyspareunia.

Cystocele and rectocele are also common problems

in postmenopausal women.

• Hormone replacement therapy. Estrogen therapy is effective in relieving vulvovaginal atrophic

symptoms, and local estrogen preparations are as

effective as systemic ones [A]. In observational

studies, ERT reduces the frequency of urinary

tract infections in the menopausal years [D].

3.3 Mastalgia (Breast Soreness/Tenderness)

In clinical trials, mastalgia has been related to

estrogen and progestin concentrations [A].

Mastalgia that is related to the menstrual period

often resolves with menopause. Compliance with

HRT can be limited by the side effect of mastalgia.

4. SOCIOCULTURAL ISSUES

• Attitudes toward and beliefs about menopause

vary historically and among cultures [C].

• Cross-cultural comparisons demonstrate that

reported symptoms can vary significantly among

countries and among ethnic groups within 

countries in type (e.g., vasomotor, psychologic)

and in the degree of distress caused [C].

• Difficulties in integrating findings from crosscultural studies stem from a number of limitations. Among these are differences among cultures in language used to describe symptoms,

use of different methodologies in study design

and in instruments used to measure symptoms,

and differences in diet and other lifestyle factors

that make it difficult to establish cultural versus

biologic causes of symptom expression.

• A better appreciation of cross-cultural differences in the experience of menopause may

derive from an emerging interdisciplinary

model in which symptoms are seen as a result

of increased vulnerability due to hormonal

changes in interaction with psychologic and

sociocultural factors.

Estrogen therapy is

effective in reducing

hot flushes.
9

5. PHYSIOLOGICAL ROLE OF ESTROGEN

AND ESTROGEN RECEPTORS AND

PHARMACOLOGIC MODULATION OF

ESTROGEN RECEPTOR ACTIVITY

• The two known estrogen receptor (ER) subtypes, ERα and ERβ, mediate many biologic

effects of estrogens and antiestrogens.

• Different ligands induce different ER 

conformations.

• Different mechanisms of target gene regulation

affect the agonist/antagonist profile of a ligand.

Selective ER modulators (SERMs) have a tissueand gene-specific mixed agonist/antagonist effect.

• Of interest are the SERMs (third-generation

HRT), nonsteroidal agents that behave as agonists in target tissues such as bone and liver and

as antagonists or partial agonists in reproductive

tissues [A/B].

• Both subtypes are also important for normal ovarian follicular development and female fertility.

• Available data suggest that ERα plays an

important role in bone maturation and homeostasis in both women and men, and that ERβ

has a specific role in bone physiology in women.

• ERα and ERβ are expressed in vascular

endothelial cells, vascular smooth muscle cells,

and myocardial cells. Beneficial effects of estrogens on cardiovascular function and reactivity

stem from direct effects on cells in the vascular

system and also from effects on liver and on 

circulating monocytes/macrophages.

• In the central nervous system (CNS), estrogen is

linked to a variety of functions, including 

learning, memory, awareness, fine motor skills,

temperature regulation, mood, reproductive

functions, and depression. The predominance 

of expression and localization of ERβ in rat

neocortex, hippocampus, and nuclei of the basal

forebrain suggests an important role for ERβ in

learning and memory.

• Estrogen and inhibins produced by the ovaries

are important feedback regulators of the 

hypothalamic-pituitary axis and serum concentrations of luteinizing hormone (LH) and FSH.

ERα seems to be more involved than ERβ in

the LH, FSH feedback loop.

• Increased knowledge of the structure of ERs

and of the mechanisms of the receptors’

synthesis and their interaction with key elements

of the transcription apparatus is facilitating 

the synthesis of new pharmacologically active

molecules.

• ERα- and ERβ-selective SERMs in development might provide improved therapy. Since

both ER subtypes are expressed in human breast

cancer, measurements of both ERα and ERβ

may help in the selection of appropriate breast

cancer therapy.

5.1 Hormone Replacement Therapy and 

Related Therapies

The regimens most commonly

used to treat climacteric symptoms and to intervene against

menopausal and postmenopausal health risks are

17β-estradiol, esterified estrogens, and conjugated equine

estrogens (CEEs) in combination with a progestin, for

example, medroxyprogesterone

acetate (MPA). The awareness

of undesired effects and serious health risks (breast

cancer, endometrial cancer, and venous thromboembolism) with existing HRT call for alternatives with improved safety profiles.

Alternative regimens for women who do not wish

to take estrogen exist. Non-ER subtype-selective

SERMs display tissue-selective estrogen agonism.

They do not increase the risk of breast and

endometrial cancer but aggravate hot flushes and

increase the risk of venous thromboembolism. The

existence of two ER subtypes provides the opporThe two known 

ER subtypes, ERα

and ERβ, mediate

many biologic

effects of estrogens

and antiestrogens.
10

tunity to develop ER subtype-selective ligands;

such agents will likely have improved therapeutic

profiles. Novel synthetic steroidal ER agonists

hold promise because of agonist activity for progesterone and androgen receptors.

6. SEXUALITY

Multiple population-based

studies imply a decrease in

female sexual function associated with the midlife years,

and there is growing evidence

that the decrease reflects hormonal changes of the

menopausal transition rather

than increasing age. Hormonal

change is only one of many factors that affect sexual function. Other factors include presence of a

sexual partner, partner’s age and health, length of

the relationship, feelings toward the partner, level

of past sexual function, social class, educational

level, experience of physical or psychologic ill

health, stressors, employment, personality factors,

and negative attitudes toward menopause.

• Declining sexual function is common but 

not universal with aging. There may be an 

additional decrement associated with the

menopausal transition.

• The causes of decreased sexual activity are 

multiple and include physiologic, psychological,

and social factors.

• Definitions and Classification of Female Sexual

Dysfunction given by the consensus panel of

the Sexual Function Health Council of the

American Foundation for Urologic Disease provide a standardized system for clinical diagnosis

and treatment and are recommended for use by

health care professionals [D].

• Sexual interest, behavior, and activity should be

routinely assessed at office visits on a regular

basis, and a plan should be developed to address

the woman’s concerns.

• HRT (estrogen or estrogen plus androgen) and

behavioral therapy have had variable success in

the treatment of sexual dysfunction [B] but

should be considered in patients who desire

treatment.

• Hormone replacement therapy. Although

estrogen is effective in relieving vulvovaginal atrophic symptoms, including increasing

vaginal lubrication, HRT has not been consistently shown to increase sexual desire or

activity [B].

7. CARDIOVASCULAR AND

PULMONARY DISEASE

• Cardiovascular disease (CVD) remains the commonest single cause of female mortality and

morbidity in the western world [C]. Despite the

protection apparently offered by endogenous

sex hormones in their premenopausal years, the

longevity of women exposes them to a lifetime

risk for coronary and other vascular diseases

similar to that of men. There is a wide variation

in CHD incidence among countries. In countries

in which the incidence is high in men, it is also

high in women; likewise, the incidence is low in

women and men in countries with low rates of

CHD. Because CVD tends to develop at a later

age in women than in men, women are more

likely to have complicating comorbidities, such

as hypertension and diabetes mellitus, which

contribute to poorer short-term outcomes after

coronary events or revascularization.

7.1 Coronary Heart Disease

• Major modifiable risk factors for atherosclerotic

CHD are similar in women and men and include

dyslipidemia, hypertension, diabetes mellitus,

cigarette smoking, lack of physical activity, and

obesity (especially abdominal obesity) [C]. 

Multiple populationbased studies imply

a decrease in female

sexual function

associated with the

midlife years.
11

The atherogenic risk profile of older women is

appreciably more adverse than that of younger

women, although it is uncertain whether age or

hormone status is the primary determinant of

the evolution of the adverse risk profile.

• Large randomized, placebo-controlled clinical

trials have shown that beta-blockers, aspirin, 

3-hydroxy-3-methylglutaryl-coenzyme A

(HMG-CoA) reductase inhibitors (statins), 

and angiotensin-converting enzyme (ACE)

inhibitors reduce risk for CHD events in women

as well as in men [A]. For some of these 

therapies, the evidence derives largely from 

secondary prevention trials; in general, therapies

that work in secondary prevention will work 

in primary prevention as well. Treatment effects

appear to be similar in women and men. For

example, meta-analysis of data from several

major lipid-lowering statin trials showed a 

29-percent reduction in risk for major CHD

events in women, similar to the 31-percent

reduction observed in men.

• HRT has consistently been shown to improve

the blood lipoprotein profile markedly, and

many large observational studies found that

menopausal women who chose to use hormone therapy had a 35- to 50-percent lower

risk for CHD than nonusers. In contrast, no

hormone benefit on hard cardiovascular outcomes, such as myocardial infarction (MI) or

cardiac death, has been demonstrated in clinical trials [B]. In fact, there appears to be an

excess risk for cardiovascular events in the

first year or two of treatment [A], although

coronary benefit over the long term remains

possible [B].

In the Heart and Estrogen/progestin

Replacement Study (HERS), the first published large trial conducted in postmenopausal U.S. women with CHD, those

assigned to daily oral CEE plus MPA had

an increased relative risk (RR) versus

placebo for nonfatal MI and coronary

death during the first year and did not

have coronary benefit across the average

followup of 4.1 years. Also, more women

in the hormone replacement group experienced venous thromboembolic events and

gallbladder disease [A].

The large Women’s Health Initiative (WHI)

trial of HRT in the United States includes

predominantly women without prior CVD

and includes women treated with daily

CEEs alone or daily CEEs with MPA, 

versus placebo. All WHI participants were

informed of an increased risk associated

with active treatment for heart attack and

stroke, during the first 2 years after enrollment (www.nhlbi.nih.gov/whi/hrt-en.htm).

The majority of participants did not have

prior CVD, and the subgroup with prior

disease did not account alone for these

findings. The trial is continuing to assess

long-term benefits and risks of HRT [B].

In the angiographic Estrogen Replacement

and Atherosclerosis (ERA) study, there

was no coronary angiographic lesion benefit from either estrogen or estrogen plus

progestin replacement therapy compared

with placebo [A].

Preliminary results from the PHASE trial

of transdermal HRT for secondary prevention have not shown cardioprotective 

benefit to postmenopausal women taking

estrogen or estrogen plus a progestin 

compared to the placebo group [B].1

Major modifiable risk factors for 

atherosclerotic CHD are similar in women and

men and include dyslipidemia, hypertension,

diabetes mellitus, cigarette smoking, lack of

physical activity, and obesity.
12

A lack of benefit may be due to countervailing

adverse changes in coagulation or inflammatory

mechanisms. In view of sex differences in atherosclerotic plaque and the vascular remodeling

effects of estrogen and progesterone, other doses,

preparations, or routes of administration may

prove to have an important role in the prevention

of CVD in women.

• Hormone replacement therapy. There is

no definitive evidence-based rationale to recommend HRT for the prevention of CHD [A].

At present, prevention of CHD should rely

on identifying and treating the classic risk

factors, such as dyslipidemia, hypertension,

diabetes mellitus,

smoking, obesity, and

sedentary lifestyle [A].

Vigilant management of

risk for CHD in women

is imperative.

Instead of HRT, HMG-CoA reductase

inhibitors (statins), beta-blockers, ACE

inhibitors, and aspirin should be recommended to all eligible women with CHD

or diabetes mellitus [A].

• Phytoestrogens and selective estrogen

receptor modulators. There are insufficient

data to make recommendations regarding the

use of soy phytoestrogens or SERMs for 

prevention of CHD [C].

7.2 Stroke

Despite similar stroke rates, women are more likely than men to die of stroke. The main risk factors

for stroke are not gender dependent. Although

strokes are more closely related to hypertension

(which is probably their most important risk 

factor) than to hypercholesterolemia, HMG-CoA

reductase inhibitors (statins) reduce risk for stroke,

as do antihypertensive medications.

• Hormone replacement therapy. HRT has

not been consistently linked to stroke protection. In the HERS trial of continuous CEEs

combined with MPA in women with prior

CHD, HRT was not significantly associated

with risk of nonfatal or fatal stroke or transient ischemic attack [B]. Results of the first

clinical trial of HRT in women with prior

stroke indicate no reduction in the risk for

recurrent stroke and death and suggest

increased risk for more severe strokes in the

first few months after initiation of HRT [B].2

7.3 Peripheral Vascular Disease

Peripheral vascular disease occurs fairly commonly in women, and, as in all atherothrombotic CVD

incidence increases with age in women. Smoking

is the most prevalent risk factor for peripheral vascular disease, as it is in men. Peripheral vascular

disease carries with it an increased risk for CHD,

which is not gender dependent.

• Hormone replacement therapy. The effect

of HRT on peripheral vascular disease is

unknown.

7.4 Venous Thromboembolism

Modifiable risk factors for venous thromboembolism include the presence of hemostatic 

disorders, immobilization, and perhaps obesity.

Although most cases of venous thrombosis are not

fatal, death from pulmonary embolism can occur,

and postthrombotic syndrome occurs in as many as

one-fourth of patients with deep venous thrombosis.

Venous thromboembolism remains a major cause of

morbidity and mortality after gynecologic surgery.

There is no definitive 

evidence-based rationale

to recommend HRT for the

prevention of CHD.

1 Clarke S, Kelleher J, Lloyd-Jones H, et al. Transdermal hormone replacement therapy for secondary prevention of coronary artery disease in postmenopausal women. Eur Heart J 2000;21(Abstract Supplment):212.

2 Viscoli CM, Brass LM, Kernan WN, et al. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001;345:1243–9.
13

• Hormone replacement therapy:

Findings from recent observational studies

and data from clinical trials show a consistent increase in risk for venous thromboembolic events in women taking estrogen compared with those that do not [A].

These studies indicate that there may be a

fourfold increase in RR initially, with a

persistent twofold increase in risk thereafter. The increased risk for venous thromboembolism was similar in women using

an estrogen plus progestin [B]. Similar risk

is associated with the SERM raloxifene.3

7.5 Pulmonary Disease

Estrogen may play a role in the pathophysiology of

asthma. Observational studies suggest a positive

dose response for use of CEEs and risk for asthma.

Otherwise, there appears to be little impact of

menopause or HRT on the pulmonary system,

although further research is warranted.

8. OSTEOPOROSIS AND ORAL BONE

LOSS: RISKS AND THERAPY

8.1 Osteoporosis

• Osteoporosis affects a large proportion of the

population of elderly women throughout the

world. More women than men are affected. The

overall lifetime risk for fractures in women in

the United States and most European countries

is from 30 to 40 percent, but there is clear variability across cultures. Worldwide for women

and men, about 1.26 million hip fractures occur

each year, a number expected to double by 2025.

• Rates of osteoporosis and related bone fractures

increase with age. Low bone mass at

menopause can be due to insufficient bone

acquisition during growth or bone loss during

adulthood. Ovarian failure heralds dramatic

changes in skeletal homeostasis. Bone loss

accelerates for a few years after natural

menopause or oophorectomy, and continues at a

lower rate for the remainder of life. The mechanism of how loss of estrogen at menopause contributes significantly to skeletal bone loss is not

completely understood. Postmenopausal bone

loss may be exacerbated by low levels of physical activity and poor nutrition, especially low

calcium intake. Severe bone loss and fractures

are not natural consequences of aging and can

be prevented or substantially delayed.

• The principal method for making the diagnosis

of osteoporosis is evaluation of the skeleton 

by using a noninvasive measurement of bone

mineral density (BMD). Fracture risk is the

most important determinant in patient selection

for treatment or intervention for osteoporosis,

although bone density is

only one of many risk factors that contribute to risk

for fracture. Although there

has been major progress in

methods for assessing risk

for osteoporotic fracture,

identifying individuals at

greatest need for treatment

remains a problem.

8.1.1 Nonpharmacologic Interventions

Adequate nutrition—in particular, but not exclusively, from intake of calcium and vitamin D—and

adequate physical activity are requisite preventive

efforts against osteoporosis throughout life.

Avoidance of tobacco use and moderation in 

alcohol intake are obvious.

• Calcium. Adequate calcium intake in older

adults can retard bone loss and reduce risk

for fracture. While it is recommended that

calcium be obtained from the diet, not all

Osteoporosis affects

a large proportion 

of the population 

of elderly women

throughout the world.

3 Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation [published erratum appears in JAMA 1999;282:2124]. JAMA 1999 281:2189-97.
14

individuals are able to increase calcium

intake in this way. In such individuals, 

supplementation may be encouraged. In the

United States, it is recommended that an

average intake of about 1,200 mg of calcium

per day should be achieved by adults ≥ 51

years of age [Dietary Reference Intake (DRI)].

• Vitamin D. Because it is inexpensive to provide vitamin D and because many of the controlled studies of calcium also used vitamin D

supplementation, supplements

of vitamin D are recommended

for at-risk populations, especially those 65 years of age and

older. For at-risk populations,

700 to 800 IU (international

units) of vitamin D per day

may be sufficient.

• Physical activity. Bone density responses to

increased physical activity in adults have

been fairly modest. The type of exercise that

promotes bone response may be different

from the type recommended for aerobic fitness: Muscle building, weight bearing, resistance exercise is required to alter bone density

[A]. Where not medically contraindicated,

increased physical activity should be encouraged for all.

8.1.2 Pharmacologic Interventions

A decade ago estrogen and injectable calcitonin

were the only available pharmacologic therapies

for menopausal women with osteoporosis. Now

there are new bone-specific drugs (e.g., bisphosphonates and parathyroid hormone (PTH)) and

broad-spectrum drugs (e.g., SERMs) that combat

osteoporosis and have potentially beneficial effects

in other organ systems, as well as calcitonin delivered as an intranasal spray.

• Hormone replacement therapy. ERT maintains bone density and favorably influences

markers of bone resorption [A].4 Long-term

and continuing use of estrogen markedly

reduces risk for fracture; discontinuation

allows bone loss to occur, and fracture protection wanes [B].

• Selective estrogen receptor modulators.

The SERM raloxifene exerts effects similar

to those of estrogen in the skeleton and has

been shown to prevent vertebral fractures [A].

• Bisphosphonate therapy. The first-generation bisphosphonate, etidronate, reduces vertebral but not nonvertebral fractures. Newer

and more potent bisphosphonates have been

shown to reduce risk for vertebral fracture by

approximately 45 percent and to reduce risk

for nonspine fracture to a lesser but clinically

important degree [A].

• Salmon calcitonin. Salmon calcitonin can

reduce resorption and help preserve bone

mass. Vertebral fracture rates may be reduced

[A/B]. Benefit in peripheral fracture risk has

been suggested, but data are not conclusive.

Choosing among estrogen preparations, raloxifene,

bisphosphonates, and calcitonin is challenging for

individual patients. Considerations are the need for

prevention versus treatment, the need for

bone-specific versus broad-spectrum effects,

patient acceptability and tolerance, and cost. The

long-term effects of many of the newer agents

(SERMs and bisphosphonates) are not known.

8.2 Oral Bone Loss

Oral bone, like the rest of the skeleton, comprises

both trabecular and cortical bone and undergoes

formation and resorption throughout the lifespan.

When oral bone loss exceeds gain, it manifests as

either loss of tooth-anchoring support or a diminuERT maintains bone

density and favorably

influences markers

of bone resorption.

4 Torgerson DJ, Bell-Syer SE. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA

2001;285(22):2891–7.
15

tion of the remaining ridge in areas of partial or

complete tooth loss.

The prevalence of oral bone loss is significant

among adult populations worldwide and increases

with age for both sexes. Oral bone loss and attendant tooth loss are associated with estrogen deficiency and osteoporosis [C]. As a consequence,

women’s experiences with postmenopausal

osteopenia may affect the need for, and outcome of,

a variety of periodontal and prosthetic procedures,

including guided tissue regeneration and tooth

implantation [D]. Furthermore, it is possible that

oral examination and radiographic findings may be

useful signs of extraoral bone diminution [C].

8.2.1 Interventions

Nonpharmacologic approaches to preserving oral

bone include oral hygiene self-care behaviors, such

as brushing and flossing; professional dental services,

including oral examination, tooth scaling, and polishing; and smoking cessation. Calcium and vitamin D supplementation and pharmacologic therapies for osteoporosis, including HRT and bisphosphonates, may yield positive oral bone effects [C].

9. GYNECOLOGIC AND URINARY ASPECTS

Atrophic changes of the vulva and vagina are 

discussed in “Vulvovaginal Atrophic Symptoms”

above (“Symptoms and the Menopause”). The 

present section highlights the assessment of uterine

bleeding in older women, the occurrence of lower

urinary tract atrophy, and abnormalities of pelvic

floor and urinary tract.

9.1 Assessment of Uterine Bleeding

• During the menopausal transition, women

request consultation for gynecologic evaluation

when cycle irregularities start or when hot

flushes and other complaints related to hypoestrogenemia occur. The gynecologist may be the

only medical contact for healthy women.

• Different patterns of uterine bleeding can be

confusing when they occur in older women, and

physicians must be alert to the possibility of

genital tract pathology. Endometrial bleeding

can be linked to endometrial pathology (atrophy,

polyps, submucosal leiomyoma, hyperplasia,

adenocarcinoma) or to general pathology, dysfunctional conditions, or drugs. Dysfunctional

uterine bleeding is common between ages 40

and 50 years. The associated endometrial histology is highly variable. In some patients with

bleeding, the endometrial histologic findings

appear out of phase with endocrine events. 

In many, the endometrium will be hyperplastic 

and may be secretory until the year before

menopause. In postmenopausal women,

endometrial atrophy is the most common histologic finding.

• Cancer is not the

most common

cause of abnormal

bleeding in perimenopausal

women, but

abnormal uterine

bleeding occurring during perimenopause should

be considered secondary to malignancy until proven otherwise.

The most important risk factors for endometrial

cancer are obesity and menopausal use of unopposed estrogen, even at low dosages. See “HRT,

Related Therapies, and Cancer Epidemiology”

below, for a discussion of HRT and risk for

endometrial cancer. Endometrial hyperplasia is a

premalignant lesion, particularly when atypia is

present. Endometrial hyperplasia but not atypia

can be reversed by the administration of progestin.

• Bleeding during the estrogen-only phase of

sequential combined HRT is much more likely

to be associated with endometrial pathology

than bleeding during the progestin phase. No

Different patterns of uterine

bleeding can be confusing

when they occur in older

women, and physicians must

be alert to the possibility of

genital tract pathology.
16

available hormone formulation suits all women.

Prolonged and/or heavy cyclical bleeding 

may be due to excess estrogen or insufficient

progestin in the sequential formulation or to endometrial pathology.

Breakthrough bleeding is associated

with a hyperplastic endometrium

but may also occur with an atrophic

endometrium. Continuous administration of progestins with estrogens

has been suggested to prevent the

cyclical withdrawal bleeding 

associated with hormone regimens.

A high incidence of irregular bleeding episodes (50 percent) has been

observed during the first year.

• Transvaginal ultrasonographic measurement of

endometrial thickness provides a noninvasive

clinical indicator of endometrial status.

Endometrial thickness < 4 mm usually corresponds to histologically atrophic endometrium;

thickness greater than 4 to 7 mm correlates with

increased incidence of endometrial pathology 

in postmenopausal women. The exact level is

uncertain in women receiving HRT whose

endometrium is often thicker than in untreated

postmenopausal women. Present-day ultrasound

scanning cannot replace histopathologic assessment of the endometrium in women receiving

HRT. Management of bleeding during HRT

includes observation, surgery, and specific

changes in the treatment regimen.

9.2 Lower Genital and Urinary Tract Atrophy

• The epithelium of the inner layer of the vagina

has high levels of ERs and undergoes progressive loss of cells during menopause due to

estrogen depletion. Estrogen-dependent secretions decrease, leading to vaginal dryness and,

in some women, vaginitis, vaginismus, and dispareunia. Local estrogen proved as effective as

systemic in treatment for vaginal dryness [A].

• Loss of glycogen-producing cells, a consequence

of vaginal and urethral atrophy, causes decreased

production of lactic acid and an environment

that favors vaginal and urethral infection. It is

important to identify and treat patients with

recurrent infections to prevent significant morbidity, which includes risk for renal impairment.

• In observational studies, ERT reduces the frequency of urinary tract infections in the postmenopausal years [D]. Its beneficial effects can

partially be explained through its support of

normal vaginal flora.

9.3 Pelvic Floor and Urinary Incontinence

• All four functional layers of the urethra—

epithelium, connective tissue, vascular tissue,

and muscle—are affected by estrogen status.

Estrogen deficiency causes atrophic changes of

the urethral epithelium and of the submucosa.

• Urinary incontinence (UI) is defined by the

International Continence Society as involuntary

loss of urine that is objectively demonstrable

and is a social or hygienic problem.

• The relationship between menopause and UI 

is unknown and not well studied. Limited data

are available to support the hypothesis that

menopause is a major risk factor for incontinence,

especially for stress and urge incontinence.

• Established UI can usually be divided as follows:

stress incontinence, which occurs in the absence

of detrusor activity; urge incontinence, when

detrusor muscle contracts during the filling

phase of the bladder; mixed incontinence, which

is a combination of both stress and urge incontinence; and overflow incontinence, which is the

result of bladder obstruction or injury. Other

factors that can cause UI include decreased

mobility, cognitive impairment, or medications.

• Evaluation and treatment for incontinence is

dependent on the type of incontinence and 

the person’s age, medical history, and desire 

for therapy.

In observational

studies, ERT

reduces the 

frequency of 

urinary tract

infections in the

postmenopausal

years.
17

9.3.1 Interventions

• In many cases, urine leakage can be prevented

or improved by improving pelvic muscle tone

through different kinds of exercises. Pelvic floor

exercises (including Kegel exercises), vaginal

weight training, and pelvic floor electrical stimulation significantly reduce incontinence in

RCTs [A].

• Behavioral therapies can help patients regain

control of bladder function. Bladder training

teaches people to resist the urge to void and

gradually expand the intervals between voiding.

Toilet assistance uses routine or scheduled 

toileting, habit training schedules, and prompted

voiding to empty the bladder regularly to 

prevent leaking.

• Pharmacological therapies for the treatment of

UI vary accordingly to the kind of incontinence

that needs to be treated.

• Muscarinic receptor antagonists. Both

tolterodine tatrate and oxybutinine significantly

increased volume-voided/micturition and

decreased micturition and incontinence episodes

per 24 hours compared to placebo, but

tolterodine only was significantly better than

placebo in reducing micturition frequency [A].

• Hormone replacement therapy.

Uncontrolled trials showed subjective

improvement of incontinence upon estrogen

treatment, while no objective improvement in

measures of urine loss was found in RCTs

[A]. HERS found HRT to be associated with

worsening of stress UI [A]. By reducing

potential afferent stimuli from the bladder,

such as lower urinary tract infections, estrogen may benefit urge incontinence [C].

• Bulking injections. Periurethral injection of

collagen in women with genuine stress

incontinence and intrinsic sphincter deficiency has a low short-term cure rate and has not

been shown to improve stress incontinence

long-term [A].

• Surgical treatment. This intervention can

be very effective in improving or curing

stress incontinence.

10. MENOPAUSAL THERAPIES

AND CANCER

Experimental, clinical, and epidemiological data

support an important role for reproductive hormones in the aetiology of some human cancers,

including breast, endometrium, and ovary.

Whereas for common adult cancers, such as lung

and colon cancers, incidence rises continuously

and progressively with age, the slope of increase

slows around the time of menopause for most hormone-dependent cancers. Worldwide, breast cancer

is by far the most frequent invasive cancer in

women and the leading cause of cancer death in

women, accounting for more than 300,000 deaths

each year. Ovarian cancer adds another 100,000

deaths each year, and cancer of the corpus uteri

adds 40,000. The issue of the effect of menopausal

therapies on risk for cancer is a critical one.

10.1 Hormone Replacement Therapy

Most of the potential favourable and adverse

effects of HRT on cancer risks are restricted to 

current users.

• Breast cancer. In observational studies, there is no

appreciable association

between less than 5 years of

use of HRT and risk for

breast cancer. Longer use is

associated with a small but

significant excess breast 

cancer risk for current users

but not for former users.

Combined HRT may be 

associated with higher breast

cancer risk compared with

unopposed estrogen.

Worldwide,

breast cancer is

by far the most

frequent invasive

cancer in women

and the leading

cause of cancer

death in women.
18

• Endometrial cancer. Estrogen use is strongly

related to increased risk for endometrial cancer. When progestins are given for 10 days or

more per cycle, combined HRT is not related

to a major excess risk for endometrial cancer.

• Ovarian cancer. Results of observational

studies of HRT and ovarian cancer have been

inconsistent. Available findings include the

possibility that HRT increases risk for cancer

of the ovary.

• Colorectal cancer. Observational studies suggest that HRT may reduce risk for colorectal

cancer. No clinical trial data are available.

• Other cancers. There is no consistent 

relationship between the use of HRT and

liver cancer, other digestive neoplasms, or

melanoma.

10.2 Selective Estrogen Receptor Modulators

Given the recognized adverse effects of HRT,

much recent attention has focused on assessing

alternative approaches to treating menopause,

including use of tamoxifen and other SERMs.

SERMs may offer many of the advantages of HRT

while eliminating some of the disadvantages.

• Breast cancer. SERMs may reduce risk for

breast cancer. Tamoxifen has been shown to

reduce the risk for breast cancer by almost 50

percent. One clinical study of raloxifene showed

a strikingly reduced risk.3 Further studies of

tamoxifen and raloxifene are in progress. 

11. NEUROLOGIC FUNCTION, MENTAL

HEALTH, AND EYE

The CNS and eye are among the many tissues

thought to be affected by hormonal changes around

the time of menopause. In the brain and eye, as in

other target organ systems, estrogen interacts with

specific intranuclear receptors and putative membrane receptors to regulate intracellular processes.

HRT with estrogen or other sex steroids has the

potential to influence brain and eye functions.

Few clinical characteristics or diagnostic procedures identify subgroups of women who can benefit from HRT for the prevention or treatment of

disorders of neurologic function, mental health, or

the eye [D]. Despite a strong biologic rationale,

clinical data are sparse. Thus, recommendations

regarding HRT to prevent or ameliorate the disorders are necessarily limited.

11.1 Cognitive Decline

Memory and other cognitive abilities change over

time during adult life. Changes that represent

«usual» or «normal» accompaniments of aging are

not viewed as pathologic. Modest cognitive decrements initially detectable in middle age are accentuated at elderly age. Many studies suggest that sex

hormones influence brain function throughout life,

but there is little evidence that menopause per se

initiates cognitive deterioration, and serum estrogen concentrations in postmenopausal women do

not appear to be closely related to cognitive skills.

• Hormone replacement therapy. ERT may

help preserve specific cognitive skills (e.g.,

verbal memory) immediately after induced

menopause [B]. Clinical trial data of cognitive function with HRT during normal aging

are limited and inconsistent [C].

11.2 Alzheimer’s Disease and Other 

Neurologic Disorders

A number of neurologic conditions are associated

with aging.

• Hormone replacement therapy

Alzheimer’s disease. HRT begun after

menopause may reduce risk of Alzheimer’s

disease [C]. In contrast, ERT begun after

the onset of dementia does not improve

Alzheimer symptoms [B].

Stroke. HRT does not appear to modify

substantially the risk of stroke in older

healthy women [A].

Other neurologic disorders. For many 

neurologic disorders, including epilepsy,

migraine headache, multiple sclerosis, and
19

Parkinson’s disease, no overall positive 

or negative impact of menopause or HRT

on neurologic symptoms or disability has

been described [C].

Sleep disorders. Some sleep disturbances

occurring during the climacteric may 

benefit from HRT [C].

11.3 Mental Health

Women of all ages have higher rates of depression

than men, and geriatric depression is a particularly

important public health concern. Hot flushes and

other climacteric symptoms clearly affect the quality of a woman’s life. The menopausal transition

does not appear to represent a time of heightened

vulnerability to affective disorders.

• Hormone replacement therapy

Mood. Hormonal changes associated with

menopause have little direct impact on

mood [C]. Limited data from studies of

women without clinical depression suggest

a beneficial effect of estrogen on mood [B].

11.4 Eye

Increasing age is often accompanied by visual loss

or blindness, and diminished visual acuity among

older persons affects women more often than men.

Some observational studies suggest the potential

relevance of estrogen in eye disease.

• Hormone replacement therapy

Maculopathy, cataract, and dry eye. There

is little evidence that HRT alters risk for

certain types of age-related maculopathy,

cataract, or dry eye [C].

12. FUTURE NEEDS

As life expectancy continues to increase, a 

challenge for the future will be to maintain and

improve the quality of life in women as they age

through better management of menopausal symptoms and health risks associated with menopause.

Despite exciting new research in the field of

menopause, including the availability of more

choices for intervention and major breakthroughs

in the understanding of ER-mediated effects, much

work remains to be done. The increasing number

of postmenopausal women and their increasing

longevity highlight the importance of women’s

health and well-being.

Key needs for the field of menopause in the near

future are outlined in table 1–3.

Note:

The Women’s Health

Initiative, NHLBI, NIH, is

referred to throughout this

International Position Paper.

As this document went to

press, the NHLBI stopped an

important component of the

WHI on the basis of recommendations by the study’s Data and Safety

Monitoring Board (DSMB), an independent advisory

committee. The reasons for stopping this major

clinical trial of estrogen plus progestin early were

due to an increased risk of invasive breast cancer

as well as increases in coronary heart disease,

stroke, and pulmonary embolism in participants on

estrogen plus progestin compared to women taking

placebo pills. There were noteworthy benefits of

estrogen plus progestin, including fewer cases of

hip fractures and colon cancer, but on balance 

the harm was greater than the benefits. The study,

which was scheduled to run until 2005, was

stopped after an average follow-up of 5.2 years.

However, because the balance of risks and benefits

of estrogen alone is still uncertain, the DSMB 

recommended that that component of the WHI be

continued unchanged.

Because of the importance of the information 

from the estrogen plus progestin study, the results

were released early in an expedited article on 

July 9, 2002 on the JAMA Website. Links to the

JAMA article and a related editorial, can be found

at http://www.nhlbi.nih.gov/whi/hrtupd/.

Limited data from

studies of women

without clinical

depression suggest 

a beneficial effect of

estrogen on mood.
20

TABLE 1–3

Women’s Health and Menopause: Future Needs

Menopause and Aging 

• Conduct more research on the biologic and psychosocial processes of menopause.

• Conduct additional longitudinal studies using prospective observational designs and large cohorts on the natural 

history of menopause representing women from a broad array of racial/ethnic and socioeconomic backgrounds.

• Undertake additional menstrual diary research with concurrent hormone measures, to establish biomarkers of

women’s proximity to menopause.

• Undertake additional research on fertility and contraception in the perimenopause.

• Further understanding is needed about the reciprocal influences of lifestyle, decision to use HRT, and quality of life.

• Providing women and their families with balanced information about menopause, fostering positive attitudes

towards aging and menopause, and encouraging healthy lifestyles may improve their health and quality of life 

related to menopause.

Symptoms and the Menopause

• Better document the natural menopausal transition through prospective investigations to distinguish 

menopause-related changes from those of aging or disease. 

• Conduct questionnaire studies validating phytoestrogen intake against metabolic measures of metabolites in 

different cultural settings.

• Conduct a larger RCT of phytoestrogen supplementation, including metabolic measures of metabolite levels.

Sociocultural Issues

• Undertake better controlled population-based studies using standardized instruments adapted to the culture studied.

• Develop an interactive psycho-bio-cultural model of menopause.

• Disseminate research results within cultures under study, so that women can make their own decisions about the

need for and choice of interventions and treatment strategies.

• Conduct more interdisciplinary research for a better understanding of interactive factors.

Physiological Role of Estrogen and Estrogen Receptors and Pharmacologic Modulation 

of Estrogen Receptor Activity

• Further characterize a possible antiproliferative role of ERβ in the uterus and mammary gland.

• Determine the physiologic functions of ERβ in the ovary (role in polycystic ovarian syndrome?), bladder, urethra,

bone, cardiovascular system, immune system, and CNS.

• Develop ERα- and ERβ-specific agonists and antagonists for experimental and therapeutic purposes.

• Attain different profiles of action for exogenous estradiol through use of different formulations.

• Obtain higher specificity of action by identification of new target molecules involved in gene transcription.

• Increase knowledge of the mechanisms involved in ER activation through membrane receptors to develop new 

pharmacologic compounds acting along these pathways.
21

TABLE 1–3 (continued)

Sexuality

• Improve understanding of the natural hormone changes that occur with aging and menopause, and of the roles of

endogenous estrogens and androgens in women’s sexuality.

• Develop standardized methods to measure libido in women.

• Better define the determinants of sexual health, including sexual desire and arousal, in postmenopausal women.

• Increase knowledge about the effects of medications on female sexuality in postmenopause, including the role of

therapeutic hormonal and nonhormonal agents in the treatment of sexual dysfunction.

• Improve the transmission of information to postmenopausal women about sexual health.

Cardiovascular and Pulmonary Disease

• Conduct urgently needed randomized controlled clinical trials to investigate the potential benefits and risks of 

different hormone preparations in women with and without prior CHD.

• Investigate low dosages of oral estrogen, nonoral preparations, SERMs, and androgens in randomized trials with

clinical outcomes.

• Except for asthma, very little data exist on the effect of menopause or HRT on the respiratory system, and 

investigation of the effects on important disease entities should be considered.

Osteoporosis and Oral Bone Loss: Risks and Therapy

• Develop noninvasive tools to measure bone quality or bone strength inexpensively.

• Develop pharmacologic agents that will stimulate bone formation and restore lost bone. All currently approved

drugs are antiresorptive.

• Develop new pharmacologic agents for osteoporosis that are bone-specific and that can be used indefinitely.

• Improve knowledge of the association between oral bone and the rest of the skeleton, in particular as related to 

therapeutic benefit.

Gynecologic and Urinary Aspects

• Obtain additional data on the determinants of endometrial function and the specific effects of ovarian hormones 

on skin and different urogenital mucosae.

• Develop new ERα and ERβ agonists and antagonists as well as new progestins.

• Develop sensitive methods for early diagnosis at the molecular level of estrogen defects in various tissues.

• Develop noninvasive methods of endometrial testing.

• Improve knowledge of the relationship between HRT and the pelvic floor, including UI.

• Develop reliable, easy-to-use diagnostic indexes for pelvic floor and urinary syndromes.

• Develop new pharmacologic agents for the treatment of UI.

• Design clinical trials to properly assess the relationship between SERMs and pelvic organ prolapse.
22

TABLE 1–3 (continued)

Menopausal Replacement Therapies and Cancer Epidemiology

• Further quantify the breast cancer risk of estrogen and estrogen-progestin regimens.

• Improve understanding of the relation between the use of HRT and risk for breast cancer according to age. 

• Further investigate the (potentially favorable) biologic effects of HRT on the biologic characteristics of 

breast tumors.

• Undertake additional studies on the use of HRT in women with a diagnosis of breast cancer. 

• Better quantify risk for endometrial cancer with combined HRT.

• Obtain additional data on the use of HRT and risks for cancers of the ovary, colon and rectum, lung, liver, 

and melanoma.

• Conduct additional research regarding cancer risks of the use of tamoxifen and other SERMs, as well as so-called

natural therapies for postmenopause. 

• Conduct RCTs to obtain data for the effects of SERMs on risks of various cancers.

Neurologic Function, Mental Health, and the Eye

• Explore the possibility that SERMs may act as estrogen antagonists as well as agonists in the brain or eye.

• Conduct cohort studies from representative populations and randomized controlled clinical trials to assess potential

hormonal effects on age-associated cognitive decline, risk for Alzheimer’s disease and vascular dementia, mood,

macular degeneration, and other disorders of neurologic function, mental health, and eye.

• Evaluate the effectiveness of combination replacement therapy with estrogen plus a cholinomimetic drug in RCTs

for women with Alzheimer’s disease.

• Evaluate in RCTs the potential effects of HRT on primary prevention of Parkinson’s disease and on symptoms of

Parkinson’s disease.

• Determine in RCTs whether estrogen combined with antidepressants or antipsychotic drugs might enhance effects 

of these medications in depressive disorders and schizophrenia, respectively.

• Determine in long-term RCTs whether HRT might reduce incidence of age–associated maculopathy, cataract, 

or dry eye.

• If beneficial effects of HRT are confirmed, undertake basic and clinical research to define mechanisms of action,

optimal choice, timing of therapy and duration of usage of estrogen or SERMs, and potential modifying effects of

progestin cotherapy.
23

1. Dramatic increases in life expectancy have led to women expecting to live more than a

third of their lives after menopause.

2. The onset of menopause may affect progressive age-related changes in function and

structure of body tissues and systems.

3. There is a lack of consensus as to whether the biological and psychological changes

occurring during the menopause transition or presenting later in life are attributable to menopause and

reduced ovarian function or to aging.

4. The timing of menopause may substantially influence subsequent morbidity and mortality.

5. Menopause cannot be said to have occurred until there have been 12 months of amenorrhea for which there

is no other obvious pathological or physiological cause. Contraception is still needed during the menopause

transition.

6. Endocrine changes begin years earlier. FSH and estradiol changes are maximal in the year of the FMP.

7. The endocrine changes of menopause do not include any acute or sudden decrease in androgens.

8. Menopause research has to address identified methodologic difficulties.

9. There is considerable individual and racial/ethnic variation among women in the age of menopause and in

their manifestation of perimenopausal signs, symptoms, and menopause-related sequelae.

10. Influences of the menopause on health may affect a woman’s quality of life.

CHAPTER 2: THE MENOPAUSE AND AGING

Martin H. Birkhäuser, M.D.;* Lorraine Dennerstein, A.O., M.B.B.S., Ph.D., D.P.M.,

F.R.A.N.Z.C.P.;† Sherry Sherman, Ph.D.;‡ Nanette Santoro, M.D.§

KEY POINTSa

* From the Division of Gynaecological Endocrinology. Department of Obstetrics and Gynaecology, University of Bern, Switzerland.

† From the Office for Gender and Health, Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia.

‡ From Clinical Endocrinology and Osteoporosis Research, National Institute of Aging, NIH, Bethesda, MD, U.S.A.

§ From the Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology, and Women’s Health, Albert Einstein College of Medicine,

Bronx, NY, U.S.A.

a Evidence categories are given in square brackets. A = randomized controlled trials (rich body of data); B = randomized controlled trials (limited data); 

C = nonrandomized trials and observational epidemiologic studies; D = Panel expert judgement. (See also table 1–1.)

Dramatic increases

in life expectancy

have led to women

expecting to live

more than a third

of their lives after

menopause.
24

1. INTRODUCTION

The third millennium begins with vast potential

from unprecedented advances in medicine, technology, and public health.

Major achievements over

the past century in the conquest of infectious and parasitic diseases, progress in

nutrition and education,

reductions in maternal and

infant mortality, although

occurring unevenly on a

global scale, have resulted

in dramatic increases in life

expectancy and burgeoning numbers of older individuals (figs. 2–1 and 2–2).1 Although the world’s

elderly have been increasing in number for some

time, the pace of population aging has accelerated

during the past century, resulting in the “graying” of

societies across the world as striking reductions in

mortality have combined with declines in fertility

to produce a rate of expansion of the older population that has outpaced total population growth.2

In the industrialized nations of Europe, Asia, and

North America, this phenomenon has been a

prominent issue. However, accelerated population

aging in less-developed countries, where increases

in the rate of growth of the older population are

surpassing those in more-developed nations, has

been underappreciated. Accommodating increases

in the proportion of older individuals may be especially challenging to countries that are less-devel-

...Remarkable increase 

in the proportion of

women over fifty in the

population, which has

tripled since the turn 

of the 19th century.

FIGURE 2–1

An Aging Population: Population Aged 65 and Above, 1996

Modified with permission from WHO, 19981

Proportion of population

< 5%

5–9%

10–14%

15–19%

No data available
25

Modified with permission from WHO, 19981

Proportion of population

< 5%

5–9%

10–14%

15–19%

20%+

No data available

FIGURE 2–2

An Aging Population: Population Aged 65 and Above, 2020

oped and are less prepared to address the economic,

social, cultural, and medical uncertainties, competing priorities vis-à-vis enhanced life expectancy,

and the desire to maintain quality of life into the

very late years of life.2

In the developed world, mean life expectancy for

women since 1900 has increased from 50 to 81.7

years. Particularly striking is the remarkable

increase in the proportion of women over fifty in

the population, which has tripled since the turn of

the 19th century.2 Population projections estimated

approximately 467 million women in the world to

be aged 50 years and older in 1990. By the year

2030, this number is expected to grow dramatically

to 1,200 million. The numbers of postmenopausal

women in the developing world are anticipated to

increase much more rapidly than those in the

industrialized world. From 1990 to 2030, the rate of

growth of the postmenopausal population will

decrease from 1.5 to 1.0 percent in the industrialized

world, while averaging between 2 and 3.5 percent

in less-developed countries. Therefore, during this

period, the proportion of postmenopausal women

in more developed countries is expected to decline

from 40 to 24 percent, whereas it will increase

from 60 to 76 percent in less-developed countries. 

Accelerated population aging has led to a major

epidemiological transition in the leading causes of

death from infections and acute diseases to the

chronic and degenerative diseases of old age (such

as malignant neoplasms (see ch. 11), cardiovascular and cerebrovascular diseases (see ch. 8), osteo-
26

porosis (see ch. 9), and dementia

(see ch. 12). The incidence of

some metabolic diseases, such

as diabetes mellitus, is increasing (figs. 2–3 and 2–4).1

Degenerative processes, such as

macular degeneration or progressive lens opacity, have been

linked to prolonged estrogen

deficiency.3 Another study shows

that HRT has a positive influence on intraocular pressure

increasing with age.4 However,

increasingly sophisticated

research in aging since the mid1970s has led us to challenge the concept of an

inevitable, inexorable, unified progression toward

debility and infirmity before death. Now aging is

appreciated as the heterogeneous product of a

genetic disposition being revealed under variable

environmental, behavioral, psychosocial, and economic conditions, many of which are amenable to

profound change with existing as well as emerging

new strategies. 

Aging is associated with progressive structural,

functional, endocrine, and metabolic alterations in

a variety of tissues and systems, many of which

have been implicated in subsequent impairments in

physiological, physical, psychosocial, and cogniFIGURE 2–3

Diabetes Mellitus. Estimated Prevalence Among Adults, 1997

Modified with permission from WHO, 19981

Approximately 467

million women in

the world ... aged

50 years and older

in 1990. By the year

2030, this number

is expected to grow

dramatically to

1,200 million.

Number of persons (000)

< 5

5–74

75–349

350–1500

>1500

No data available
27

FIGURE 2–4

Diabetes Mellitus. Estimated Prevalence Among Adults, 2025

Modified with permission from WHO, 19981

tive functioning. A critical tenet in aging research,

which is aimed at understanding, modifying, or

preventing age-related morbidity, disability, and

death, is the importance of differentiating changes

due to disease and other pathologic processes from

those attributable to aging per se. To better understand the etiology of age-related disease in women,

it is important to additionally ascertain the independent role of menopause and its interaction with

aging. There is little consensus as to the significance of menopause in healthy aging, and considerable controversy exists as to the scope of the

physiological and psychological changes surrounding menopause or presenting later in life that are

attributable to menopause and reduced ovarian

function. Future advances in preventing and managing diseases and disorders in middle-aged and

older women will require more careful delineation

of those diseases and disorders that are attributable

to menopause and reduced ovarian hormone levels

versus those diseases that are not. Such advances

are critically needed to clarify ambiguities in the

presentation of age-related disease, to improve

diagnosis and treatment, and to constrain health

care costs.

The most profound and universal alteration in the

mature aging endocrine system occurs in women

and is due to menopause. However, while

menopause is a universal phenomenon in women,

Number of persons (000)

< 5

5–74

75–349

350–1500

>1500

No data available
28

there is considerable individual variation among

women in the age of menopause and in the manifestation of perimenopausal signs and symptoms as

well as what may be considered menopause-related

sequelae. The perimenopausal and postmenopausal

experience encompasses a complex interaction of

sociocultural, psychological, and environmental factors as well as biological

changes relating strictly to

altered ovarian hormone

status or deficiency. In the

United States and many

Western countries, the perimenopausal experience is

usually perceived largely in negative terms—as a

transitional phase dominated by disturbing physical

and mental symptoms. It has been suggested that

highly negative characterizations of menopause

may be due to an over-sampling of clinic-based

populations of perimenopausal women, who, seeking treatment for symptoms, were more readily

available for study and whose experiences represented the extremes of a difficult transition.

Importantly, our knowledge base on menopause is

extremely narrow in that the majority of studies

have been of white women (of northwest European

ancestry); very little is known about the range of

perimenopausal experiences in women of other

racial/ethnic groups. The sociocultural and behavioral antecedents and consequences of menopause

have also not been well addressed, and major gaps

exist in understanding factors that may profoundly

influence the perception of, and response to, perimenopausal symptoms and sequelae. (See ch. 4).5

The age of menopause and the timing of the onset

of changes in the endocrine milieu may have 

profound implications for subsequent morbidity

and even mortality. Women reporting an earlier

menopause are reported to be at greater risk of

CVD disease6 and osteoporosis7 but at a reduced

risk of breast cancer.8 However, data are conflicting, and methodological difficulties in assessing

the relationship between age at menopause and the

risk of subsequent conditions and diseases of aging

abound in the literature base. 

Although estimates for the median age of

menopause range from 45–55 years of age worldwide9 and between 50 and 52 years of age in white

women from industrialized countries, our understanding of the determinants of, or factors which

influence the age at, menopause is limited, with

conflicting findings between studies commonly

found. A prominent role appears to be played by

race/ethnicity and lifestyle and sociocultural factors.10 Recent studies have suggested that compared

to white women, menopause is experienced at a

later age in Japanese women and at a younger age

in African-American11 and Latin American12 women

and in women living in less-developed countries.

Of all the variables studied, the most consistent

relationship has been for smoking, which is associated with a menopause which occurs 1 to 2 years

earlier than in nonsmokers.13 Reproductive variables,

including later age at menarche, oral contraceptive

use, longer menstrual cycle length, and parity, have

been (albeit inconsistently from study to study)

associated with an older age at natural menopause.

Other studies have shown an earlier menopause to

be associated with lower socioeconomic status,

lower educational attainment, low body mass

index (BMI), or being on a weight-reducing diet.14 

2. AGING IN WOMEN

Aging is associated with profound changes in body

composition. For reasons that are incompletely

understood, as they age, both men and women lose

bone and muscle and increase their proportion of

fat mass. These changes are of great public health

significance, particularly as their associated structural (e.g., diminished muscle and bone strength)

and metabolic (e.g., glucose intolerance, hyperinsulinemia) sequelae have been implicated in the

development of frailty and morbidity (including

heart disease, hypertension, osteoporotic fractures,

and osteoarthritis). 

Smoking is associated

with a menopause

which occurs 1 to 2

years earlier than in

nonsmokers.
29

Sarcopenia, defined as reduced muscle mass, is a

well-known consequence of aging and occurs in

parallel with reductions in muscle strength and, to

some extent, muscle quality.15 Importantly,

decreased muscle mass and strength can impair

physical performance in the elderly and are associated with an increased risk of physical frailty,

declines in functional capacity, impaired mobility,

and falls.16

A recent study suggests that the menopause transition is associated with deleterious changes in body

composition and fat distribution, promoting the

selective accumulation of fat in the intra-abdominal compartment. However, while increases in total

and central adiposity were observed, no differences

in fat-free mass were noted, which suggests that

menopause may have less impact on the processes

promoting muscle loss.17

As both men and women age, collagen synthesis is

reduced, and the skin becomes progressively thinner and wrinkled. The decrease in collagen synthesis is similar in other connective tissues and in 

tissues rich in collagen, such as the conjunctiva

and articulation capsules. Although ERs are 

present in the skin,18 thus defining this tissue as a

target tissue—and it is widely believed that estrogen deficiency affects epithelial tissues—there is a

dearth of prospective observational data using validated methods to assess skin quality in different

racial/ethnic groups exposed to varying environmental factors. Importantly, the ability to differentiate the effects of menopause from those of aging

is very limited as skin quality can be substantially

influenced over time by genetic, smoking, and

environmental influences, particularly ultraviolet

exposure, which can cause premature aging of the

skin. There is evidence from experimental studies

that estrogen can stimulate collagen biosynthesis

and maturation in animal models19 and increase

skin collagen content in humans.20 Estrogen use in

humans has been associated with greater collagen

content, thickness, elasticity, and vascularization.21

Increases in facial hair, temporal hair loss, and

deepening of the voice often observed in elderly

women have been linked to the relative androgen

dominance after menopause.

Evidence suggests that estrogen administration can prevent hair loss,18,22 and the frequent complaint of “dry eyes”

(keratoconjunctivitis sicca).23

However, there have been few

RCTs demonstrating major

benefits of HRT on the skin,

hair, or sensory organs, such

as the eye. 

Because aging is associated

with decrements in both skin

thickness and BMD, it has

often been postulated that

measurement of the thickness

of skin can be used to predict

the risk of osteoporosis after

menopause. However, despite

significant statistical correlations between skin thickness and bone mineral

content (BMC), the risk for osteoporosis cannot be

accurately deduced from skin thickness in an individual patient.24, 25

3. DEFINITIONS

The word “menopause” (“ménespausie”) was used

for the first time in 1816 by Gardanne.26 Initially,

the phenomenon of menopause was explained as a

deficiency of ganglionic regulatory functions. In

1910, Marshall27 recognized that the ovary should

be classified as an endocrine organ. From the

endocrine perspective, the menopause represents a

primary ovarian insufficiency and has an inception

between the ages of 40 and 56 years, with a mean

age of 51 years.28 From a scientific perspective,

natural menopause coincides with the FMP, and

this cannot be determined until there have been12

months of amenorrhea.9 This definition is based on

clinical epidemiological evidence that the probabilRecent studies have

suggested that 

compared to white

women, menopause 

is experienced at a 

later age in Japanese

women and at a

younger age in

African-American

and Latin American

women and in

women living in lessdeveloped countries.
30

ity of resumption of menstruation after 12 months

of amenorrhea is vanishingly small.29,30

Much confusion has been caused by differing definitions used in relationship to changing ovarian

status. Definitions were provided by the World

Health Organization (WHO) Scientific Group on

Research on the Menopause in the 1990s.9 More

recently, these definitions and others were considered

by the Council of Affiliated Menopause Societies

(CAMS) of the International Menopause Society

(IMS). The only change recommended to the WHO

definitions was the inclusion of the term “climacteric,” considered by many clinicians to be descriptive of this phase of life. The list of menopauserelated definitions given below was approved by

the IMS in October 1999, in Yokohama, Japan.31

TERMS SOURCE

Menopause (natural menopause) WHO

The term “natural menopause” is defined as the

permanent cessation of menstruation resulting

from the loss of ovarian follicular activity. Natural

menopause is recognized to have occurred after 

12 consecutive months of amenorrhoea, for which

there is no other obvious pathological or physiological cause. Menopause occurs with the FMP,

which is known with certainty only in retrospect a

year or more after the event. An adequate biological marker for the event does not exist.

Mean age

51 years

Climacteric

1 year

later

Menopausal transition

Perimenopause

Postmenopause

Final menstrual period (FMP)

Menopause

FIGURE 2–5

Relationships Between Different Time Periods Surrounding the Menopause
31

Perimenopause WHO

The term “perimenopause” should include the 

period immediately prior to the menopause (when

the endocrinological, biological, and clinical 

features of approaching menopause commence)

and the first year after menopause.

Menopausal transition WHO

The term “menopausal transition” should be

reserved for that period of time before the FMP

when variability in the menstrual cycle is usually

increased.

Climacteric IMS

This phase in the aging of women marks the transition from the reproductive phase to the nonreproductive state. This phase incorporates the perimenopause by extending for a longer variable 

period before and after the perimenopause.

Climacteric syndrome IMS

The climacteric is sometimes, but not necessarily

always, associated with symptomatology. When

this occurs, it may be termed the “climacteric syndrome.”

Premenopause WHO

The term “premenopause” is often used ambiguously to refer to the 1 or 2 years immediately

before the menopause or to refer to the whole of

the reproductive period prior to the menopause.

The group recommended that the term be used

consistently in the latter sense to encompass the

entire reproductive period up to the FMP.

Postmenopause WHO

The term “postmenopause” is defined as dating

from the FMP, regardless of whether the

menopause was induced or spontaneous.

Premature menopause WHO

Ideally, premature menopause should be defined 

as menopause that occurs at an age more than 

two standard deviations below the mean estimated

for the reference population. In practice, in the

absence of reliable estimates of the distribution of

age at natural menopause in populations in developing countries, the age of 40 years is frequently

used as an arbitrary cutoff point, below which

menopause is said to be premature. 

Induced menopause WHO

The term “induced menopause” is defined as the

cessation of menstruation, which follows either

surgical removal of both ovaries (with or without

hysterectomy) or iatrogenic ablation of ovarian

function (e.g., by chemotherapy or radiation).

Figure 2–5 shows the relationships between 

different time periods surrounding the menopause.

4. PHYSIOLOGY

The process of the menopausal transition appears to

take about a decade. The earliest signs of this transition are (1) shorter menstrual cycles by 2–3 days and

(2) infertility. After birth, the number of oocytes 

continuously decreases. At puberty, 1 million oocytes 

are left.32 This number decreases to 0.3 million by 

the age of 20 years.32 Menopause is marked by the

exhaustion of the ovarian supply of oocytes.33

Although only approximately 400 follicles or less

than 0.01 percent of all oocytes proceed through

ovulation between menarche and menopause,33,34

long-standing amenorrhea or the prolonged intake of

a contraceptive pill does not seem to postpone

menopause.13 Reduced fertility due to the aging

process of the oocytes and to abnormal follicular

maturation is the first sign of ovarian aging. After the

age of 40, about 30–50 percent of all cycles show 

an abnormal basal temperature.35,36 Two to eight years

before menopause, the incidence of luteal insufficiency and anovulatory cycles increases,37 resulting

in a higher incidence of persisting follicles and dysfunctional bleeding. Shorter menstrual cycles appear

to be detectable at about age 38–40.38,39 The subtle

but common shortening of the intermenstrual interval

is clinically valuable, as it seems to be predictive of

other perimenopausal changes.
32

Subtle reproductive hormonal changes occur in the

face of these minor cycle changes. FSH appears to

rise throughout reproductive life, but the elevation

becomes obvious in the late thirties/early forties in

women.40 Although it is elevated for most of the

menstrual cycle, early follicular phase FSH concentrations are most easily discriminated from “normal” concentrations on cycle days 2–5. An elevated FSH is a harbinger of menopause, although it

may still be many years away, and has clearly been

shown to augur poorly for future fertility.41 It is a

poor predictor of age at menopause, however, and

the clinician cannot make any conclusions on the

timing of an individual woman’s menopause based

upon the presence or degree of FSH elevation.42

On the other hand, as long as the active follicular

phase permitting the maturation of healthy follicles

remains stable and the luteal phase normal, fertility

is maintained. Therefore, contraception is still

needed during the menopause transition, despite

moderately elevated FSH levels. An isolated elevated serum FSH level is not proof of the occurrence of menopause and is not sufficient to consider

a perimenopausal woman infertile so that she

could cease reliable contraception.43

4.1 Clinical Factors

Environmental influences may alter the ovarian

aging process. Smoking advances the age of

menopause by about 2 years.28 Recent studies suggest that high levels of galactose consumption may

do the same. However, most of the determinants of

menopause are innate. Familial and genetic factors

appear to be the most predictive at present.44 One

recent study described an ERα polymorphism that

is associated with a 1.1 year advancement in the

age at menopause and a nearly threefold RR of

hysterectomy for benign disease.45 Ovarian surgery,

adhesions, and pelvic endometriosis appear to be

associated with poor ovarian stimulation for in

vitro fertilization and perhaps are also risk factors

for early age at menopause.46

Menstrual cyclicity is currently the best indicator

of menopausal status. The large variability in intermenstrual intervals that occurs at this time of life

probably reflects a combination of short cycles38

and skipped cycles. Treloar et al.37 reported a

detailed analysis of intermenstrual intervals of

women encompassing over 20,000 menstrual

cycles. Variability of cycle length was enormous in

both the perimenarcheal years and the years of

menopausal transition. Cycle length shortening is

probably due to elevated FSH levels in the early

follicular phase/late luteal phase of the cycle.

The classic characterization of the menopause transition was provided by Sherman and Korenman

(1975).47 Six women were followed in detail up to

and including the actual last menstrual period.

Their data described the key features of the

menopause transition, which are still under investigation today, almost 20 years later: (1) a

monotropic rise in FSH secretion, (2) continued

folliculogenesis and evidence of ovulation up to the

FMP, and (3) periods of hypoestrogenemia concomitant with large FSH rises. The loss of inhibin

restraint was first hypothesized by this group.

Metcalf followed perimenopausal women longitudinally throughout their forties and fifties.48 This

characterization of the perimenopause included the

observation that the key feature of passage

“through” menopause was the subsequent complete

absence of luteal activity. Therefore, a permanent

failure of ovulation is the cardinal observation.

Within the first year after a woman’s FMP, variable estrogen excretion was observed; thereafter,

estrogen excretion was abidingly low and basal.48,49

These results have been confirmed by others in

serum studies.

Using 6 years of prospective annual measures,

Burger et al. reported that mean FSH levels began

to increase from about 2 years before the FMP,

increasing most rapidly about 10 months before

the FMP, and had virtually plateaued by 2 years

after the FMP.50 Mean estradiol levels started to
33

decrease about 2 years before the FMP, decreased

most rapidly around the time of the FMP, and had

virtually plateaued by 2 years after the FMP. 

Klein et al. reported the endocrinology of follicles

and peripheral hormones in women in their early

forties.51 Shortened follicular phases, apparent

accelerated folliculogenesis, and a monotropic

FSH rise were all confirmed in these women.

Follicle fluid was aspirated and compared to

younger controls. Follicle fluid in reproductively

aged women contained more estradiol and less

insulin-like growth factors than younger women,

despite fewer granulosa cells per follicle.51 Oocytes

contained aberrant meiotic spindles in abundance,

evidence for chromosomal damage to the oocyte

either due to its age alone or to inappropriate

paracrine/endocrine cues.52 These data emphasize

that reproductive aging begins earlier than previously believed (as early as age 40) and is happening in a very significant way before menstrual

cycles become irregular and certainly before

women notice any symptoms. This becomes particularly poignant in the office setting when healthy

women in the older reproductive age group are

informed of their poor fertility potential despite

their robust, asymptomatic status.

Santoro et al.53 observed a small cohort of women

in the mid-perimenopausal years when menstrual

cyclicity was beginning to deteriorate. Compared

to younger women, these perimenopausal women

had evidence of greater estrogen excretion in conjunction with elevated FSH and LH concentrations

and decreased luteal phase progesterone metabolite

excretion.53 Irregularities of menstrual cyclicity

were characterized by occasionally dramatic excursions of estrogen well beyond the normal range for

younger women. Thus, “skipped” cycles in the

perimenopause may be due to either failure of folliculogenesis and hypoestrogenemia or accelerated

and sustained estrogen secretion. These findings

have recently been confirmed in a larger, epidemiologic sample of perimenopausal women.54 The

common gynecological problems of women in the

perimenopause, such as dysfunctional uterine

bleeding, growth of uterine leiomyomata, and the

frequent utilization of dilatation and curettage

(D&C) and hysterectomy for women in this age

group, may be explained by the persistence of

these hormonal patterns.

4.2 FSH, Inhibins, and Reproductive Aging

The monotropic rise in FSH that accompanies the

onset of the menopause transition has

been known since the 1970s.47 At that

time, the prevailing notion was that a

lack of inhibin “restraint” of FSH

caused the elevation, the so-called

“inhibin hypothesis.”47 Inhibins are

molecules in the transforming growth

factor-β (TGF) peptide superfamily.

(See also ch. 5, sec. 6.) They are 

produced by the granulosa cells of the

ovary. They are heterodimeric, consisting of a

common alpha subunit and a specificity-providing

beta subunit. Inhibin A appears to be expressed in

large, dominant follicles and the corpus luteum

while inhibin B appears to be a product of small 

follicles.55 Although they were believed to act via

specific binding to a cell surface receptor, inhibin

receptors have only recently been identified.56

Thus, two decades after it was proposed, the inhibin hypothesis has been confirmed by measurement.

Diminished inhibin A and B have been reported in

the circulation of older reproductive-aged

women.57–60 Elevated FSH in perimenopause may

be more tightly linked to this loss of inhibitory

tone, rather than to decreased estradiol production

by the perimenopausal ovary. At the early stages of

the menopause transition, women appear to be

estrogen replete and do not demonstrate evidence

of decreased estradiol until they are within several

years of their FMP.50–53 In fact, in some perimenopausal women, the elevated FSH may lead to

“overshoot” and the consequent production of supraphysiological amounts of estradiol.53–61 Follicular

phase inhibin B appears to be detectably decreased

The available

data shows

that after 

hysterectomy

menopause

occurs earlier.
34

in the early perimenopause, concomitant with the

rise in FSH.50 As the transition progresses, follicular phase inhibin A declines detectably as well,

perhaps as a later event.50

In addition to these early changes in inhibin A and

B, activin A has been shown to be elevated in perimenopausal women.58,60 Activins are the beta

homodimers of the inhibin molecules and exist as

activin A and B. While they clearly play a local

role in pituitary FSH secretion, their ability to 

act as endocrine factors influencing the production

of FSH is not established.

Moreover, activins circulate

bound to follistatin, their serumbinding protein. The relatively

high affinity of follistatin for

activin, as well as its abundance

in serum, suggests that activin

may exert most of its effects in a

paracrine or autocrine, and not

endocrine, fashion.

4.2.1 Androgens in the Perimenopause

Circulating androgens in women reflect contributions from adrenal, ovarian, and peripheral

sources. When relatively stable adrenal hormones,

such as dehydroepiandrosterone sulfate, are measured, a dramatic decline is observed across the

adult lifespan.62, 63 An independent effect of the

process of menopause on circulating adrenal

androgens has not been observed.

Together with the age-related decline in adrenal

androgen production, ovarian androgens, particularly testosterone and androstenedione, decrease

throughout adult life as well.64,65 Metabolites of

dihydrotestosterone demonstrate the most precipitous declines between the ages of 20 to 40 years.63

While some studies suggest that a small

menopause-associated decrease in testosterone

occurs,66,68 other longitudinal, prospective studies

have not documented any acute decrease in testosterone or androstenedione associated with the

menopause transition.69,70 The modification of

testosterone bioavailability by sex hormone 

binding globulin (SHBG) may play a role in perimenopausal physiology; however, it is controversial

as to which direction SHBG changes across

menopause, with some studies observing a

decline67,70 and others an increase.69 It seems clear

that the major decline in circulating testosterone

occurs well before the menopause transition.65

Based upon current well-designed studies and

including observations about both adrenal and

ovarian androgens, the medical “myth” that

menopause is associated with an acute drop in

androgens does not appear to be tenable any longer.

4.2.2 Neuroendocrine Changes

The loss of “positive feedback,” that is, the ability

to respond to an estradiol challenge with an LH

surge, appears to be another feature of the perimenopause which leads to potential morbidity for

women.71 It is unclear why this ability is lost, as it

appears to be regained in the postmenopause,

when LH surges in response to estrogen challenge

have been well documented.72,73 Perhaps the other

concurrent abnormalities of the endocrine milieu

predispose women to this temporary state. It may

be the result of enhanced susceptibility to the negative feedback of estradiol.60,74

Whereas in young premenopausal women estradiol

is the major circulating estrogen, estrone becomes

the dominant estrogen after menopause. Estrone is

produced primarily by peripheral aromatization of

androgens.75 Aromatization takes place in the adipose tissue, muscle, bone marrow, skin, brain, and

other tissues. Estrone is less potent than estradiol.

The postmenopausal concentration (20 to 60

pg/mL) of estrone equals or surpasses the range

observed in healthy premenopausal women. The

conversion of androgens to estrogens (mostly

estrone) increases from approximately 1.4 to 2.7

percent in premenopausal compared to postmenopausal women.

Considering the

high incidence of

hysterectomy in

some countries,

this observation is

clinically relevant.
35

4.3 Menstrually Defined Menopausal Status

Most observational studies of changes in health

outcomes related to menopause have tried to subcharacterize the perimenopausal years based on

changes in menstrual status.76 The Korpilampi

Workshop in 198577 defined the boundary between

the premenopausal and perimenopausal states by the

reporting of changes in menstrual flow and/or regularity. They identified that the reliability of such

definitions for predicting the further movement to

postmenopause had not been sufficiently studied.

Brambilla et al.29 proposed a method for operationally defining the onset of perimenopause as (1)

a self-report of 3 to 12 months of amenorrhea, and

(2) for those without amenorrhea a self-report of

increased menstrual irregularity. They stated that

validation of this definition would require the

examination of longitudinal hormonal changes

with changes in the menstrual cycle.

Using prospective data, the Melbourne Women’s

Midlife Health Project76 found that women who

reported not having had a menstrual period in the

last 3–1 months were older, had lower estradiol

and inhibin levels and higher FSH, and were more

likely to report hot flushes and to self-rate themselves as having started the menopausal transition,

compared with women who had menstruated in the

last 3 months. Subsequent analysis from the same

project compared retrospective self-reports of menstrual status with prospectively kept menstrual

diary data78 for women reporting at least one menstrual period during the previous 3 months. This

study found that no significant agreement exists

between retrospective self-reports and prospective

diary-based measures of change for cycle frequency nor for flow. Thus, retrospective self-reports at

interview of changes in menstrual frequency and

flow should not be regarded as reliable measures

for the purpose of determining menopausal status.

4.3.1 Hormone Measures

Relatively few studies have undertaken any hormonal determinations. Endocrine change occurs

for some years prior to the cessation of

menopause,50 so it is important to acquire measures

while women are still menstruating regularly, some

years before menses cease. Other issues involved

in hormone measures have been those of the frequency of sampling (annual versus daily or weekly),

type of sampling (plasma, urine, salivary), phase

of the cycle sampled, and the presence of floor

effects due to the lack of sensitivity of assays at

the lower levels of estradiol and inhibin, which

occur in the postmenopause.

4.3.2 Age and Length of Followup

Age at baseline and length of followup are important issues. Followup has often been only in the

order of 3 years.79–81 The Melbourne Women’s

Midlife Health Project found that after 3 years of

followup, only 12 percent

of women had become naturally postmenopausal (12

months of no bleeding

after reaching their FMP).

At the end of 7 years of

followup, only 39 percent

of the women in this

cohort were naturally postmenopausal, reflecting

splintering of the sample as

well as length of followup. 

4.4 Natural Menopausal Transition Versus

Induced Menopause

A major problem in menopause research has been

to establish the health experiences associated with

natural menopause and how these may differ when

menopause is induced. A number of studies suggest

that symptom experience is likely to be worse

when women have undergone surgical menopause.82

Documentation of medical treatment, which may

impact ovarian functioning (surgery, chemotherapy, irradiation), and documentation of medication

Whereas in young 

premenopausal women

estradiol is the major

circulating estrogen,

estrone becomes the

dominant estrogen after

menopause.
36

taken by women are needed so that these women

may be treated separately in the analysis. The

available data show that after hysterectomy

menopause occurs earlier. The mean age of ovarian

failure in the hysterectomized group was 45.4 ±

4.0 years (standard deviation) and was significantly lower than the mean age of 49.5 ± 4.04 years in

the nonhysterectomized control group (p < 0.001).83

Considering the high incidence of hysterectomy in

some countries, this observation is clinically relevant. In the United States, one woman in three

undergoes hysterectomy by age 65. The rate in the

European Union nations ranges from 6 to 20 percent.84 In the 1980s, of a total sample of women in

six European countries, 11.4 percent had undergone hysterectomy, the highest percentage being

found in Italy (15.5 percent) and the lowest in

France (8.5 percent).85 In Europe, the prevalence of

surgical procedures is higher in privately insured

persons than in persons with only basic insurance.

Among 25- to 74-year-old privately insured

women, the lifetime prevalence of a hysterectomy

is 30 percent with low educational status and 13

percent with high educational status (p < 0.001).86

A European woman without education has a RR of

2.2 (1.1–4.4) for hysterectomy compared to an

educated woman.87 Similar data are reported from

the United States.88 In the United States, hysterectomy rates increased with age, and rates for black

women slightly exceeded the rates for whites.89

Hysterectomy with ovarian preservation is associated with increased risk of high diastolic blood

pressure, diagnosis of hypertension, and increased

BMI but is not associated with other heart diseases.90 Women who underwent hysterectomy

reported more discomfort and frequent symptoms

of urogenital atrophy.91

4.5 Exogenous Hormones

Exogenous hormones may mask the effects of

changing ovarian function, so that women taking

the oral contraceptive pill or any HRT must also be

treated separately in analyses. In many countries, an

increasing number of women are choosing to adopt

HRT, and this may lead to a splintering of the sample and even to insufficient numbers to examine

the effects of the natural menopausal transition.

Holte reported that sample size in a longitudinal

study over 5 years was reduced from 200 to 56.92

Prospective studies allow the profile of those who

adopt HRT to be compared with that of nonusers,

in order to elucidate any biases which are related

to hormone selection and which may affect the

endpoint.93

5. QUALTIY OF LIFE AND MENOPAUSE

Concepts of quality of life vary from measures of

subjective well-being, symptoms, or other indicators of health status to that of functional status.

Assessing the impact of a condition on quality of

life is particularly relevant. A range of measurement tools are available for monitoring how climacteric symptoms affect patients with regard to

their well-being, sleep disturbance, other somatic

symptoms, and cognitive and sexual functioning.

Only standardized and well-validated measurement

tools should be used.

The close association between lifestyle and health

is generally recognized. Much is still to be learned

about the reciprocal influences of lifestyle, decision to use HRT, and quality of life. The most relevant factors influencing a woman’s quality of life

during the menopause transition appear to be her

previous emotional and physical health, her social

situation, her experience of stressful life events

(particularly bereavements and separations), as

well as her beliefs about menopause and aging.

Those who seek medical help for menopausal

problems tend to report more physical and psychological problems in general. They are more likely
37

to be under stress and to hold particular beliefs

about the menopause.94

Health and quality of life related to menopause

may be enhanced by providing: (1) balanced information about the menopause to women and to their

families; (2) discussion of attitudes towards the

menopause, with the promotion of positive attitudes

towards aging and menopause; and (3) health promotion sessions focusing upon healthy lifestyles 

of balanced diet, daily exercise, and cessation of

smoking.94

6. FUTURE NEEDS

• Markers of a woman’s proximity to menopause

are lacking. More menstrual diary research studies

with concurrent hormone measures are needed

to identify biomarkers of menopausal status.

• More research is needed on fertility and contraception in the perimenopause.

• Further understanding is needed about the 

reciprocal influences of lifestyle, decision to use

HRT, and quality of life.

• Providing women and their families with balanced information about menopause, fostering

positive attitudes towards aging and menopause,

and encouraging healthy lifestyles may improve

their health and quality of life related to

menopause.
38

1 World Health Organization. The World Health Report

1998. Geneva: World Heath Organization 1998.

Available at: http://www.who.int/whr/1998/whren.htm. Last update 16 February 1999.

2 U.S. Department of Commerce, Economic and

Statistics Administration, Global Aging into the

21st Century. Bureau of the Census. 1996.

3 Smith W, Mitchell P, Wang JJ. Gender, oestrogen, hormone replacement and age-related macular degeneration: results from the Blue Mountains Eye

Study. Aust N Z J Ophthalmol 1997;25(Suppl

1):S13–5.

4 Sator MO, Joura EA, Frigo P, Kurz C, Metka M,

Hommer A, Huber JC. Hormone replacement 

therapy and intraocular pressure. Maturitas

1997;28:55–8.

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Metab 1993;7:33–45.
43

CHAPTER 3: SYMPTOMS AND THE MENOPAUSE

1. Conflicting findings regarding which symptoms are related to hormonal

changes of menopause reflect different research methodologies and their

limitations.

2. When symptom checklists are used, middle-aged women are highly 

symptomatic.

3. Age related symptoms may be differentiated from those related to the

menopausal phase.

4. Only vasomotor symptoms, vaginal atrophic symptoms, and breast tenderness consistently vary with the phase of the menopause transition and are

significantly affected by the administration of hormones in double blind

RCTs [A].

5. Other symptoms, such as insomnia and mood, may be affected by the 

presence of bothersome vasomotor symptoms.

6. Symptoms are influenced by psychosocial and lifestyle factors.

Lorraine Dennerstein, A.O., M.B.B.S., Ph.D., F.R.A.N.Z.C.P., D.P.M.;* Janet Guthrie, M.Sc., Dip. Ed. Ph.D.;† Martin

Birkhäuser, M.D.;‡ Sherry Sherman, Ph.D.§

KEY POINTSa

* From the Office for Gender and Health, Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Australia.

† From the Office for Gender and Health, Department of Psychiatry, Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne,

Australia.

‡ From the Division of Gynaecological Endocrinology, Department of Obstetrics and Gynaecology, University of Bern, Switzerland.

§ From the Clinical Endocrinology and Osteoporosis Research Branch, National Institute on Aging, NIH, Bethesda, MD U.S.A.

a Evidence categories are given in square brackets. A = randomized controlled trials (rich body of data); B = randomized controlled trials (limited data); 

C = nonrandomized trials and observational epidemiologic studies; D = Panel expert judgement. (See also table 1–1).

Conflicting findings

regarding which 

symptoms are related

to hormonal changes

of menopause reflect 

different research

methodologies and

their limitations.
44

1. INTRODUCTION

A large number of symptoms have been variously

linked with the menopause transition. Important

clinical questions include the following:

1. What are the most frequent symptoms experienced by middle-aged women?

2. Which of these are related to the hormonal

events reflected in the different phases of the

menopausal transition, and which relate to aging?

3. What is the role of other psychosocial and

lifestyle factors in determining women’s experience of symptoms?

4. What evidence is there for the effectiveness of

treatment interventions for symptoms linked to

the transition to menopause?

2. QUALITY OF LIFE AND SYMPTOMS

The term “quality of life” refers to

a subjective perception on the part

of both researcher and subject.

Areas covered range from health

status (SF–36),1 life satisfaction,2

coping,3 and depression (Center

for Epidemiologic Studies

Depression scale)4 to scales measuring symptoms thought to be characteristic of

specific states, such as menopause. This breadth of

coverage and absence of a single, widely accepted

definition may be a limiting feature of the concept

of quality of life.5 There are two different types of

measures: global quality of life or aspects specific

to a particular disease (such as osteoporosis) or a

physiological state such as the hormonal changes

underlying the menopause transition. Scales

designed to measure the latter make the assumption that the more symptoms are present and the

more severe those symptoms are, the lower is the

ensuing quality of life. Yet there has been surprisingly little research linking symptom presence with

the other more global aspects of quality of life

described above.

There is debate as to whether the term “sign” or

“symptom” should be used when referring to the

events of the menopausal transition. The term

“sign” is often used to refer to objective clinical

manifestation of a disease, such as a lump or a

bruit, whereas the term “symptoms” is used to

refer to those bodily perceptions presented as 

complaints by the individual. This chapter uses the

term “symptom” in this context. 

3. METHODOLOGICAL ASPECTS OF

MEASURING SYMPTOMS

Conflicting findings as to the etiology of symptoms in midlife reflect some of the methodological

difficulties inherent in menopause research as well

as specific issues pertaining to the measurement of

symptoms, such as sample selection, validity of

symptom measures, age at baseline and length of

followup, separation of the effects of the natural

menopausal transition from that of induced

menopause, statistical and experimental design.

The most obvious methodological issue is the

potential to confuse studies evaluating the effects

of estrogen or differences between estrogen users

and nonusers on various outcomes as “studies of

menopause.” In order to distinguish menopauserelated changes (due to changes from altered levels

of estrogen and/or other sex hormones) from those

of aging or disease, it is necessary to elucidate the

processes of the transition from premenopause to

postmenopause. Although there is an abundance 

of studies and findings on the effects of ERT on

various physiological and psychological outcomes,

the actual processes and mechanisms of follicular

depletion which underlie the transition to

menopause are poorly understood.

3.1 Study Type

Clearly a number of different research modes can

be used to explore whether the menopause transition affects quality of life, varying from studies of

primates (often involving extirpative surgery and

then hormonal intervention), to clinical trials of

Symptoms are

influenced by

psychosocial and

lifestyle factors.
45

women who may have reached natural menopause

or had menopause induced. However, clinical

experience is based on a small proportion of selfselecting, predominantly ill women and may not

be representative of most women’s experience of

the menopause.6,7 Population-based studies have

demonstrated that women who seek treatment 

differ in systematic ways from those who do not.6,7

Patient-based samples are biased in terms of 

education, socioeconomic status, other health 

problems, and incidence of general depression.8

Clinical trial samples often included women who

had undergone surgical menopause, and the hormones administered were usually synthetic, so

these studies do not inform us of the relationship

of symptoms to the natural menopause transition.

Only studies of women derived randomly from 

the general population provide findings which 

can be confidently generalized to be the experience

of most women of that particular culture and 

geographic location. Reliable transcultural comparisons are rare because rating scales and questionnaires cannot be easily translated to other languages:

a specific term may not exist in the target language

or may have a slightly different meaning. This

problem exists even for translations within the

group of western languages and points to the

importance of validation.

There are intercultural and intracultural differences

in symptom reporting. Kaufert and Syrotuik9

describe how stereotypes held by differing social

and cultural groups act as a framework within which

an individual can select and organize and label

experience. Moreover, in menopause research there

is a risk that stereotypes will become operative

whenever subjects know the topic of the research.

3.2 Rating Scales

Health outcomes and their determinants can be

measured by validated rating scales. The failure to

use adequately validated scales has been a major

problem in menopause research. In the classical

Kuppermann Menopausal Index,10 a numerical

summation of 11 menopausal complaints derived

from clinical experience in New York in the 1950s,

as well as in other rating scales, the importance of

“neurovegetative symptoms” is overestimated,

whereas other changes are neglected. This particularly applies to the measurement of sexuality and

of symptom experience. For example, with regard

to sexuality, relatively few of the population-based

studies of the menopause transition have made any

inquiry about sexual functioning. Differing measures of sexual functioning have been used but

studies often fail to offer any data on the validity

or reliability of these measures in their local population. The research process itself may result in

response bias. This includes interviewer bias in the

phrasing of questions and specification bias if the

variable under study is not well specified to the full

understanding of the subject.

3.3 Symptom Measure 

A major methodological issue is that of the symptom measure utilized and its validity and reliability

for the cultural group studied. The standard

method used for collecting information on the

prevalence and severity of symptoms has been a

checklist of symptoms. But the checklist in itself

introduces a number of biases, including the problem of elicitation. For example, Wright,11 interviewing women of the Navajo tribe, found that virtually all respondents reported no bodily changes

since menopause in relation to open-ended questions, but most responded positively to symptoms

in the checklist. Holte12 noted that the sounder the

methodology, the lower the prevalence of symptoms. When frequency or bothersomeness of complaint are included, the reporting rate goes down

further: irritability was reported by 57 percent of

premenopausal women as being present occasionally, but only 10 percent of the same women

reported that it was there frequently.12 The presence

of symptoms “occasionally” does not indicate their

impact on the woman and may not be clinically

relevant or indicative of treatment needs. Porter et

al.13 assessed the impact and prevalence of symp-
46

toms in a Scottish postal survey of 6,096 women

aged 45–54. Fifty-seven percent of the cohort had

experienced a hot flush, but only 22 percent said

that it had been a problem. Similar disparity existed for night sweats (55 percent and 24 percent)

and dry vagina (34 percent and 14 percent). Only 

4 percent had experienced none of the symptoms.

The most frequently used checklist has been based

on a numerical summation of 11 menopausal complaints, the Kupperman Menopausal Index, derived

from clinical experience in New York in the 1950s.

The index was a combination of self-report and

physician ratings. The index included 11 symptoms (vasomotor, paraesthesia, insomnia, nervousness, melancholia, vertigo, weakness (fatigue),

arthralgia and myalgia, headaches, palpitations and

formication) rated on a 4-point scale. In a critical

review, Alder14 noted that terms were ill defined,

categories included overlapping scores, and scores

were summed without being based on independent

factors. Symptoms seemed to be arbitrarily selected; omitted were measures of vaginal dryness, dyspareunia, and breast tenderness. The following

year Kupperman and coworkers, including Blatt,15

described a modification, which allowed for some

symptoms to be weighted more than others.

Weighting was used without statistical justification. Later, investigators, such as Neugarten and

Kraines,16 extended the list to 28 symptoms but

found that only 9 of these distinguished

menopausal women from those at other developmental phases. These authors, and many since,

arbitrarily categorized groups of symptoms.

Greene17 was the first to use factor analysis as the

basis for categorizing symptoms into three factors,

vasomotor, somatic, and psychological. But

Greene’s study contained a number of flaws.

Although his 30-symptom list was constructed

from the scale of Neugarten and Kraines,16 he

failed to include breast pain, somewhat curiously

as Neugarten and Kraines had found this symptom

to be associated with menopausal women. Nor did

he include symptoms of vaginal atrophy. These

symptoms (mastalgia and atrophy) were still not

included in a later amended 20-item list.18

Whether psychological complaints vary with the

menopause transition has been a key concept, yet

the capacity of most symptom checklists to adequately measure psychological morbidity is

unknown.9 In their Manitoba study, symptoms

measuring psychological morbidity had to conform

to scales used by psychological epidemiologists,

and concurrent validity was sought. The symptom

checklist was not restricted to items with an association with menopause but was embedded in an

18-item general symptom list adapted from one

used in a community health survey. The 11 symptoms forming the menopausal index were derived

from the International Health Foundation studies

(hot flush, night sweats, dizziness, rapid heart beat,

pins and needles in hands and feet, tiredness, irritability, headaches, depression, nervous tension,

and insomnia). Interestingly, the list did not

include vaginal atrophy symptoms, yet the

International Health Foundation list was supposedly chosen as a “succinct summary of the core

symptoms as described in the clinical literature.”

Four factors were found. Hot flushes and night

sweats group together as a separate factor, and five

symptoms burdened on a psychological factor.

These were five of the six symptoms in the

International Health Foundation arbitrary classification of “symptoms of the nervous system.” A

strong association was found between the five psychological symptoms and the two standardized

measures of psychological morbidity used for concurrent validity.

Greene18 compared the findings of seven factor

analytic studies. Despite different methodologies

and sampling, he found that vasomotor symptoms

(hot flushes, night sweats) always formed a separate cluster, totally independent of other symptoms.

There was also agreement that a number of symptoms cluster together to form a general somatic or

perhaps psychosomatic factor: pressure or tightness in head or body, muscle and joint pains,
47

numb-tingling feelings, headaches, feeling dizzy or

faint, breathing difficulties, and loss of feeling in

hands or feet. A further group of symptoms cluster

together to form a psychological factor, which in

some studies can be subdivided into anxiety and

depression.

3.4 Cross-Sectional Versus 

Longitudinal Design 

As indicated above, observational studies of population-based samples are the best way to determine

the symptom experience of women in relationship

to the phases of the natural menopause transition.

However, they often suffer from being cross-sectional in design19 rather than having the power of

longitudinal analysis of the same women through

the menopause transition.20 Cross-sectional studies

can only indicate whether associations exist and

are unable to determine causality. Cross-sectional

studies have certain advantages. They are more

convenient and less expensive to carry out.

Subjects are only asked to participate on one occasion so that the response rate is likely to be higher

than when subjects are asked to contribute time for

assessments on a regular basis. Those who accept

to participate in a longitudinal study may differ in

certain systematic ways from those who decline

and this may introduce bias into the sample.21

Thus, the sample participating in a cross-sectional

study may be more similar to a general population

sample than that of a longitudinal study sample. 

Splintering of the study population can continue

for other reasons during the accrual process.22

From the target group, only those persons available

to the investigator are potentially eligible for study.

Further splintering occurs after applying inclusion

and exclusion criteria. After being admitted to the

study, the subject’s records must be properly filled

in: missing data on some variables can lead to

exclusion of the subject with some analytic techniques. If the reason for drop-out or premature

early termination of the study is related to the studied endpoint, this can induce further bias. Another

source of error is that of confounding, which

necessitates the need for multivariate analytic

methods to control for the influence of the various

factors that can affect an outcome. The majority of

community-based studies have been cross-sectional

and thus limit researchers to inferring apparent

associations. Cross-sectional studies cannot control

for premenopausal characteristics nor separate the

effects of aging from those of menopause. 

These studies are less satisfactory than longitudinal

studies in which the same women are followed

over time with the same instruments, so that what

is being observed is change in the same population

with time. Longitudinal cohort designs facilitate

the identification of causal pathways and allow the

effects of aging to be disentangled from those of

menopause.8 However, most longitudinal studies

have used inadequate statistical methods, often

resorting to a cross-sectional approach to data,

which, as repeated measures, are no longer independent in nature.23 Longitudinal collection of 

data reduces reliance on memory for long recall

periods. The length of the recall period in crosssectional studies can lead to further inaccuracy of

data. This is not only true for the studied endpoints, but also for possible covariates at the time

of occurrence. In longitudinal studies, there is the

opportunity for measures to be made prospectively

(such as menstrual diaries) rather than relying on

self-recall, which may be substantially less accurate. When change over time is the key concern, a

prospective design is mandatory.

3.5 Statistical Analysis

Most studies have only utilized univariate analysis

and thus been unable to take into account the role

of confounding or interacting factors. The findings

of these studies are thus often contradictory. A

major problem in the longitudinal studies has been

the lack of a sensitive enough statistical analysis,

which would use a within-subject-repeated-measures

method, allowing for the various factors which

may affect the quality-of-life measure, changes in

those factors, and interactions with the menopausal

transition to be identified.23
48

The analysis of longitudinal studies becomes more

complex as the temporal dimension is added to the

other possible components of the study. Many statistical approaches are possible. A simple and powerful technique is to calculate mean values prior to

and following an event such as the FMP. To allow

for the influence of multiple factors, linear regression is preferred to logistic regression where continuous data are available. For more information

about evolution in time, more complex techniques

are needed. A suitable technique is repeated 

measures multivariate analysis of variance using 

a number of contrasts to estimate various effects.

Simple split plot or randomized block designs 

cannot be recommended as they often violate compound symmetry assumptions. For series involving

more than 100 observations for each subject, time

series and spectral analysis techniques should be

considered. Structural equation modeling is recommended for examination in detail of a range of 

factors that may influence the studied endpoint, the

presence of feedback and of latent or nonmeasurable variables.

In reviewing the extensive observational literature

in this field accessible in Medline, we will concentrate on those studies which use adequate study

design.24 These include random sampling; describing the study as a general health survey, so that

bias caused by emotional response to menopause is

lessened; collecting information on current symptomatology, so that the problem of recall bias is

minimized; utilizing an age range that encompasses

the menopause transition, for example, 45–55

years for cross-sectional studies or a younger

(mean) age group for longitudinal studies of the

menopause transition, to ensure that women are

premenopausal at outset; longer followup in longitudinal studies; and collection of data on menstrual

status, hormone usage, and induced menopause, so

that the phase of the menopause transition can be

adequately determined. Where there are methodological problems such as poor response rate, these

are outlined.

4. PREVALENCE OF SYMPTOMS IN

MIDDLE-AGED WOMEN: RELATIONSHIP

TO HORMONAL EVENTS OF THE

MENOPAUSE TRANSITION AND AGING

A few studies have tried to address this question by

examining different symptom experiences for women

of different age groups and menopausal status. 

Two studies compared symptom checklist results

for men and women of different age groups using

lists from general practices. Results were presented

by age groups rather than by menopausal status.

Bungay et al.,25 in a United Kingdom postal survey,

found that four different patterns occurred by age

and sex. Peaks of prevalence of flushing and

sweating were closely associated with the mean

age of the menopause. Less impressive peaks of

minor mental symptoms were associated with an

age just preceding the mean age of menopause.

Complaints about aching breasts, irritability, and

low backache diminished after menopause. Male

and female curves were parallel for loss of

appetite, crawling or tingling sensations on skin,

headaches, difficulty with intercourse, indigestion,

constipation, diarrhea, shortness of breath, coldness of hands and feet, dryness of skin, dryness 

of hair, aching muscles, aching joints, feelings of

panic, feelings of depression, and stinging on 

passing urine.

A Dutch national study26 of the symptoms in the

Kupperman index experienced by men and women

aged over 25 years, reported female/male ratios for

each symptom. Only transpiration (excessive

sweating) showed a significant increase at age

45–54, compared to younger age groups and then

remained raised. No other symptom showed a significant increase in the age group 45–54, including the

General Health Questionnaire score of mental health.

Most observational studies using symptom checklists find that middle-aged women are highly

symptomatic. An Australian study27 of women aged

45–54 found the symptoms most commonly experienced in the prior 2 weeks to be very dry skin

(68 percent), backache (49 percent), forgetfulness
49

(47 percent), problems sleeping (39 percent), irritability (37 percent), and mood swings (36 percent).

Hot flushes were reported by 25 percent of women

(rank order 10) and sweating attacks by 13 percent

(rank order 19). Vaginal dryness and discomfort

was reported by 16 percent (rank order 17).

As noted earlier, there is consensus about the

marked temporal relationship of vasomotor symptoms to menopause.28 These begin to increase in

perimenopause, reach a peak within 1–2 years of

the FMP,12 and remain elevated for up to 10

years.29–31 McKinlay et al.,32 in a followup study

over 4 years of 1,178 premenopausal women,

found increasing hot flushes—10 percent in early

premenopause, 30 percent in early perimenopause

increasing to 50 percent of women 1 year prior to

the FMP—coinciding with late perimenopause,

with reports of hot flushes starting to decline significantly 2 years after FMP and reaching 20 percent of women 4 years after FMP. Thus, hot flushes are not the most frequent symptoms reported,

nor are they pathognomonic of menopause, being

reported by younger menstruating women. A number of studies have shown an association between

hot flushes and night sweats,33 and some show an

association between these vasomotor symptoms

and insomnia.34 Women who had an artificially

induced menopause were more likely to still report

flushing than were naturally menopausal women

and to report more symptoms.34 Only a few studies

included any reported measure of dryness of the

vagina. Oldenhave reports that dry vagina

increased in the perimenopause to postmenopause,

with a slight decrease > 10 years postmenopause,

which may be explained by lack of a partner.31 This

complaint is related to hot flush reporting. There

was less consistency regarding other symptoms. 

A number of cross-sectional studies, including the

two Ede studies,29,31 report a small but transient

increase in nonvasomotor symptoms in perimenopause. There was no attempt to differentiate

whether any increase in such symptoms is due to

distress caused by vasomotor symptoms. A

Norwegian 5-year prospective study found that

vasomotor symptoms, vaginal dryness, heart palpitations, and social dysfunction increased with the

menopausal transition, but that headache and

breast tenderness decreased.35 However, these

results were based on only 59 of the 200 premenopausal women selected for the study. The

author notes that the finding of heart palpitations

must be treated with caution since it differs from

all previous factor analytic studies.35 Recently

released results from the cross-sectional phase of

the Study of Women’s Health Across the Nation

(SWAN) study have also found an increase in

vasomotor symptoms and in psychological and

psychosomatic symptoms related to menopause.36

Analyses of data from 14,906 women aged 40 to

55 years found vasomotor symptoms burden on a

different factor to psychosomatic symptoms.

Perimenopausal and postmenopausal women, HRT

users, and women who had a surgical menopause

were all significantly more likely to report vasomotor symptoms compared to premenopausal

women, with postmenopausal women having the

higher OR. Psychosomatic symptoms (tense,

depressed, irritable, forgetful, headaches) were

reported more often by perimenopausal women,

hormone users, and women with a surgical

menopause than by premenopuase or postmenopausal women. A number of other studies,

including recent longitudinal studies using validated mood scales, have not found an association

between mood and menopausal status.37

The Melbourne Women’s Midlife Health Project

reported on the analysis of those women who after

7 years of followup had progressed through the

menopause transition. Annual measures included a

33-item symptom checklist. Increasing significantly

from early to late perimenopause were the total

number of symptoms, hot flushes, night sweats, and

dry vagina. Breast soreness/tenderness (mastalgia)

decreased significantly with the menopause transition. Trouble sleeping showed a smaller increase,

which was found to in part reflect bothersome hot
50

flushes.38 (See figs. 3–1 to 3–5.) The onset of hot

flushes was found to be related to decreased estradiol levels (p < 0.01), and the onset of night sweats

was related to the change

in estradiol level (p <

0.05).38 Interestingly, breast

tenderness was not included in the SWAN study

reported above. The

SWAN study found that

vaginal dryness was related

to vasomotor symptoms

but did not reach the criteria for inclusion in the factor analysis, and results

were not reported by

menopausal status.36

Longcope et al.39 also report a significant negative

association of hot flushes with estrone and 

estradiol levels amongst their sample of 241

Massachusetts women followed for 3 years. Thus,

a number of epidemiological studies have found

that only vasomotor and vaginal atrophic symptoms significantly increase as women pass through

the natural menopause transition.

Although many theories have been suggested to

explain the mechanism of menopausal flushing,

none provide a satisfactory explanation.40 Core

body temperature elevations precede the

menopausal hot flush and serve as one trigger of

this heat loss phenomenon.41 What is responsible

for the core temperature elevation is a matter of

speculation. Although vasomotor symptoms are

associated with increasing FSH and decreasing

estradiol levels,38,42 it may be that vasomotor symptoms relate to the activity of another substance, in

whose absence the activity of the thermoregulatory

center is disturbed.42 This substance may be common to both ovaries and testes and explain the fact

that the male flushes after orchidectomy and the

woman after ovarian failure. Each hot flush is

accompanied by a gonadotrophin-releasing hormone (GnRH) pulse with a consecutive episode of

FSH and LH secretion.43 Because hypophysecEpidemiological studies

have found that only

vasomotor and vaginal

atrophic symptoms 

significantly increase 

as women pass through

the natural menopause

transition.

FIGURE 3–1

Proportion of Women Bothered by Hot Flushes by Menopausal Status

1.00

0.75

0.5

0.25

0

Pre Early 

Peri

Late 

Peri

Post 

+1 yr

Post 

+2 yr

Post 

+3 yr

Proportion

pre = premenopausal

early peri = change in menstrual frequency

late peri = 3–11 months amenorrhoea

post 1 year = 12–23 months amenorrhoea

post 2 years = 24–35 months amenorrhoea

post 3 years ≥ 36 months amenorrhoea
51

FIGURE 3–2

Proportion of Women Bothered by Night Sweats by Menopausal Status

1.00

0.75

0.5

0.25

0

Pre Early 

Peri

Late 

Peri

Post 

+1 yr

Post 

+2 yr

Post 

+3 yr

Proportion

pre = premenopausal

early peri = change in menstrual frequency

late peri = 3–11 months amenorrhoea

post 1 year = 12–23 months amenorrhoea

post 2 years = 24–35 months amenorrhoea

post 3 years ≥ 36 months amenorrhoea

FIGURE 3–3

Proportion of Women Bothered by Dryness of Vagina by Menopausal Status

1.00

0.75

0.5

0.25

0

Pre Early 

Peri

Late 

Peri

Post 

+1 yr

Post 

+2 yr

Post 

+3 yr

Proportion

pre = premenopausal

early peri = change in menstrual frequency

late peri = 3–11 months amenorrhoea

post 1 year = 12–23 months amenorrhoea

post 2 years = 24–35 months amenorrhoea

post 3 years ≥ 36 months amenorrhoea
52

FIGURE 3–4

Proportion of Women Bothered by Breast Soreness by Menopausal Status

1.00

0.75

0.5

0.25

0

Pre Early 

Peri

Late 

Peri

Post 

+1 yr

Post 

+2 yr

Post 

+3 yr

Proportion

pre = premenopausal

early peri = change in menstrual frequency

late peri = 3–11 months amenorrhoea

post 1 year = 12–23 months amenorrhoea

post 2 years = 24–35 months amenorrhoea

post 3 years ≥ 36 months amenorrhoea

FIGURE 3–5

Proportion of Women Bothered by Trouble Sleeping by Menopausal Status

1.00

0.75

0.5

0.25

0

Pre Early 

Peri

Late 

Peri

Post 

+1 yr

Post 

+2 yr

Post 

+3 yr

Proportion

pre = premenopausal

early peri = change in menstrual frequency

late peri = 3–11 months amenorrhoea

post 1 year = 12–23 months amenorrhoea

post 2 years = 24–35 months amenorrhoea

post 3 years ≥ 36 months amenorrhoea
53

tomized hypogonadotropic women experience hot

flushes in the same way as women with an intact

pituitary, vasomotor instability is induced by a

common higher cerebral center and not by the

gonadotropin-pulse. The vasodilatation occurring

during hot flushes leads to an increase of skin temperature and finger volume and to an augmented

oxygen consumption.44 Due to peripheral vasodilatation, there is an increase of the pulse rate by

about 15 percent. Body core temperature then

decreases. The increase of finger perfusion starts

1.5 min before the start of the hot flush and lasts

for several minutes after its subjective end. Serum

LH levels increase only after the beginning of

peripheral vasodilatation and reach their maximal

value approximately 12 minutes later. Most likely

as a consequence of the cooling down of the body

core temperature, an elevation of adrenocoticotropic

hormone (ACTH) and of human growth hormone

(hGH) occurs respectively 5 and 30 minutes after

the rise of skin temperature. Because hot flushes

occur not only after menopause, but also during

the down-regulation by GnRH analogues, the primary decrease of serum estradiol is essential for

vasomotor symptoms. Anorexia nervosa or other

conditions of hypothalamic amenorrhea do not

provoke hot flushes. Furthermore, hot flushes are

only observed in women previously exposed to

endogenous or exogenous estrogen activity. The

pathophysiological mechanism provoking hot

flushes involves catecholamines, catecholestrogens,

serotonin, histamine, endorphins, and prostaglandins.

The endorphin neurons are inactivated by low

estrogen levels, a phenomenon that is reversible.

5. ROLE OF PSYCHOSOCIAL

AND LIFESTYLE FACTORS IN

DETERMINING WOMEN’S

EXPERIENCE OF SYMPTOMS

Cross-sectional studies have explored associations

between symptom experience and a large range of

other factors. In keeping with other studies from

Australia, North America, Scandinavia, and

Europe, an Australian study found lower symptom

experience in the midlife years to be associated

with increasing years of education, better self-rated

health, the use of fewer nonprescription medications, absence of chronic conditions, a low level of

interpersonal stress, not currently smoking, exercise at least once per week, and positive attitudes

to aging and to menopause.45

A previous history of premenstrual complaints was

reported to be associated with the occurrence of

vasomotor symptoms during menopause in crosssectional analyses of this population-based sample

of midlife women.42,46 Longitudinal analysis of the

same cohort found that a prior history of both

physical and psychological premenstrual complaints was associated with a more symptomatic

perimenopause characterized by dysphoria, skeletal, digestive, and respiratory symptoms.47

The cross-sectional phase of the SWAN study

found that reports of vasomotor symptoms were

negatively associated with educational level and

self-assessed health and positively associated with

difficulty in paying for basics. Psychosomatic

symptoms decreased with age and were reported

less often by those with better self-reported health

and with less difficulty in paying for basics.36

Longitudinal populationbased studies are best able

to establish the likely relationship between experience

of symptoms, psychosocial

and lifestyle factors. The

Massachusetts Women’s

Health Study found that

prior physical and psychological symptoms explained

physical symptoms, while

psychological symptoms were explained by low

education and perceived health.6 A further analysis

of the 454 women from this sample who were premenopausal at baseline and postmenopausal by the

Cross-sectional 

studies have 

explored associations

between symptom 

experience and a large

range of other factors.
54

6th followup found that variables related to greater

frequency of vasomotor reporting included a

longer perimenopause, more symptoms reported

prior to menopause, lower education, and more

negative attitudes to menopause prior to

menopause.48 Symptom bothersomeness was related to a greater frequency of vasomotor symptom

reporting, smoking, and being divorced. Variables

that predicted consultations were greater frequency

and bothersomeness of symptoms, higher education, and greater health care utilization.48 Women

with negative attitudes to menopause were more

likely to subsequently experience bothersome

symptoms.49

A British study50 found that women who had experienced an early natural menopause had a strongly

increased risk of vasomotor symptoms (hot flushes

or night sweats), sexual difficulties (vaginal dryness or difficulties with intercourse), and trouble

sleeping. However, there was little or no excess

risk of the other somatic or psychological symptoms studied. In contrast, all types of symptoms

were more common among women who had had a

hysterectomy or were users of HRT. Using

prospective data collected when the women were

36, symptom reporting was predicted by low education, stressful lives, or a previous history of poor

physical and psychological health. Adjustment for

these factors in a logistic regression model did not

affect the relationship between symptoms and current menopausal status. For vasomotor symptoms,

postmenopausal women had an adjusted OR of 4.7

(95 percent confidence internval (CI) 2.6–8.5), and

perimenopausal women had an adjusted OR of 2.6

(95 percent CI 1.9–3.5) compared with premenopausal women. Corresponding adjusted ORs

for sexual difficulties were 3.9 (95 percent CI

2.1–7.1) and 2.2 (95 percent CI 1.4–3.2) and for

trouble sleeping were 3.4 (95 percent CI 1.9–6.2)

and 1.5 (95 percent CI 1.1–2.0).

A postal survey of men and women aged between

49–55 years and registered with a London general

practice51 found no gender differences in reporting

of self-rated health, life satisfaction, and healthrelated quality of life, although women reported

more physical problems. Menopausal status was

not significantly related to life satisfaction or to

health-related quality of life. Significant predictors

of health-related quality of life were serious illness, employment, and marital status. Sample size

was relatively small in this study (n = 189),

response rate was only 47 percent, and the age

range may have meant that most women were

already in the menopausal transition.

Using structural modeling of data from the first 6

years of followup of the Melbourne Women’s

Midlife Health Project, the presence of bothersome

symptoms was found to adversely affect wellbeing.52 Repeated measures multivariate analysis of

covariance also found that bothersome symptoms

adversely impacted negative mood.37

Greene28 suggested a vulnerability model to explain

the role of psychosocial factors in symptom experience during the menopausal transition. The Greene

vulnerability model hypothesizes that adverse 

psychosocial factors render women vulnerable to

develop nonspecific physical and psychological

symptoms at this time. Response to stress interacts

with personality and sensitivity to biological changes

to determine the actual symptoms experienced.

Hot beverages can cause flushing through counter

current heat exchange mediated through the thermoregulation center of the anterior hypothalamus.

Foods containing nitrites and sulphites and spicy

foods, such as those containing the active agent in

red pepper or capsaicin, may also provoke severe

flushing. Alcohol intake is also associated with

flushing reactions, although there are no controlled

trials examining the effect of alcohol intake on the

severity of menopausal symptoms, in particular

vasomotor symptoms. The mechanism of alcoholprovoked flushing is complex but is probably related

to the fact that fermented alcoholic beverages contain tyramine or histamine, which induces flushing.53
55

5.1 Exercise

It has been suggested that physical activity may

have a beneficial effect on reducing vasomotor

symptoms in menopausal women. Physical exercise involving increased energy expenditure

increases hypothalamic β-endorphin production,

and β-endorphins are reported to stabilize thermoregulation.54 However, conflicting evidence

exists as to whether exercise has an effect on

menopausal symptoms.

In a cross-sectional study of a population-based

sample of 728 Australian-born women,55 physical

activity had no significant effect on women’s experience of troubling symptoms, including those

symptoms associated with their menopausal status,

such as vasomotor symptoms. Hammar et al.56

reported that women who participated in organized

physical exercise on a regular basis had a lower

prevalence of moderate to severe vasomotor symptoms compared with women of the same

menopausal status from the population. A further

study by these researchers54 reported that from a

population of 793 women, only 5 percent of highly

physically active women experienced severe vasomotor symptoms as compared with 14–16 percent

of women who had little or no weekly exercise.

The latter study collected data on physical habits

and on current and previous experience of vasomotor symptoms. There is the risk of women overestimating the time spent in physical activities as well

as the problems of retrospective reporting of vasomotor symptoms. A prospective or intervention

study would avoid these problems. However, the

fluctuating nature of the experience of vasomotor

symptoms and the expectations of participants

could affect such studies. A case-control study57

(82 cases and 89 controls) found that habitual

exercise prior to the FMP did not reduce the likelihood of experiencing vasomotor symptoms during

the perimenopause.

6. EFFECTIVEMESS OF TREATMENT

INTERVENTIONS FOR SYMPTOMS

LINKED TO THE TRANSITION TO

MENOPAUSE

Available treatments aimed at reducing symptoms

related to the menopausal transition include HRT,

phytoestrogens, and natural therapies, which have

been shown to possess different degrees of efficacy.

6.1 Hormone Replacement Therapies (HRT)

Most RCTs of HRT have been carried out on postmenopausal women, many of whom have already

received HRT and may have undergone a surgical

menopause. Nevertheless, there is considerable

consensus in findings that the symptoms which

consistently respond to HRT are the vasomotor and

vaginal atrophic symptoms. These beneficial

effects of HRT persisted after adjusting for baseline symptom level and uterine status.58

There is a substantial body of

evidence showing that HRT is

effective in reducing hot flushes.

Randomized double-blind placebo controlled trials have reported that CEE at dosages of 0.3,

0.625, and 1.25 mg/day significantly reduced hot flushes compared with placebo.59–61

Similarly, other preparations of

estrogen, administered either orally or by transdermal patch, have also shown effectiveness in the

relief of vasomotor symptoms.62–70 Gordon et al.67

compared the efficacy of estradiol patches and oral

conjugated estrogen and found no statistically significant difference between the preparations with

regard to their effect on the reduction of hot flushes. The response to the 0.1 mg estradiol patch was

greater, and the response to the 0.05 mg estradiol

patch was less than the response to conjugated

estrogens, although these differences were not statistically different. Percutaneous estradiol delivered

in an alcohol-water gel has been reported to be

effective in treating vasomotor symptoms.71 The

Conflicting 

evidence exists as

to whether exercise

has an effect 

on menopausal

symptoms.
56

use of either continuous or sequential progestins

with estrogen does not reduce the efficacy of the

preparation in the reduction of hot flushes.58,65,72

Recently, an intranasal 17β-estradiol spray has

been shown to be significantly better than placebo

and similar to oral estradiol in reducing hot flushes

and is also well tolerated.73

Vaginal symptoms

related to atrophy

have been reported

to be alleviated by

ERT. Local low-dose

treatment with a

small vaginal tablet

of 25 micrograms

of 17β-estradiol

was shown to significantly relieve postmenopausal

symptoms related to vaginal atrophy when compared to placebo.74 Preparations of estradiol vaginal

cream have a similar effect75 and also result in an

increase in plasma levels of estradiol. Percutaneous,

transdermal, and oral estradiol treatments have all

been reported to improve the vaginal cytology profile in comparison with placebo therapy.67,71,76 Sleep

disturbances do not appear to be helped by transdermal or oral ERT.69,77 The benefits and risks of

HRTs are discussed in other chapters.

A number of nonestrogen preparations have been

evaluated for their effects on menopausal symptoms with varying results. The progestational agent

megestrol acetate (20 mg twice daily) has been

reported to significantly decrease the frequency of

hot flushes in women with a history of breast cancer.78 Veralipride, an antidopaminergic treatment,

reduced vasomotor symptoms and was significantly more effective than placebo in three trials.79–81

Other dopamine agonists and antagonists have also

been found to be more effective than placebo in

alleviating hot flushes.78 In one trial, opipramol

treatment was reported as being significantly better

than placebo in reducing hot flushes.82 Trials with

clonidine,83 propranolol,84 and dong quai85 have

shown these treatments to be no more effective

than placebo in controlling hot flushes. Dong quai

did not have any effect on vaginal cell maturation.85 More promising results for non-hormonal

treatment of hot flushes have come from trials of

antidepressants, particularly the selective serotonin

reuptake inhibitors (SSRIs) and related drugs such

as venlafaxine. Pilot studies presented at conferences have found significant reduction in hot flush

frequency and severity, but evidence from larger

double-blind randomized trials is needed.86

Studies of the effects of HRT on mood, cognitive

and sexual functioning are discussed elsewhere.

The symptom of breast soreness/tenderness

(mastalgia) has been shown in clinical trials to be

related to estrogen/progestin balance.58 The

Postmenopause Estrogen/Progestin Intervention

(PEPI) trial58 found a significant reduction in muscle and joint pain in women who adhered to estrogen- and progestin-containing regimes. This beneficial effect on muscle and joint pain was not evident in intention-to-treat analyses. Aches or stiff

joints were reported by over 40 percent of women

in the Melbourne Women’s Midlife Health Project

at each phase of the menopause transition,38

although there was no demonstrable variation with

the menopause transition. Given the prevalence 

of these symptoms among middle-aged women,

further research is needed.

6.2 Phytoestrogens 

Phytoestrogens are plant compounds that have a

close similarity in structure to estrogens. Evidence

for the effects of phytoestrogens on reducing

menopausal symptoms, hot flushes, and vaginal

dryness come from two main sources—observational studies and clinical trials. The first source is

from epidemiological data of populations who

have high dietary intakes of phytoestrogen compounds and who have a very low rate of hot flushes

(for example, 5–10 percent of Japanese women

report hot flushes compared with 70–80 percent of

Western women).87 Japanese women are reported

Considerable consensus in

findings that the symptoms

which consistently respond to

HRT are the vasomotor and

vaginal atrophic symptoms.
57

to consume 20–150 mg/day of isoflavones88 compared to Western women, where less than 

5 mg/day is consumed.89

The second source is from placebo-controlled clinical trials. Five studies90–94 have reported improvement in hot flushes after dietary supplementation

with phytoestrogens. In three of these studies,90,93,94

there was no significant improvement in these

symptoms in subjects in the treatment compared to

the placebo group. In one study,93 there was an

increase in urinary isoflavone excretion in the

placebo group. There was a strong negative correlation between the level of urinary isoflavone

excretion and the incidence of vasomotor symptoms

in both treatment and placebo groups. This further

emphasises the problem with intervention studies

using naturally occurring dietary compounds.

There are problems with both sources of information. Whether Japanese women do in fact experience a significantly lower frequency of hot flushes

has been challenged,95 and there is no data from

this population on the prevalence of vaginal dryness. Evidence from controlled trials is limited by

several problems—finding an effective control

group, as phytoestrogens are present in so many

foods that it is difficult to eliminate them from the

diet, and the fact that natural improvement of

menopausal symptoms occurs with time. Of five

studies that looked at changes in vaginal cytology

with and without phytoestrogen supplementation,

there was a significant improvement in three

instances91,96,97 but not in two.90,98 The variations in

response may depend on populations studied,

source of phytoestrogen, and study design, particularly with respect to duration of exposure.

6.3 Natural Therapies

Evening primrose oil, containing gamma-linolenic

acid, has been evaluated as a therapy for treating

hot flushes and sweating associated with

menopause in a randomized, double-blind, placebo-controlled trial.99 Although there is no good 

scientific rationale for the use of this preparation in

treating hot flushes and although neither clinicians

nor the pharmaceutical industry have ever promoted evening primrose oil for this purpose, there is a

current view among the lay public that it is effective

in the control of menopausal symptoms. Chenoy

and colleagues99 reported that gamma-linolenic acid

provided by evening primrose oil offers no benefit

over placebo in treating menopausal flushing.

7. FUTURE NEEDS

Clearly there has been a great deal of research 

documenting the relationship of symptoms of the

menopause transition. In this section, we expand

on those areas that require further detailed studies.

In the field of observational studies, there is a 

need for better documentation of the processes of

the natural menopause transition using prospective

investigations to distinguish menopause-related

changes from those of aging or disease. Design

features needed in these longitudinal epidemiological studies are:

• Randomized population sampling including

minority women of the country concerned

• Baseline age 45 or less, so that women are more

likely to be premenopausal

• Symptom checklists which include all symptoms shown to vary directly (vasomotor, vaginal

atrophic, breast tenderness) or indirectly

(insomnia, mood) with hormonal change

• Validated measures of psychosocial and lifestyle

factors which may mediate hormonal effects

• Prospectively kept menstrual calendars so that

phase of the menopause transition can be determined without bias of retrospective recall

• Regular hormonal measures

• Power analysis for sample size, so that effects

of hormones and other factors can be delineated
58

• Long-term followup until women are at least 10

years postmenopausal, so that longer term

effects can be studied, including the natural history of untreated symptoms

• Studies of different populations worldwide, representing women from a broader array of racialethnic and socioeconomic backgrounds

In the field of treatment interventions, there have

been many RCTs of different forms of HRT on

symptoms, and larger studies are in progress. On

the other hand, there is a need for—

• Questionnaires validating phytoestrogen intake

against metabolic measures of metabolites in

different cultural settings before either RCTs or

observational studies of the role of phytoestrogens can proceed

• A larger RCT of phytoestrogen supplementations, including metabolic measures of metabolite levels
59

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64
65

1. Attitudes toward and beliefs about menopause vary historically and

among cultures [C].

2. Cross-cultural comparisons demonstrate that reported symptoms can vary significantly among countries 

and among ethnic groups within countries in their type (e.g., vasomotor, psychological) and in the degree of

distress caused [C].

3. Difficulties in integrating findings from cross-cultural studies stem from a number of limitations. Among

these are differences among cultures in language used to describe symptoms; use of different methodologies

in study design and in instruments used to measure symptoms; and differences in diet and other lifestyle 

factors that make it difficult to establish cultural versus biologic causes of symptom expression.

4. A better appreciation of cross-cultural differences in the experience of menopause may derive from an

emerging interdisciplinary model in which symptoms are seen as a result of increased vulnerability due to

hormonal changes in interaction with psychological and sociocultural factors.

The sociocultural aspects of menopause have not

been the focus of attention or research interest to

the same extent as menopause as a physiological

event. Historically and cross-culturally, perspectives on menopause have varied widely. The 19thcentury Victorian image was an aging woman with

a decaying body, prone to illness and insanity.1 In

contrast, the view of menopause among Asian

women has focused on freedom from pregnancy

and a sense of liberation.2 Bowles emphasized that

women’s experience of and attitude toward

menopause are influenced by beliefs and expectations inherent in the prevailing sociocultural paradigm.3 Thus, factors such as cultural beliefs, values,

and attitudes toward menopause determine the

experience of individual women of that stage of

life as negative and troublesome or positive and

liberating.

CHAPTER 4: SOCIOCULTURAL ISSUES IN MENOPAUSE

Aila Collins, Ph.D.* 

KEY POINTSa

* From the Psychology Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

a Evidence categories are given in square brackets. A = randomized controlled trials (rich body of data); B = randomized controlled trials (limited data); 

C = nonrandomized trials and observational epidemiologic studies; D = Panel expert judgment. (See also table 1–1.)

Cross-cultural comparisons

demonstrate that reported 

symptoms can vary significantly

among countries and among 

ethnic groups within countries.

1. THE MEANING OF MENOPAUSE
66

Hällström wrote that the psychological significance ascribed to menopause in Western countries

should be regarded as a sociocultural myth.4 By

generating expectations in women, the myth can

act as a self-fulfilling negative prophecy.

Reproduction and child-rearing have been the primary roles defined for women. Osofsky and

Seidenberg argued that many of those writing

about the psychology of menopause assumed, on

the basis of their own cultural biases, that women

derive greater meaning from and place greater significance on their reproductive capacity than do

men.5 Barnett and Baruch emphasized the need to

revise our view of

women’s roles, including

broadening our concept of

midlife by taking into

account women’s roles in

the workplace as well as

the social contexts within

which they live.6

Research on menopause has long been polarized.

The medical model of menopause has focused on

identifying symptoms of the climacteric syndrome.

Endocrinologists have defined menopause as a

deficiency disease requiring treatment, with symptoms believed to be directly linked to the lack of

estrogen. Social scientists, on the other hand, have

emphasized the social and cultural construct of

menopause, holding that whether and how climacteric symptoms are experienced is influenced by

that meaning. There is evidence, for instance, that

negative attitudes and beliefs before menopause

may predict depressed mood or other symptoms at

menopause.7,8

Recent trends in epidemiological research have

highlighted the need to integrate these opposing

views into an interactive model. Flint suggested a

psycho-bio-cultural model of menopause for interdisciplinary research and for a better understanding

of the different aspects of women’s health.9 It is

being recognized that menopause research needs

multidisciplinary teams to address its different

aspects. Research from disciplines such as gynecology, endocrinology, neurology, psychiatry, psychology, and anthropology may be integrated to

characterize what changes menopause entails and

the individual and cultural differences that occur as

a result. A central question to be addressed is

whether menopause is universally associated with

similar physical changes and symptoms or whether

there is, indeed, cross-cultural variation. Evidence

of cultural diversity in perception of symptoms

lends support to the hypothesis that how

menopause is experienced is not ubiquitous but

distinct according to cultural groups.

It may be difficult to compare the results from different studies because of methodological problems

associated with the research. (See also ch. 3, sec. 3.)

Many studies have used less than ideal research

designs, unvalidated rating scales that have been

translated from one language to another, and small

clinical samples. Obermeyer et al. in a recent

review10 pointed out shortcomings of many of the

studies used for cross-cultural comparisons. She

emphasized the need for studies using a longitudinal design, standardized questionnaires, and an

agreed-upon definition of menopause, criteria that

most of the cross-cultural comparison studies do

not fulfill.

2. CROSS-CULTURAL COMPARISONS

Cross-cultural comparative data can help clarify

the extent to which the experience of menopause is

universal, provide information about symptom

variability, and identify important factors influencing symptoms. Prevalence comparisons among

countries of somatic symptoms of menopause,

such as hot flushes, and of psychological symptoms, such as depression and changes in sexual

interest, show considerable, though not always significant, differences. Among the major findings,

one of the best known is the marked contrast

between the relatively high prevalence of vasomotor symptoms reported in North American and

Menopause research

needs multidisciplinary

teams to address its 

different aspects.
67

European women and the low prevalence reported

by Asian women.

Lock’s classic studies of Japanese perimenopausal

women11–13 have been widely cited. She collected

data on these women using a self-administered

questionnaire. The study was carried out in southern Kyoto, where the women were employed in

factory or other blue-collar jobs; in Nagano, a rural

area where the women worked on farms; and in the

suburban area of Kobe, where most of the women

were homemakers. The prevalence of hot flushes

was low: 3 percent of the homemakers and 10 percent of the working women reported them. The

Japanese women more often reported shoulder

stiffness, headache, and, to a lesser extent, lumbago,

symptoms not specifically linked to the menopausal

state. The most striking result was that for most of

the symptoms in the symptom list about 85 percent

of the women gave a negative response.

A comparison of U.S., Canadian, and Japanese

women by Avis et al. showed the Japanese women

to have the lowest prevalence of hot flushes and of

depression as well as the lowest intake of medication.14 Such findings may lead us to believe that

Asian women do not experience the intense symptoms reported by North American, European, and

African women. With regard to hot flushes, however,

Lock found that the Japanese women did not have

a word for the concept, which had to be explained

using different words.12

Lock’s interpretation of these findings was that

Japanese women do not think the same way about

menopause as, for example, women in the United

States. The Japanese word for midlife transition,

konenki, has a social rather than biologic connotation. According to Lock, middle age in Japan is

thought of foremost as a social process; the biologic changes are generally viewed as playing only a

small part. Konenki is seen as a “luxury disease”

suffered only by those women who have too little

to do. The strong work ethic in Japanese society

coupled with a certain moralistic attitude may

influence women and make them less likely to

complain of any physical discomfort associated

with konenki. Lock also noted that women are

explicitly encouraged by the government to provide nursing care for elderly relatives, since there

is a marked shortage of programs to care for the

aged population. Only recently women’s groups

have begun to debate issues associated with konenki and have argued that middle-aged women ought

to focus more on their own health. Among these

activists is Albery, who challenged the belief that

Japanese women do not suffer from hot flushes.15

She also advocated a more evidence-based

approach to the understanding of female aging as

well as endorsement by the government for gynecologists to treat menopausal symptoms using HRT.

Thus, it may be premature to accentuate social factors in the interpretation of Lock’s findings. Biologic

factors may have an important role. Recent

research has shed light on the role of dietary factors. In much of Asia, particularly Japan, the diet is

rich in phytoestrogens. Several studies have found

a decrease in the frequency of hot flushes frequency in postmenopausal women in response to soy

protein supplementation.16,17 Larger, well-controlled

clinical trials are needed, however, to better

address the positive and possible negative effects

associated with the intake of soy protein.18,19 (See

ch. 3, sec. 6.2.)

Is it possible that Asian lifestyle could have such

dramatic effects on women’s health? More recent

studies in Asia present a somewhat different picture of symptom reporting. Among them is a welldesigned, large-scale study by Boulet et al., conducted in Hong Kong, Indonesia, Korea, Malaysia,

the Philippines, Singapore, and Taiwan.20 The climacteric syndrome was, indeed, experienced by the

participants, although in a milder form than generally reported in Western countries. The prevalence

of hot flushes and of sweating was lower than in

Western countries but not negligible. The percentages of women reporting more psychological types

of complaint were similar to those in Western
68

countries. Perhaps, as the authors suggested, distress

related to vasomotor symptoms is translated into

psychological complaints, which are more frequently considered to warrant consulting a physician.

Other studies of Asian women that compared

symptom reporting include a cross-sectional study

of Thai women in Bangkok.21 The women were

asked to report symptoms in the prior 2 weeks.

They did experience hot flushes, although the most

common complaints were dizziness, headache,

joint pain, and backache. The sample was not representative, and the conclusions must be considered tentative, because the women were recruited

as they accompanied family members or friends to

the hospital. In a study of Thai women attending

health clinics in Bangkok, 22 percent of the

women with irregular menses and 7 percent of the

postmenopausal women reported hot flushes,

although the most common symptoms were dizziness (45 percent) and irritability (41 percent).22

Among perimenopausal Chinese women living in

Hong Kong, 20 percent of those surveyed experienced hot flushes, and, again, psychological complaints such as anxiety and nervousness were more

prevalent.23 In another study of urban women, perimenopausal Canadian and Chinese women differed

markedly in symptom prevalence: 60 percent and

18 percent, respectively, reported vasomotor symptoms, and the Chinese women ranked other symptoms as more important, including boredom, poor

memory, numbness in the hands or feet, change in

appearance, and change in ability to see, taste, or

smell.24 Both groups in the study reported sleeprelated problems and fatigue. Ho et al. studied perimenopausal Hong Kong Chinese women and

found that although 10 percent experienced hot

flushes, musculoskeletal complaints were the most

prevalent.25

Thus, the prevalence of hot flushes appears to be

lower in Asian women, although some of the more

recent studies have shown rates closer to western

figures. Also, the types of symptoms reported and

the degree of distress caused are often different.

There are no good explanations for the observed

differences. Hot flushes were previously thought to

be linked directly only to estrogen deficiency and

not modulated by other factors. Our study26 and

that of Avis et al.27 showed that hot flushes are

modulated by psychosocial factors, such as satisfaction with work role and stress at work. In an

ongoing study, we found that women with highstress jobs report the most frequent hot flushes

(Collins A and Ahs A, unpublished results). Many

of the assumed truths about climacteric symptoms

may have to be modified. Because all symptoms

are individual and modulated by cognitive processes to a certain extent,28 they can be influenced by

cultural factors. A clear, and perhaps related,

example of such influences is the cultural variation

in pain perception.29

There are probably important factors within cultures that can mediate symptom experience. They

include differences in expectations and attitudes

toward aging and menopause, as well as socioeconomic factors and women’s roles and opportunities

in society. A very important area of research that

has been largely neglected until recently is the

study of different ethnic groups within Western

countries. Our ongoing population-based longitudinal study has shown that among perimenopausal

women residing in the Stockholm area, women

born outside Scandinavia report more frequent hot

flushes than do Swedish-born women (Collins A

and Ahs A, unpublished data). Researchers in the

United States found that African-American women

were significantly more likely than white women

to report hot flushes.30 The difference remained

after adjustment for BMI, educational level, and

menstrual and gynecologic history. The authors

attributed the difference mainly to psychosocial

factors and stress. Despite the high prevalence of

symptoms, few African-American women had discussed menopausal management with their physicians.30 A study31 of women of the Indian subcontinent living in the United Kingdom showed that the
69

majority regarded menopause as a natural event.

However, only 33 percent were happy about

menopause, and 46 percent were worried about

possible adverse effects, such as ill health or

weight gain. Over 75 percent of the women stated

that they would like to seek medical advice about

management of menopause. They also stated that

they would prefer a female doctor who would be

able to communicate with them in their own language. Thus, the overall results suggest a great

need for information and education.

The large-scale, population-based SWAN in the

United States compared symptom reporting among

white, African-American, Chinese-American, and

Japanese-American women.32 The Asian-American

women had significantly fewer symptoms than the

white women, and the African-American women

had the highest prevalence of vasomotor symptoms.32 At the same time, among premenopausal

through postmenopausal women, attitudes toward

menopause and aging were found to differ among

the ethnic groups; African-American women were

the most positive, and Chinese- or Japanese-speaking women who received their schooling outside

the United States were the least positive.33

Menopause was described as a natural transition of

life by Chinese-American and Chinese women in

the United States.34 It is important to consider

where women obtain their information about

menopause. Study results suggest distinct differences among ethnic groups. Several U.S. studies

showed that, in general, African-American women

and in particular less educated African-American

women have less knowledge of menopause, are

less likely to discuss menopause with a physician,

and have less awareness of and less knowledge

about HRT,35–38 although they are more likely to

have had a hysterectomy.39 There can be distinct

biases in prescribing HRT, and African-American

women are less likely than white women to use

it.40 The findings should be related to those of a

recent ethnographic study by Agee of AfricanAmerican and Euro-American women of

menopausal age.41 The women were interviewed in

depth about the transfer of knowledge about

menopause and aging from mother to daughter.

The African-American women more than the white

women recounted that their mothers had provided

them with the knowledge and tools to negotiate

difficulties associated with menopause. They relied

more on their own capacity to cope with problems

encountered during the menopausal transition, and

they were more prone to resist a biomedical model

and, thus, less willing to follow their doctors’ suggestions to start hormonal treatment. Many EuroAmerican women stated that their mothers had not

talked about their menopausal problems, and many

felt that their own life experiences set them apart

from their mothers. The relative lack of a role

model made them more dependent on a medical

approach to solving problems related to

menopause.

Also, the age at natural menopause differs between

white and African-American women; the AfricanAmerican women reached menopause significantly

earlier.42 In trying to explain the reasons for these

differences, the authors focused on marginalization

and psychosocial stress as the most significant predictors of earlier menopause among AfricanAmerican women. 

3. ETHNOGRAPHIC STUDIES

The degree of development of a society may also

be important, and we may have to look more

closely at nonwestern societies that are not as

developed as those of Asia. There are unique studies of populations of rural women with a low level

of formal education, and living simple lives, who

show no signs of distress at menopause. Data 

collection was adapted to the women’s lifestyle

and adjusted for traditional expectancies. The findings may provide us with important indications of

the role of cultural norms in symptom experience

and reporting.
70

Beyene used a systematic ethnographic approach

to collect data on 107 rural Mayan women aged 33

through 57 years.43 The women lived in southeastern Yucatán, Mexico, where the residents were

subsistence farmers practicing traditional Mayan

ceremonies. The onset of natural menopause was

earlier than in developed Western countries. The

Mayan women became menopausal at ages 41

through 45.

The women did not consider menopause a major

crisis. In general, they reported looking forward to

menopause and likened it to being young and free.

Menopause in the rural Mayan culture was largely

unrecognized except as marking the end of menstruation and childbearing. The women indicated

that the only recognized symptom of menopause

was menstrual irregularity followed by the final

cessation of menses. None reported hot flushes or

cold sweats. The premenopausal Mayan women

did not seem to have cultural knowledge or expectations relating to the onset of menopause other

than the cessation of menstruation. Mayan women

considered menopause to be a life stage free from

taboos and restrictions. They reported better sexual

relationships with their husbands, because of no

risk of pregnancy. 

The findings were particularly valuable because of

another study’s analysis of the hormonal profiles

of rural Mayan women.44 It was hypothesized that

their menopause would be endocrinologically distinct. Determination of FSH, estradiol, prolactin

(PRL), androstenedione, and testosterone values as

well as BMD of 52 postmenopausal and 26 premenopausal rural Mayan women showed the same

endocrinological profile as in U.S. women. Even

with specific questioning through a native interviewer, however, it was not possible to elicit familiarity with hot flushes.44 Interestingly, some

Mayans who had moved to a nearby city experienced hot flushes.

Beyene also studied rural Greek women.43 Data

were collected from women living in a village in

the eastern part of the island of Evia. The villagers

were farmers using traditional farming methods,

including plowing with horses and mules. Like the

Mayans, the Greek women experienced menopause

as a life stage free from taboos and restrictions.

They, too, reported better sexual relationships with

their husbands. They reported that, without risk for

pregnancy, they felt more relaxed about sex.

However, women also associated menopause with

growing old, lack of energy, and a generally downhill course. Premenopausal women reported anxiety, negative attitudes, or anticipation, with some

mixed feelings. When asked about experience of

menopausal symptoms, 73 percent of the menopausal

and postmenopausal women reported having had

hot flushes, and 30 percent reported having cold

sweats. Unlike Mayans, Greek women understood

the concept of hot flush, and the older women even

offered the Greek word for this symptom. They

were also able to give detailed accounts of the

process of hot flushes and the times they most

often felt the sensations and changes in their

bodies. Women said they experienced more hot

flushes at night and around the times they usually

expected to have their menstrual periods.

These two cultures are very different from the

other cultures studied, since these are rural women

living in a village, where the form of life is still

very traditional. In both of them, the women were

farmers with physically strenuous work. Possible

explanations for reduced symptomatology in the

rural groups could relate to physical exercise45 or

dietary habits, although studies of such lifestyle

components have yielded mixed results. (See ch. 3,

sec. 5.1.) Social or socioeconomic status probably

plays an important part. Not all women have

access to modern medical care. In an interview

study of women with spontaneous menopause in

Karachi, Pakistan, 6 percent of slum dwellers

sought treatment for symptoms, compared with 26

percent of middle class clinic attendees and 38 percent of the most privileged group, wives of retired

military officers.46 Only one-fifth of the slum
71

dwellers reported symptoms, whereas 57 percent of

the middle class and 50 percent of the most privileged group reported hot flushes. In a study in India,

women living in a culture in which social status

increased with age experienced few symptoms.47

A study of menopausal Nigerian women of Yoruba

descent found 30 percent to have had hot flushes.48

Joint pain was the most frequently reported symptom. The authors suggested that the Yoruba women

may not have been as aware of hot flushes as

white women and that they may have wrongly

attributed their sensations to environmental temperature or to fever.

In an ongoing population-based study of Arab

women, Obermeyer reported on the occurrence of

symptoms and on help seeking by perimenopausal

women in Beirut, Lebanon.49 The proportion of

women reporting hot flushes was 45 percent, similar

to figures in the United States, Canada, and Sweden.

Reported depression was similar to that in Canada

but lower than the U.S. figure of 36 percent. The

frequency of hot flushes was higher in smokers,

and women who were employed reported fewer

symptoms. Thirty-nine percent had sought help for

their symptoms, and 15 percent reported using

HRT, figures the authors interpreted as consistent

with the high educational level of Beirut women

and the degree of medicalization in the country.

4. WHAT CAN CROSS-CULTURAL

COMPARISONS TELL US?

Flint and Samil50 and Obermeyer et al.10 in reviews

of the literature emphasized the need for integration of the biomedical and developmental views of

menopause.

Attempts to verify menopausal symptoms in different cultures have proved difficult. (See ch. 3.)

Results from different studies are hard to compare

because the quality of data can differ and studies

differ in design and subject representativeness.

Often, the subjects were patients or volunteers.

Much research has used rating scales translated

from European or North American studies; concerns

have been raised about the appropriateness of

translations without consideration of the cultural

relevance of the questionnaires’ content. Many

studies cited above demonstrated that symptom

types and patterns vary from country to country.

Vasomotor symptoms are the most frequently

reported symptoms in Europe and North America,

but in Asia psychological complaints appear to be

more common. Yoruba women in Nigeria described

joint pain most commonly. The interpretation of

bodily states and, thus, symptom experience may

be different in different cultures. Boulet et al. suggested that Asian women may report vasomotor

symptoms less frequently because vasomotor distress is experienced more in psychological terms.20

There is a need to know how to ask the right 

questions and a need for more knowledge of the

cultures being studied. In addition, more reliable

scales are needed, and these have to be developed

in a cultural context.

Overall, there is an association between hormonal

changes and climacteric symptomatology, and the

association is modulated by cultural factors. There is

a considerable variation in the prevalence and pattern of symptoms in different countries, a variation

probably due to diversity in cultural norms and traditions as well as in diet and other lifestyle factors.

5. ACCESS TO HEALTH CARE

Kaufert developed a model of menopause in which

there are important social implications of becoming menopausal that vary from one society to

another.51 The definition of menopause for any culture will be derived from the meaning and consequences of menopause and from how women’s

roles are defined in that society. Women are aware

of these stereotypes and interpret their bodily

changes in accordance with what they have

learned. The experience of menopause is associated with a woman’s health history as well as a wide
72

range of variables, such as genetic factors, diet,

education, marital status, number of pregnancies,

the kind of work she has carried out, social support, and access to health care.52

Access to health

care varies widely

among countries.

Women’s choices

around menopause

are said to bear

consequences for

their health in old

age. For a long time, hot flushes and night sweats

were considered to be core symptoms of menopause

and the most important reason for using HRT.

More recently, HRT has been widely promoted for

prevention against osteoporosis, CVD, and an

array of other conditions. Educated women in

industrialized countries with well-developed medical care are a privileged group with access to the

most recent information on HRT, whereas other

groups have less access and less knowledge. On

the other hand, medicalization of menopause in

cultures in which menopause is not perceived as a

problem is an important issue that should be debated. Some critics have questioned the role of the

pharmaceutical industry in influencing health care

through product promotion.53 Developing countries

with scarce resources are less likely than developed countries to allocate funds for care of

menopausal women. In addition, the inequality

among social groups within countries can result in

very different access to information and care.

Promoting positive attitudes to aging and to

menopause could be important in modifying symptoms and improving the health of women.54

Women need education and balanced information

to make personal decisions regarding whether to

use HRT. An important goal for health care

providers should be to educate women. Such education should lead to greater equality among

women in different cultures and social levels and

help women control their own health.

6. CONCLUSIONS

Menopause has long been considered a turning

point in women’s lives in western cultures.

Although menopause as a physiologic event

remains constant, attitudes toward and beliefs about

menopause vary considerably historically and

cross-culturally. In the past decade, there has been

a heated debate among biomedical and social scientists as to whether menopause should be seen as

a deficiency disease rather than a natural event.

Cross-cultural comparisons fuel the debate by

showing that the relation between hormones and

symptoms is, indeed, complex. There are significant differences in patterns and prevalence of

symptoms between countries and, interestingly, in

the types of symptom reported in different ethnic

groups within countries. It is difficult, however, to

draw firm conclusions from available cultural and

ethnographic comparison studies because of a

number of limitations. Among these are differences

among cultures in language used to describe symptoms and in women’s inclination to report symptoms; use of different methodologies in study

design and instruments used to measure symptoms;

and differences in diet and other lifestyle factors

that make it difficult to establish cultural versus

biologic reasons for symptom expression. (See ch. 3.)

Women need education and

balanced information to make

personal decisions regarding

whether to use HRT.
73

7. FUTURE NEEDS

• As cross-cultural research on menopause has

been hampered by methodological difficulties,

better controlled, population-based studies are

needed which use standardized instruments

adapted to the culture studied.

• There is growing recognition that investigators

in different disciplines have to work together for

a better understanding of women’s health at

menopause; such collaboration is particularly

needed for cross-cultural work.

• An interactive psycho-bio-cultural model of

menopause is needed, which recognizes the

interplay between the individual and her psychosocial and cultural environment. From such

a perspective, symptoms can be seen as the

result of increased vulnerability due to hormonal changes interacting with psychological and

sociocultural factors.

• Access to health care has been shown to vary

among countries and among socioeconomic

groups within countries. It is important that

research results be disseminated within the cultures under study so that women can make their

personal decisions about possible interventions

and treatment strategies.
74

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opinions of climacterium by Finnish women. Eur J

Obstet Gynecol Reprod Biol 1995;62(1):81–7.
77

CHAPTER 5: PHYSIOLOGICAL ROLE OF ESTROGEN AND

ESTROGEN RECEPTORS

1. There are two different ER subtypes, ERα and ERβ, that mediate the 

biological effects of estrogens and antiestrogens. Different ligands induce

different ER conformations.

2. Different mechanisms of target gene regulation affect the agonistantagonist profile of a ligand. SERMs have a tissue- and gene-specific 

mixed agonist-antagonist effect.

3. Both ERα and ERβ are expressed in human breast cancer. Measurement of both ERα and ERβ is suggested

for selection of appropriate breast cancer therapy.

4. Both ERα and ERβ are important for normal ovarian follicular development and female fertility. 

5. ERβ-selective agonists may protect from abnormal prostate growth and may be the therapy of choice for

urge incontinence in women.

6. Available data suggest that ERα plays an important role in bone maturation and homeostasis in both women

and men but that ERβ also has a specific role in bone physiology in women.

7. ERα and ERβ are expressed in vascular endothelial cells, smooth muscle cells, and myocardial cells.

Potential beneficial effects of estrogens on cardiovascular function and reactivity stem from direct effects on

cells in the vascular system but also from effects on liver and circulating monocytes-macrophages.

8. Estrogens are linked to a variety of functions in the CNS: learning, memory, awareness, fine motor skills,

temperature regulation, mood, reproductive functions, and depression. The predominant expression and

localization of ERβ in rat neocortex, hippocampus, and nuclei of the basal forebrain suggest an important

role for ERβ in learning and memory.

Jan-Åke Gustafsson, M.D., Ph.D.* and Stefan Nilsson, Dr. Med. Sci.†

* From the Department of Medical Nutrition; Chairman, Department of Biosciences, Karolinska Institute, Novum, Huddinge University Hospital,

Huddinge, Sweden.

† From the Department of Medical Nutrition, Karolinska Institute, Novum, Huddinge University Hospital, Huddinge, Sweden.

a Evidence categories are given in square brackets. A = randomized controlled trials (rich body of data); B = randomized controlled trials (limited data); 

C = nonrandomized trials and observational epidemiologic studies; D = Panel expert judgment. (See also table 1–1.)

KEY POINTSa

There are two different ER

subtypes, ERα and ERβ,

that mediate the biological

effects of estrogens and

antiestrogens. Different 

ligands induce different 

ER conformations.
78

9. Estrogen and inhibins produced by the ovaries

are important feedback regulators of the 

hypothalamo-pituitary axis (HPA) and the

serum levels of LH and FSH. ERα seems to 

be more involved in the LH, FSH feedback

loop than ERβ.

10. ERα and ERβ subtype-selective SERMs may

better provide the benefits of estrogen replacement therapy (third generation HRT) than currently used treatments.

EXTENDED SUMMARY

Introduction: Nuclear

receptors such as the ER are

ligand-dependent transcription factors. There are two

different ER subtypes, ERα

and ERβ, that mediate the

biological effects of estrogens and antiestrogens. ERβ

exists in multiple isoforms. Different ligands

induce different ER conformations, and there is a

dramatic difference in the topology of the ER surface between agonist- and antagonist-bound receptor. Coactivators and corepressors interact with ligand-bound ERα and ERβ and play, together with

the receptor, an important role in the regulation of

ER target-gene expression. Different modes or

mechanisms of target gene regulation affect the

agonist-antagonist profile of a ligand. SERMs have

a tissue- and gene-specific mixed agonist-antagonist effect. Alternative indirect activation pathways,

other than binding of natural or synthetic small

organic hormones or drugs, can also modulate the

ER activity. Estrogens have also very rapid effects,

so-called nongenomic effects. Nonreceptor-dependent antioxidant effects by estrogens have been

reported, protecting from neurodegenerative disorders and atherogenesis.

Breast Tissue: There is no pubertal breast development in aromatase-deficient women due to lack

of or too low levels of circulating estrogens.

Estrogen therapy of aromatase-deficient female

patients led to normal prepubertal and postpubertal

breast development. ERα has been shown to be

necessary for mouse mammary gland development.

ERβ is abundantly expressed in rat breast. Both

ERα and ERβ are present in human breast cancer.

Measurement of both ERα and ERβ is suggested

for selection of appropriate breast cancer therapy.

Urogenital Tract: ERα and ERβ are both

expressed in uterus, ovary, testes, and prostate in

the mouse. Absence of ERα results in infertility in

both male and female mice. Absence of ERβ

results in partial infertility in female mice but no

impaired fertility in male mice. ERβ-deficient mice

display hyperplasia, dysplasia, and prostatic

intraepithelial neoplasia (PIN)-lesions of the

prostate. Deficiency of aromatase in human

females led to ambiguous genitalia and polycystic

ovaries. ERT of aromatase-deficient female

patients led to resolution of the ovarian cysts and

menarche. Male patients with estrogen deficiency

or estrogen insensitivity are reported with

macroorchidism or oligozoospermia. ERβ-selective agonists may protect against abnormal prostate

growth and may be the therapy of choice for urge

incontinence. 

Bone: Estrogens have an important role in maintaining a balanced bone metabolism. In addition,

estrogens protect postmenopausal women from

bone loss and the development of osteoporosis.

Estrogens may play an important role in the maintenance of bone mass in aging men. Estrogens are

important for the pubertal growth spurt and epiphyseal closure in girls as well as in boys. There

are likely both direct and indirect (systemic)

effects of estrogens on bone metabolism and

homeostasis. Both ERα and ERβ are expressed in

the bone-forming osteoblasts. Estrogen insensitivity in a male patient caused by ERα deficiency led

to osteopenia and continuous longitudinal growth

due to unfused epiphyses. Male and female

patients with aromatase deficiency have increased

bone turnover, delayed bone maturation, low

Estrogens have

an important role

in maintaining a

balanced bone

metabolism.
79

BMD, and tall stature due to unfused epiphyses.

ERT of both female and male aromatase-deficient

patients resulted in growth spurt, closure of the

epiphyses, and increased BMD. Lack of ERβ

expression in the female ERβ-/- mice led to a masculinized bone phenotype of the long bones but no

effect on the bone phenotype in male mice. Available

data suggest that ERα plays an important role in

bone in both men and women but that ERβ perhaps has a role in bone physiology only in women.

The Cardiovascular System: A number of gender-related cardiovascular differences have been

reported, for example, (1) lower risk for young

women than for young men to develop atherosclerosis and CVD, (2) higher prevalence of left ventricular hypertrophy in men than in women, (3)

significantly greater intimal thickening after vascular injury in men than in women, and (4) the rapid

vascular response to estrogen in women but not in

men. ERα and ERβ are expressed in vascular

endothelial cells, in smooth muscle cells, and in

myocardial cells. Both ERα and ERβ can mediate

the vascular injury response to estrogens, suppressing smooth muscle cell proliferation and intimal

thickening. Estrogens have both genomic and

nongenomic effects on vascular tissue. Part of the

beneficial effects of estrogen on cardiovascular

function and reactivity comes from liver-specific

effects of estrogens on the serum lipid/cholesterol

profile. ERα most likely mediates the liver-specific effects of estrogens. Also monocytesmacrophages are potential targets for the beneficial

effects of estrogens on the cardiovascular system

and the development of atherosclerosis.

Central Nervous System and the HypothalamoPituitary Axis: Estrogens are reported to influence

a variety of functions in the CNS such as learning,

memory, awareness, fine motor skills, temperature

regulation, mood, and reproductive functions.

Estrogens are also linked to symptoms of depression and treatment of depressive illness. Different

brain structures and neurotransmitter systems are

involved in the different effects of estrogens. The

predominant expression and localization of ERβ in

rat neocortex, hippocampus, and nuclei of the

basal forebrain suggest an important role for ERβ

in learning and memory. Estrogen, through effects

on the HPA, modulates the expression and secretion of several hormones from the anterior pituitary gland, such as LH, FSH, growth hormone

(GH), and PRL. Female and male patients with

aromatase-deficiency have elevated levels of LH

and FSH and elevated circulating levels of androgens. Substitution with conjugated estrogens in

both male and female aromatase-deficient patients

resulted in normalization of gonadotropin and

testosterone levels. Clinical data on a male patient

with an ERα nonsense mutation also showed

increased circulating LH and FSH levels despite

high estrogen levels. In ERα-/- mice, the serum

LH but not the FSH levels were elevated despite

tenfold higher circulating levels of estrogen.

Available data indicate that estrogens rather than

testosterone (in both men and women) together

with inhibins are the major regulators of serum

gonadotropin levels and that ERα seems to be

more involved in this process than ERβ.

Hormone Replacement Therapy: Traditional

Alternatives and Future Perspectives: The most

common regimens in use to treat symptoms of the

menopause and postmenopausal health

risks are 17β-estradiol,

esterified estrogens, or

CEEs, each in combination with a progestin,

for example, MPA. The

awareness of undesired

effects and serious

health risks (breast cancer, endometrial cancer, and venous thromboembolism) with existing HRT (first generation HRT)

warrants alternatives with improved safety profile.

Alternative regimens for women who do not wish

to take today’s first generation HRT exist. Non-ER

subtype-selective SERMs (second generation

ERα and ERβ are

expressed in vascular

endothelial cells, 

smooth muscle cells 

and in myocardial cells.
80

HRT) display tissue-selective estrogen agonism.

Although the most frequent and serious health

risks of first generation HRT are obviated by these

SERMs, they still suffer from low efficacy compared to first generation HRT, and they aggravate

hot flushes. The existence of two ER subtypes,

ERα and ERβ, gives the opportunity to develop

ER subtype-selective ligands that will most likely

better provide the benefits of ERT, with an

improved therapeutic profile (third generation HRT).

1. INTRODUCTION

Around 1960, Jensen and colleagues came to the

conclusion that the biological effects of estrogen

had to be mediated by a receptor protein.1 Since

then, two ER subtypes have been cloned, ERα2

and ERβ.

3 The discovery of rat ERβ was rapidly

followed by the cloning of ERβ from other

species4–6 and the identification of several ERβ isoforms with: (1) extended N-termini,7,8 (2) a variant

with an 18 amino acid residue insertion into the

ligand-binding domain (LBD), with altered ligandbinding characteristics,9,10 and (3) C-terminal splice

variants unable to bind ligand or activate reporter

gene transcription.11,12 Various alternatively spliced

forms have been described also for ERα.

13,14 The

biological and physiological significance of different isoforms of ERα and ERβ is unknown and

remains to be investigated. Whether there is still

another ER subtype (e.g., ERγ) to be found remains

an open question. However, the vascular protective

effect of estrogen in the absence of ERα and ERβ15

and the fact that ERα and ERβ double knockout

(DERKO) mice survive to adulthood16 may suggest

that yet another unidentified ER exists. 

ERα and ERβ are similar in their architecture to

the other members of the steroid-thyroid hormone

superfamily of nuclear receptors17,18 in that they are

composed of independent but interacting functional

domains: the N-terminal A/B domain, the least

conserved among nuclear receptors, enables the

receptor to interact with members of the transcriptional apparatus; the C domain, involved with

binding of DNA, contains two zinc-binding motifs

and a dimerization interface that mediates cooperativity in DNA binding; the D domain, also referred

to as a “hinge region,” necessary to give the receptor some flexibility between the DNA and the LBDs,

binds heat shock protein hsp 90, and probably harbors the sequence representing the nuclear localization signal; and the E/F multifunctional domain

recognizes and binds a ligand and is involved in

receptor dimerization and interaction with transcription factors and cofactors.19 The gene modulatory effect of a receptor following binding of a ligand depends on the conformational change of the

receptor induced by the ligand and the subsequent

events, including release of inhibitory proteins

(heat shock proteins), receptor dimerization, receptor:DNA interaction, recruitment of and interaction

with coactivators and other transcription factors,

and the formation of a preinitiation complex.20

In particular, two regions in the ERα participate in

transcriptional activation of target genes by forming

protein:protein contacts with other transcription

factors or coactivators, the ligand-independent, 

N-terminal activation function 1 (AF–1) and the

ligand-dependent, C-terminal activation function 

2 (AF–2).17, 20–23 Synthetic ligands with mixed agonist-antagonist activity, so-called SERMs, such 

as tamoxifen and raloxifene, display a low but 

significant partial estrogen agonist activity via

ERα on an estrogen-responsive element (ERE).24

In contrast, these mixed agonists-antagonists display pure antagonism via ERβ on an ERE site. 

The partial agonism of the SERM tamoxifen by

ERα is mediated by a slightly different part of the

ERα AF–1 region than required for estradiol (E2)

signaling.25 The pure antagonism of tamoxifen by

ERβ was recently explained by the lack in human

ERβ of this particular function of hERα AF–1.26

Thus, differences in the amino-terminal regions of

ERα and ERβ most likely explain the differences

in their response to mixed agonists-antagonists,
81

such as tamoxifen and raloxifene, on an ERE site.

(See also ch. 6, sec. 3.2.4 for mechanism of antagonist action.)

The ER LBD, similar to other intracellular receptors, is made up of 12 α-helices, named H1–H12.

Helix 12 (H12), together with amino acid residues

in helices H3, H4, and H5, constitute the AF–2

coactivator recruitment and interaction surface.20,27

The resolution of 3D structures of ERα in complex

with agonists and antagonists has given a molecular mechanism for agonism and antagonism,

respectively.28–30 When the ER LBD is complexed

with estradiol or diethylstilbestrol (DES), H12 is

positioned over the ligand-binding pocket, generating the AF–2 surface that promotes interaction

with coactivators29 and transcriptional activation.

In contrast, in the ERα or ERβ LBD-raloxifene

complexes28,30 or in the ERα LBD–4-hydroxytamoxifen complex,29 H12 was instead positioned in

the hydrophobic cleft formed by H3, H4, and H5,

foiling the coactivator interaction surface. (See

also ch. 6, sec. 3.2.4 for molecular mechanisms of

antiestrogen action.) It is evident that different 

ligands induce different receptor conformations31,32

and that different conformations of the receptor

affect the efficiency by which coactivators and

corepressors interact with the liganded receptor29

and, consequently, the agonist-antagonist profile 

of ligands.33

In recent years, there has been a strong focus on

the cloning and characterization of nuclear receptor coactivators, corepressors, and their associated

histone acetyl transferases (HATs) or deacetylases,

respectively.20 Integrator molecules like CREB

(cAMP responsive element binding protein) binding protein (CBP/p300) and coactivator and corepressor proteins form protein:protein complexes

with liganded nuclear receptors, bringing HATs or

deacetylases in juxtaposition to chromatin. These

events play a key role in the transcriptional regulation of target genes by liganded nuclear receptors

and determine the final outcome on target gene

expression. 

The presence of different ER subtypes and isoforms and different coactivators and corepressors

and our increasing knowledge of mechanisms by

which ERα and ERβ, respectively, can modulate

target gene expression have significantly added to

our understanding of the physiology and pharmacology of estrogens and antiestrogens and have

given a plausible explanation of why antiestrogens

and SERMs sometimes behave more like estrogen

agonists than estrogen antagonists. Initially it was

believed that the ER affected the transcription of

estrogen-sensitive genes only by direct binding of

the ligand-activated receptor to EREs on DNA. We

now know that ERα and ERβ also can modulate

the expression of genes in an indirect manner,

either by blocking the ability of a transcription 

factor to bind to its response element on DNA,34

thereby inhibiting gene expression, or by stimulating gene expression by indirect binding of ER to

DNA response elements through protein:protein

interaction with other transcripton factors.35–38

The different mechanisms by which ERα and ERβ

modulate gene expression have changed our view

of the pharmacology of estrogens and antiestrogens. The terms “agonism” and “antagonism”

should be used with care. Natural or synthetic hormones that we now categorize as estrogen agonists

and estrogen antagonists should perhaps not, in general

terms, be categorized in this way.

The reason for the

caution is exemplified by the transcriptional effect of

ERα and ERβ via

an activator protein

1 (AP1) site in the presence of estrogens and antiestrogens.39 With ERα, typical agonists such as

estradiol and DES but also the antagonist tamoxifen function as equally efficacious agonists in the

AP1 pathway, the antagonist raloxifene being only

The different mechanisms by

which ERα and ERβ modulate

gene expression have

changed our view of the 

pharmacology of estrogens

and antiestrogens.
82

a partial agonist. In contrast, with ERβ, estradiol

acts as an antagonist inhibiting the agonistic activity of the two antagonists tamoxifen and

raloxifene.39

In addition to the classical activation of the ERs by

natural or synthetic hormones, alternative, indirect

activation pathways of the ER (at least α) in the

absence of ligand has been described40–43 as a consequence of the activation of membrane receptors

like those for insulin-like growth factor (IGF)-I,44

epidermal growth factor (EGF)45 and TGF and

dopamine.46 Still debated is the exact mechanism

involved in this process. Several studies utilizing

specific inhibitors of trandsduction signals, like

ras, and protein kinase A and C (PKA and PKC),

have clearly shown that the full activity of these

molecules is essential for unliganded ER activation. Furthermore, point mutation studies have

shown that two serines located in the N-terminal

A/B domain are required for this process.42 These

findings indicate that phosphorylation of ER or of

molecules interacting with ER is involved in transcriptional activation of the unliganded ER. More

studies are necessary, particularly to better define

whether this mechanism is conserved among different cell types. In fact, studies in various cell

systems favor the hypothesis of differential mechanisms depending on the system examined.47,48 The

current hypothesis for the physiological significance of these alternative pathways implies that

they may be of relevance in those phases of

embryologic development in which neither estradiol nor its metabolites are available (e.g., during the

maturation of the reproductive and the nervous

systems).47 These mechanisms might also be of

pharmacological interest in the treatment of neoplastic forms that express the ER but have lost the

responsiveness to treatment with ER antagonists

(e.g., certain type of mammary carcinomas). 

Another emerging and potentially important pathway involves the very rapid so-called nongenomic

effects of ligands on nuclear receptors.49 In

endothelial cells, estrogen-ER complex-mediated

membrane effects lead to sequential activation of

ras, raf, mitogen-activated protein kinase kinase

(MEK) and, subsequently, activation of mitogenactivated protein kinase (MAPK).50 It is proposed

that this may lead to activation of endothelial nitric

oxide synthase (eNOS) and stimulated release of

nitric oxide (NO). In neurons, membrane effects of

estrogen lead to stimulation of src, ras, MEK, and

MAPK, resulting in neuroprotection, and in the

bone-specific osteoblasts, the membrane effects of

estrogen may be involved in control of apoptosis,

cell proliferation, and differentiation.50

An important aspect of the physiology and pharmacology of estrogens, which does not require the

presence of the receptor protein, is their described

antioxidant effects, suggested to protect from neurodegenerative disorders caused by oxidative

stress, as in Alzheimer’s disease or atherogenesis

due to excess uptake of oxidized low density

lipoproteins (LDLs) by macrophages in the vascular wall.51,52 Components of CEEs have also been

tested for their antioxidant effects.51 Equilin and its

derivatives were reported to be better antioxidants

than estradiol in inhibiting peroxidation of fatty

acids and cholesterol in LDL particles. Other

agents reported to exert neuroprotective or

antiatherogenic effects caused by oxidative stress

are phenolic compounds, vitamin E, insulin-like

growth factor-1, and mifepristone (RU486).51–55 In

the context of antioxidant effects, antiestrogens

(trans-hydroxytamoxifen, tamoxifen, and Imperial

Chemical Industries PLC [(ICI) 182,780] but not

E2 have been shown to activate the transcription of

the quinone reductase gene and to increase

NAD(P)H:quinone oxidoreductase enzyme activity

via an electrophilic/antioxidant response element

(EpRE/ARE).56 Furthermore, E2 inhibited the 

agonistic effect of the antiestrogens, and ERβ was

more efficacious than ERα in stimulating

EpRE/ARE-containing reporter gene expression.35

These findings suggest that antiestrogens are also

potent antioxidants and stimulators of phase 2

detoxification enzyme genes, protecting cells from
83

damage by radicals and other toxic byproducts of

metabolic oxidation.

ERα gene polymorphisms may also provide

important information about the physiology of

estrogen action. Different ERα polymorphic forms

have been linked to increased pig litter size57 and

human breast cancer susceptibility,58 low BMD,

osteoporosis,59 hypertension,60 spontaneous abortion,61 and increased body height.62

2. BREAST TISSUE

The importance of estrogens in the development 

of female breast tissue is well documented. Female

aromatase-deficient patients, unable to convert C19

steroids (e.g., testosterone) to estrogens, showed

no sign of breast development at the onset of

puberty63. Administration of estrogen to the two

described female patients led to normal prepubertal

and postpubertal breast development.

ERα knockout (ERKO or ERα-/-) female mice

have lost their capacity to develop mammary gland

tissue beyond the embryonic and fetal stages

despite elevated levels of circulating estrogens

(17β-estradiol). This impairment of breast development has been attributed to the lack of both direct

and indirect (regulation of growth factor, e.g.,

EGF, and progesterone receptor (PR) expression)

stimulatory effects of estradiol on breast epithelial

and stromal tissues, due to missing ERα expression.64 Applying tissue recombinant experiments

and making a series of wild-type and ERα-/- breast

stromal and epithelial tissue combinations, it was

concluded that ERα expression in the stromal cell

layer was essential for growth stimulation of the

ductal epithelium in the mammary gland in mice.65

PRL, also expressed and secreted from the anterior

pituitary, plays a crucial role in mammary gland

physiology. In ERKO female mice, the expression

of PRL from the anterior pituitary and the circulating levels of PRL in serum are decreased by twentyfold and fivefold, respectively. It is conceivable

that the impaired mammary tissue development in

ERKO female mice is also due to decreased levels

of PRL, in part due to lack of ERα expression in

ERKO pituitary.57

More than 70 percent of primary breast cancers in

women are ER (should be read ERα) positive and

show estrogen-dependent growth that undergoes

regression when deprived of supporting hormones.

Patients whose breast tumors lack significant

amounts of ERα rarely respond to endocrine ablation or treatment with antiestrogens, whereas most

patients with ER-containing breast cancers benefit

from such treatment.

Immunochemical determination

of ER in tumor biopsies has

become a routine clinical procedure on which the choice of

therapy is based. However, the

currently available immunochemical procedures for ER

measurements are based on

ERα-specific antibodies that do

not detect ERβ protein (unpublished observations). 

ERβ mRNA and protein, together with ERα

mRNA and protein, have been detected in human

breast cancer biopsies and in human breast cancer

cell lines.66 With the use of receptor-specific antibodies, both ERα and ERβ were found to be

expressed in the normal rat mammary gland, but

the presence and cellular distribution of the two

receptors were distinct.67 While the level and percentage of cells expressing ERβ was more or less

constant during prepubertal and pubertal stages

and throughout pregnancy, lactation, and postlactation, the level and percentage of ERα-containing

cells varied dramatically. The possible role of ERβ

in normal breast tissue development and physiology

and in breast cancer development and/or therapy

is, however, as yet unknown.68

The importance of

estrogens in the

development of 

female breast tissue 

is well documented.
84

3. UROGENITAL TRACT

ERα and ERβ are both expressed in uterus, ovary,

testes, and prostate, but with different cellular

localization. In the ovary, ERα is mainly expressed

in thecal cells and in the prostate mainly in the

stromal compartment. ERβ is expressed mainly in

glandular epithelium of the uterus, primarily in the

granulosa cells of the ovary, and mainly in the

epithelium of the testes and prostate. 

Aromatase-deficiency

in female patients led

to excess circulating

androgens in the fetus

and at puberty, resulting in virilization and

ambisexual development. The two aromatase-deficient

female patients63 were reported with ambiguous

genitalia at birth, a phenotype that was further 

pronounced at pubertal age, and with polycystic

ovaries, characterized by a disproportionate number of atretic follicles and dense fibrotic subcortical

stroma. The elevated serum levels of FSH and LH

in these patients, as a result of perturbed estrogendependent negative feedback on gonadotropin production, were suspected to be the cause of the

polycystic ovaries. Estrogen replacement in these

affected female patients led to normalized

gonadotropin and androgen levels, resolution of the

ovarian cysts, and menarche.63 Like female 

aromatase-deficient patients, aromatase knockout

(ArKO) female mice had low serum estrogen levels and high testosterone and gonadotropin levels.69

Female ArKO mice also displayed genital anomalies, with underdeveloped external genitalia and

uteri; and the ovaries contained numerous follicles

that appeared arrested before ovulation. The stroma

of the ovaries was hyperplastic, with structures that

appeared to be atretic follicles. No corpora lutea

were present.69

Male patients with either defective estrogen production63 and the male patient with estrogen insensitivity caused by a nonsense mutation in ERα

gene70 are reported to have macroorchidism or

oligozoospermia and/or decreased sperm viability

or motility. The fertility of the aromatase-deficient

or estrogen-resistant male patients is not known.

Male ArKO mice were initially fertile but developed progressive infertility71 due to arrested spermatogenesis. These findings suggest that estrogen

has a direct effect on male germ cell development

and fertility.

Deletion of the ERα gene in mice results in infertility in both females and males. ERα-/- female

mice show complete infertility with hypoplastic,

estrogen-resistant uteri and hyperemic ovaries with

no ovulatory capacity.64 Similar to the aromatasedeficient female patients, ERKO female mice have

elevated testosterone and LH levels. Treatment of

these mice with a GnRH antagonist reduced the

serum levels of LH and reverted or prevented the

cystic ovarian phenotype,72 in agreement with the

disappearance of polycystic ovaries in aromatasedeficient female patients following estrogen substitution and subsequent normalization of serum

gonadotropin levels. To challenge the ovulatory

deficiency of ERKO female mice, immature mice

were treated with exogenous gonadotropins.

Although the ovulatory capacity was reduced compared with age-matched wild-type mice, the collected

oocytes were fully competent to undergo successful

in vitro fertilization,72 suggesting that ERα is not

critical for follicle maturation and ovulation.

ERβ knockout (BERKO or ERβ-/-) mice also have

been generated. Female animals showed reproductive defects (20 percent of normal fertility),64 while

males showed normal fertility. The LH and estrogen levels in BERKO females are comparable to

wild-type, but their fertility is compromised due to

reduced ovarian efficiency. Superovulation of

BERKO female mice exhibited several mature but

unruptured follicles. The number of corpora lutea

was considerably less than in wild-type mice, suggesting an attenuated response to the ovulatory

hormone surge in the absence of ERβ.

ERα and ERβ are both

expressed in uterus, ovary,

testes, and prostate, 

but with different cellular

localization.
85

Female mice unable to express either ERα or ERβ,

DERKO mice, exhibited normal reproductive tract

organ development but were, as expected,

infertile.16 Similar to ERKO female mice, the

DERKO females showed uterine hypoplasia but no

polycystic ovaries. The ovaries of prepubertal

DERKO females, displayed precocious maturation

evidenced by multiple, large antral follicles, not

observed in control wild-type females. The very

high serum levels of LH in these animals explain

the prepubertal, precocious ovary phenotype of the

DERKOs.16 The ovarian phenotype of the adult

DERKO female was distinct from the ERKO and

BERKO female phenotypes, most notably by the

presence of structures resembling seminiferous

tubules of the testis. The sex-reversal of the adult

DERKO ovary phenotype was judged to be caused

by a redifferentiation of ovarian components rather

than by a developmental phenomenon.16 In summary, based on the ovarian phenotype in DERKO

females, it was concluded that both ERα and ERβ

are required for the maintenance of germ and

somatic cells in the postnatal mouse ovary.

Male ERKO mice are infertile, with atrophy of the

testes and seminiferous tubule dysmorphogenesis

resulting in decreased spermatogenesis and inactive sperm.64 Recently, a more detailed study of the

cause of the infertility of male ERKO mice provided biological evidence that ERα plays an important role in the reabsorption of luminal fluid from

the efferent ductules during the transit of spermatozoa from the testis to the head of the

epididymis.64 Concentration of sperm is claimed to

improve their survival and maturation during epididymal storage. Administration of high levels of

estrogen to men is known to cause infertility. Thus,

another possible explanation that may contribute to

the nonreproductive phenotype of ERKO male

mice is the relatively high levels of estrogens in

ERKO mice and the presence of ERβ in seminiferous epithelium, spermatids, and spermatocytes,

causing infertility by a direct action on the testes.

In contrast to male ERKO mice, male BERKO

mice are fertile,64 suggesting a different role for

ERβ compared to ERα in the male reproductive system. As expected, DERKO male mice are infertile,

with an 80-percent reduction in the number of

sperm produced in the testis.16

Estrogens are claimed to be effective in the treatment of urge incontinence in postmenopausal

women. It has recently been shown that ERβ is

highly expressed in the inner epithelial cell layer

of the rat bladder and urethra.73 These results suggest that female patients with UI might benefit

from ERβ-selective agonist therapy.

Estrogens have also been linked to prostate disease.

In different species, estrogens synergize with

androgens in inducing glandular hyperplasia and

dysplasia and in inducing adenocarcinoma in the

prostate.74 Immunohistochemical studies revealed

that ERβ is the predominant ER subtype in the

prostate, located in the epithelial cells along the

ductal network of the prostate. ERα has been

detected only in the stromal compartment of the

prostate.73–75 It has been suggested that ERβ is regulated by androgens in the prostate, since the

abundance of ERβ mRNA was rapidly reduced following castration but restored after testosterone

replacement.76 Exposure of wild-type mice to the

estrogen 5α-androstane-3β,17β-diol, a metabolite

of dihydrotestosterone, caused a decrease in the

level of androgen receptor (AR) in the prostate.75

In ERβ-/- mice, however, the level of AR is elevated, and 5α-androstane-3β, 17β-diol was without

effect, suggesting that the AR gene is an ERβ target

in the prostate.75 Exogenous estrogens have a negative effect on epithelial cell differentiation, ductal

morphogenesis, and prostate growth,74 and the

prostate of adult rats neonatally exposed to estrogens shows hyperplasia, dysplasia, and presence of

in situ carcinoma. It was hypothesized that ERβ is

a marker of epithelial differentiation and that the

decline in epithelial cells in neonatally estrogenized rats is a result of altered epithelial cell differentiation.74,76 ERβ-/- mice display signs of prostatic

hyperplasia with aging.75 This suggests that ERβ

may protect against abnormal prostate growth.
86

4. BONE: DEVELOPMENT AND

HOMEOSTASIS

It is well established that estrogens exert an important influence on bone physiology; clinically this is

manifested by the occurrence of osteoporosis in

postmenopausal women. There is also compelling

evidence that estrogens protect postmenopausal

women from bone loss and the development of

osteoporosis, maintaining a balance between bone

resorption and bone formation.77,78 The level of

estrogens may play a more important role than

testosterone for the maintenance of bone mass also

in aging men,79,80 with a positive correlation

between BMD and serum estradiol concentrations

rather than testosterone levels.

As in other tissues, there are most likely both

direct and indirect effects of estrogens in maintaining a balanced bone metabolism. The likelihood of

important direct effects of estrogens on bone is

based on the presence of ERα in the bone-forming

osteoblasts81,82 and in the bone-resorbing osteoclasts.83 ERβ mRNA has been found in primary rat

osteoblasts, in rat osteosarcoma cells,84 and in

immortalized human fetal osteoblasts.85 Evidence

for indirect effects of estrogens on bone metabolism stems from studies in mice, rats, and

humans,86–91 suggesting a coupling and cooperativity between GH and estrogen in bone metabolism.

Taken together, these studies indicate that estrogen

substitution can increase the circulating levels of

GH87 and the levels of GH receptor on osteoblasts90

and that there is a mutual dependence of GH and

estrogen action on bone growth, mineral density,

and maintenance.86,88,89,91 In addition, estrogens may

have indirect effects on osteoclast differentiation,

maturation, and activity by inhibition of cytokine

expression92–95 and via stimulation of osteoprotegerin expression from human osteoblasts.96 The

importance of these interactions for the maintenance of bone health needs to be evaluated.

Despite approximately tenfold higher levels of 

circulating estradiol in ERα-/- mice, there was a

significant decrease in the length and size of the

femur in females but only slight decrease in

males.64 In contrast, the decrease in BMD and

BMC was more pronounced in ERKO males than

females.64 In BERKO mice, the bone phenotype of

male mice was unaffected compared to wild-type

male mice, while there was a masculinization of

the long bones (femur) in the female BERKO

mice.97 Lack of ERβ expression in the female

BERKO mice led to increased length of the femur,

thicker cortical bone (increased BMC due to

increased periosteal circumference), and increased

size of the vertebrae, approaching the corresponding characteristics of wild-type male mice. There

was no effect on trabecular architecture or BMD in

the male or female BERKO mice. Ovariectomy of

female mice leads to loss in trabecular BMD to a

similar extent in both BERKO and wild-type animals,97 suggesting an important role for ERα in the

maintenance of trabecular BMD and architecture

in mice. A further support for the importance of

ERα in bone physiology was obtained from examination of a male estrogen-insensitive patient with a

nonsense mutation of the ERα gene.70 Similar to

the ERKO mice, he had elevated levels of LH,

FSH, and estrogen. Despite the elevated levels of

estrogen, he had low BMD and continuous linear

growth because of unfused epiphyses, suggesting

an important role for ERα in human bone biology.

The decrease in length and size of femur in the

female ERKO mice may be indicative of an effect

of ERβ in the presence of excessive amounts of

estradiol or its metabolites. The possible effects of

disrupted ERα and ERβ expression in ERKO and

BERKO mice, respectively, on GH expression and

its consequences for the bone phenotype in these

animals are not yet known.

Male and female patients with aromatase-deficiency63

have increased bone turnover, delayed bone maturation, low BMD, and tall stature due to unfused

epiphyses. They have elevated circulating levels of

androgens, FSH, and LH but very low or undetectable levels of estrogen. ERT of both female and

male aromatase-deficient patients resulted in
87

growth spurt, closure of the epiphyses, and

increased BMD,63 suggesting a very important role

for estrogens not only in females but also in males. 

The pubertal growth spurt starts earlier in girls

than in boys,98 beginning at midpubertal stage in

boys. The average duration of pubertal growth

spurt in girls is shorter than in boys, possibly

explained by higher levels of estrogen in prepubertal girls than in prepubertal boys, hypothesized to

cause a more rapid skeletal maturation and epiphyseal closure in girls than in boys. Using an ultrasensitive assay for determination of serum estrogen

levels, the rise and decline in estrogen levels in

boys have been assessed in correlation to age,

pubertal growth peak velocity, bone maturity, and

epiphyseal closure.99 In this study, there was a

close correlation between the rise in estrogen level

and the rise in the level of testosterone, and the

rise in estrogen level correlated with the time of

peak growth velocity.99 Following growth spurt in

these boys, there was a further increase in estrogen

levels that was sustained toward the end of puberty,

hypothesized to accelerate epiphyseal fusion.99

5. CARDIOVASCULAR SYSTEM

Women’s risk for the occurrence of CVD clinical

events at an early age is less than that for men. The

CVD risk increases with age for women,

approaching the same incidence rate as for men,

starting from the age of 50. (See also ch. 8.) Based

on observational epidemiological studies, HRT is

described to have a cardiovascular protective effect

in postmenopausal women, decreasing the risk of

developing atherosclerosis and CVD. (See ch.

8.)100–102 The cardioprotective effect of estrogens is

debatable as no such data from clinical trials are

available yet. On the other hand, the outcome of

HERS,103 which did not show any overall cardiovascular benefit in postmenopausal women (treated

with oral CEE plus MPA) with established CHD,

may be explained on the basis of recent findings,

according to which medroxyprogesterone antagonizes positive effects of estrogens on the vasculature. (See ch. 8, sec. 3.2.) The recommendation

drawn from HERS was not to initiate hormone

treatment for secondary prevention of CHD.

Despite an early increase in risk in treated women,

fewer CHD events were observed over time in the

hormone treatment compared with the placebo

group; it was therefore recommended that women

with CHD already on HRT may well continue the

treatment.

ERα and ERβ are

expressed in vascular

endothelial cells,102

smooth muscle cells,104

and myocardial cells.105

A number of direct effects

of estrogen on vascular

tissue have been 

reported:101,102,106,107 nongenomic vasodilation 

as an effect of estrogen on

ion-channel function108

and NO synthesis,109 longterm effects by modulation of prostaglandin synthase, NO synthase and endothelin gene expression,105,110 regulation of angiotensin AT1 receptor

density on vascular smooth muscle cells,111 and

inhibition of injury induced vascular intimal thickening.112 Furthermore, reduced heart contractility in

ovariectomized female rats normalized following

estrogen replacement,113 an effect, in part,

explained by estrogen-mediated changes in expression of contractile proteins.106,114

Besides a higher risk for men to develop atherosclerosis and CVD at an early age compared to

women, there are other gender-related cardiovascular differences. Men have a higher prevalence of

left ventricular hypertrophy than women,106,115,116

hypothesized as an effect of the difference in the

level of circulating estrogens in men compared to

women106 but possibly also due to gender-specific

differences in ER levels and in the induction of

endogenous gene expression in cardiac myocytes

Besides a higher risk for

men to develop 

atherosclerosis and 

CVD at an early age

compared to women,

there are other genderrelated cardiovascular 

differences.
88

in response to estrogen.106,105 In rats, intimal thickening after vascular injury is significantly greater

in males than in females.107 Male level of intimal

thickening occurred in female rats after ovariectomy, an effect that was reversed by estrogen therapy.112 The primary inhibitory effect of estrogen on

intimal thickening was mediated by its direct effect

on vascular smooth muscle cells, inhibiting their

migration and proliferation.112 Another gender difference is the rapid response to estrogen after

acetylcholine-induced coronary arterial constriction in women and men with coronary artery disease (CAD).117 In female patients, administration of

estrogen reversed the vasoconstriction response to

acetylcholine, while there was no response to

estrogen in male patients. Coronary blood flow was

significantly enhanced in the

presence of estrogen in the

female patients, but no response

to estrogen occurred in the

men. A plausible explanation

for these differences may be

that vascular endothelium in

women produces more NO in

response to estrogen than in

men. The specific role of ERα

and ERβ in maintaining normal

cardiovascular function and in

prevention of the development

of atherosclerosis and CVD is

still largely unknown.

However, disruption of the ERα gene, as in ERKO

mice, showed a reduced production of NO.64 ERα

also seems involved in neovascularization, as there

was no angiogenic response to estrogen in ERKO

mice.64 An increased number of L-type Ca2+ channels was reported in ERKO male mice,64 suggesting an involvement of estrogen and ERα in the

regulation of cardiac excitability. In the man bearing an ERα nonsense mutation,64 there was

absence of endothelium-dependent vasodilation of

the carotid arteries following ischemic cuff occlusion.118 However, this lack of ischemic response

may relate more to atherosclerosis-induced

endothelial dysfunction than to a direct consequence of lack of ERα-mediated responses in the

vascular endothelium.107,119 Sublingual estrogen

delivery caused a rapid vasodilator response in the

ERα-deficient man,118 possibly suggesting a role

for ERβ in rapid vascular responses to estrogen. In

contrast, there was no negative effect of vascular

endothelium-dependent vasodilation in ERα-/-

mice.64 Estrogen treatment protects against vascular injury, suppressing smooth muscle cell proliferation and intimal thickening, in ERKO mice.64 The

expression of ERβ but not ERα was dramatically

increased in wild-type mice after vascular injury.102

These data suggest an important role for ERβ in

vascular injury response and protection. However,

a similar estrogen-dependent vascular injury protection was also seen in BERKO mice, suggesting

an ERα and ERβ redundancy in vascular injury

protection or that an unknown signaling pathway

or a still unidentified ER is involved.102 In this context, the estrogen resistant man70 showed intimal

thickening of the common carotid arteries118 despite

elevated circulating levels of estrogen.

Part of the beneficial effects of estrogen on cardiovascular function and reactivity relates to liverspecific effects, regulating serum lipid-cholesterol,

levels.101 Estrogens increase the level of

apolipoprotein A1 in postmenopausal women.120

Apolipoprotein(a), the major protein component of

the atherogenic lipoprotein (Lp(a)), is down-regulated in the liver by estrogen at the mRNA level

resulting in decreased plasma levels of Lp(a).121

Estrogen also increases the expression of angiotensin

in postmenopausal women,122 regulates the level of

HMG CoA reductase at the protein level, and

increases LDL receptors on the surface of liver

cells.101 Regulation of the apoE gene by estrogen

has been demonstrated in the rat123 and mouse.64

As in skeletal tissue, GH may play an important

role for estrogen effects in liver,91 with hypophysectomy blunting the cholesterol-lowering effect of

estrogen in ovariectomized rats.91 The liver in

The specific role of

ERα and ERβ in

maintaining normal

cardiovascular 

function and in 

prevention of the

development of 

atherosclerosis 

and CVD is still 

largely unknown.
89

female rats has more GH receptors than in male

rats,124 and liver GH receptor expression positively

correlates to estrogen status in female and male rats.125

So far ERα but not ERβ has been shown to be

expressed in liver;126 thus all effects of estrogen

reported on liver-specific gene expression are ERα

mediated. Further support for the physiological

role of ERα and estrogens in the regulation of

liver-specific gene expression and lipid-lipoprotein

homeostasis stems from the analysis of the ERαdeficient70 and the aromatase-deficient patients63

and from the ERKO mice,64 demonstrating glucose

intolerance and lipid abnormalities as a consequence

of estrogen resistance or estrogen insufficiency.

In addition to liver and cardiovascular cells, monocytes-macrophages also are involved in health and

disease of the cardiovascular system.127,128 Several

studies, both in vitro and in vivo, have indicated

that growth factors and cytokines that mediate the

critical processes of inflammation and wound healing also play a central role in vascular disease and

during the initiation and progression of atherosclerosis. The cytokines interleukin-1b (IL–1b) and

tumor necrosis factor α (TNFα) have been implicated in the processes of vascular injury and

atherogenesis.129 Both ERα and ERβ are reported

to be expressed in monocytes-macrophages.130

Estradiol has been shown to inhibit LDL oxidation,

to inhibit and cholesteryl ester formation and accumulation in macrophages,131 and to reduce the

uptake of acetylated LDL into macrophages, resulting in a reduced rate of foam cell formation.132

Estrogen down-regulates the expression of TNFα

in human macrophages133 by a mechanism that

involves ERβ but not ERα.

134 These results suggest

that monocytes-macrophages also are potential targets for the protective effects of estradiol on the

cardiovascular system and the development of 

atherosclerosis.128

6. CENTRAL NERVOUS SYSTEM AND THE

HYPOTHALAMO-PITUITARY AXIS

Estrogens are reported to influence a variety of

functions in the CNS, such as learning, memory,

awareness, fine motor skills, temperature regulation,

mood, and reproductive functions.135 Estrogens are

also linked to symptoms of depression and treatment of depressive illness. (See also ch. 12.) 

Different brain structures

and neurotransmitter systems are involved in the

different effects of estrogens.135 The serotonin

5–hydroxytryptamine

(5–HT) system, with neurons projecting from the

dorsal and medial raphe

of the midbrain/brainstem

raphe nuclei to multiple

forebrain areas such as

the hypothalamus, hippocampus, and cortex,135 is involved in the modulation of reproduction, mood, sleep, and cognition.

Serotonin levels and activity in CNS are altered by

serum estrogen fluctuation in rodents, and estrogen

substitution in ovariectomized rats positively

affects the serotonergic system.135,136 Estrogen has

been reported to increase the expression of tryptophan hydroxylase (TPH), the rate-limiting enzyme

for serotonin synthesis,137 and to suppress the

expression of the serotonin reuptake transporter

(SERT) in raphe nuclei of ovariectomized monkeys.138 Estrogen reduced the level of the 5–HT1A

autoreceptor subtype in the dorsal raphe nucleus of

spayed monkeys139 and reduced agonist stimulated

5–HT1A receptor inhibition of dorsal raphe neuron

firing in rats,140 suggesting that estrogen may facilitate 5–HT neurotransmission.139 The level of postsynaptic 5–HT1A receptors, mainly localized in the

limbic brain areas and the cerebral cortex, is also

affected by estrogen.141 5–HT2A receptors, suggested to be involved in the control of hormone and

transmitter release, control of sexual activity, reguEstrogens are reported

to influence a variety of

functions in the CNS,

such as learning, 

memory, awareness, fine

motor skills, temperature

regulation, mood, and

reproductive functions.
90

lation of sleep, motor behavior, and psychiatric

disorders such as anxiety and depression,142 are

positively regulated by estrogen in the dorsal raphe,

olfactory bulb, and cerebral cortex.143–145 In male rats,

5–HT1A receptor levels also are regulated by estrogen.146 ERβ mRNA has been reported within the

dorsal raphe of the rat,147 and an ERα immunoreactive protein has been detected in neurons adjacent

to serotonergic cells in rat dorsal raphe.135 An

autoradiographic study in ERα-/- mice indicated

an abundant presence of ERβ in mouse dorsal

raphe,148 and no ERα protein has been detected in

the macaque raphe,135 suggesting that ERβ may

play a more important role than ERα in mediating

estrogen effects on the serotonergic system.

The dopaminergic system, involved in motor 

function, motivation, reward, cognition, and hypothalamic-pituitary control, is also affected by estrogen.149,150 Dopamine levels and turnover fluctuate

during the estrous cycle,151 and administration of

estrogen, following ovariectomy, potentiates the

release of dopamine.152,153 Estrogen also increases

dopamine transporter binding sites in the striatum154 as well as the densities of dopamine receptors D1 and D2.

155 In the hypothalamus, the

dopaminergic tuberoinfundibular neurons inhibit

PRL release from the anterior pituitary by release

of dopamine into the hypophyseal portal system,

an effect that is inhibited by estrogen.156

The basal forebrain cholinergic neurons project to

the cerebral cortex and hippocampus and are

implicated in learning and memory.135 Long-term

ovariectomy results in impaired learning due to

decline in high-affinity choline uptake and choline

acetyl transferase (ChAT) activity in rats.135

Estrogen substitution following ovariectomy in rats

induced ChAT enzyme levels and increased ChAT

activity in the basal forebrain and possibly ChAT

activity in projection areas ending in the cerebral

cortex and hippocampus.135 ChAT mRNA levels

fluctuate in the basal forebrain cholinergic neurons

during the estrous cycle in the rat.135 The colocalization of ERα with nerve growth factor (NGF)

receptors in cholinergic neurons of the rat basal

forebrain,135 and the stimulation of estrogen of both

NGF receptor mRNA and ChAT mRNA in the rat

basal forebrain,135 suggest a possible role for ERα

in learning and memory functions. However, the

predominant expression and localization of ERβ in

rat neocortex, hippocampus, and nuclei of the

basal forebrain suggest an important role for ERβ

in learning and memory.147,157 This assumption is

further supported by the maintained normal 

memory and learning function in ERKO mice.64

In a recent study on human brain, the predominant

presence of ERβ message in the hippocampal formation, entorhinal cortex, and thalamus suggests a

putative role of ERβ in cognition, memory, and

motor functions.158

Additional transmitter systems shown to be 

influenced by estrogens are vasopressin and 

oxytocin,159,160 somatostatin,161 galanin,162 the 

γ-aminobutyric acid (GABA) system,163 and the

glutamate system.164,165

The expression patterns of ERα and ERβ, based

on mRNA, autoradiographic, or immunohistochemical studies of rat and mouse brain, indicate a

more abundant or distinct presence of the two ER

subtypes in certain areas of the brain but also areas

where they seem to overlap. ERα seems to be

more abundant in the hypothalamus (preoptic,

arcuate, periventricular, and ventromedial nuclei)

and amygdala (amygdala hippocampal area, medial and cortical nuclei).147,166 High levels of ERβ

mRNA have been found in the medial preoptic,

paraventricular and supraoptic nuclei of the rat

hypothalamus. In the amygdala, ERβ is primarily

expressed in the medial amygdala nucleus.

Moderate to high ERβ mRNA levels are found in

olfactory bulbs, bed nucleus of the stria terminalis,

hippocampus, cerebral cortex, cerebellum, midbrain raphe, and basal forebrain.135,147,148,157,166–168

The HPA regulates overall endocrine homeostasis

in the body. Estrogen, through effects on the HPA,

modulates the expression and secretion of several
91

hormones from the anterior pituitary gland, such as

LH, FSH, GH, and PRL.64 Both ERα and ERβ are

expressed in the pituitary gland, but ERα predominates,64 in particular in the gonadotrophs and lactotrophs. Both ER subtypes are also expressed in

the preoptic area of the hypothalamus and are

believed to be involved in regulating the expression of pituitary hormones, but ERβ

predominates.147

Although serum levels of LH and FSH are directly

controlled by hypothalamic GnRH, it is the circulating level of estrogen, other sex steroids, and the

inhibin glycoproteins that are the most important

physiological determinants of serum gonadotropin

levels.64,169,170 There is a strong inverse correlation

between the circulating levels of inhibin and FSH.

The main source of inhibin (inhibin A and inhibin

B) production in females is the ovary, inhibin B

being expressed in the early follicular phase with a

peak at the mid-follicular phase and inhibin A

being expressed by the dominant follicle and the

corpus luteum with a peak in the late follicular

phase and in the midluteal phase.169,170 In men,

inhibin B, proposed to be the main inhibin

involved in FSH regulation, is primarily produced

by the Sertoli cell.169

Female and male patients with aromatase-deficiency have elevated levels of LH and FSH, elevated

circulating levels of androgens, but very low circulating levels of estradiol and estrone.63 Therapy

with conjugated estrogens in both female and male

aromatase-deficient patients resulted in normalization of gonadotropin and testosterone levels.63

Clinical data on the male patient with the ERα

nonsense mutation70 also showed increased serum

LH and FSH levels despite normal levels of testosterone and high estrogen levels. Transdermal

ethinyl-estradiol therapy of this man did not lower

serum LH or FSH. Estradiol substitution of

ovariectomized rats prevented the expected

increase in LH but only partially blocked the rise

in FSH. In ERα-/- mice, the circulating LH levels,

but not FSH, are elevated despite tenfold higher

serum levels of estrogen.64 Taken together, these

data indicate that estrogen is more important than

testosterone (also in men171–173) in regulating circulating gonadotropin levels and that ERα plays a

major role in mediating the effect of estrogen in

this process. The effect of activin-inhibin feedback

regulation of pituitary FSH expression is independent of ERα. Whether ERβ has a role in ovarian

activin-inhibin expression and the feedback regulation of gonadotropin expression remains to be

investigated. 

LH and FSH surge is critical to female ovarian

cycle and fertility;64 elevated estradiol levels in

proestrous are required for the preovulatory LH

surge from the anterior pitutary, triggered by a discharge of GnRH into the hypophyseal portal system.174 The anteroventral periventricular nucleus

(AVP) of the preoptic region, a sexually dimorphic

part of the hypothalamus, is thought to play a critical role in transducing the gonadotropin surge.64

The AVP is larger in female mice and contains a

greater number of dopaminergic neurons than in

males.64 Testosterone exposure of neonatal females

reduces the number of dopaminergic neurons and

precludes an LH surge. The AVP provides direct

projections to a subpopulation of GnRH neurons in

the preoptic region that are thought to participate

in the initiation of the preovulatory LH surge.64

Also progesterone and the PR are necessary components of the LH surge.64,175 Both ERα and ERβ

have been shown to trigger PR expression in the

preoptic nucleus,167 suggesting that either of the

two ER subtypes or both may participate in triggering the LH surge. Also other neurotransmitter

systems in the brain are suggested to contribute to

the induction of the LH surge.64 ERα-containing

histaminergic neurons located in the tuberomammillary complex were shown to be involved in the

positive feedback effect of estrogen in the induction

of the LH surge, mechanistically via histaminergic

axo-dendritic and axo-somatic appositions onto

GnRH neurons and the histamine H1 receptor.174
92

7. HORMONE REPLACEMENT THERAPY:

TRADITIONAL ALTERNATIVES AND

FUTURE PERSPECTIVES

The most common regimens

used to treat symptoms of

the menopause and postmenopausal health risks,

such as osteoporosis and

CVD, are 17β-estradiol,

esterified estrogens, or

CEEs, each in combination

with a progestin, for example, MPA, to avoid

increased risk of endometrial or uterine cancer in

women with an intact

uterus. Another combination

used is estrogen with testosterone, claimed to increase

libido and decrease depression. The awareness of

undesired effects (e.g.,

resumption of monthly bleeding, breast tenderness,

and headaches) or health risks (breast cancer,

endometrial cancer, venous thromboembolism,

ovarian cancer, asthma, and gall bladder disease)

with existing HRT (first generation HRT) warrants

alternatives with improved safety profiles.

Recently developed nonsteroidal ER ligands with

mixed agonist-antagonist activity, the so-called

SERMs (second generation HRT), display a tissueselective estrogen agonism in for example, bone

and liver, but estrogen antagonism in breast and 

uterine tissue.176–178 Additional ER ligands with similar mixed agonist-antagonist activity (SERMs) are

in development.177 Although the increased risk of

breast cancer and endometrial cancer is obviated

by the SERMs, they have not shown the same efficacy as estrogen to prevent bone fractures of the

hip, though they have proved efficacious in reducing vertebral fracture risk. Current SERMs

increase the incidence of or aggravate hot flushes

in postmenopausal women, and the incidence of

venous thromboembolism is the same as for first

generation HRT. A serious disadvantage for this

category of drugs became evident as the SERMs

levormeloxifene and idoxifene were withdrawn

from further development due to increased incidence of UI and uterine prolapse in postmenopausal women. The discovery of a second ER

subtype, ERβ, has revitalized the search for

improved drugs for HRT that most likely will better provide the benefits of ERT. Several large pharmaceutical companies are engaged in the development of ERα- and ERβ-selective SERMs (third

generation HRT), but as yet there is no information

regarding their development. However, synthetic

ER subtype-selective ligands have been reported.179

The most ERα-selective ligand showed 120-fold

higher agonist potency for ERα than for ERβ.

Another ER subtype-selective ligand, synthesized

by the same group, showed full ERα agonism but

pure ERβ antagonism.

Current alternatives for women who do not wish to

take the HRT cited above are: (1) synthetic progestins, megestrol acetate (a synthetic derivative of

androgens), or tibolone (a synthetic steroid with

estrogenic, progestational, and androgenic activity)

for alleviation of hot flushes; (2) bisphosphonates

or calcitonin for prevention of osteoporosis; and

(3) statins or antioxidants for prevention of CVD.176

The most common 

regimens used to 

treat symptoms of 

the menopause and

postmenopausal 

health risks, such as

osteoporosis and 

CVD, are 17β-estradiol, 

esterified estrogens, 

or CEEs, each in 

combination with a

progestin.
93

8. FUTURE NEEDS

Further characterization of the phenotypes of ERα

and ERβ knockout mice will be of continuing

importance, not least regarding the effects of ERα

and/or ERβ deficiency in aging mice. That

ERα/ERβ double knockout mice are viable needs

an explanation: the role of redundant systems to

secure viability and functionality, the importance

of membrane or non-genomic effects of estrogens,

and/or the possible existence of a third ER subtype

have to be clarified. Other compelling questions to

be answered about the biological role of ERα and

ERβ stem from the observation that both ERα and

ERβ are expressed in normal and malignant breast

tissue. Phenotypic characterization of the ERβ-/-

mice revealed a role for ERβ as an antiproliferative

receptor. In several tissues it operates to oppose the

effects of ERα (yin-yang principle). Male BERKO

mice develop prostate hyperplasia, which becomes

malignant with age, and aging female BERKO

mice develop lymphoma. Furthermore, BERKO

mice have severely impaired ovarian function related to the dysregulation of AR. Treatment of

BERKO females with antiandrogens reversed the

phenotype. We have concluded that the major role

of ERβ in the ovary is down-regulation of the AR

in maturing follicles. In BERKO mice ovaries, AR

remains high, for example, the ovary is in a hyperandrogenic state and is similar to ovaries seen in

polycystic ovarian disease in humans. There is a

need not only to identify genes, which are regulated by ERβ, but also to understand the regulation 

of the ERβ gene itself. Furthermore, it will be of

importance to identify possible mutations in ERβ

and to investigate the role mutated ERβ might play

in human diseases.

Priority issues:

• Understand whether breast tumors arise in cells

that already contain one or more of the ERs.

• Investigate the roles of the two ERs in the breast

(synergistic or opposing).

• Compare BERKO mice susceptibility to development of breast cancer to that of controls or of

ERKO mice.

• Determine whether both ERα- and ERβ-containing stromal cells secrete growth factors 

in response to estrogens.

• Investigate, if present, the

role of mutations in ERβ

in human breast cancers.

• Recognize the role of the

splice variants of ERβ in

the normal breast and in

breast malignancy.

• Unravel the mechanism of

activation of ER in postmenopausal breast.

• Identify genes that are

regulated by ERα and

ERβ in normal breast and

in breast malignancy.

More specifically there is a need to:

• Understand why epithelial cells in the prostates

of ERβ knockout mice are never in G0 and

identify the stage in the cell cycle in which they

are arrested.

• Identify the genes involved in the change 

from hyperplasia to malignant phenotype in 

the prostate.

• Characterize the lymphoma which develops in

BERKO females.

• Characterize the role of ERβ in the immune 

system.

• Investigate the role of ERβ mutations in women

with polycystic ovarian syndrome.

Current SERMs

increase the incidence

of or aggravate 

hot flushes in 

postmenopausal

women, and the 

incidence of venous

thromboembolism 

is the same as for

first generation HRT.
94

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G. Multihormonal control of pre-pro-somatostatin

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Katzenellenbogen JA, Katzenellenbogen BS. Novel

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103

Natural estrogens modulate the activity of target cells

by binding at least two intranuclear receptors. ERα

and ERβ belong to a large family of structurally

related transcription factors that are well conserved

from the evolutionary and functional points of view.1

The considerable progress made recently in comprehending ER structure (figs. 6–1 and 6–2) and

mechanism of action (fig. 6–2) provides a basis for

the development of new synthetic ligands aimed at

modulating ER functions in an organ-specific fashion.

Transcriptionally inactive ERs reside in the target

cell nucleus; they are generally bound to inhibitory

proteins. Their activation can occur either by binding of the cognate hormone (ligand-dependent activation) or by posttranslational modifications (ligand-independent activation) that enable them to

dissociate from the inhibitory proteins and associate with EREs, which are specific DNA sequences

in the promoters of target genes.2–7 Although currently little is known about ligand-independent

activation of ERs, analyses of crystal structures of

CHAPTER 6: THE PHARMACOLOGIC MODULATION OF

ESTROGEN RECEPTOR ACTIVITY

Adriana Maggi, Ph.D.* and Rodolfo Paoletti, M.D.†

KEY POINTSa

* From the Milano Molecular Pharmacology Laboratory, Department of Pharmacological Sciences, University of Milan, Milan, Italy.

† From the Department of Pharmacological Sciences, University of Milan, Milan, Italy.

a Evidence categories are given in square brackets. A = randomized controlled trials (rich body of data); B = randomized controlled trials (limited data); 

C = nonrandomized trials and observational epidemiologic studies; D = Panel expert judgement. (See also table 1–1).

1. Cell specificity of estrogen action. Increased knowledge of the structure of ERs

and of the mechanisms of the receptors’ synthesis and their interaction with key

elements of the transcription apparatus is facilitating the synthesis of new pharmacologically active molecules.

2. Pharmacologic modulation of ERs. Synthetic ER modulators can be classified as

steroidal or nonsteroidal. Novel synthetic steroidal ER agonists hold promise for

use in HRT because of agonist activity on the progesterone and androgen receptors. Of particular interest are the nonsteroidal agents that can act as SERMs by

behaving as agonists in target tissues, such as bone and liver, and as antagonists

or partial agonists in reproductive tissues [A and B].

1. INTRODUCTION

Increased knowledge of

the structure of ERs and

of the mechanisms of

the receptors’ synthesis

and their interaction

with key elements of the

transcription apparatus

is facilitating the 

synthesis of new 

pharmacologically

active molecules.
104

the hormone-binding domains of ERβ and Erα

complexed with agonists and antagonists provide

some insight into the intramolecular modifications

leading the ligand-receptor complexes to interact

with the transcription machinery.8,9 In addition,

several coregulators involved in the generalized

and tissue-specific activities of the receptors have

been identified.10–13 ERs may also influence the

transcription of genes lacking EREs through binding other transcription factors (e.g., AP1) and

thereby hindering these factors’ capability to act on

their responsive elements.14,15

2. CELL SPECIFICITY OF ESTROGEN

RECEPTOR ACTION

It is now well known that estrogens produce a

wide variety of physiologic effects and that ERs

are expressed in most mammalian tissues. To

design drugs able to mimic estrogen activity in

only selected target tissues, it is mandatory to

understand how the same hormone can exert so

many different effects in the various cells targeted.

One hypothesis is that the genes regulated by the

hormone are different in each type of target cell.

Because the hormone-receptor complex acts

through the binding of the same EREs in all the

cells, the question arises as to the factors determining the specificity of estrogen action. A number of

FIGURE 6–1

Structural features of ERs. Mutation studies have identified six functional domains within the ER molecule (see ch. 5 for 

a more detailed description of ER functional domains): the N-terminal A/B domain, C domain, or DNA binding domain, 

D domain, the so-called “hinge region,” and E/F domain, or ligand-binding domain. Ligand-independent AF-1 is located in

the A/B domain, while ligand-dependent AF-2 is harbored by C-terminal E/F domain. C domain mediates the interaction

between the receptor and the DNA through “zinc finger” structures.
105

factors listed below may contribute, although, in

spite of very active research in the field, more

studies are needed to clarify which of the mechanisms predominate in the various targets. 

Developmental Cues: During the process of cell

differentiation, fragments of the genome are modified enzymatically or are bound by specific proteins and become inaccessible to transcription factors. The process will undoubtedly involve some of

the ER-inducible promoters, which will become

insensitive to the hormone activity.

Complexity of the Target Promoters: In complex

promoters, in which different responsive elements

control the transcriptional activity of a single gene,

the activity of estrogens will be influenced by the

presence of the other factors involved in gene transcription control.

Tissue-specific Transcription Elements: As

mentioned above, an ER must interact with transcription factors to initiate the transcription of target genes. The factors are in part ubiquitous and in

part cell-specific. Therefore, the abundance of

these cell-specific proteins will contribute to affect

estradiol-ER action on individual promoters. 

Receptor Dosage: Like other membrane receptors, ERs can be up- or down-regulated. It is most

likely that higher concentrations of the receptor

protein will allow the hormone to stimulate most

of the target promoters, whereas lower concentrations will allow generation of subgroups of transcripts, for example, from genes whose promoters

possess multiple EREs.

Ligand Characteristics: ERs bind estradiol and

some of its metabolites. Depending on the ligand

FIGURE 6–2

Panel a. Graphic of the three-dimensional structure of the ER hormone-binding domain. The binding of the agonist induces

a series of conformational changes that expose sites of the receptor capable of interaction with co-activators. The binding of

antagonists induces a very different conformation of the receptor, mainly in the displacement of helix 12 (solid cylinder),

and prevents the exposure of the domains involved in co-activator recruitment. Panel b. Mechanism of ligand-dependent

activation of ERs. On binding to the receptor (ER), estradiol induces release of inhibitory proteins, which allow the receptor to dimerize and associate with the responsive elements in the promoters of target genes. Once bound to the target DNA,

the receptor initiates a series of protein-protein interactions that result in the activation of the transcriptional apparatus.
106

bound, the conformation of the receptor differs,

thus changing its functional activity.

Receptor Subtype: The

type of ER expressed in a

single cell type may also be

important for the selectivity

of estrogen action. In addition to the different effects

exerted by ERα and ERβ

homodimers, it is possible

that ER heterodimers act

differently and that the two

receptors exert mutual

control. That has been

reported to occur with other

members of the intracellular receptor superfamily.16

Influence of Other Members of the Nuclear

Receptor Superfamily: Orphan receptors highly

homologous to ERα—for example, ER-related

receptors α, β, and χ may interfere with ER activities, also by heterodimerization.

3. PHARMACOLOGIC MODULATION OF

ESTROGEN RECEPTORS

Pharmacologic treatment of endocrine dysfunction

involves the control of (1) endocrine signaling, by

acting on the synthesis, storage, or release, or

intracellular transport and metabolism, of the specific hormone; (2) sensitivity of a single target tissue to the hormone, by blocking or enhancing synthesis of the receptor of interest; or (3) activity of

the receptor, by the use of specific ligands with

agonist or antagonist activity. The synthetic compounds generated and in use to date for ER modulation belong to the third category, with the exception of progestins. In several organs, progestins

antagonize the activity of estrogens by a dual

mechanism: down-regulation of the synthesis of

new ERs and control of the transcription of genes

that interfere with estrogen action. Therefore,

progestins are administered in combination with

estrogens to limit the undesired side effects of

estrogens on uterine cells.

The ligands for the ER can be grouped as ER 

agonists, ER antagonists and SERMs. Subgroups

are based on chemical structure, categorized as

steroidal and nonsteroidal compounds.

3.1 Estrogen Receptor Agonists

Known agonists of the ER consist of both steroidal

and nonsteroidal molecules, with the latter including examples of different chemical structures.

3.1.1 Steroidal Agonists 

Natural human estrogens are the follicular hormone

17β-estradiol and its main metabolites, estrone,

estriol, and 2-hydroxyestradiol—together with

their sulfated and glucuronidated counterparts. A

more extended definition of natural estrogens

includes the mare equilin and equilenin. Critical

structural characteristics of this class of compounds

include (1) a phenol at the C–3 position of the aromatic A ring, (2) a relatively flat and rigid hydrocarbon core, and (3) a ketone or alcohol function at

the C–17 position. A detailed pharmacophore

model suggests the important contribution of the

two hydroxyl groups of 17β-estradiol to receptor

binding, with C–3 hydroxy acting as the major

contributor to the binding free energy. The model

is supported by recent X-crystallography data.8,9

When natural estrogens

are administered orally,

they undergo rapid

catabolism in the

intestinal mucosa and

liver; shortly after

estradiol ingestion,

there are high concentrations of the metabolites, predominantly estrone,

in the systemic circulation. Peak concentrations are

observed at 1 to 4 hours after ingestion; subsequently, concentrations rapidly decline. For this

reason, major efforts have been made, particularly

In replacement therapy,

natural steroids are 

currently preferred over

synthetic molecules.

To design drugs able to

mimic estrogen activity

in only selected target

tissues, it is mandatory

to understand how the

same hormone can

exert so many different

effects in the various

cells targeted.
107

in the past, to synthesize steroid analogues of

estrogens with longer half-lives. All the synthetic

molecules developed are far more potent than the

natural estrogens and have, when administered

orally, much longer half-lives. Some, like DES are

no longer used in clinical practice. The finding of a

high incidence of clear cell adenocarcinoma of the

vagina in daughters born to DES-treated mothers

led to the hypothesis that the compound was a carcinogen. However, further studies did not show a

significant increase in breast cancer in the DEStreated mothers, and studies of male offspring

showed genital abnormalities, suggesting that DES

should be considered more as teratogenic than cancerogenic. Other synthetic estrogens, such as

ethinyl estradiol, have been and are largely used in

oral contraception. Ethinyl estradiol is obtained by

the addition of an ethinyl radical in position C–17

and is much more resistant than natural estrogens

to liver metabolism. Orally administered ethinyl

estradiol has a half-life of about 48 hours.

In replacement therapy, natural steroids are currently preferred over synthetic molecules. In the

United States, the most commonly used natural

estrogens are CEEs, extracted from the urine of

pregnant mares. CEEs are mainly composed of

estrone and estrone sulfate; other components

include the ring-B unsaturated sulphoconjugated

estrogens equilin, equilenin, and their 17α-derivatives. The metabolites account for a great part of

the estrogenic effects of CEEs. In addition, equilin

can be stored in adipose tissue and released for

several weeks after withdrawal of the treatment.

17β-estradiol is also used in HRT, particularly in

Europe. Preparations of estradiol valerate or

micronized estradiol were shown to have half-lives

compatible with therapeutic effects when administered orally.17 To avoid the intensive first-pass

metabolism, nonoral routes of administration of

17β-estradiol have been studied. Several parenteral

delivery systems are available: 17β-estradiol can

be administered through injections, vaginal rings,

percutaneous gels, or transdermal therapeutic systems (TTS). Of particular interest are the TTS that

allow the rate-controlled delivery of estrogen. The

hormone is suspended in an ethanol solution or, in

second-generation TTS, in a matrix, which ensures

the programmed release of the hormone for several

consecutive days. 

More recently,

novel synthetic

molecules such as

(7α, 17α)-17-

hydroxy-7-methyl19-norpregn5(10)en20-yn-3-one

(tibolone) have

raised considerable

interest because

they combine with

the estrogenic

activity progestogenic and androgenic properties

that relieve climacteric symptoms without stimulation of the

endometrium.18,19

3.1.2 Nonsteroidal Agonists 

Pioneering studies published more than 60 years

ago showed the effects of subcutaneous administration of nonsteroidal compounds on the onset of

estrus in mammals and on uterine growth. They

enabled the identification of several nonsteroidal

molecules with estrogenic activity. The studies

were also instrumental in the subsequent development of antiestrogens and of partial agonistsantagonists, including SERMs. 

The major categories of the nonsteroidal agonists

are (1) 1,2-diarylethanes and ethylenes; (2)

flavones, isoflavones, coumestans, and lignans; (3)

macrolactones; (4) alkylphenols and arylphenols;

and (5) nonaromatic estrogens.

1,2-Diarylethanes and Ethylenes: DES and

hexestrol (fig. 6–3) represent a milestone in the

identification of orally active nonsteroidal agents

Observational epidemiologic

studies indicate that women

who ingest phytoestrogens,

particularly in soy products, 

in large amounts seem to 

have lower rates of CVD,

breast cancer, and uterine 

cancer as well as fewer 

climacteric symptoms than

women consuming typical 

western diets.
108

with extremely potent estrogenic activity. The

medical uses of compounds with 1,2-diarylethylene and 1,2-diaryl ethane include maintenance of

pregnancy, HRT, suppression of lactation, postcoital contraception, and cancer treatment, as has

been reviewed.20

Flavones, Isoflavones, Coumestans, and

Lignans: The best studied plant-derived estrogens,

or phytoestrogens, belong to these classes of

chemicals with estrogenic activity. A significant

source of isoflavones is soybeans. The most abundant and active components of isoflavones are

genistein (fig. 6–3) and daidzein, which appear to

have selective estrogenic actions. In some tissues,

they provoke proestrogenic responses; in others,

they inhibit estrogenic effects. This finding is perhaps explained by different affinities for the two

described ERs. Indeed, genistein has a thirtyfold

higher affinity for ERβ than for ERα.

21,22 The estrogenic activity of flavones and isoflavones is dependent on ER binding affinity, which is determined

by the presence of the aromatic ring as well as

hydroxyl groups at specific sites.

Compared with estradiol, genistein and daidzein

bind to ERs with significantly less affinity.23

Nevertheless, in the quantities that can be consumed in the diet, isoflavones can have biologic

effects. Soybean isoflavones do not have feminizing effects in male primates as reflected by

unchanged weights of the reproductive organs in

the animals,24 although prenatal exposure of rats

resulted in diminished weights of ovaries and

uteri.25 Observational epidemiologic studies indicate that women who ingest phytoestrogens, particularly in soy products, in large amounts seem to

have (1) lower rates of CVD, breast cancer, and

uterine cancer and (2) fewer climacteric symptoms

than women consuming typical western diets.26

(See ch. 3, 8, and 10.) Preclinical and clinical studies have shown that isoflavones can improve plasma lipid profiles as well as the ability to inhibit

oxidation of low-density lipoproteins.26 Isoflavones

have been shown to normalize vascular reactivity

in estrogen-deprived primates.27 Antineoplastic

activity of the compounds has been postulated on

the basis of their inhibitory activity on angiogenesis.28 In addition to climacteric symptoms, bone

density appears to be favorably influenced by 

phytoestrogens.26 (See also ch. 9.)

Other known phytoestrogens are coumestans (e.g.,

coumestrol), found in alfalfa sprouts, and lignans

(e.g., enterolactone), found in cereals and oil seeds

such as flaxseed.

Macrolactones: Macrolactones were first identified when hyperestrogenicity was seen to develop

in swine fed mold-infected corn. Katzenellenbogen

and colleagues extensively studied these mycotoxins, exemplified by zearalenone (fig. 6–3), which

was shown to bind ERs with high affinity and

induce uterotropic responses in rats.29 Zearalenone

has been used to relieve the incidence and severity

of hot flushes in women.30

FIGURE 6–3

Structural Characteristics of

Estrogen Receptor Agonists
109

Alkylphenols and Arylphenols: Alkylphenols are

used in the synthesis of detergents and as antioxidants. The detergents are not estrogenic; upon

degradation during sewage treatment, however,

they can release estrogenic compounds, such as

para-octyl phenol and para-nonyl phenol, which

have been shown to possess uterotropic activity in

vivo and in vitro.31 The structural requirements of

alkylphenols indicate that both the position (para >

meta > ortho) and the branching (tertiary > secondary) of the alkyl group dramatically affect

estrogenicity.32 In addition to alkyl substitution 

at the para position of the halogenated or the

hydroxy-substituted aromatic ring, aryl substituents have estrogenic activity. Compounds in

the class include bisphenol A; polychlorinated

biphenyls; diphenylmethanes, such as

DDT (dichlorodiphenyltrichloroethane); and tricyclic aromatic hydrocarbons, such as dioxin.33

Many of these compounds are used in the manufacture of plastics, and their estrogenic activity

was discovered by accident because they are

released by polystyrene and polycarbonate test

tubes used in laboratory experiments. Bisphenol A

was found to contaminate the content of canned

food because tin cans are lined with polycarbonate.

Bisphenol A is also used in dental sealants and

composites. 

Nonaromatic Estrogens: Interest in nonaromatic

estrogens has increased because xenoestrogens of

this class can derive from commercial sources,

such as pesticides. Most of the agents are halogenated carbocycles, such as hexachlorocyclohexane, chlordecone (Kepone) (fig. 6–3), chlorobornane (Toxaphene), dieldren, and endosulfan.

Studies with hexachlorocyclohexane showed it to

have estrogen agonist activity in human breast cancer cell lines. It and others of the class have not

been shown to bind to ERs. Therefore, the origin

of the estrogen activity of the compounds is not

clear; it is believed to occur through nonclassic

pathways.34

3.2 Estrogen Receptor Antagonists

Antiestrogens can be grouped according to basic

structure as steroidal or nonsteroidal.

3.2.1 Steroidal Antagonists

The difficulty in modifying the basic steroid structure discouraged research into steroidal antagonists

of ERs until Raynaud et al. demonstrated that the

7α-estradiol derivatives with a long, unbranched

alkyl chain retained high affinity for ERs.35 The

compound ICI 164,384 was developed and shown

to act as a pure ER antagonist, stimulating further

research. The most active compounds that emerged

from the studies are ICI 164,384 and ICI 182,780

(fig. 6–4a). Both avidly bind to ERs and retain a pure

antiestrogen activity in all tissues studied to date.

3.2.2 Nonsteroidal Antagonists

For the rational design of nonsteroidal antiestrogens,

essentially two basic structures were systematically

altered: the triphenylethylene and stilbene structures. The first nonsteroidal antiestrogen discovered was ethamoxytriphetol (MER–25) (fig. 6–4b).

FIGURE 6–4a

Structural Characteristics of

Estrogen Receptor Antagonists
110

Its potency as an antiestrogen was rather low, and

serious side effects in the CNS were found during

clinical development.36 The antagonist activity 

of the molecule may be

due to the hydrophilic

hydroxy group in the

center of the molecule,

which most likely interferes with the receptor

binding. Clomiphene 

(fig. 6–4b), the second

ER antagonist developed,

lacks the central hydroxy

group, and a double bond

with a chloro substituent

improves its lipophilicity.

Clomiphene is used as a

gonad-stimulating agent

in subfertile women. With the identification of the

ER antagonist activity of nafoxidin (fig. 6–4b), it

became evident that a certain steric arrangement at

the double bond favors the antiestrogenic activity.

The most prominent among the group of drugs is

tamoxifen, which was developed by ICI and is

marketed as a citrate salt. The activity of tamoxifen in postmenopausal patients with hormonedependent breast cancer has been demonstrated in

many clinical studies, and the agent has become a

treatment of choice for the malignancy. Tamoxifen

is used in patients with advanced disease, as well

as in the adjuvant setting after surgical removal of

the primary tumor. 

Other triphenylethylene derivatives were synthesized with the objective of obtaining an antiestrogen that would have a lower rate of metabolism

and a different pharmacodynamic profile compared

with tamoxifen and would not present its cis/trans

isomerization. The knowledge that 4-hydroxytamoxifene is more potent in vitro than the parent

drug but is more readily catabolized provided the

basis for the development of the 3-hydroxy derivative droloxifene and of the iodo derivative idoxifene (fig. 6–4b). Droloxifene and idoxifene were

shown to have minimal uterotropic activity, to

reduce plasma cholesterol concentrations, to stimulate osteoclast apoptosis, and to block gene expression in endometrial cells.37 Despite the fact that 

the basic side chain is one of tamoxifen’s most

important structural elements, only a very limited

number of variations of that part of the molecule

have been synthesized. Interestingly, when the 

2-(dimethylamino)ethoxy fragment was replaced

by acrylic acid, the agonist activity was lost in the

uterus but was retained in bone and the cardiovascular system.38

Studies carried out principally at Eli Lilly and

Company demonstrated that the geminal arrangement of the two phenyl rings of tamoxifen is not

The activity of tamoxifen

in postmenopausal

patients with hormonedependent breast cancer

has been demonstrated

in many clinical studies,

and the agent has

become a treatment of

choice for the malignancy.

FIGURE 6–4b

Structural Characteristics of

Estrogen Receptor Antagonists
111

essential and can be replaced by structures in

which all three phenyl groups are located at different atom groups. Several compounds were generated (fig. 6–4c), among them LY 117,018, the first to

undergo detailed study of its endocrine activities.39

A series of modifications of LY 117,018 led to the

synthesis of keoxifene (LY 156,758), which is now

known as raloxifene.40 In raloxifene, the presence

of two free hydroxy groups in the benzothiophene

and phenyl rings gives rise to an ER-binding affinity higher than in compounds lacking those polar

functions.

Another basic structure that has been utilized for

the rational design of antiestrogen drugs is 

2-phenylindole. Zindoxifene (fig. 6–4c) belongs to

the compounds synthesized with this structure. Its

endocrine profile is that of an antiestrogen with

partial agonist activity. The preclinical and clinical

data thus far obtained suggest that zindoxifene is a

new lead structure of interest for the design of

drugs acting through ERs.

3.2.3 Estrogen Receptor Subtype–

Specific Antagonists

The substantial structural homology between ERα

and ERβ has raised the question of whether the

two receptors are, indeed, responsible for different

physiologic responses. Localization studies performed in mature and developing mammals suggest different roles for the two receptors. In fact,

ERα and ERβ are often differentially expressed in

developing and mature tissues (e.g., mammary

gland and brain) and seldom colocalize in a given

cell type.41 Ablation of one or the other of the two

receptors in gene knockout experiments further

supports the hypothesis of a different effect of the

two receptors. ERα activity seems to predominate

in the uterus and breast, whereas ERβ may have

significant roles in the CNS, cardiovascular system, immune system, urogenital tract, kidney, and

lung. (See also ch. 5.) ERβ appears to be the only

form expressed in the embryonic CNS.42–44 On the

other hand, the two receptors can co-localize; it is

possible that they form heterodimers, the transcriptional activity of which may significantly differ

from the homodimers.45,46 Finally, in vitro studies

evaluating the response of reporter genes or more

physiologic parameters of pharmacologic activation of the two receptors have demonstrated significant differences between ERα and ERβ activities.

In spite of the remarkable similarity in their

response to synthetic ligands, the two receptors

seem to activate distinct target genes, with divergent consequences for cell physiology.47,48 The differential activity can be attributed to the significant

structural diversity of the A/B region carrying the

ligand-independent, N-terminal activation function

AF–1. This hypothesis is supported by studies with

a chimera receptor in which the A/B domain of

ERα was substituted to the same domain of ERβ.

49

Thus, because of the potential physiologic differences in the activities of the two receptors, differences in ligand interaction or activity could translate into important differences in their biological

and pharmacological profiles.

FIGURE 6–4c

Structural Characteristics of

Estrogen Receptor Antagonists
112

The observation that the degree of homology of

the two hormone-binding domains of ERα and

ERβ is approximately 56 percent suggests the possibility of developing ligands with different agonist

or antagonist characteristics with regard to the two

receptor subtypes. Recently, novel compounds

with pronounced subtype-selective differences in

binding affinity and transcriptional potency or efficacy were identified.50 An aryl-substituted pyrazole

was shown to be an ERα potency-selective agonist: in fact, it showed a higher binding affinity for

ERα than for ERβ and, in transactivation assays, a

potency of ERα of about two orders of magnitude

higher than ERβ.

Another compound, a tetrahydrochrysene (THC),

was shown to have a fourfold preferential binding

affinity for ERβ; it was an agonist for ERα and a

complete antagonist for ERβ. Interestingly, the

antagonist activity appeared to be associated with

the R,R-enantiomer (R,R-THC); the S,S-THC was

an agonist for both ERα and ERβ but had a twentyfold lower affinity for ERβ than R,R-THC.

3.2.4 Molecular Mechanisms of 

Antiestrogen Action

The molecular mechanisms of antiestrogen blockade of ER activities have been the object of several

studies addressing all the steps necessary for ER

transcriptional activation. 

Receptor Binding: Generally, the affinity of

antagonists for ERs is similar to or even higher

than the affinity of estradiol. It was initially proposed that the binding of an antagonist, in particular the binding of pure antagonists,51 prevents the

dimerization and limits the affinity of the complex

for DNA. Those studies were highly controversial,

and the mechanism cannot be extended to tamoxifen, which was clearly shown to allow the formation of ER dimers.52

DNA Binding: Most in vitro studies have shown

that DNA binding activity of the ER complexed

with agonists and antagonists is very similar, even

though the DNA binding of antagonist-ER complex seems to be slower than that of agonist-ER

complex. Dissociation of the former complex is

much slower than dissociation of the latter.

Protein-Protein Interaction: The availability of

crystals of the ERα and ERβ hormone-binding

peptides bound to 4OH-tamoxifen and raloxifene

provides important new information about the

mechanism of these agents’ activity. Studies show

that the additional side chain of the antagonists

protrudes from the ligand-binding cavity, so that

helix 12 is translocated to a position in which the

co-activator binding side is obscured. As a consequence, the antagonist-ER complex can still dimerize and bind to DNA, but this event cannot be followed by the series of protein-protein interactions

indispensable for AF–2-dependent transcription

initiation, mediated through ligand-dependent, 

C-terminal activation function.

Those findings underline the importance of protein-protein interactions (ER with co-activators or

co-repressors) in the mechanism of action of ER

antagonists. Furthermore, they provide an explanation for the mixed agonist-antagonist activity

reported for both raloxifene and tamoxifen bound

to ERα. (See fig. 6–5.) In fact, the binding of this

antagonist prevents interactions of AF–2, but not

AF–1, with the transcription machinery. Therefore,

the receptor, once bound to the ERE, may still

attract transcription factors with the AF–1 region

and allow the transcription of selected genes.

Deletion and mutation studies have demonstrated

that the full transcriptional activation of ERα is

observed when both AF–1 and AF–2 are present

and activated.53 When access to AF–2 is prevented

by the presence of an antagonist, the activity of the

receptor is limited to those cells and those promoters that contain factors that activate AF–1. (See

also ch. 5 for mechanisms of differential actions of

antagonists on ER subtypes α and β.)

Receptor Turnover: ER antagonists may affect

the kinetics of ER degradation. This represents

another potential mechanism of action of antago-
113

nists; it has been shown to be of importance for

pure ER antagonists, such as ICI 164,884 and ICI

182,780, but not for nonsteroidal antagonists.54

3.3 Selective Estrogen Receptor Modulators

(SERMs)

A SERM is defined as a compound that has estrogen agonism in one or more of desired target 

tissues, such as bone and liver, and antagonism

and/or minimal agonism in reproductive tissues

such as breast and uterus.55

The path leading to SERM development began

with the synthesis of the first nonsteroidal estrogen

antagonist, MER–25, which was shown to inhibit

the action of estradiol in the endometrium without

itself causing endometrial stimulation. Later, the

nonsteroidal triphenylethylene compounds

clomiphene citrate and tamoxifen were reported to

be capable of inducing ovulation by blocking the

negative feedback of estradiol on the HPA56,57 and

to block the development of dimethylbenzanthracene-induced mammary tumors in rats58

(tamoxifen). The results clearly demonstrated the

antiestrogenic activity of the molecules and stimulated interest in their development for antineoplastic activity. In the 1980s, two seminal studies, by

Beall et al.59 and Jordan et al.,60 demonstrated that

clomiphene and tamoxifen had a more varied portfolio of action in that the agents were able to

decrease bone loss in ovariectomized rats. The

FIGURE 6–5

Mechanism of action of SERMs in different cell settings. Binding with a SERM results in blockage of activity of the AF–2

region of the ER; the AF–1 region, however, is free to interact with other proteins, which allows the interaction of the

DNA-bound ER with other elements of the transcription apparatus. Thus, depending on the proteins expressed in the host

cell, the SERM-bound receptor will be able to act as a full agonist (cell A) or a partial agonist (cell B). In cells that lack

proteins able to interact with the AF–1 region of the receptor, the SERM will completely prevent the activation by 

estrogens and, therefore, will be a complete antagonist (cell C).
114

findings were remarkable because a pure antiestrogen would have been expected to promote rather

than inhibit bone loss. Because clomiphene is a

racemic mixture of enclomiphene and

zuclomiphene, primacy in the SERM field must be

accorded to tamoxifen. However, the discovery

that tamoxifen was, in some patients, capable of

endometrial stimulation leading to hyperplasia or

neoplasia61 precluded its development as a bone

antiresorptive agent that would be free of uterine

bleeding and, it was hoped, breast safe.

The concept of selective ER modulation has been

demonstrated subsequently for a number of compounds, including raloxifene, droloxifene, GW5638,

idoxifene, and FC–1271. Toremifene and idoxifene

are molecules similar to tamoxifen; despite their

potential as SERMs, they have been targeted for

the treatment of advanced breast cancer.

Droloxifene is known to have efficacy as a breast

cancer drug but is also a SERM at bone sites.62

Raloxifene was developed because it held promise

for multiple applications. It is used in the prevention of bone loss and fracture in postmenopausal

women and is being tested against tamoxifen in the

Study of Tamoxifen and Raloxifene (STAR) for

the prevention of breast cancer in high-risk postmenopausal women.63 Additionally, raloxifene

reduces circulating cholesterol concentrations64 and

may be efficacious to reduce risk for endometrial

cancer.55 The main drawback of the drug is that it

does not reduce the occurrence of hot flushes,

which could hinder compliance. Similar pharmacologic profiles are shared by idoxifene and

FC–1271, which were shown to have beneficial

effects on bone metabolism in rat models and to

act like estrogens in bone and on circulating

lipoprotein concentrations, with little estrogenic

activity in the uterus.37,65 A number of SERMs are

in preclinical or clinical development (table 6–1).

The molecular mechanisms of the different effects

of SERMs in different organs are summarized

above (“Molecular Mechanisms of Antiestrogen

Action”) and in figure 6–5.

The challenge for the future in the development of

ligands for the ERs will be to refine the target

specificity of SERMs and, it is hoped, amplify

their scope of action. For instance, a SERM with a

profile similar to idoxifene or raloxifene in the

peripheral organs and CNS might protect against

Alzheimer’s disease and hot flushes, while helping

prevent osteoporosis, CAD, and breast and

endometrial cancers.

4. FUTURE NEEDS

The availability of drugs selective for ERα and

ERβ will constitute a major milestone toward the

development of drugs with specificity of action.

On the other hand, the acquired knowledge of the

molecular mechanisms of estradiol activity in 

different cells might suggest novel paths to be 

followed for the development of molecules active

through the ERs. For example, ER turnover is 

differentially regulated in various organs (e.g., 

following gonadectomy, ERα mRNA is increased

in the uterus but significantly decreased in the

liver66). Drugs aimed at modulating the synthesis

of ERs in specific organs may enable fine tuning

of the activity of the hormone. Antisense oligonucleotides have been able to block ER synthesis in

cells in culture. The development of such molecules as drugs might allow their future clinical

use.67 Alternatively, novel preparations of estradiol

in which its bioavailability is modified might have

pharmacologic profiles of interest. For instance, a

formulation allowing a very rapid intraplasmic

release of estradiol and its rapid clearance (e.g.,

transnasal administration of appropriately modified

estrogens) could have a quite different profile of

action compared with estradiol administered orally

or transdermally. Such a drug could rapidly activate the receptors but, because of its rapid clearance from the blood, might have little effect on ER

down-regulation or might affect it differently in the

various targets. 
115

TABLE 6–1

Selective Estrogen Receptor Modulators Under Development

Drug Pharmaceutical Company Phase of Development Therapeutic Class

SERM 339 Aventis Phase IIa 

HM 144 Hormos Medical Preclinical Anti-Alzheimer 

LY 139,478 Eli Lilly and Company Preclinical Bone calcium regulation 

LY 326,391 Eli Lilly and Company Preclinical Cytostatic, 

bone calcium regulation 

ERA 932 Ligand Pharmaceuticals Phase I Cytostatic 

NNC 450,320 Novo Nordisk Preclinical Bone calcium regulation 

NNC 450,781 Novo Nordisk Preclinical Bone calcium regulation 

M.D.L 101,986 Aventis Pharma Preclinical Cytostatic, 

bone calcium regulation 

Fc1271A Hormos Medical Phase II Other drugs for the 

musculoskeletal system 

Arzoxifene Eli Lilly and Company Phase II Cytostatic 

Research program Signal Pharmaceutical Preclinical Cytostatic, 

SERMs bone calcium regulation 

Lasozifene Pfizer Phase II Bone calcium regulation 

Research Program Ligand Pharmaceuticals /Pfizer Preclinical Cytostatic, 

SERMs bone calcium regulation, 

anti-Alzheimer 

SR 1,634 SRI International Preclinical Cytostatic
116

Recently, the use of phage display has allowed the

identification of peptides that interact specifically

with estradiol- or tamoxifen-activated ERα. Some

peptides were shown to regulate ER transcriptional

activities.68 Such studies demonstrate that ER

activity can be regulated even by targeting sites

that are outside the ligand-binding pocket of the

protein. This is not surprising within the current

view of ER interactions with other proteins relevant in transcription. Such results have pharmacologic implications of interest because they provide

new targets for drug activities and more opportunities for the development of drugs that will modulate the activity of ERs in selected cells or even at

specific genes. Finally, increased knowledge of the

physiologic relevance of unliganded activation of

ERs might lead to the development of pharmacologic compounds that will activate ERs through

membrane receptors. 

These and other molecular developments will in

the near future represent starting points for the preclinical and clinical development of estrogen compounds, of both natural and synthetic origins, with

selective spectrums of action, as the following

points summarize:

• Developing drugs with receptor specificity

(ERα or ERβ)

• Modulating the activity of the hormone interfering with the synthesis of ERs

• Attaining different profiles of action for exogenous estradiol through use of different formulations

• Obtaining higher specificity of action by identification of new target molecules involved in

gene transcription

• Increasing knowledge of the mechanisms

involved in ER activation through membrane

receptors to develop new pharmacologic compounds acting along these pathways
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Mol Endocrinol 1997;11(7):938–49.

68 Norris JD, Paige LA, Christensen DJ, et al. Peptide

antagonists of the human estrogen receptor. Science

1999;285(5428):744–6.
121

CHAPTER 7: SEXUALITY

“Sex is a biologic expression of love and part of 

a universal human behavior with roots stretching

back to the beginning of humankind.”

Won-whe Kim, M.D., Ph.D.

As women live longer, are healthier and more educated, have more leisure time, and are more aware

of their own sexuality, they become inquisitive and

sometimes apprehensive about changes in sexual

function after menopause. Sarrel and Whitehead,

Susan Hendrix, D.O.;* Lorraine Dennerstein, A.O., M.B.B.S., Ph.D., D.P.M.,

F.R.A.N.Z.C.P.;† and Vivian W. Pinn, M.D.‡

KEY POINTSa

1. Declining sexual function is common with aging. There may be an additional

decrement associated with the menopausal transition.

2. The causes of decreased sexual activity are multiple and include physiologic,

psychologic, and social factors.

3. Definitions and Classification of Female Sexual Dysfunction, given by the

consensus panel of the Sexual Function Health Council of the American Foundation for Urologic Disease,

provide a standardized system for clinical diagnosis and treatment and are recommended for use by health

care professionals [D].

4. Sexual interest, behavior, and activity should be routinely assessed at office visits on a regular basis, and a

plan should be developed to address the woman’s concerns.

5. Hormonal and behavioral therapy have had variable success in the treatment of sexual dysfunction but

should be considered in patients who desire treatment for their dysfunction [B].

1. INTRODUCTION

* From the Division of Gynecology; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Hutzel Hospital, Detroit, MI,

U.S.A.

† From the Office for Gender and Health, Department of Psychiatry, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia

‡ From the Office of Research on Women‘s Health, NIH, Bethesda, MD, U.S.A.

a Evidence categories are given in square brackets. A = randomized controlled trials (rich body of data); B = randomized controlled trials (limited data); 

C = nonrandomized trials and observational epidemiologic studies; D = Panel expert judgement. (See also table 1–1.)

Declining sexual function

is common with aging.

There may be an 

additional decrement

associated with the

menopausal transition.
122

in their survey of postmenopausal women, found a

high prevalence of sexual problems, corroborating

these changes in sexual function after menopause.1

When women experience changes in their sexual

function, they frequently turn to their health care

provider for help with their problems.

The prevalence of female sexual disorders, in both premenopausal and postmenopausal women, ranges

from 25 to 63 percent.2–4 The

recently published U.S.

National Health and Social Life

Survey included survey data

from 1,749 women between the

ages of 18–59 years (table

7–1).5 Sexual dysfunction was

more prevalent in women 

(43 percent) than men (31 percent). One-third of

women lacked sexual interest, and almost onefourth stated that they were unable to experience

orgasm in menopause. According to the survey, 

20 percent of those women reported lubrication

difficulties, and another 20 percent reported that

sex provided them little pleasure. Relevant to this

survey, sexual dysfunction appeared to be more

common in menopausal women than in premenopausal women. Similarly, more than 86 percent of postmenopausal women in Sarrel and

Whitehead’s survey reported a variety of psychosexual problems.1 Due to the high prevalence of

sexual dysfunction and the importance that patients

attach to sexual function, it is essential to identify

and address these problems in our patients.

Ultimately, it will assist them in improving their

quality of life and interpersonal relationships.

Much attention has been given to male sexual dysfunction, and only recently has attention shifted to

better understand and identify female sexual dysfunction as a research priority. Clinicians receive

little or no training in the diagnosis or treatment of

sexual dysfunction and lack information on its

causes and ways to prevent the changes that may

occur. The clinician’s individual clinical impressions and previous experience are frequently used

as the basis for clinical practice and are conveyed

to the patient as truth, without evidence to support

those views. Regrettably, most practitioners’

clinical experience is not representative of most

women’s experience in the menopause. This is in

part because those presenting for treatment are

only a small proportion of women troubled. Those

who choose to identify themselves to the clinician

as having a problem represent only a fraction of

women with problems.6,7 Armed with the appropriate facts, the clinician will be rewarded because 

all patients appreciate clinician awareness and

competency in this field.

Because of these barriers, many studies in this

review have methodologic weaknesses, including

sample bias, low measurement sensitivity, and lack

of detail on sexual preference. Population-based

surveys suggest a link between menopause and

changes in sexuality. Yet, relatively few studies of

the menopausal transition in middle-aged women

have inquired about sexual functioning. Of those,

only a minority have used a validated questionnaire to assess the different aspects of sexual functioning. In addition, cross-sectional studies are

unable to distinguish between effects of social

change on different age groups and aging, and

some improperly infer causation from associations.

(See also ch. 3, sec. 3.)

Not insignificant is the controversy surrounding

the study of sexual relationships. Kim noted that in

some ethnic groups it is almost impossible to get

an accurate answer from women about their sexual

activities (Kim WW, personal communication). 

He accurately commented that there are very few

norms set biologically or statistically, and, as a

consequence, analyses done with questionnaires

and interviews might not be reliable. Some interviewees are not sincere in answering the questions,

and some give false information, as they feel shy

about presenting their thoughts and feelings

frankly. He emphasized that in most Asian countries,

The prevalence 

of female sexual 

disorders, in both

premenopausal and

postmenopausal

women, ranges from

25 to 63 percent.
123

TABLE 7–1

Prevalence of Female Sexual Disorders (Percent of Women)

Age (years) 

18–29 32 26 21

30–39 32 28 15

40–49 30 22 13

50–59 27 23 8

Marital Status 

Currently married 29 22 14

Never married 35 30 17

Divorced, separated, widowed 34 32 16

Race 

Caucasian 29 24 16

Black 44 32 13

Hispanic 30 22 14

Other 42 34 19

Lacked Interest 

in Sex

(n = 1,486)

Unable to 

Achieve Orgasm 

(n = 177)

Experienced Pain

During Sex 

(n = 1,479)
124

where over half the world’s population lives, the

situation is even more complicated. Women are

raised under the influence of Confucian ideology

from early childhood and are taught that they should

not even be allowed to express their desire to have

sex. All the myths and misconceptions concerning

female sexuality, especially in old women, remain.

They believe, “It is natural to be away from sex

when you are old” or “Remarriage after the death

of your spouse should never be thought of.”

Other methodological problems

limit study in this field. Until

recently, there were no objective,

standardized definitions of

both the physiologic and psychologic basis of female sexual

dysfunction and menopause.

On the other hand there is still

no consensus on an age cohort

that covers the menopausal transition. Should it be

45–55 years of age, or should it be defined by

shorter intervals? There are differences between

naturally and iatrogenically induced menopausal

women and these distinctions are often not made in

discussions of sexual dysfunction. Furthermore, the

differences between those who choose to take

exogenous hormones and those who wish to make

the menopausal transition without pharmacotherapies are not well defined. Therefore, how we

approach these women differently is confusing.

Objective measures of hormonal change are not

defined or standardized; instead, the absence of

uterine bleeding repeatedly defines menopause.

(See ch. 2 for definitions.) Questionnaires are not

designed to reflect how women experience, problems and data analysis techniques have to be more

appropriate. (See ch. 3 and 4 for biases in women

sampling.)8 The studies reviewed in this chapter

represent the available current evidence and must

be used as a basis for best practice.

This chapter is designed to provide the best

answers to the following questions based on the

current evidence in the literature:

• Do changes in sexual behavior, interest, or

response, occur with age or menopause, or both?

• If changes occur, what are they, and what 

causes them?

• How do we define the changes?

• Do we treat the changes, and if so, what 

therapies have proven efficacy?

2. INFLUENCE OF AGE ON SEXUALITY

The most frequent measures of change in sexual

function used in the literature are coital and orgasmic frequency. To understand the changes of the

menopausal transition, we must first review the

changes leading up to the years most commonly

used to define menopause.

The Kinsey studies conducted in the 1950s were

the earliest to examine the relationship between

sexuality and age. In 1953, in a cross-sectional

descriptive analysis, Kinsey et al. described the

aging patterns of sexual activity in unmarried men

and women.9 The frequency of orgasm reported by

women remained relatively constant at 0.5

episodes per week from puberty through age 55.

Men reported a constant decline from 2.3 episodes

per week at age 15 to 1 episode per week at age 50.

Married women and men showed similar declines

in frequency, with women having lower levels of

activity than men at all ages. The authors surmised

that the married woman’s decline might be a result

of her husband’s and not her own aging. Women

also indicated that their sexual activity reflected

whether or not they had a partner and, if they did,

their partner’s preferences. Their report lacks indication of a decline in a woman’s sexual function

secondary to age, and it was unable to determine

whether a decline in function with age was due to

physiologic, psychologic, or social factors.

Population-based

surveys suggest 

a link between

menopause and

changes in sexuality.
125

A legitimate question to ask is whether this information obtained from two generations past applies

today. The answer awaits further study. There have

clearly been changes in sexual mores over the

years. Nowadays, the orgasmic frequency of

women may be much higher than 0.5 episodes per

week. Many women experience orgasm in different ways than is classically described, and this

may explain the relatively low frequency of

orgasm reported in the Kinsey studies. Moreover,

many women get sexual satisfaction without

achieving orgasm, especially those who value intimacy and the relationship with their partner. This

is often not accounted for in research studies.

Some of the earliest studies of sexuality attempted

to define the factors that influenced sexual activity.

In 1960, Newman and Nichols reported cross-sectional data on 250 men and women between the

ages of 60 and 93.10 In the 100 persons in the single, divorced, or widowed group, only 7 percent

were sexually active. In the remaining 150 persons

in the married group, 54 percent were sexually

active, suggesting that a socially permitted and

legally approved partner significantly influenced

the continuance of sexual activity. There was a

gradual decline in activity through adulthood,

although some level of activity persisted into late

adulthood.

In 1972, Pfeiffer et al. attempted to report the various sexual behaviors in middle-aged and older

both women and men.11 Using a subsample from a

larger longitudinal study on the determinants of

adaptation in middle life (the Duke study), they

showed a pattern of declining sexual activity with

age in both sexes. The frequency of intercourse

was lower for women than for men at all ages;

however, 98 percent of the men versus 71 percent

of the women were married. Both women and men

attributed the choice of discontinuing sexual intercourse to the man. Only 7 percent of women

reported no sexual interest. Of those who did note

a decline, the sharpest increases were noted

between ages 45 and 50 and between ages 51 and

55. These findings contradicted earlier work.

In 1981, George and Weiler reported on 502 married men and women 46–71 who were followed

from the original Duke cohort at 2-year intervals

for 4 years.12 Of those who attended all interviews

and remained married (278), 20 percent of the total

group reported a decrease in sexual activity while

5 percent reported an increase. Only a small 

portion of the sample (n = 57) were women aged

46–55 at the beginning of study. Despite the overall decrease, the authors concluded that sexual

activity remained more stable over time than was

previously suggested. One limitation of the Duke

Study was that it obtained its sample from

enrollees of an insurance company and was therefore a biased sample of middle, and upper-class

healthy, employed people 55 years and older.

As evidenced by the above reports, there had been

only small, descriptive reports up to the late 1970s.

This led Hallstrom to recruit 800 perimenopausal

Swedish women aged 46, 50, and 54 years and a

premenopausal group, 38 years of age to attempt

to better define changes in sexual functioning

which may be related to the menopausal

transition.13 All of the women had intact uteri and

ovaries, and none were using oral contraceptives

(OCs). All were cohabiting with a man. Factors

assessed were sexual interest, orgasm with coitus,

change in sexual interest, change in capacity for

orgasm, and mean frequency of coitus—all stratified by age cohort. There was a striking decline in

sexual interest, capacity for orgasm and coital frequency from age 38 to 54. Not all women reported

a decrease, but the majority of the menopausal

women did. The Gothenburg Women Study refuted

a century-old belief that sexual interest abruptly

increases during the climacteric. Although a small

group reported increases in sexual interest or

capacity for orgasm, the numbers were small and

decreased with age.
126

The Danish study of Koster and Garde involved a

general population sample of 474 women, all born

in 1936, who were subsequently examined at the

ages of 40, 45, and 51.14 Personal interviews were

conducted in 1976 and 1981, and questionnaires

were mailed for the last followup. Of the 51-yearold women, 59 percent reported no change in sexual desire over the study period of 11 years, 30

percent reported decreased desire, and 11 percent

reported an increase. However, this was based on

recall from 11 years earlier. Decrease in sexual

desire correlated significantly with the woman’s

subjective assessment of being climacteric.

One of the more recent investigations was by

Hallstrom and Samuelsson, who utilized the

women in the original Swedish cross-sectional

study for a prospective study on sexual desire.15

The study surveyed 497 married or cohabiting

women, on two occasions, 6 years apart, about

their sexual desire. They found significantly

decreased sexual desire between ages 46 and 60.

After the age of 50 years, none reported a strong

sexual desire; 27 percent reported a decrease, and

10 percent reported an increase in desire between

the interviews.

To assess what changes women complained of,

Osborn et al. surveyed 436 women with a male

sexual partner (94 percent married) and found 33

percent to have at least one operationally defined

sexual dysfunction. (See sec. 6).16 The most frequent dysfunctions were reduced sexual interest

(17 percent), vaginal dryness (17 percent), and

infrequent orgasm (16 percent). Dyspareunia was

described by 8 percent. Significant factors were

assessed, with age emerging as the most important

determinant of operationally defined dysfunction.

One or more dysfunctions occurred in 49 percent

of women aged 50 and older and in 21 percent of

women younger than age 50.

In 1997, Barlow et al. reported on their study of

2,045 women between the ages of 55 and 85

years.17 Their aim was to describe urogenital aging

and its associated problems in older British

women. The survey reported 73 percent of the

women were not sexually active, with the lack of a

partner being a major reason. There was decreasing sexual activity with increasing age; however,

women aged 65–74 had a frequency of activity

similar to the younger women studied.

Dyspareunia and/or vaginal dryness were

described as a severe problem by 12 percent,

among which 33 percent did not seek professional

advice and 36 percent used “over-the-counter”

remedies. HRT was of short duration and declined

with age.

2.1 Influence of Menopausal Status and

Ethnicity on Sexuality

Sarrel and Whitehead were among the earliest to

associate a decline in sexual activity with

menopause. They interviewed 185 women attending a menopause clinic to define what issues, 

concerns, and dysfunctions were present.1 More

than 86 percent reported a sexual problem. Most

women (121/185) reported developing their sexual

problem immediately preceding and following the

transition through menopause. Problems they identified included disorders of sexual desire, sexual

response, and sexual behavior. Newman and

Nichols also showed a decline in sexual interest

with age, with an implied association with the

menopause transition.10 In contrast, Pfeiffer et al.

reported that, in comparison to age, menopausal

status made a small contribution.11

In 1996, Myers performed a meta-analysis of 

sexuality and menopause.18 Empirical studies performed from 1972 to 1992 that assessed sexuality

and perimenopausal and postmenopausal women

were collected and reviewed. A blinded review of

the methodologies was performed. The findings of

the analysis of viable studies indicated that hormones, both exogenous and endogenous, had some

importance to perimenopausal and postmenopausal

sexuality, suggesting an influence of sex hormones

on menopausal sexuality.
127

It makes sense intuitively that there are ethnic variations in sexual function at menopause; however,

few reports address this important issue. The most

common complaints of naturally postmenopausal

Thai women are loss of libido, orgasmic dysfunction,

and dyspareunia.19 Menopausal status appeared to

impact sexual function, as both sexual desire and

activity decreased after menopause. Only 14 percent

occasionally reached an orgasm, while the other 86

percent never had orgasm after menopause.

Although many studies suggest some relationship,

albeit ill-defined, between sexuality and

menopause, Cawood and Bancroft did not concur.

They recruited 141 women into a survey study of

the determinants of sexuality and well-being in the

menopause.20 They found no relationship between

menopausal status and interest or frequency of 

sexual activity and no support for the direct role of

estrogens or androgens in the sexuality of women

between the ages of 40 and 60. Only 54 women in

their study were menopausal. Testing for hormone

levels did not significantly predict measures of

sexuality, while other aspects of the sexual relationship that were predictive were sexual attitudes

and measures of well-being. They also identified

vaginal lubrication as an important factor in the

sexuality of women of this age group.

2.2 Summary

It is difficult, if not impossible, to separate the

effect of aging effects on sexual function from that

of menopause. Also, the menopausal transition is a

time of psychosocial as well as biological change.

It appears that there is a decline in sexual function

as women age, but whether these changes are due

to aging, the hormonal changes of menopause,

psychosocial factors or health status remains

uncertain. The most frequent complaints of women

were reduced sexual interest, vaginal dryness,

infrequent orgasm and dyspareunia.

3. CAUSES OF DECREASED

SEXUAL INTEREST

Controversy exists over whether a reduced level 

of sexual interest is the cause of, or is caused by,

infrequent or decreasing sexual activity in women

or a decline in estrogen and/or androgen levels.

Adaptation theory postulates a declining interest 

of the husband induces a similar response in the

woman. Seemingly, the most common cause of

declining sexual drive in men is age. However, the

Gothenburg Study15 showed no difference between

the husbands of women with declining sexual

interest and those with no change. In fact, a higher

percentage of the women with declining interest

reported that their partners’ sexual interest was

stronger. The same group admitted to submitting 

to their husbands’ desire for intercourse without

having desire themselves.

Zumoff et al. observed that

endogenous androgens may

play an important role in psychosexual functioning in the

menopausal transition, during

which testosterone levels are

approximately 50 percent of

the levels between 20 and 30

years of age.21 Two studies

have shown a correlation

between endogenous androgen

levels and optimal sexual function. McCoy et al.22

evaluated 16 perimenopausal women who recorded

their menstrual and sexual activity daily. Estradiol

and testosterone levels showed significant declines

during the menopausal transition; however, testosterone showed the most consistent association with

coital frequency. Floter et al.23 used the McCoy

questionnaire to correlate the total score (for sexual

enjoyment, orgasm, frequency, and vaginal state)

with levels of testosterone, dehydroepiandrosterone

sulfate, androstenedione, and the ratio of testosterone to SHBG (an indicator of free testosterone).23

Androstenedione correlated with increased sexual

functioning of perimenopausal women.

The most frequent

complaints of 

women were reduced 

sexual interest, 

vaginal dryness, 

infrequent orgasm, 

and dyspareunia.
128

Many studies of sexual interest in premenopausal

women suggest a cause-effect relationship between

hormone levels and sexual function. Schiavi found

a relationship between circulatory androgens and

sexual desire and arousability in a large group of

reproductive-aged women with regular menstrual

cycles.24 A higher sex drive at midcycle, during the

testosterone peak, has been reported; however, it is

difficult to relate these changes in sexuality to a

single factor.25

4. CHANGES IN SEXUAL BEHAVIOR,

INTEREST, AND RESPONSE

The cross-sectional baseline study of the

Melbourne Women’s Midlife Health Project surveyed 1,879 women by telephone with three aims:

to describe women’s subjective assessment of the

changes that they experienced in sexual interest

and reasons for those changes; to relate changes in

interest, coital frequency, and dyspareunia with

menopause; and to attempt to identify those variables that are associated with change in sexual

behavior.26 The majority reported no change in

interest (62.3 percent), while a large number (31.1

percent) reported a decline in interest associated

with menopause rather than age. Only 6.6 percent

of women reported an increase in sexual interest.

Natural menopause was associated with decreased

interest and likelihood of intercourse and an

increase in dyspareunia. Hysterectomy, with or

without oophorectomy, had little influence on sexual activity.

Subsequently, 354 of these women participated in

a longitudinal study and reported menopausal 

status significantly affected vaginal dryness and

dyspareunia.27 There was also an effect on sexual

responsivity mediated through symptoms and 

well-being. Feelings for partner, sexual responsivity, frequency of sexual activities, and libido all 

significantly decreased with time, while vaginal

dryness/dyspareunia and partner problems increased.

Another common condition that impacts sexual

functioning is urinary and fecal incontinence. In a

report by Hilton, 46 percent of women reporting

UI felt that it had a negative impact on their sexual

functioning.28

5. ANATOMIC AND PHYSIOLOGIC

CHANGES ASSOCIATED WITH AGING

Masters and Johnson described how anatomic and

physiologic changes associated with aging could

negatively affect sexual response.29 It may take a

longer time to reach the excitement phase because

of a reduction in the blood flow to the vagina, a

reduction in engorgement of the genital organs,

including the clitoris, as well as decreased amount

of vaginal lubrication and a delay in time to lubrication. These factors may cause dyspareunia. The

plateau phase may be prolonged as a result of

reduced uterine elevation, decreased nipple erection,

and vasocongestion of the breasts. Although orgasmic capacity is retained, there is a reduction in the

number and intensity of vaginal contractions.

6. DEFINING SEXUAL DYSFUNCTION

Classically, the definitions of female sexual dysfunction have been modeled on the human sexual

response cycle first described by Masters and

Johnson29,30 and later enriched by Kaplan.31 Their

work formed the basis for the diagnostic systems

of both the International Statistical Classification

of Diseases and Related Health Problems

(ICD–10)32 and the Diagnostic and Statistical

Manual of Mental Disorders, 4th edition (DSM

IV).33 Recently, the Sexual Function Health

Council of the American Foundation for Urologic

Disease convened a consensus panel to reevaluate

and better define and classify female sexual 

dysfunction.34 Retaining the categories of both systems, several changes were made in the definitions

and classifications; the new format is shown
129

below. One of the major changes in the classification schema was to add the criterion of personal

distress to the diagnosis.

1999 Consensus Classification System

Sexual Desire Disorders

Hypoactive Sexual Desire Disorder

Hypoactive sexual desire disorder (HSDD) is the

persistent or recurrent deficiency (or absence) of

sexual fantasies/thoughts, and/or desire for or

receptivity to sexual activity, which causes personal distress. This allows for trigger of sexual desire

to be secondary to the partner’s initiative. If the

choice is made to not be sexual, there is no disorder present.

Sexual Aversion Disorder

Sexual aversion disorder (SAD) is the persistent or

recurrent phobic aversion and avoidance of sexual

contact with a sexual partner, which causes personal distress. Because often this disorder is secondary

to sexual or gynecologic trauma, some experts

believe that it belongs in the category of phobias.

Sexual Arousal Disorders

A sexual arousal disorder is a persistent or recurrent inability to attain or maintain sufficient sexual

excitement, causing personal distress, which may

be expressed as a lack of subjective excitement or

genital (lubrication/swelling) or other somatic

responses. Goldstein and Berman theorize that the

etiology in some women experiencing difficulties

with vaginal engorgement or clitoral erectile insufficiency may be secondary to atherosclerosis.35

Orgasmic Disorder

Orgasmic disorder is a persistent or recurrent difficulty, delay in, or absence of attaining orgasm following sufficient sexual stimulation and arousal,

which causes personal distress. This disorder occurs

in 20–30 percent of women, not infrequently with

vaginal intercourse.

Sexual Pain Disorders

Dyspareunia

Dyspareunia is a recurrent or persistent genital pain

associated with sexual intercourse. The prevalence

of this disorder has been reported to affect between

10–15 percent of women.36 Consideration should

be given to physical causes such as endometriosis,

episiotomy scarring, or skin sensitivity.

Vaginismus

Vaginismus is a recurrent or persistent involuntary

spasm of the musculature of the outer third of the

vagina, that interferes with vaginal penetration,

which causes personal distress. Vaginismus occurs

in 12–17 percent of all women in reports from the

United States. However, in Asia, it is very rare to

see it (Kim WW, personal communication).

Other Sexual Pain Disorders

Other sexual pain disorders are recurrent or persistent genital pain induced by noncoital sexual stimulation.

Each of the categories above has the following

subtypes on the basis of the medical history, physical examination, and laboratory tests:

a) Lifelong versus acquired.

b) Generalized versus situational.

c) Etiologic origin (organic, psychogenic, 

mixed, unknown).

Health care professionals and the lay public are

encouraged to implement this new classification

system in the conduct of future research, the clinical diagnosis and treatment of women with sexual

dysfunction, and the education of women with

these problems.
130

7. ASSESSING SEXUAL ACTIVITY

Clinicians should routinely ask their patients about

their sexual functioning. Many elderly couples

wonder if it is still possible or safe to have coitus

after the menopause or how long they can enjoy

sex without harming their health. Sexual history

questions particularly pertinent to postmenopausal

patients include the following:

• Are you satisfied with your sexual life?

• Do you have any questions about sex?

• Has there been a change in your sex drive,

lubrication, or orgasm?

• Do you have any sexual problems? Would you

like help with the problem or problems?

• Can you describe when the problem started, and

how often it occurs?

• Have you tried anything to correct the problem?

Has it worked?

• Does your partner have any sexual problems?

It is important to be alert to the possible effects of

aging, illness, or medical or surgical treatment on

libido and sexual responsiveness. Sexual dysfunctions may have a negative influence on a woman’s

self image, her physiologic response, or her partner’s response. One of the most controversial

issues is whether hysterectomy impacts sexual

function. If done for symptoms, such as pain or

bleeding, a hysterectomy can result in improved

sexual functioning.37 Alternatively, some women

view it as causing a loss of their female identity

that negatively impacts sexual functioning.38,39

Possible medical causes of sexual problems

include the following:

Illnesses: Any physical or emotional chronic disease—physical or emotional, including liver, renal,

cardiac, anemia, hypertension, stroke, cancer, neurologic disease, colostomy, neostomy, bladder

surgery, incontinence, herpes virus or HIV infection, venereal warts, and cystitis—may cause sexual dysfunction.

Medications: Hypoglycemic agents, antihypertensive drugs, vasodilator and other cardiac drugs,

antineoplastic drugs, major or minor tranquilizers

(depending on dose), diuretics, and antihistamines

may cause sexual problems. (See table 7–2.) Some

studies suggest antidepressants (including SSRIs)

may reduce desire and delay orgasm.40 Decreased

libido occurs in 20 percent of patients on tricyclic

antidepressants, and 30 percent have impaired

orgasm.

Treatments: Major surgery (hysterectomy, mastectomy, coronary artery bypass, organ transplant),

dialysis, radiotherapy, and chemotherapy may

cause sexual dysfunction.

8. TREATMENT FOR SEXUAL DYSFUNCTION

Sexual function for any person at any age involves

sexual thoughts, desires, feelings of arousal, potential for orgasm, and physical and mental relaxation. The treatment of sexual dysfunction is

dependent adequate research showing efficacy of

the treatment over another medication, a placebo

or another treatment. Compared to with treatments

for other mental health diagnoses, treatment for

sexual dysfunction has lagged behind. The causes

are multiple and include such issues as a lack of a

standardized approach to therapy, the lack of control groups, and the dominance of the techniques

described by Masters and Johnson.30 However, one

of the most probable causes for the lack of treatment options for sexual dysfunction has been the

lack of research funding to study these disorders.

Behavioral and medical treatments for sexual dysfunction are reviewed below, and where evidence

exists, recommendations are made as appropriate.

8.1 Behavioral Therapy for Sexual Dysfunction

A literature review of the application and outcome

of sex therapy and other treatments for sexual dysfunction showed the format of effective conjoint sex

therapy may be of significant benefit to couples

with sexual dysfunction.41 Sarwer and Durlak con-
131

ducted a field trial of behavioral sex therapy for 365

married couples presenting with a range of sexual

dysfunctions at an outpatient sexual dysfunction

clinic of a large medical center.42 The number of

sensate focus exercises completed in the last week

of treatment was the strongest predictor of successful treatment. The results of this study confirmed

that behavioral sex therapy is effective in the treatment of married couples with sexual dysfunction.

8.1.1 Anorgasmia

The approach to treatment of primary anorgasmia

utilizes the techniques of sensate focus, desensitization, and/or directed masturbation exercises. The

primary elements of sensate focus developed by

Masters and Johnson are physical caresses coupled

with nonsexual progressing to sexual touching

exercises.30 The success rate was 84 percent in just

over 1 year and 82 percent at 5 years. Desensitization

is used when anxiety plays a major role in the 

dysfunction; however, it alone does not improve

orgasmic capacity.43 Directed masturbation exercises

have had varying success in the treatment of 

primary anorgasmia.

Kilmann et al. investigated the differential effectiveness of various treatments for 55 couples

where the woman reported secondary orgasmic

dysfunction.44 Compared with women in the control group, a significantly greater number of treated women reached or exceeded the project’s 50-

percent criterion for coital orgasmic functioning.

However, these differences were not significant at

the followup visit.

TABLE 7–2

Medications Associated With 

Adverse Effects on Female Sexual 

Function and Response

Antihypertensive drugs 

Antidepressants and anxiolytics (especially SSRIs)

Anti-inflammatory drugs 

Antiparkinsonian drugs 

Antiseizure drugs 

Beta-blockers 

Bromocriptine (painful clitoral tumescence) 

Cimetidine 

Digoxin 

Diuretics 

Gemfibrozil 

Gonadotropin-releasing agents 

Methyldopa 

Psychoactive drugs 

Sleeping pills 

Tranquilizers

Abusive Drugs Associated with 

Abnormal Sexual Response 

Alcohol 

Narcotics 

Nicotine
132

None of these studies evaluated the effects of treatment of individuals without partners and of, combining sex therapy with marital therapy and with

physical methods of treatment. Thus, no evidencebased recommendations can be made.

A thorough review of behavioral therapies for sexual dysfunction is beyond the scope of this review

but is available.45

9. THE INFLUENCE OF ENDOGENOUS

HORMONES AND EXOGENOUS

HORMONE THERAPY FOR SEXUAL

BEHAVIOR, INTEREST, AND RESPONSE

9.1 Endogenous Hormones

The influence of the sex hormones, including

estrogens, androgens, and progestogens, in the

menopause remains debatable.

Two studies have shown

the importance of adequate

estrogen levels in maintaining genital health and

vaginal lubrication and

preventing insertional 

dyspareunia. Semmens and

Wagner reported on 14

women between the ages

of 51 and 70 years who

had decreased vaginal pH,

vaginal fluid, and vaginal

blood flow, all of which

improved with HRT.46

Sarrel showed a correlation

between serum estradiol

levels (concentrations) and

sexual dysfunction.47 At a level of less than 50

pg/mL, women reported vaginal dryness, increased

frequency and intensity of dyspareunia, pain with

penetration and deep insertion, and burning, all of

which were significantly bothersome.

At the cellular level, Ginkel et al. compared the

vaginal pH and microbial environment in women

before and after starting HRT.48 With HRT, the

vaginal pH became more acidic, there was an

increase in superficial cells, and most importantly,

there was a significant decrease in the number of

anaerobes and an increase in Lactobacillus species

in the vagina.

Similarly, in an interview survey of 52 perimenopausal women with adequate records, Cutler

et. al. reported women with estradiol levels below

35 pg/mL described reduced coital frequency compared with those with levels greater than 35

pg/mL.49 Women with higher estradiol levels had

no complaints related to sexual desire, response, 

or satisfaction.

Additionally, in observational study, 59 healthy,

postmenopausal women between 60 and 70 years

of age were evaluated for sexual function.50

Two-thirds were sexually active. The sexually

active group reported higher levels of sexual

desire, greater sexual satisfaction, more comfort 

in expressing sexual preferences, and greater 

premenopausal sexual satisfaction than women

who were not sexually active. On pelvic examination, the sexually active group had less genital

atrophy than the abstinent group. Of the hormones

studied, higher serum levels of free testosterone

were associated with reports of increased 

sexual desire.

9.2 Estrogen/Hormone Replacement Therapy

Although estrogen and estrogen/progestin replacement therapy have been shown to be an effective

treatment for vaginal atrophy, increasing vaginal

lubrication, they have not been shown to consistently increase sexual desire or activity.

In the 1970s, three double-blind studies on the

effects of HRT on sexual response reported conflicting results. Campbell found vaginal dryness

was significantly decreased with estrogen treatment

compared with placebo, but participants noted no

change in masturbation, orgasm, and frequency of

coitus or coital satisfaction.51 Previous reports by

Utian52 and Coope et al.53 failed to show improveAlthough estrogen and

estrogen/progestin

replacement therapy

have been shown to be

an effective treatment

for vaginal atrophy,

increasing vaginal 

lubrication, they have

not been shown to 

consistently increase

sexual desire or activity.
133

ment in sexual desire in surgically and naturally

menopausal women with CEEs.

Fedor-Freybergh showed significant benefit of

ERT on libido, sexual activity, satisfaction, pleasurable experience, sexual fantasies, and capacity

for orgasm.54 This was corroborated in a randomized, double-blind, placebo-controlled, crossover

trial of estrogen and progestin, alone and in combination, which found beneficial effects of estrogen

alone or combined with the progestin on sexual

desire, enjoyment, orgasmic frequency, and vaginal

lubrication.55 There were no differences between

groups in coital frequency.

In a more recent study of estrogen transdermal

replacement therapy in postmenopausal women,

there was an improvement in patient satisfaction

with frequency of sexual activity, sexual fantasies,

degree of enjoyment, vaginal lubrication, and lack

of pain during intercourse, without impacting frequency of orgasm or sexual arousal.56

9.3 The Role of Androgens in Sexual Function

and Estrogen/Androgen CoTherapy for HRT

The role of sex steroids, including androgens, in

sexual function remains controversial. As previously discussed, sexual desire can be influenced by

many factors. In addition, the decline in serum

testosterone is not unique to the menopause. In a

study of 33 healthy volunteers, 24-hour serum levels of testosterone decreased steadily between ages

20 and 50.21

Ovarian and adrenal changes associated with the

menopause lead to a decline in all androgen concentrations, with androstenedione production

decreased more substantially than testosterone production.57 Postmenopausal women obtain most of

their circulating estrogen from peripheral aromatization of these androgens. SHBG is an important

determinant of sex steroid activity, since the

unbound steroid fraction is the biologically active

component. SHBG is increased by estrogens,

decreasing biologically available androgen. SHBG

is decreased by androgen, increasing biologically

available androgen.58 Applying the evidence from

animal studies, this may influence sexual desire at

the level of the CNS.59,60

Geist and Salmon, although not the first, were

among the early investigators to supplement ERT

with androgens.61 They studied the effects of

testosterone propionate administered twice weekly

at a dose of 25 mg, starting on the 12th day of the

menstrual cycles for its effects on menopausal

symptoms. Maintenance doses of 10 mg of either

testosterone propionate or methyltestosterone

monthly thereafter were also studied. They found

that menopausal symptom relief was particularly

helpful in women on estrogen alone with menorrhagia and in those who only had partial symptom

relief with estrogen.

Shortly thereafter, Greenblatt reported on the use

of androgens for hot-flush relief and an added benefit of improving libido.62 Again in 1950,

Greenblatt and colleagues studied the safety and

efficacy of multiple estrogen-androgen formulations in a prospective, double-blind, placebo-controlled, crossover study.63 They reported improved

well-being and libido, with better relief of hot

flushes and other menopausal symptoms than

either HRT or placebo. Additionally, those on

estrogen-androgen reported less breast tenderness,

pelvic congestion, and nausea. In 1950, Glass reinforced the benefit of testosterone on women’s sexual response.64 He reported that combination therapy with estrogen and androgen produced a

“smoother transition” and “provides reassurance to

the menopausal woman that she is not failing in

her psychosexual life.”

Sherwin and Gelfand published a case series of

surgically menopausal women and confirmed earlier studies showing the role of androgens in the

maintenance of sexual functioning.65 Sexual

arousal, desire, and fantasies increased in women

with estrogen-androgen replacement therapy as

opposed to estrogen alone. They also noted that the

rates of coitus and orgasm were higher in the
134

estrogen-androgen group during the first two post

injection weeks. Additionally, they performed a

crossover study of 53 surgically menopausal

women and showed that the major impact of

androgen in women was on sexual motivation, not

increased sexual activity. Although there has been

concern about the potential of negative impact of

androgens on lipids and heart disease, research has

not confirmed any increase in risk secondary to the

addition of androgens in HRT.66,67

Sarrel et al. reported in 1998 on

20 postmenopausal women

unhappy with their estrogen/

hormone replacement therapy

regimen who were randomized

to receive either esterified estrogens or esterified estrogens with

androgen for 8 weeks.68 They

described significantly improved

sexual sensation and desire after

4-8 weeks of double-blind treatment with estrogen and androgen. They showed increased

SHBG in the estrogen-only

group with decreased free androgens and showed the reverse in

the estrogen-androgen group.

This led to the explanation that

improvement in sexual sensation

and desire may be related to the increased availability of endogenous or exogenous androgens.

In a pilot case series of 17 nonresponders to oral

ERT, estradiol-testosterone combination implants

appeared to significantly improve libido, enjoyment of sex, the ability to climax, and the initiation

of sex, as examined by an analog scale, in a majority of women.69

9.4 Other Agents

Newer hormonal agents in research trials have

indicated a possible benefit in reducing vaginal

dryness, which may impact sexual function.

Tibolone, a preparation with weak estrogen, progestin, and androgen activity not yet released for

use, was studied in 437 women with postmenopausal complaints; they showed improvement

of vaginal dryness, similar to 17β-estradiol/

norethisterone acetate, with fewer bleeding problems.70 In an RCT of tibolone versus 17β-estradiol,

sexual frequency, satisfaction, and enjoyment were

significantly improved over estradiol alone.71

Bupropion is an antianxiety medication which

appeared to increase libido and orgasm in combination with sertraline.72 It may be used as an antidote in women who have sexual dysfunction while

on SSRIs.73,74 A dose of 150 mg of trazodone daily

has been reported to increase sex drive in a woman

postmastectomy with low sex drive.75 A recent

small study of oral phentolamine in six postmenopausal women with female sexual arousal

disorder showed self-reported improvement of

vaginal lubrication and pleasurable vaginal sensations and deserves future study.76

Although there has been much interest in the use

of sildenafil (Viagra®) in the sexual dysfunction of

women, the only published study on the efficacy of

this agent for female sexual arousal disorder was

not shown to improve sexual response in women

receiving estrogen.

Herbal remedies for sexual dysfunction lack rigorous study. A few small trials have assessed efficacy. A drug-monitoring study investigated 12 weeks

of treatment with St. John’s Wort extract, one

tablet three times daily (900 mg Hypericum, Kira),

in 111 women from a general medical practice in

Germany. Patients were between 43 and 65 years

of age, and had climacteric symptoms characteristic of the premenopausal and menopausal state.

The Menopause Rating Scale,78 a self-designed

questionnaire for assessing sexuality, evaluated

Although there has

been concern

about the potential

of negative impact

of androgens on

lipids and heart

disease, research

has not confirmed

any increase in

risk secondary to

the addition of

androgens in HRT.
135

treatment efficacy. Sexual well-being improved

after treatment with St. John’s Wort extract.79

Although there are anecdotal reports of other

herbal agents, no clinical trials have been performed to date. Of interest, clinicians in Asia do

not expect herbal remedies to be effective in treating a woman’s sexual dysfunction, since after

thousands of years of use of oriental medicine,

they still could not find appropriate therapy, even

for men (Kim WW, personal communication).

10. CONCLUSIONS

Multiple population-based studies imply a decrease

in female sexual functioning associated with the

midlife years, and there is growing evidence that

this reflects hormonal changes of the menopausal

transition rather than increasing age. Hormonal

change is only one aspect of the many factors that

impact sexual functioning. These include presence

of a sexual partner, partner’s age and health, length

of the relationship, feelings towards the partner,

level of past sexual functioning, social class, educational level, experience of physical or psychological ill health, stressors, employment, personality factors, and negative attitudes towards the

menopause.

Changes in sexual behavior, interest, and response

should be assessed in the office on a regular basis

and a plan developed with the woman to address her

needs. Therapeutic options include the use of estrogen and estrogen-androgen replacement therapy.

11. FUTURE NEEDS

As life expectancy continues to increase, the challenge for the future will be to improve the quality

of aging years. Sexual health and well-being is an

important part of that quality of life. Future needs

are to:

• Improve understanding of

the natural hormonal

changes that occur with

aging and menopause.

• Understand the role of

endogenous estrogens and

androgens in the sexuality

of women.

• Develop standardized methods to measure libido in

women.

• Better define the determinants of sexual health,

including sexual desire and

arousal, in menopausal

women.

• Increase understanding of

the effect of medications on

female sexuality in the

menopause.

• Understand the role of therapeutic hormonal

and nonhormonal agents in the treatment of 

sexual dysfunction.

• Improve the transmission of information about

sexual health to postmenopausal women.

Changes in sexual

behavior, interest,

and response should

be assessed in the

office on a regular

basis and a plan

developed with the

woman to address

her needs.

Therapeutic options

include the use 

of estrogen and 

estrogen-androgen

replacement therapy.
136

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140
141

CVD afflicts more women than any other disease.

It is by far the commonest cause of morbidity and

mortality in women, and there is a steep increase in

the incidence of CVD with age, especially after

menopause. Ovarian hormones are thought to be

protective of the cardiovascular system; 17β-estradiol and progesterone. Hormones that are effective

for the short-term treatment of symptoms of perimenopause may not necessarily be the best choices

for preventing CVD. HRT is not a single entity but

encompasses a diverse number of agents, which

may have differing effects on the cardiovascular

system. It is therefore important, from a public

health standpoint, to perform studies using different

CHAPTER 8: CARDIOVASCULAR AND PULMONARY DISEASE

Peter Collins, M.D.;* Nanette K. Wenger, M.D.;† Jacques E. Rossouw, M.D.;‡ and Rodolfo Paoletti, M.D.§

KEY POINTSa

* From Cardiac Medicine, NHLI, Imperial College School of Medicine, London, United Kingdom.

† From Emory University School of Medicine, Atlanta, GA, U.S.A.

‡ From the WHI, NHLBI, NIH, Bethesda, MD, U.S.A.

§ From the Department of Pharmacological Sciences, University of Milan, Milan, Italy.

a Evidence categories are given in square brackets. A = randomized controlled trials (rich body of data); B = randomized controlled trials (limited data); 

C = nonrandomized trials and observational epidemiologic studies; D = Panel expert judgment. (See also table 1–1.)

1. CVD is the commonest cause of morbidity and mortality in women [C].

2. The risk factors contributing to CVD are generally the same in women and men,

with the possible exception of hormonal effects [C].

3. Evidence-based medicine has demonstrated that beta-blockers, aspirin, statins,

and ACE inhibitors can reduce the risk of cardiovascular events in women. The

main causes, prevention, and treatment of CVD in women are similar to those in men [A].

4. Although the use of HRT has been associated with a lower risk of CVD in epidemiological studies, this has

not been borne out in clinical trials to date [C].

5. Until the long-term benefit of HRT is proven, attention should focus on identifying and treating the same

risk factors in women as in men [A].

1. INTRODUCTION

CVD is the commonest

cause of morbidity and

mortality in women.
142

routes of administration and different doses and

combination of hormones to arrive at firm conclusions about the role of HRT in the prevention of

CHD in postmenopausal women. CHD prevention

is conventionally divided into primary and secondary

prevention. Primary prevention addresses interventions in the absence of clinically recognized 

disease, although atherosclerosis may be present.

In secondary prevention, 

a cardiovascular event has

already been documented.

In this chapter we have

made no distinction

between primary and secondary prevention of CHD,

since therapies that work

for secondary prevention

usually work for primary

prevention and vice versa.

Although HRT has been the focus of much attention in menopausal women, the approach to the

prevention of CVD should be multifaceted. There

is increasing information on the beneficial effects

of lifestyle changes (e.g., nutrition and exercise),

which can contribute greatly to the reduction in

risk of CVD. One of the problems in CVD

research in women is that some of the major pharmacologic studies have been conducted in men or

have included only a small proportion of women.

Nonetheless, a number of drug interventions,

including beta-blockers, aspirin, statins, and ACE

inhibitors, have been shown to decrease events

associated with CHD in women as well as in men.

Future studies have to include adequate numbers

of women in order to make valid assessments of

treatment effects in women.

This chapter identifies important areas of CVD that

have been studied and reported in women and that

provide a basis for future research in this area of

women’s health. Only with large, well-conducted

clinical trials can important and accurate information

be accrued on CVD in postmenopausal women.

2. RISK FACTORS FOR CORONARY

HEART DISEASE IN WOMEN

The term “risk factor” is used to describe characteristics found in healthy individuals that have

been observed in epidemiological studies to be

related to the subsequent occurrence of CHD. The

risk factors for CHD are multifactorial, and many

of these are similar in women and men.

• Age

• History of CHD, stroke, or peripheral vascular

disease

• Family history of premature CHD

• Dyslipidemia

• Cigarette smoking

• Hypertension

• Diabetes mellitus

• Obesity (especially central)

• Lifestyle—diet, physical activity, psychosocial

factors, alcohol

• Homocysteine and C-reactive protein (CRP)

Some risk factors are modifiable, such as smoking

habit, alcohol intake, lifestyle, and biochemical

and physiological characteristics. Other personal

characteristics, such as age, gender, and family 

history of early onset of CHD, are nonmodifiable.

Countries with high rates of heart disease in men

also have higher rates in women; and conversely,

low rates in men correspond to low rates in women

(fig. 8–1). In developed countries, death rates for

CHD in women aged 35–74 are decreasing (fig.

8–2); in contrast, rates are static or increasing in

developing and eastern European countries.

Women appear to be protected from CHD especially at younger ages, and it has been postulated

that sex-specific hormones may be implicated.2

Data from the Framingham Heart Study3 reveal

that the risk of CHD in an asymptomatic woman

who has both elevated systolic blood pressure and

smokes cigarettes is significantly less than the risk

HRT is not a single

entity but encompasses

a diverse number of

agents, which may have

differing effects on the

cardiovascular system.
143

in a man of the same age. This applies to women

and men at younger ages (age 50) but the differences between women and men no longer apply at

older age (beyond the age of 80).4 Established

major modifiable risk factors for CHD in women,

based on prospective studies, include raised total

cholesterol (or LDL cholesterol), low high density

lipoprotein (HDL) cholesterol, high blood pressure, cigarette smoking, diabetes, obesity, and

physical inactivity. High triglycerides, raised

Lp(a), and raised fibrinogen levels are also considered to be major risk factors by some authorities.

The modifiable risk factors shown to be of cardiovascular benefit in randomized trials include

FIGURE 8–1

Age-Adjusted Death Rates* for Coronary Heart Disease 

by Country and Sex, Aged 35–74, 1996✝

* Age adjusted to European Standard.

✝ Data for 1996 unless otherwise noted in parentheses.

‡ Eighth revisions of the ICD.

HUN (95)

ROM

SCO

IRE (95)

BUL (94)

NIR

FIN (95)

E&W

NZE (94)

DEN‡ (93)

POL

NOR (95)

AUS

USA

GER

SWE

AUL (95)

CAN (95)

NTH (95)

GRE

ITA (93)

ISR

SWI‡ (94)

POR

SPA (95)

FRA (95)

JPN (94)

400 200 0 200 400 600

Female Male

Deaths/100,000 Population
144

reduction of blood pressure and blood cholesterol.

Many studies have not included sufficient numbers

of women to detect gender-specific differences.

Factors such as homocysteine have clearly been

identified as a risk factor in men,5 and recent data

suggest that higher homocysteine levels are

observed among both male and female children

with a positive family history of CHD:6 in

menopausal women increasing levels of homocysteine are associated with an increased risk of

CVD.7 More data are required before conclusions

can be made about this and other postulated “new”

risk factors, such as CRP levels.

FIGURE 8–2

Change in Age-Adjusted Death Rates* for Coronary Heart Disease 

in Females by Country, Aged 35–74, 1986–1996✝

* Age adjusted to European Standard.

** Based on a log linear regression of the actual rates.

✝ Data for 1996 unless otherwise noted in parentheses.

‡ Eighth revisions of the ICD.

AUL (95)

ISR

FRA (95)

FIN (95)

CAN

JPN (94)

NZE (94)

SWE

ITA (93)

SCO

NIR

E&W

IRE (95)

NTH (95)

NOR (95)

DEN‡ (93)

USA

SWI‡ (94)

GER

POR

SPA (95)

GRE

HUN (95)

AUS

BUL (94)

POL

ROM

-60 -50 -40 -30 -20 -10 0 10 20 30 40

Percent Change**
145

2.1 Dyslipidemia

There is a strong graded positive association

between plasma total cholesterol (or LDL cholesterol) and risk of CHD events in middle-aged 

(< 65 years) and older (> 65 years) women, but the

strength of the association diminishes with age.8

Although the general level of CHD risk is lower in

women than in men, the association with total cholesterol remains powerful. Treatment of elevated

total and LDL cholesterol in women has been

shown to reduce CHD risk.9 A low level of HDL

cholesterol is a risk factor for CHD in both

younger and older women.10 Hypertriglyceridemia

may be a more reliable risk factor for CHD in

menopausal women than in men.11,12 Lp(a) is 

associated with an increased risk of CHD13,14

and is probably a determinant of CHD in both 

premenopausal and postmenopausal women.15

2.2 Cigarette Smoking

There is overwhelming evidence for an adverse

effect of smoking on the risk of CHD and other

vascular disease in women and men. The adverse

effect of smoking cigarettes is dependent on both

the daily amount smoked and the duration of cigarette smoking. However, the evidence derives from

multiple observational studies rather than clinical

trials.16,17 The detrimental effects of cigarette smoking on CHD may be even more pronounced in

women. In Europe, the impact of cigarette smoking on the risk of CHD is smaller in Mediterranean

populations than in the northern European population.18 Dietary factors probably explain this difference in the effects of cigarette smoking.

2.3 Hypertension

There is a strong association between high levels

of blood pressure, both systolic and diastolic, and

the risk of CHD in both women and men.19

Isolated systolic hypertension is particularly

important in older women as it affects up to a onethird of women older than 65 years and is associated with a significant increase in risk of CHD and

stroke.20 Treatment of older women in the Systolic

Hypertension in the Elderly Program (SHEP) trial

demonstrated a 25 percent reduction in CHD and a

36 percent reduction in stroke in both women and

men combined,21 as well as decreased late occurrence of heart failure.22 In a meta-analysis of the

trials, the greatest benefit of control of blood pressure of the trials is in subjects at high combined

overall risk. Following a MI for example, elevated

blood pressure is associated with an increased risk

of reinfarction and death.23

2.4 Diabetes Mellitus

Diabetes mellitus is an important risk factor for

CVD in women.24 It negates the female sex-related

differences in CHD prevalence, and diabetic women

have as high a risk of MI as nondiabetic women

with a previous MI.25,26 Data from the Framingham

Study show that for subjects aged 50–59 years,

diabetes mellitus was a greater risk factor in women

compared to men.27 Even when corrections are

made for other established risk factors, diabetes is

associated with more than double the risk of CHD

compared with women without diabetes.26 Elderly

women have a relatively high incidence of diabetes,

contributing to a higher CVD risk. There are many

reasons why a diabetic woman is at excess risk.

She has dyslipidemia with lower HDL cholesterol,

elevated triglyceride levels, and more atherogenic

(oxidized) LDL.28

Treatment of elevated LDL

in diabetics reduces CHD

risk.29–31 Other factors

include abnormalities of

coagulation and fibrinolysis

as well as abnormalities of

platelet function. Endothelial

cell dysfunction has also

been shown in diabetics.28

2.5 Obesity

In the Third National Health and Nutrition

Examination Survey (NHANES III), 55 percent of

the adult female American population was classiThere is overwhelming

evidence for an adverse

effect of smoking on

the risk of CHD and

other vascular disease

in women and men.
146

fied as overweight or obese.32 The cardiovascular

health burden of obesity includes a strong predisposition to both type 2 diabetes and to hypertension. The prevalence of these conditions in the

presence of obesity is increased by twelvefold and

fivefold respectively, in women younger than 55

years.32 Although there remains no causal evidence

for the relationship between a sedentary lifestyle

and obesity, the association between the two factors is strong.33 In a female twin study, twins discordant for intensity of physical activity displayed

significant differences in total and central body

fat.34 In that study, physical activity was the

strongest predictor of total body fat, even after

accounting for age, diet, smoking, and HRT. In an

18-month randomized behavioral study of sedentary obese women, there was a dose response

effect of exercise duration on weight loss.35 Women

who were given access to home exercise equipment showed the greatest weight

loss and maintained significantly

greater exercise duration at the

completion of the trial. HRT

decreased central abdominal fat in a

small prospective study of obese

women with type 2 diabetes.36

Obesity in women is a complex metabolic disorder

with strong genetic components. The peroxisome

proliferator-activated receptors (PPARs) consist of

three receptors α, β, and γ. PPAR-γ is expressed in

adipose tissue. It has recently been shown that two

polymorphisms in the PPAR-γ gene are associated

with severe overweight among obese women.37 The

exact mechanisms by which the PPAR-γ variant

affects adipose tissue mass are not known. Changes

in the activity or structure of the PPAR gene in

vivo may result in changes in expression of target

genes in differentiating cells. Alterations in

adipocyte differentiation may then lead to obesity.

2.6 Lifestyle

A number of lifestyle factors (other than cigarette

smoking) have been implicated in CHD. These

include diet, physical activity, psychosocial factors, and excessive alcohol intake. There appears

to be a synergistic effect of lifestyle readjustments,

such as the combination of diet, exercise and abstinence from smoking, in the primary prevention of

CHD in women.38

2.6.1 Diet

Diet is an important determinant of CHD risk both in

women and in men.

Epidemiological studies show

that diets low in saturated fat

and high in fruits, vegetables,

whole grains, and fiber are

associated with a reduction in

the risk of CHD. Consistent with early metabolic

feeding studies, recent epidemiological studies

suggest that replacing saturated and trans-unsaturated fats with unhydrogenated monounsaturated

and polyunsaturated fats may be more effective in

preventing CHD in women than in reducing total

fat intake.39 Clinical trials have shown reductions

in CHD events or angiographic outcomes for a

variety of dietary interventions: very low fat

diets,40 diets low in saturated fat and high in

polyunsaturated fat,41–42 a Mediterranean diet high

in oleic acid and ω-3 fatty acids,43 and diets rich in

antioxidant fruits, vegetables, and legumes.44 The

effect of food supplements such as vitamins B6,

B12, and folate, as well as flavonoids and soy

isoflavones, require further investigation in clinical

trials before firm conclusions can be made about

their potential to favorably affect cardiovascular

outcomes in healthy women and those with established CHD.

2.6.2 Physical Activity

Diet alone failed to lower LDL cholesterol levels

in women with high-risk lipoprotein levels who

did not engage in aerobic exercise. A combination

of the NHLBI’s National Cholesterol Education

Program (NCEP) Step II Diet plus exercise beneficially reduced LDL cholesterol compared with the

The use of alcohol

has a U-shaped

relationship with

regard to the risk 

of CHD.

Diabetes mellitus

is an important

risk factor for

CVD in women.
147

diet alone.45 The Lifestyle Heart Trial showed that

intensive lifestyle changes in both women and 

men with severe CHD resulted in regression of

coronary atherosclerosis at both 1 and 5 years. 

The benefit was greater at 5 years.40 In a cohort of

women after coronary bypass surgery, depressed

women (comprising 23 percent of the entire

cohort) not only improved their mental health in

response to a formal rehabilitation program but also

lost more weight and increased their HDL levels to

a greater degree than the nondepressed patients.46

This study confirms that the benefits of an exercise

program extend beyond weight reduction and fitness to include psychosocial and even risk factor

modification. In a recent report from the Nurses’

Health Study, brisk walking, as compared with

vigorous walking, was associated with a similar

and substantial reduction in the incidence of 

coronary events among women aged 40–60 years.47

2.6.3 Psychosocial Factors

Psychosocial factors, such as anger and hostility,

are positive predictive factors for an increase in

intimal medial thickness of the carotid arteries

over a 10-year period; this may be predictive of

early atheroma development.48 In a Swedish study,

lack of social support contributed to the severity of

CAD in women, independent of standard risk factors.49,50 Hostile attributes, fasting insulin level, and

weight gain in mid-life, may contribute to the

development of visceral adipose tissue in healthy

menopausal women, which may then lead to the

increase in risk of CHD. Socioeconomic status had

an independent association with factor VII level,

suggesting an increase in thrombotic tendency.51

2.6.4 Alcohol Intake

The use of alcohol has a U-shaped relationship

with regard to the risk of CHD. Nondrinkers have

a higher risk than moderate drinkers (10–30 g

ethanol daily), but the risk increases with increasing alcohol consumption.52 Importantly, alcohol

intake in women may also be related to an increase

in blood pressure and risk of breast cancer.53

2.7 Homocysteine and C-Reactive Protein

Increasing levels of homocysteine are associated

with an increased risk of CVD in postmenopausal

women.7 Homocysteine has been shown to damage

vascular endothelial cells, which may contribute to

a consequent increase in the tendency to thrombosis. One study54 demonstrated low plasma homocysteine levels in premenopausal women compared

with high values in postmenopausal women, suggesting a close relationship between homocysteine

metabolism and estrogen status. Several other

studies demonstrated that HRT decreases homocysteine levels in postmenopausal women.55–59 In

some reports, this effect was found especially in

women with initially elevated pre-treatment homocysteine values. Although recent data on vitamin B

administration (as a potent homocysteine lowering

drug) are promising, randomized clinical trials are

needed to investigate whether decreasing plasma

homocysteine levels by any means will result in a

reduction of CVD risk in women.

With the recognition that atherosclerosis is an

inflammatory process, several plasma markers of

inflammation have been evaluated as potential tools

for prediction of the risk of CHD. CRP appears to be

a potent predictor of the risk of coronary events in

postmenopausal women.60 Adding CRP to lipid

screening may provide an improved method of

identifying women at risk for coronary events. A

guide to risk reduction for

women is given in the American

Heart Association (AHA)/

American College of Cardiology

(ACC) Scientific Statement:

“Consensus Panel Statement.

Guide to Preventive Cardiology

for Women” (table 8–1).61

2.8 Gender Differences in

Atherosclerotic Plaque

Endothelial erosion and plaque rupture are regarded as sequelae of an inflammatory process involving activated macrophages and their response to

oxidized LDL within the intima of the vessel wall.

Changes in vascular

function directly

attributable to

menopause are 

difficult to identify.
148

Recommendations1. At each visit, strongly encourage patient and

family to stop smoking. If complete cessation is not achievable, a reduction in intakeis beneficial as a step toward cessation.

2. Reinforce nonsmoking status.3. Provide counseling, nicotine replacement,

and other pharmacotherapy as indicated inconjunction with behavioral therapy or a formal cessation program.

1. Encourage a minimum of 30 min of moderate-intensity dynamic exercise (e.g., brisk

walking) daily. This may be performed inintermittent or shorter bouts (≥ 10 min) ofactivity throughout the day.

2. Women who already meet minimum 

standard may be encouraged to become morephysically active or to include more vigorousactivities.

3. Incorporate physical activity in daily activities

(e.g., using stairs).

4. Muscle strengthening and stretching 

exercises should be recommended as part of an overall activity program.

5. Recommend medically supervised programs

for women who have had a recent MI orrevascularization procedure. 

Lifestyle FactorsCigarette SmokingPhysical Activity

Goal(s)1. Complete cessation.2. Avoid passive cigarette smoke.1. Accumulate ≥ 30 min of moderate-intensity physical activity on

most, or preferably all, days of theweek.

2. Women who have had recent cardiovascular events or procedures

should participate in cardiac rehabilitation, a physician-guidedhome exercise program, or a comprehensive secondary preventionprogram.

Screening1. Ask about current smoking status and exposure to others’ cigarette smoke as part of

routine evaluation.

2. Assess total exposure to cigarette smoke

(pack-years) and prior attempts at quitting.

3. Evaluate readiness to stop smoking.1. Ask about physical activity (household work

as well as occupational and leisure-timephysical activity) as part of routine evaluation.

2. In women with symptoms that suggest CVD

or in previously sedentary women > 50 yearsold with ≥ 2 risk factors for CVD, consider astress test* to establish the safety of exerciseand to guide the exercise prescription.

TABLE 8–1Guide to Risk Reduction for Women
149

LV: Left VentricularSBP: Systolic Blood PressureTC: Total CholesterolTG: Triglycerides

*The choice of test modality should be based on the resting ECG, physical ability to exercise, and local expertise and technology.†The ACC and the AHA recommend cholesterol screening guidelines as outlined by the NCEP (measure total and HDL cholesterol at least once every 5 years in all

adults ≥ 20 years old. The consensus panel recognizes that some organizations use other guidelines, such as the U.S. Preventive Services Task Force, which recommends that cholesterol screening in women without risk factors begin at age 45 years.

Modified from Mosca L, Grundy SM, Judelson D, et al., 1999. 61

Recommendations1. Encourage a well-balanced and diversified

diet that is low in saturated fat and high infiber.

2. Use skim milk instead of milk with a higher

fat content.

3. Diets rich in antioxidant nutrients (e.g., 

vitamin C, E, and beta-carotene) and folateare preferred over nutritional supplements. Note: Daily supplements of 0.4 mg of folic acid are recommended for women ofchild-bearing age to help prevent neural tube defects.

4. Limit alcohol intake to ≤ 1 glass of alcohol

per day (1 glass = 4 oz wine, 12 oz beer, or11/2 oz 80-proof spirits). Pregnant womenshould abstain from drinking alcohol.

1. Encourage gradual and sustained weight loss

in persons whose weight exceeds the idealweight for their height.

2. Formal nutritional counseling is encouraged

for women with hypertension, hyperlipidemia, or elevated glucose levels associatedwith overweight.

3. The recommended weight gain during pregnancy is 25–35 lb if the patient’s prepregnancy weight is normal. Adjust for multiple

gestation and prepregnancy weight (e.g.,overweight women should gain 15–25 lb,obese women, < 15 lb)

Lifestyle FactorsNutritionWeight Management

Goal(s)1. AHA Step I Diet in healthy women

(≤ 30% fat, 8–10% saturated fat,and < 300 mg/d cholesterol).

2. AHA Step II Diet in women with

CVD or if a further reduction incholesterol is needed (≤ 30% fat,< 7% saturated fat, and < 200mg/d cholesterol).

3. Limit sodium chloride (salt) intake

to 6 mg/d. Women with high bloodpressure may require furtherrestriction.

4. Attain total dietary fiber intake of

25–30 mg/d from foods.

5. Consume ≥ 5 servings of fruits

and vegetables per day. 

1. Achieve and maintain desirable

weight.

2. Attain target BMI (weight in kilograms divided by height in meters

squared) between 18.5 and 24.9kg/m2 (BMI of 25 kg/m2 = 110%

of desirable body weight).

3. Achieve desirable waist circumference of < 88 cm (< 35 inches)

in women with a BMI of 25–34.9kg/m2.

Screening1. Assess nutritional habits as part of a routine

evaluation in all women.

2. Consider formal dietary assessment in

women with hyperlipidemia, diabetes, obesity, and hypertension.

1. Measure patient’s weight and height, calculate BMI, and measure waist circumference

as a part of a periodic evaluation. Note: BMI

and waist circumference are used for diagnosis, and measurement of height and weightare used for followup.

TABLE 8–1 (continued)
150TABLE 8–1 (continued)

Recommendations1. Encourage positive coping mechanisms for

stress (e.g., substitute physical activity forovereating or excessive smoking in responseto stress).

2. Encourage adequate rest and relief for

women who are caretakers of others.

3. Consider treatment of depression and anxiety

when appropriate.

4. Encourage participation in social activities or

volunteer work for socially isolated women.

1. Promote the lifestyle behaviors described

above (weight control, physical activity,moderation in alcohol intake) and moderatesodium restriction.

2. If blood pressure remains ≥ 140/90 mmHg

after 3 months of lifestyle modification or ifinitial level is > 160 mmHg systolic or 100mmHg diastolic, then initiate and individualize pharmacotherapy based on the patient’scharacteristics.

3. In pregnant women with hypertension,

reduction of diastolic pressure to 90–100mmHg is recommended.

Lifestyle FactorsPsychosocial FactorsBlood Pressure

Goal(s)1. Adapt positively to stressful 

situations.

2. Improve quality of life.3. Maintain or establish social 

connections.

1. Achieve and maintain blood pressure < 140/90 mmHg and lower if

tolerated (optimal < 120/80mmHg).

2. In pregnant women with hypertension, the goal of treatment is to

minimize short-term risk of elevated blood pressure in the motherwhile avoiding therapy that maycompromise the well-being of thefetus.

Screening1. Assess presence of stressful situations 

and response to stress as part of a routineevaluation.

2. Evaluate for depression, especially in

women with recent cardiovascular events.

3. Assess social support system and evaluate

for social isolation.

1. Measure blood pressure as part of a routine

evaluation.

2. Followup is based on initial measurement as

follows:

SBP, DBP,mmHg mmHg Followup < 130 < 85 Recheck in 2 yr130–139 85–89 Recheck in 1 yr140–159 90–99 Confirm in 2 mo160–179 100–109 Evaluate in 1 mo≥ 180 ≥ 110 Evaluate in 1 wk

(Followup screening may be modified on thebasis of prior history, symptoms, presence ofother risk factors, and end organ damage.)

3. In pregnant women with hypertension, 

evaluate for preeclampsia. 
151

Recommendations1. Promote lifestyle approach in all women

(diet, weight management, smoking avoidance, and exercise as described above). Ruleout other secondary causes of dyslipidemia.

2. Suggested drug therapy for high LDL levels

(defined as (a) ≥ 220 mg/dL in low-risk, premenopausal women, (b) ≥ 190 mg/dL in

postmenopausal women with < 2 risk factors,and (c) ≥ 160 mg/dL with ≥ 2risk factors) is

based on triglyceride level as follows:

TG < 200 mg/dLStatin, Resin, Niacin Note: ERT is an option for postmenopausalwomen, but treatment should be individualized and considered with other health risks. TG 200–400 mg/dLStatin, Niacin TG > 400 mg/dLConsider monotherapy with statin, niacin,fibrate, or a combination of the above.

1. Encourage adoption of the American

Diabetes Association Diet (< 30% fat, < 10%saturated fat, 6–8% polyunsaturated fat, cholesterol < 300 mg/d).

2. A low-calorie diet may be recommended for

weight loss.

3. Encourage regular physical activity.4. Pharmacotherapy with oral agents or insulin

should be used when indicated.

Lifestyle FactorsLipids, lipoproteinsDiabetes

Goal(s)Primary goal: Women without CVDLower risk (< 2 risk factors)LDL

goal < 160 mg/dL (optimal < 130mg/dL)Higher risk (≥ 2 risk factors)LDL

goal < 130 mg/dL

Women with CVDLDL ≤ 100 mg/dLSecondary goals:HDL > 35 mg/dLTriglycerides < 200 mg/dLNote: In women, the optimal level oftriglycerides may be lower (≤ 150

mg/dL) and the HDL higher (≥ 45

mg/dL).

For patients with diabetes:

1. Maintain blood glucose:

Preprandial = 80–120 mg/dLBedtime = 100–140 mg/dL.

2. Maintain Hb A1c < 7%.3. Maintain LDL < 130 mg/dL (< 100

mg/dL if established CVD). Note: Many authorities believethat LDL should be < 100 mg/dLin all patients with diabetes.

4. Maintain triglycerides < 150 mg/dL.5. Control blood pressure.

ScreeningWomen without CVD*Measure nonfasting total and HDL cholesterol,and assess nonlipid risk factors. Followup isbased on the following initial measurements:TC < 200, HDL > 45, followup in 5 years; TC< 200, HDL < 45, followup with fastinglipoprotein analysis. TC 200–239, HDL ≥ 45,

and < 2 risk factors, followup in 1–2 years. TC200–239, HDL < 45 or ≥ 2 risk factors, followup with fasting lipoprotein analysis. TC ≥

240, followup with fasting lipoprotein analysis.(All cholesterol values in mg/dL)

Women with CVDFasting lipoprotein analysis (may take 4–6 wksto stabilize after cardiovascular event or bypasssurgery).1. Monitor glucose and hemoglobin A1c as part

of a routine periodic evaluation in womenwith diabetes.

2. Screen for diabetes (fasting glucose > 125

mg/dL or > 200 mg/dL 2 h after 75 g glucose) as part of a periodic examination inwomen with risk factors for diabetes, such asobesity.

TABLE 8–1 (continued)
152TABLE 8–1 (continued)

Recommendations1. Counsel all women about the potential 

benefits and risks of HRT, beginning at age40 or as requested.

2. Individualize decision based on prior history

and risk factors for CVD as well as risks forthromboembolic disease, gallbladder disease, osteoporosis, breast cancer, and other healthrisks.

3. Combination therapy with a progestin is 

usually indicated in a woman with an intactuterus and prescribed estrogen. The choiceof agent should be made on an individualbasis.

1. Use of OCs is relatively contraindicated in

women ≥ 35 years old who smoke.

2. Women with a family history of premature

heart disease should have lipid analysis before taking OCs.

3. Women with significant risk factors for diabetes should have glucose testing before taking OCs.4. If a woman develops hypertension while

using OCs, she should be advised to stoptaking them.

PharmacologicalInterventions HRTOCs

Goal(s)1. Initiate or continue therapy in

women for whom the potentialbenefits may exceed the potentialrisks of therapy. (Short-term therapy is indicated for treatmentof menopausal symptoms.)

2. Minimize risk of adverse side

effects through careful patientselection and appropriate choice of therapy.

1. Minimize the risk of adverse cardiovascular effects while preventing pregnancy.2. Use the lowest effective dose of

estrogen/progestin.

Screening1. Review the menstrual status of women > 40

years old.

2. If menopausal status is unclear, measure

FSH level.

Determine contraindications and cardiovascularrisk factor status of women who are considering the use of OCs.
153

Recommendations1. If there are no other contraindications,

women with atherosclerotic CVD shoulduse aspirin 80–325 mg/d.

2. Other antiplatelet agents, such as newer

thiopyridine derivatives, may be used to prevent vascular events in women who cannot take aspirin.

Start within hours of hospitalization in womenwith an evolving MI without contraindications.If not started acutely, treatment should beginwithin a few days of the event and should continue indefinitely.1. Start early during hospitalization for MI

unless hypotension or other contraindicationsexist. Continue indefinitely for all with LVdysfunction (ejection fraction ≤ 40%) orsymptoms of congestive heart failure;otherwise, ACE inhibitors may be stopped at6 wks.

2. Discontinue ACE inhibitors if a woman

becomes pregnant.

PharmacologicalInterventions Antiplatelet agents/anticoagulantsβ-blockers 

ACE inhibitors

Goal(s)Prevent clinical thrombotic andembolic events, DBP, in womenwith established CVD.Reduce the reinfarction rate, incidence of sudden death, and overallmortality in women after MI.Reduce morbidity and mortalityamong MI survivors and patientswith LV dysfunction.

Screening1. Determine if contraindications to therapy

exist at the time of the initial cardiovascularevent.

2. Evaluate ongoing compliance, risk, and 

side effects as part of a routine followupevaluation.

1. Determine if contraindications to therapy

exist at the time of the initial cardiovascularevent.

2. Evaluate ongoing compliance, risk, and 

side effects as part of a routine followupevaluation.

1. Determine if contraindications to therapy

exist at the time of the initial cardiovascularevent.

2. Evaluate ongoing compliance, risk, and side

effects as part of a routine followup evaluation.

TABLE 8–1 (continued)
154

Interesting differences in atherosclerotic plaque

morphology between men and women have been

reported. In a study of 113 cases of sudden death

due to MI in men, 59 men had culprit thrombotic

lesions, 69 percent of the lesions were due to atherosclerotic plaque rupture, and 31 percent were

due to endothelial erosion.62 This is in marked contrast to a study in women, which showed that 69

percent of the thrombi were associated with

endothelial erosion.63 These eroded plaques were

characterized by smooth muscle cells and proteoglycans rather than lipid-laden macrophages. These

data suggest that gender may influence plaque

morphology, which may allow the development of

gender-specific therapy in the future.

3. MENOPAUSE AND

VASCULAR FUNCTION

Changes in vascular function directly attributable to

menopause are difficult to identify. Most studies

have found little change in blood pressure associated

with the menopause.64–66 Healthy cohort studies suggest a change in endothelial function at approximately the appropriate age for the menopause to have an

effect.67,68 This is supported by a study which suggests

that menopause is associated with an impairment in

endothelial function, even in

hypertensive women.69

Whether these changes are

due entirely to menopause or

aging is not definite, as there

have been no longitudinal

studies to examine this question in detail. A recent review

discusses menopause and

vascular and ventricular 

function in depth.70

3.1 Hormone Replacement Therapy and

Cardiovascular Function

There is extensive concordant physiological evidence supporting an important role of HRT in the

modulation of vascular function. This is particularly true in acute and chronic arterial endotheliumdependent effects, both in the periphery and in the

coronary arteries. Apart from effects on responsiveness, arterial structural remodeling changes

due to estrogen are suggested by animal models

but have not been universally supported by large

human cross-sectional studies. Clinical studies of

aortic compliance have also led to inconsistent

results. Studies of ventricular function are still limited and do not allow definitive conclusions. A

consistent problem is the lack of prospective studies. Interpretation of studies which suggested a

positive effect of HRT is limited by relatively

small numbers and nonrandomized or unblinded

designs.

3.2 Hormones and the Vessel Wall

A range of alternate mechanisms explaining the

nonlipid-related cardiovascular benefit attributable

to HRT have been proposed, particularly effects of

hormones on the arterial wall. These actions are

varied and include induction of endothelial prostacyclin,71 improvement or restoration of endothelial

function,72,73 NO release,74,75 attenuation of endothelin effect76 and production,77 calcium blockade,78,79

direct effects on vascular depolarization80 and

smooth muscle relaxation,81 and modulation of

autonomic function.82 Early reports of increases in

renin or renin substrate may have been related to

the higher estrogen doses used previously,83 as

recent work suggests that ERT is associated with

decreased plasma renin substrate.84

A common endpoint of many estrogen actions,

suggesting a beneficial effect, involves arterial

vasodilatation. Systemic vasodilatation due to HRT

has been associated with increased cardiac output

and diminished systemic vascular resistance, both

in experimental animals and in humans.85,86

Coronary vascular reactivity has also been used as

a surrogate marker for beneficial cardiovascular

effect. Numerous studies have shown improvement

in coronary diameter in response to estrogen,87–89

particularly in the presence of atherosclerotic disExtensive concordant

physiological 

evidence supporting

an important role of

HRT in the modulation

of vascular function.
155

ease. Clinical studies have also shown decreases in

exercise induced myocardial ischemia which may

be due either to improved hemodynamics or direct

coronary vasomotion.90,91

It has been suggested that the mechanism of estrogen

action may vary according to the concentration of

estrogen, with low concentrations relying on induction of NO release from the endothelium and higher

concentrations being associated with smooth muscle

relaxation and, therefore, endothelium-independent

mechanisms.92 A number of studies have confirmed

improved endothelial function in postmenopausal

women receiving HRT, both estrogen alone72 and

estrogen in combination with progesterone.93

The mechanisms by which estrogen alters vascular

function have received extensive study, and the

molecular mechanisms of its actions have recently

been reviewed. (See also ch. 5.)94 ERα is found on

vascular smooth muscle cells95 as well as endothelial cells.96 Estrogen has also recently been shown

to have nongenomic activity via ERα on the cell

surface,97 helping to explain acute vascular effects

of estrogen found in numerous studies. The acute

rapid ER-dependent but nongenomic actions result

from activation of the MAPK cellular signaling

pathway in a number of different cells.98 The other

known ER, ERβ, has been suggested to explain

estrogenic action on both vascular smooth muscle

and endothelial cell activity in ERα-deficient mice.99

Apart from estrogen, other sex hormones have significant vascular effects. Because estrogen is prescribed in combination with a progestin in women

with an intact uterus, recent work has examined

the modulating effect that this might have on cardiovascular function. Importantly, while the beneficial fibrinolytic100 and lipid effects101 of estrogen

do not appear to be impaired with concurrent

medroxyprogesterone use, experimental102 and clinical studies103 show how beneficial vascular effects

of estrogen can be reversed by MPA. If further

substantiated, these findings could be important in

understanding results of some recently published

studies, such as the HERS,101 the first large trial

conducted in postmenopausal women with CHD.

(See sec. 4.2 below.) The effects of ERA104 also

showed no benefit either from estrogen or estrogen

plus progestin in an angiographic study.

3.3 Selective Estrogen 

Receptor Modulators

SERMs have been developed

to avoid the potential harmful effects of estrogen on a

number of tissues, including

the breast and uterus. They

appear to share the beneficial

effects of estrogen on bone

and lipids but are not associated with an increased risk of

breast or uterine carcinoma,

with the exception of tamoxifen, which increases endometrial cancer risk in

women aged 50 years or older.105 The possibility of

a beneficial effect of SERMs on the cardiovascular

system is intriguing. SERMs, such as raloxifene,

have effects on both ERα and ERβ, which may be

important in its vascular actions.106 It is possible

that SERMs may significantly contribute to the

improvement of women’s health in this century.107

Evidence is emerging that the newer SERMs may

have effects on cardiovascular and other systems

which may contribute to improvement in vascular

health and function. Research over the next 5 to 10

years may provide definitive data as to whether the

newer SERMs will provide cardioprotection in

postmenopausal women.

3.3.1 Effects of SERMs on the Vasculature

SERMs may have beneficial effects on the cardiovascular system in a way similar to estrogen.

Randomized studies with cardiovascular endpoints

are in progress.

3.3.2 Effects of SERMs on Serum Lipids and

Myocardial Infarction

Studies investigating the effects of SERMs on

serum lipids and lipoproteins have demonstrated

SERMs have been

developed to avoid

the potential harmful

effects of estrogen on

a number of tissues,

including the breast

and uterus.
156

similar effects in both patients with breast cancer

and healthy women. The SERMs tamoxifen and

raloxifene reduce total cholesterol, LDL cholesterol, and Lp(a).108–110 These changes in lipid profile

may be clinically favorable with regard to the incidence of CVD.10,111 Data from randomized breast

cancer clinical trials suggested that tamoxifen may

be of benefit in protecting women from MI. Three

adjuvant trials show a reduction of cardiac morbidity in patients with low risk of death from breast

cancer when treated with tamoxifen,112–114 although

none of them had been designed for this purpose.

The results of a cardiovascular endpoint study—

RUTH (Raloxifene Use for The Heart)—will test

whether raloxifene HCl (60 mg/day), compared

with placebo, will reduce the combined endpoint

of non-fatal MI, CHD death, and hospitalized

unstable angina other than MI (primary outcome)

in postmenopausal women at high risk of cardiac

events.115 A co-primary endpoint of invasive breast

cancer incidence has been added to the primary

endpoint.

3.3.3 SERMs and Vascular Reactivity

There are few data on the effect

of SERMs on the vasculature in

humans. One report has shown a

beneficial effect of droloxifene

on brachial flow-mediated dilatation. Two conflicting reports have

been published regarding the

effect of raloxifene on atherosclerosis, one showing no effect in

ovariectomized cynomolgus monkeys,116 the other showing beneficial effects in sexually mature

female rabbits.117 The effects of

raloxifene on coronary artery

vasoreactivity in vitro showed

significant dose-dependent relaxation of coronary

arterial rings with endothelium by an endotheliumand NO mediated effect.118

3.4 Phytoestrogens

It has been suggested that phytoestrogens represent

a “natural SERM.” Genistein has approximately

only 4 percent of estrogen’s affinity for ERα, but

more than 80 percent of estrogen’s affinity for

ERβ.

106 This marked difference may contribute to

the conflicting findings

on controlling

menopausal symptoms.119,120 The ERβ activity appears to be sufficient in in vitro studies to

inhibit smooth muscle

cell proliferation and

migration compared with

17β-estradiol.121 At least

one study has shown that supplemental isoflavones

may improve arterial stiffness in postmenopausal

women.122 A number of phytoestrogens, including

genistein and daidzein, have calcium antagonistic

properties in experimental coronary studies.123

3.5 Hormone Replacement Therapy and

Hypertension

Because hypertension is so prevalent in

menopausal women and even low-dose contraceptive pills continue to be associated with excess

hypertension,124 there has been controversy over

whether HRT may be beneficial or detrimental.125

While most studies do not show an increase in

blood pressure in response to HRT,101,125,126 occasional

patients have idiosyncratic increases in blood pressure in response to estrogen.127,128 This may be related

to excessive renin activation in these subjects.127

Most case reports date from an era of higher estrogen dose, and it may be that current regimens

would not incite such a response. A recent study

using a current HRT regimen found, in general, a

decrease in plasma renin substrate associated with

treatment.84 It has also been recognized that the type

and dose of supplemental estrogen may be important in determining blood pressure response.129 A

well conducted crossover study of two doses of

The PEPI trial

confirmed that

there was no

effect of any 

hormone regimen

on blood pressure

in normotensive

postmenopausal

women.

Cross-sectional data

show that as women

age they gain body

weight, their blood

pressure rises, and

their levels of serum

LDL increase.
157

estrogen found a small, but significant, decrease in

systolic and diastolic blood pressure largely due to

a prominent fall in peripheral resistance.130 Results

from the PEPI trial confirmed that there was no

effect of any hormone regimen on blood pressure

in normotensive postmenopausal women.126

4. THE MENOPAUSE AND CORONARY

RISK FACTORS

Cross-sectional data show that as women age they

gain body weight, their blood pressure rises, and

their levels of serum LDL increase,131 with little

change in triglycerides and a slight reduction in

HDL cholesterol.64 Other blood factors such as

serum fibrinogen and plasminogen activator

inhibitor (PAI), which are powerful predictors of

CHD in women and men are significantly

increased in older women.132 Abnormal glucose

metabolism is more common in older women, with

some reports showing approximately 30-percent

reduction in insulin sensitivity.133 Older postmenopausal women are more likely to have

endothelial dysfunction,69 which contributes to an

impairment of vascular function and may synergize with the adversely altered lipid metabolism

and decreased fibrinolytic tendency. These factors

may collectively contribute to the increased incidence of CHD in older women.

It is not clear whether the adverse changes in risk

factors are an age effect or are due to lowered

estrogen levels as women go through the menopause.

Cohort studies following women as they approach

and pass through the menopause have yielded conflicting results, especially in regard to HDL cholesterol. Some concluded that the menopause is not

associated with change in HDL cholesterol, while

others concluded that the menopause is associated

with a decline in HDL levels.134,135 The most recent

of these studies found an unexplained rise in HDL

cholesterol prior to the FMP, followed by a decline

thereafter; thus, there was no net effect.136 The 

levels of HDL cholesterol 3 years before the

menopause were identical to those 3 years after

menopause. All other changes in the risk factors

measured, including body weight, blood pressure,

LDL cholesterol, and triglycerides, were related

either to increasing age or to a simultaneous

change in one of the other risk factors (in particular, increases in body weight).

4.1 The Effect of Hormone Replacement

Therapy on Risk Factors

4.1.1 Lipids

Many studies have shown that that HRT lowers total

cholesterol irrespective of the type or route of

administration.137,138 The LDL cholesterol-lowering

activity of estrogen occurs by an up regulation of

apolipoprotein-B–100 receptors. HDL cholesterol

increases, particularly the HDL2 subfraction, by an

inhibition of hepatic lipase activity.139 Although

transdermal estrogen has a similar effect on LDL

cholesterol, it has a less-marked effect on HDL cholesterol levels because of a lack of the first-pass

liver effect.140 Oral estrogen decreases LDL cholesterol by about 10–15 percent, increases HDL cholesterol by 10–15 percent, increases triglycerides by

20–25 percent, and decreases

Lp(a) by about 20 percent.126

The type and route of administration of estrogen are more

important for its effects on

plasma triglycerides than they

are for its effects on cholesterol. While CEEs result in a

25-percent increase in triglycerides,126 transdermal estrogen

either has no effect or

decreases triglycerides.140

Progestogens have differing effects on lipids and

lipoproteins, dependent on the androgenicity of the

particular agent. Testosterone-derived progestins

reverse the HDL-increasing effect of estrogen140

because of an increase in hepatic lipase activity.

The less androgenic C–21 progestins do not impair

the estrogen-induced increase in HDL cholesterol

to any great degree. Androgenic progestins result in

Observational studies

comparing current

hormone users with

non-users have

shown consistent

reductions in CHD

risk of 35–50 percent.
158

a lowering of triglycerides,140 and the more androgenic steroids lower Lp(a) by approximately 20 percent.141,142 This effect could prove beneficial as Lp(a)

may be an independent risk factor for CHD in

women.15 Recent evidence from HERS suggests that

Lp(a) is an independent risk factor for recurrent

CHD events.14 In the placebo arm of the study,

women in the second, third, and fourth quartiles of

Lp(a) levels had increased relative hazards compared with the lowest quartile. Treatment with HRT

significantly reduced Lp(a) levels compared with

placebo. In a randomized subgroup comparison,

women with higher baseline Lp(a) levels had a less

adverse-trend during the first year and more benefit

thereafter.

4.1.2 Inflammatory Factors

Two studies of oral CEEs plus or minus MPA or

progesterone have shown rapid increases in the

concentration of the inflammatory factor CRP

and a reduction in the concentration of soluble 

E-selectin.143 In a crosssectional study, CRP

levels were increased in

postmenopausal women

taking HRT,144 and in

postmenopausal women

exposed to short-term

HRT of either oral estrogen or estrogen sequentially combined with a

progestin.145 In another prospective randomized

controlled study of oral 17β-estradiol combined

with 5 or 10 mg of dydrogesterone, there was a 15-

percent decrease in plasma levels of endothelin-1,

a 21-percent decrease in soluble thrombomodulin,

and a 14-percent decrease in von Willebrand factor.146 These changes were observed at 3 months

and sustained after 15 months. It is possible that

the increase in CRP is due to first pass effect on

hepatic synthesis of the protein, while the decrease

in markers of endothelial function and other

inflammatory markers is due to direct vascular

effects. It is unclear whether estrogen increases or

decreases vascular inflammation or whether different forms, doses, and routes of administration have

different effects on vessel physiology. One potential mechanism by which there may be an early

adverse effect (such as that found in the HERS

trial) followed by a later favorable effect is

through effects on matrix metalloproteinases

(MMP).147 Preliminary reports indicate that

MMP–9 is increased markedly by estrogen and

may play a role in the destabilization of vulnerable

plaques, thus precipitating a clinical event.

However, over the long term, MMP–9 may help

keep vessels compliant as it may play a role in

removing excess connective tissue. Monocyte 

activation is associated with atheromatous plaque

disruption and acute coronary syndromes (ACS).

Increased serum concentration of neopterin, a

pterydine derivative secreted by macrophages 

after stimulation by interferon-gamma, has been

observed in patients with ACS as compared with

control subjects and patients with stable angina

pectoris.148 Women with unstable angina have 

significantly higher neopterin concentrations than

women with chronic stable angina. Neopterin concentrations may be a marker of risk in women with

CHD.149 HRT has also been shown to significantly

reduce the levels of the cell adhesion molecules 

E-selectin, intracellular adhesion molecule 1

(ICAM–1) and vascular cell adhesion molecule–1

(VCAM–1) with similar magnitude of reduction

from placebo values in women on CEE alone 

compared with women on combination HRT.150

4.1.3 The Effect of Hormone Replacement

Therapy Combined With Other LipidLowering Agents

A number of studies have recently reported the

effects of a combination of statin and HRT on

serum lipid levels in menopausal women.151–154

One study also assessed the vascular effects of this

combination in hypercholesterolemic postmenopausal women.155 The studies investigated the

effect of differing doses of CEEs, either alone or

combined with MPA, and compared the lipid-lowering effects to simvastatin or pravastatin.

Standard prevention

therapies, including lipid

lowering, are as effective

in women as in men.
159

Overall, these studies show that oral CEEs plus

MPA in combination with a statin is complementary, in that the statins are better at lowering LDL

cholesterol levels, the hormones are better at raising HDL cholesterol levels, and the effects on

triglycerides cancel each other: thus the combination

yields the most optimal lipid profile. The combination is only modestly additive, that is, hormones

add little to the LDL-lowering effect of statins, and

statins add only modestly to the HDL-raising

effect of hormones. Hormones reduce Lp(a) levels,

while statins do not. No studies have yet been published comparing other types and routes of administration of HRT combined with a statin.

In one study,155 28 women were randomized to

continuous equine estrogen (0.625 mg daily), simvastatin 10 mg, and their combination daily for 6

weeks. As shown in the previous studies, all therapies lowered total and LDL cholesterol levels from

baseline, with a greater effect on LDL cholesterol

from simvastatin and from the combination of

HRT and simvastatin. This study also assessed the

vascular effects of this therapy; flow mediated

dilatation of the brachial artery improved on CEE,

simvastatin, and continuous equine estrogen combined with simvastatin, and this was similar among

the therapies. Only therapies including CEE lowered levels of PAI–1 and the cell adhesion molecule E-selectin. Only therapies including estrogen

improved markers of fibrinolysis and vascular

inflammation. Thus, it may be that such a combination will be synergistic in vascular protection.

4.1.4 Coagulation Factors

The effects on coagulation factors are complicated,

diverse, and contradictory. For example, lowering

of fibrinogen and PAI–I could be counterbalanced

by increases in factor VII and decreases in

antithrombin III. In general, it appears that estrogen is procoagulant but, at the same time, profibrinolytic.156 The net effect is likely to be procoagulant, as evidenced by the observational studies and

the HERS clinical trial (see elsewhere). However,

the net effect of estrogen on coagulation can

depend on the form of estrogen used and on the

dose, route, and duration of therapy. There may be

critical differences between oral and transdermal

delivery of estrogen. In contrast to oral administration, transdermal estrogen does not result in any

measurable perturbation of coagulation factors.156

4.2 Hormone Use and Prevention of CHD Risk

Observational studies comparing current hormone

users with non-users have shown consistent reductions in CHD risk of 35–50 percent. In the Nurses’

Health Study, the risk reduction was seen at the

most commonly used dose of CEEs (0.625

mg/day).157 There appeared to be a similar risk

reduction at the lower dose of 0.3 mg/day, but this

was not statistically significant. At higher doses,

there was no apparent benefit. The findings from

these observational studies have been important in

promoting the belief that HRT prevents CHD.

However, the findings have to be viewed with caution because several

sources of potential bias

could result in an overestimation of potential

benefits and an underestimation of risks.158,159

These biases include

that women who elect to

take hormones are

healthier, and those that

remain on hormones for

many years are by definition good compliers

and are under medical

surveillance. (See also

ch. 4 for biases in sampling.) Thus, they would

be taking other steps to improve their health, and

early detection and treatment of risk factors would

also reduce disease risk. Furthermore, women who

stop therapy often do so because of the development of a health condition; thus those who remain

on therapy are the healthy survivors. These biases

Women are approximately

half as likely as men to

receive known beneficial

therapies, such as betablocking agents, aspirin,

thrombolysis, acute 

cardiac catheterization,

percutaneous transluminal

coronary angioplasty

(PTCA), or bypass surgery.
160

may account for a substantial proportion (or all) of

the apparent CHD risk reduction.

The information on the effects of hormones on

lipids and markers of vascular function must be

seen in the light of one very important fact: no

clinical trial has yet shown a beneficial effect on

any CVD. To the contrary, all the evidence to date

suggests a harmful effect, at least in the first years

of taking HRT. With the exception of the pooled

data from a number of small short-term studies,160

the clinical trials have all been in the area of secondary prevention. In men with CHD given higher

doses of estrogen, the trials were stopped early for

safety reasons after there was a higher rate of cardiovascular events in the treatment group than in

the control group.161 In HERS, women assigned to

daily oral CEE plus MPA also experienced a higher

rate of CHD events versus placebo in the first year,

with no difference in the second year and with a

trend toward decreased risk in the

treatment group in the final 2 years.

Over the entire 4.1-year study period,

there was no difference between the

groups. A reanalysis of the Nurses’

Health Study observational data for

women with prior heart disease disclosed a similar pattern of early risk

followed by apparent benefit. The

first placebo-controlled angiographic

trial of estrogen or estrogen plus

progestin also failed to show benefit

in women with CHD.104 Transdermal

estrogen and progestin also failed to

show benefit in a preliminary report

of a randomized trial in women with

CHD.162 No clinical trial data on the

role of HRT in primary prevention

are available yet, but at least two

large studies testing both estrogen and estrogen plus

progestin are being conducted.163 (WHI and the

Women’s International Study of Long Duration

Oestrogen After Menopause (WISDOM)). The first

of these, the large WHI trial of HRT in the United

States, includes women predominantly without

prior CVD and has arms testing daily CEE alone

and CEEs with MPA versus placebo. All WHI participants were informed of an increased risk associated with active treatment for each of heart attacks,

strokes, and blood clots in the legs and lungs during the first 2 years after enrollment.164 The vast

majority (> 90 percent) of participants did not have

prior CVD, and the subgroup with prior disease did

not account alone for the findings. Over time, the

differences between the active treatment and placebo groups seemed to become smaller. The trial is

continuing (estimated followup of 9 years) in order

to assess long-term benefits and risk of HRT. There

is a need for a clinical trial of transdermal estrogen, which may have less thrombotic potential than

oral estrogen.

4.3 Statin Use in Women and Reduction of CHD

Since evidence for a protective effect of estrogen is

currently lacking, it is encouraging that the standard prevention therapies, including lipid lowering,

are as effective in women as in men. This is not

surprising since the RRs associated with blood

lipids are the same in middle-aged women as in

men.8 One difference worth noting is that a combination of metabolic risk factors may occur more

frequently in women and may account for a higher

proportion of the CHD burden than in men.165 For

lipid lowering, the pooled data from the major

statin trials show that women had a 29-percent (CI

13–42 percent) risk reduction, similar to the 31

percent (CI 26–35 percent) found in men.9 From

these data it has been calculated that 31 women

and 27 men have to be treated to prevent 1 major

coronary event. A gender bias does exist even in

the statin trials that have been reported.166 In the

secondary prevention trials conducted, 31,683

patients were randomized with a combined mean

age of 58.1 years, and only 23 percent of the trial

population were women. The figures are even

worse for primary prevention: in the four primary

prevention trials published, only 10 percent of the

study population, out of a total of 14,557 subjects,

Gender remains

a significant

independent

predictor of

death after

adjusting for

other risk 

factors, such 

as older age,

diabetes, and

hypertension

following PTCA.
161

were women. It can be concluded that extrapolation of evidence from these trials to older people

and women requires further evaluation.

4.4 Other Prevention Therapies in Women

Similar to the lipid-lowering trials, CHD prevention

through treatment of hypertension is as effective in

women as in men, and ACE inhibitors are as effective in preventing CHD in women as in men.167–169

In the recently published Heart Outcomes Prevention

Evaluation (HOPE) study, 2,480 women were

enrolled as a part of larger study to determine the

effect of the ACE inhibitor ramipril (10 mg once

daily orally) versus placebo.169 The study investigated the effect of this therapy over a 5-year period on

the risk of the composite endpoint: MI, stroke, or

death from cardiovascular causes. The study participants were patients at high risk for cardiovascular

events with a mean age of 66 years an without left

ventricular dysfunction or heart failure. Ramipril

decreased the risk of the primary outcome significantly in women as well as men. There was also a

significant decrease in secondary outcomes, such as

revascularization and hospitalizations for heart failure. The novelty of this study is that ramipril significantly reduced the rates of the primary endpoint in

a broad range of high-risk patients who were not

known to have low ejection fraction or heart failure. In particular, this beneficial effect was shown

in women with diabetes mellitus. The trialists that

estimated the treatment of 1,000 patients with

ramipril for 4 years prevented about 150 events in

approximately 70 patients. Aspirin and beta-blockers are also effective for secondary prevention in

women.170,171 Thus, although efforts to prevent CHD

in women are successful using the same approaches

as in men, more data are still required.

5. MYOCARDIAL INFARCTION:

PROGNOSIS

Initial evaluation suggests that gender affects the

course of acute MI in the general population.

However, after adjustment for baseline differences,

the gender disparities in the outcomes become

more uncertain. In a study of 204 consecutive

cases (99 men and 105 women) older than 75

years of age and admitted with the first acute MI,

elderly women experienced a more complicated

hospital course than men. The higher mortality risk

(40 percent versus 23 percent) seemed to be related more to the impact of cardiovascular risk factors on left ventricular function than to gender

itself.172 The Framingham Heart Study confirmed a

greater 1-year mortality in women compared with

men (44 percent versus 27 percent).173 Early hospital mortality is also greater in women than in men

(16 percent versus 11 percent).174,175 The larger

placebo-controlled trials, such as the International

Studies of Infarct Survival-1 and -4 (ISIS–1 and

ISIS–4), both suggested an increased short and

long-term mortality in women.176,177 More recent

data from the National Registry of Myocardial

Infarction (NRMI) suggest that, after MI, younger

women (but not older women) have higher rates of

death during hospitalization than do men of the

same age.178 Data from the Swedish National Acute

Myocardial Infarction Register confirms this

observation.179 Much of the excess mortality seen

in young women in this study was associated with

diabetes mellitus. Some other reasons for these

observations is that women are approximately half

as likely as men to receive known beneficial therapies, such as beta-blocking agents, aspirin, thrombolysis, acute cardiac catheterization, percutaneous

transluminal coronary angioplasty (PTCA), or

bypass surgery; however, age probably still plays a

major role in these differences.171 Sex differences

in the presentation and outcome of patients with

ACS have been reported in the Global Use of

Strategies To Open Occluded Coronary Arteries in

Acute Coronary Syndromes (GUSTO IIb) cohort.180

In this study, which enrolled 3,662 women, women

had more complications than men during hospitalization, had a higher mortality rate at 30 days (6

percent versus 4 percent, p < 0.001), but had similar rates of reinfarction. It is of interest that among

patients with unstable angina, female sex was
162

associated with an independent protective effect. It

was concluded from this study that some of the differences observed may reflect pathophysiologic

and anatomical differences between men and women.

6. PERCUTANEOUS TRANSLUMINAL

CORONARY ANGIOPLASTY

Most reports suggest that gender remains a significant independent predictor of death after adjusting

for other risk factors, such as older age, diabetes,

and hypertension, following percutaneous revascularization. Early studies suggested that women had

a greater risk than men of procedural and postprocedural complications, including death and MI following PTCA.181 Women have been found to suffer

more acute vessel closure than men,182 possibly

related to their smaller vessel diameter. When acute

closure does occur, women are more likely to die

as a consequence of this.183 An important contributor to higher procedure-related mortality in women

is the greater age and coronary

risk factor profile in women.181,184

Nonetheless, analysis of the

1993–94 NHLBI registry has

shown that despite their greater

risk profile, both clinical success

and mortality have improved

twofold to threefold in women

undergoing PTCA.185 Many of the

reported studies show that sexrelated differences in mortality

rate after intervention antedate the

use of stents, platelet inhibitors,

and other recent advances in coronary intervention.186 In particular,

intracoronary stent implantation (with optimal

expansion) and ticlopidine have greatly reduced the

incidence of acute vessel closure and significantly

reduced the combined incidence of death, MI, and

urgent revascularization after coronary intervention.187 More recently, coronary artery stenting has

become a very important catheter-based intervention for patients with CHD.188 One-year outcomes

of women with CHD undergoing coronary artery

stenting are similar to those of men.189 There is,

however, a sex difference in the prognostic value

of baseline characteristics, the strongest being diabetes in women. Other efforts at treatment synergy

between intracoronary stenting and platelet IIb-IIIa

inhibition are encouraging, showing an improvement in clinical outcomes of primary angioplasty

in acute MI in both men and women.190 The combination of abciximab and stenting was more favorable than balloon angioplasty, with improved

angiographic and clinical results at 30 days.

Analysis of the Evaluation of IIb/IIIa Platelet

Inhibitor for Stenting (EPISTENT) data shows that

diabetic women treated with a combination of

coronary stenting and abciximab resulted in a significant reduction in 1-year rate of death, MI and

target vessel revascularization compared with

stent-placebo or balloon-abciximab therapy.191

These recent advances in techniques may have

changed the impact of acute vessel closure as a

cause of death in women. The risk of acute complications was documented only in women undergoing PTCA for stable angina pectoris and not ACS.

Long-term outcome is similar in the two sexes

once the initial PTCA had been successfully performed.192 Data from the Primary Angioplasty in

Myocardial Infarction (PAMI) trial suggest that the

two most powerful determinants of freedom from

death, reinfarction, and recurrent ischemia are

young age and treatment by primary angioplasty.193

This initial benefit of primary angioplasty is maintained over a 2-year followup.194 Recent reports

from this database would suggest that coronary

stenting provides even greater benefit than balloon

angioplasty in the acute MI setting.195 Recent data

provide evidence that in primary PTCA for acute

MI, gender is not an independent predictor of 30-

day and 7-month survival after control for baseline

characteristics. However, mortality was much higher in women both at 30-day followup (10 percent

versus 0.9 percent) and during a mean 7-month 

followup (15 percent versus 4.4 percent). Women

Despite a similar

prevalence of

heart failure in

women compared

with men, women

have largely been

excluded from 

clinical trials of

heart failure. 
163

also experienced more unfavorable cardiovascular

events, such as recurrent unstable angina or acute

MI, and target vessel revascularization than men.196

6.1 Hormone Replacement Therapy and PTCA

Some studies have reported a benefit of outcome

of PTCA in postmenopausal women if they were

already receiving HRT. In a study of 428 patients,

postmenopausal women divided into two groups

based on ERT at the time of the procedure, there

appeared to be protection against clinical coronary

events in those women taking HRT.197 This benefit

appeared to be independent of age, smoking, presence of diabetes mellitus, or the number of diseased coronary vessels. HRT did not, however,

reduce the repeat revascularization procedures,

suggesting no effect on restenosis.197 One study

suggested a decrease in restenosis in women using

estrogen, which was particularly apparent in

women undergoing atherectomy, an effect which

could relate to this procedure.198 An improved longterm outcome after PTCA in women on HRT was

also reported by another group.199 In this observational study women taking ERT prior to intracoronary stenting had a significantly reduced target

lesion revascularization requirement after a three

year follow up when compared to women not taking estrogen prior to the procedure. This adds support to the notion that women should continue

ERT after intervention if they are taking it prior to

the intervention. Overall, HRT appears to be beneficial in women who continue to take it after percutaneous revascularization procedures; however,

these conclusions are based on observation and

could be confounded by a number of variables.

7. CORONARY ARTERY BYPASS

GRAFT SURGERY

Women undergoing coronary artery bypass graft

(CABG) surgery are, on the whole, older than

males and more frequently have associated risk

factors, such as diabetes and hypertension. They

are also more likely to present with unstable angina consequently, resulting in urgent/emergency

surgery. It is not surprising, therefore, that women

show higher rates of mortality200 and recurrent

angina.201 Adverse operative and long-term mortality was shown in a large study, the National

Cardiac Surgery Database of the Society of

Thoracic Surgeons (STS), which compared outcomes in more than 97,000 women with those in

250,000 men.202 In the Bypass Angioplasty

Revascularization Investigation (BARI) study, a

stable population of 489 women with symptomatic

multivessel CHD was randomized to CABG

surgery or PTCA.203 Although

the age-adjusted mortality rate

suggested that women and men

undergoing these procedures

should have a similar 5-year

mortality, when these were

adjusted for multiple risk factors, female sex was an independent predictor of improved 5-

year survival after surgery. This was a study of stable patients and patients, requiring urgent CABG

surgery were excluded, which may have contributed to the 

more favorable result.203

Effective secondary prevention programs do not

appear to be effectively instituted in women following CABG surgery. After CABG surgery, women

continued to have high cholesterol levels, putting

them at higher risk for future events.204 This is particularly important since in women aggressive cholesterol lowering in women delays saphenous vein

graft atherosclerosis and should be recommended to

all women undergoing this procedure.205 This obviously may contribute to poorer postsurgical survival.

7.1 Quality of Life After CABG Surgery

Women generally report a worse quality of life

after CABG surgery than men. In a study of 212

women who underwent CABG surgery in

1988–1991, quality of life was assessed.206 Women

were older than men with more concomitant disWomen undergoing

CABG surgery

show higher rates

of mortality and

recurrent angina.
164

eases preoperatively. Quality of life was improved

on all postoperative occasions for both sexes.

Improvement in the physical activity score was

greater in males, although this was not significant.

It appears that the quality of life is significantly

improved after CABG surgery in both sexes, and

there appears to be a complex association between

improvement in various aspects of quality of life

and gender.205 Women’s patterns of exercise following cardiac rehabilitation are well below the recommended guidelines for exercise after cardiac

events.207 In 40 women who had MI or CABG

surgery, exercise frequency and duration intensity

were measured. In a 3-month study, only 50 percent of the women were still exercising regularly,

suggesting that there is considerable room for

improvement in establishing exercise regimens

after MI or CABG surgery. Women are less likely

to be referred to rehabilitation.

8. HEART FAILURE

Despite a similar prevalence of

heart failure in women compared with men,208 women have

largely been excluded from

clinical trials of heart failure. As

discussed earlier, women tend

to be older at presentation with

cardiac disease and may fall

outside recruitment guidelines.

Secondly, women are more likely than men to have diastolic

heart failure and may be excluded when systolic ejection fraction is an entry criterion.

Two large studies have reported

improved survival in women

with heart failure.209,210 Of the

randomized trials with beta-blockers in heart failure, the U.S. Carvedilol Heart Failure Study group

found a statistically significant reduction in the

number of deaths in both women and men with

heart failure.211 Other large beta-blocker trials have

not been able to discern a sex-specific mortality

difference.212–214 In the trials of ACE inhibitors in

heart failure, the Cooperative North Scandinavian

Enalapril Survival Study (CONSENSUS-I) did not

show a reduction in mortality in women.215,216

However, most trials contain such small numbers

of women that they are unable to discern a specific

mortality benefit for women. A meta-analysis of

ACE inhibitor trials has shown a similar survival

benefit for both women and men.217 In the Acute

Infarction Ramipril Efficacy (AIRE) study of

ramipril in patients with post-MI left ventricular

dysfunction, there was a significant mortality benefit in both sexes.218 Three other studies of ACE

inhibitors in patients with left ventricular dysfunction after MI did not show a significant mortality

benefit for women. Again, this may be due to the

relatively small numbers of women included in

these trials.219–221

9. STROKE

Despite similar stroke rates,222 women are more

likely than men to die of stroke, and this is possibly related to the age at which stroke presents.

About 16 percent of women die of stroke compared with only 8 percent of men.222 Age is an

important predictor of survival in stroke victims,

and as the incidence of stroke is increased in older

women, this contributes to the adverse mortality.

The main risk factors for stroke are fairly consistent and nongender dependent. Hypertension probably is the most important, with diabetes mellitus,

cigarette smoking, CHD, atrial fibrillation, and

transient ischemic attacks comprising the major

other risk factors.223 Hypertension is a major risk

factor for stroke, with about a 45-percent increase

in stroke risk for every 8 mmHg increase in diastolic blood pressure.19 Unlike many cardiovascular

trials, hypertension treatment has been definitively

shown to substantially reduce the morbidity and

mortality in women following stroke. Studies such

as the Swedish Trial in Old Patients (STOP) and

Despite similar

stroke rates, women

are more likely than

men to die of

stroke, and this is

possibly related to

the age at which

stroke presents.

About 16 percent of

women die of stroke

compared with only

8 percent of men.
165

SHEP have shown that drug treatment reduces the

incidence of stroke in hypertensive women.167,168

Current smoking is associated with an increased

risk of stroke, and in the Nurses’ Health Study this

increased the RR for ischemic stroke by 2.5.224,225

Diabetes mellitus doubles the risk of ischemic

stroke, and also increases the mortality associated

with stroke. Cardiovascular conditions such as

abnormal left ventricular (LV) wall motion,

increased LV mass, carotid artery stenoses, and

atrial fibrillation are significantly associated with

an increased risk of stroke. Although elevated

blood cholesterol is not a powerful risk factor for

stroke, lowering of LDL cholesterol with statins

reduces stroke risk. A meta-analysis of the statin

trials done for CHD risk reduction showed a statistically significant 29-percent risk reduction for

stroke, accompanying the 33-percent risk reduction

for CHD.222,226 Transient ischemic episodes are also

related to an increased risk of subsequent stroke.227

Use of HRT has been associated with a lower risk

of fatal stroke, but no change in overall incidence

of stroke, compared to nonusers. In the Nurses’

Health Study, current hormone use was associated

with an increased risk of ischemic, but not hemorrhagic, stroke. For all strokes, there was a doseresponse effect, with higher doses of estrogen

associated with a higher risk.228

In terms of active treatment of stroke, there are no

clear recommendations. Early administration of

aspirin seems to reduce the stroke-related death

and recurrence, as shown in the Chinese Acute

Stroke Trial (CAST).229,230 Where transient ischemic

episodes and stroke are associated with atrial fibrillation, warfarin may reduce the risk of stroke.231

Carotid endarterectomy and aspirin therapy may be

helpful in symptomatic severe carotid stenoses.232

The only clinical trial to assess the effect of continuous CEEs combined with MPA is the HERS

trial.233 Over a followup of 4.1 years, 149 women

had 1 or more strokes out of a total of 2,763

women. HRT was not significantly associated with

risk of nonfatal or fatal stroke or transient ischemic

attack. It was therefore concluded that HRT had no

significant effect on the risk of stroke in this higher risk group of menopausal women with CVD.

10. PERIPHERAL VASCULAR DISEASE

Peripheral vascular disease occurs relatively commonly in women, and like all CVD, there is an

accelerated incidence with age in women.234

Smoking is the most prevalent risk factor for

peripheral vascular disease in women, as it is in

men.235 Insulin resistance,

increased BMI, elevated fibrinogen, and elevated blood

pressure are also risk factors.235–237 Cessation of smoking

and treatment of the underlying

metabolic problem, if possible,

may lead to improvement.

Peripheral vascular disease carries an increased risk for CHD,

which is nongender-dependent.237 If surgery is indicated

for severe peripheral vascular disease, smoking

cessation is essential, and antiplatelet therapy may

also be helpful.238,239 The effect of HRT on peripheral vascular disease is not known.

11. VENOUS THROMBOEMBOLISM

Recent epidemiological studies and limited clinical

trial data have shown consistently that there is an

increase in risk of venous thromboembolic events

in women taking estrogen compared with those

that do not. The studies to date indicate that there

may be a fourfold increase in RR initially, with a

persistent twofold increase in risk thereafter.240–243

The increased risk for venous thromboembolism

was similar in women using an estrogen plus a

progestin.240,243 In unselected women, observational

studies report an annual incidence of 6–18 events

per 10,000 in subjects of all ages; thus a twofold

increase in risk due to HRT might result in an

There is an increase

in risk of venous

thromboembolic

events in women 

taking estrogen 

compared with

those that do not.
166

excess risk of 6–18 per 10,000 per year, and a

fourfold increase might result in 18–54 excess

cases per 10,000 per year. The recent large randomized HERS study reported a statistically significant increase in risk of venous thromboembolic

events among women randomized to hormone

compared to placebo.101 In a more detailed evaluation of the HERS population,244 HRT was associated with a relative hazard of 2.7 and an excess risk

of venous thrombosis of 39 events per 10,000

women per year. This higher risk was associated

with older age, lower limb fractures, and cancer.

An interesting observation was that the relative

hazard for pulmonary embolism appeared to

decline with time, but the relative hazard for deep

venous thrombosis did not. This may have been a

chance finding. The relative hazard for venous

thrombosis seemed to remain elevated for 30 days

after the discontinuation of HRT. The mechanisms

for the increase in venous thromboembolism may

involve alterations in coagulation factors; to date,

no clear mechanism has been identified. Possible

interactions with deficiencies of antithrombin-III,

protein C and S, the prothrombin 20210G➝A

mutation, and factor V Leiden may result in the

increased risk for venous thromboembolism. The

interaction of activated protein C resistance with

estrogen or estrogen plus progestin therapy has been

confirmed in at least one study.245 Women with

thrombophilia should be counseled about the further

increase in risk if they use HRT. It should be recommended that women who take HRT discontinue

the therapy perioperatively or following trauma

during the period of immobilization and restart

HRT when they return to normal activity.246 Women

at very high risk of venous thromboembolism, such

as those with cancer, disorders of blood viscosity,

or a prior history of venous thromboembolism

should avoid menopausal HRT.244 An association

has been shown between the use of HRT and MI in

postmenopausal hypertensive women with the prothrombin 20210G➝A variant. Confirmation of this

finding in other studies may allow better risk

assessment associated with HRT in women.247

12. PULMONARY DISEASE

At present, we have only little knowledge of the

influences of sexual hormones on respiratory function. In fact, ERs (specifically ERβ) have only

recently been found in lung, thus providing a rationale to further investigate new mechanisms for

otherwise well-known pathologies.

12.1 Asthma in Postmenopausal Women

Estrogen may play a role in the pathophysiology of

asthma. A prospective review of HRT and asthma

incidence in premenopausal and postmenopausal

women aged 34–68 years conducted during a 135

person-year followup of 1 year, 726 new cases of

asthma were documented. Postmenopausal women

with no previous history of hormone use had a 

significantly lower age-adjusted risk of asthma than

premenopausal women (RR = 0.65; 95 percent CI

0.46–0.92.). Users of 10 or more years duration had

twice the age-adjusted risk of asthma compared

with women who never used HRT (95 percent 

CI = 1.39–2.87). There appears to be a positive

dose response between the daily dose of CEE and 

asthma risk.248 In a study in asthmatic women, it

was demonstrated that peak expiratory flow was

adversely affected by HRT.

In the treatment of asthma, inhaled corticosteroids

have been shown to decrease serum osteocalcin

levels in postmenopausal asthmatic women.249

Although it is clear that oral corticosteroids can

result in an enhancement of postmenopausal osteoporosis, inhaled corticosteroids (beclomethasone)

have also been shown to disturb Type I collagen

synthesis when high-dose corticosteroids are

used.250 It is unknown, however, whether inhaled

beclomethasone impairs the ability of osteoblasts

to form bone. It is also unknown whether there are

any detrimental longer term effects on bone with

prolonged inhaled corticosteroids.
167

12.2 Miscellaneous Conditions

Pulmonary lymphangioleiomyomatosis is a disease

confined to women in their reproductive, years and

there are some reports that hormonal factors play a

role in the development of the disease before and

after the menopause and that hormonal treatment

may be beneficial in older women.251 There is one

report which suggests that estrogen medication

without progesterone in postmenopausal heterozygous women with cystic fibrosis can cause falsenegative tests. This report suggested a balance

between progesterone and estrogen for cystic

fibrosis lectin activity.252 Obstructive sleep apnea

syndrome has been associated with massive obesity in the appearance of this syndrome in women.253

13. CONCLUSIONS

CVD remains the commonest single cause of

female mortality and morbidity in the Western

World. Despite the apparent protection offered by

endogenous sex hormones in their premenopausal

years, the greater longevity of women exposes

them to a similar lifetime risk of coronary and

other vascular disease compared to men. Women

tend to develop disease at a later age than men, and

are more likely to have complicating co-morbidities

such as hypertension and diabetes mellitus, which

contribute to poorer short term outcomes following

coronary events or revascularization. The atherogenic risk profile of older women is appreciably

more adverse than that of younger women, though

it is uncertain whether age or hormones are the 

primary determinant of the evolution of the adverse

risk profile. HRT has been shown to consistently

and markedly improve the lipid risk profile,

though a benefit on cardiovascular outcomes, such

as MI or cardiac mortality, has not yet been

demonstrated. A lack of benefit may be due 

to countervailing adverse changes in coagulation

or inflammatory mechanisms. In view of gender

differences in atherosclerotic plaque and the vascular remodeling effects of estrogen and progesterone, HRT may still prove to have an important

role in the management of CVD in women.

Except for asthma, there appears to be little impact

of menopause or HRT on the pulmonary system

although further research is warranted.

14. FUTURE NEEDS

• RCTs are urgently required to investigate the

potential benefits and risks of different hormone

preparations (different estrogens, progestins,

combinations, and routes of administration) in

women with and without prior CHD. Low-dose

oral estrogens, nonoral preparations, SERMs

and androgens have to be

investigated in trials with 

clinical outcomes.

• Future clinical trials of prevention treatments and treatments

of existing disease should

include sufficient women to

allow for an adequate assessment of the effects in women

and men.

• Except for asthma, very few data exist on the

effect of the menopause or HRT on the respiratory system, and investigation of the effects on

important disease entities should be considered.

CVD remains the

commonest single

cause of female

mortality and 

morbidity in the

Western World.
168

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181

CHAPTER 9: OSTEOPOROSIS AND ORAL BONE LOSS IN

AGING WOMEN: RISKS AND THERAPY

1. Osteoporosis affects a large proportion of the population of elderly women throughout

the world.

2. The loss of estrogen at menopause contributes significantly to skeletal bone loss,

although the mechanism is not completely understood.

3. Although there has been major progress in methods for assessing risk for osteoporotic

fractures, identifying individuals at greatest need of antiosteoporosis treatment remains

an unmet need. 

4. Low bone mass at menopause can be due to insufficient bone acquisition during growth or bone loss during

adulthood. Adequate nutrition—in particular, but not exclusively, from intake of calcium and vitamin D—

and adequate physical activity are the first line of prevention against osteoporosis [C].

5. ERT has been a mainstay in the prevention and treatment of osteoporosis for menopausal women in many

countries. HRT has been shown to maintain bone density and favorably influence markers of bone resorption

[A]; observational data and some, but not all, controlled clinical trials have demonstrated reduced fracture

risk with estrogen or hormone treatment [B].

6. SERMs are two recently developed classes of drugs that have been shown to stabilize bone mass and 

prevent fracture in postmenopausal women [A]. The long-term effects of these agents are not known.

Robert Lindsay, M.D. Ph.D.;* Bruce Ettinger, M.D.;† Joan A. McGowan, M.N.S., Ph.D.;‡

Maryann Redford, D.D.S., M.P.H.;§ Elizabeth Barrett-Connor, M.D.**

KEY POINTSa

* From the Department of Medicine, Columbia University, College of Physicians Surgeons, and Director, Clinical Research Unit, Helen Hayes Hospital,

New York, NY, U.S.A.

† From the Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA, U.S.A.

‡ From the Musculoskeletal Diseases Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, U.S.A.

§ From the Clinical Trials and Epidemiologic Studies Program, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, U.S.A.

** From the Division of Epidemiology, Department of Family and Preventive Medicine, UCSD School of Medicine, La Jolla, CA, U.S.A.

a Evidence categories are given in square brackets. A = randomized controlled trials (rich body of data); B = randomized controlled trials (limited data); 

C = nonrandomized trials and observational epidemiologic studies; D = Panel expert judgement. (See also table 1–1.)

Osteoporosis

affects a large

proportion of the

population of

elderly women

throughout 

the world.
182

7. A connection between menopausal estrogen

deficiency and oral bone loss is biologically

plausible, and many research findings to date

[C/D] are consistent with that link. Some early

findings support the hypothesis that treatments

used to maintain or improve skeletal bone density may favorably affect oral bone status and

attendant tooth loss.

1. INTRODUCTION

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture.1 It has been

widely recognized in recent years by the medical

profession and the public as a significant health

concern, especially for elderly women, among

whom osteoporosis is more prevalent than among

men.2 In most cases, bone loss proceeds for many

years without any symptoms, and a fracture is

often the first manifestation of the disease.

Although rates of osteoporosis and associated bone

fractures increase with age, research findings suggest that severe bone loss and fractures are not natural consequences of aging but may be prevented

or substantially delayed.

Measurement of BMD is the

most common clinical diagnostic

method for assessing skeletal status and fracture risk. Dual energy

x-ray absorptiometry (DEXA) of

the hip and spine is the preferred

measurement. It is validated by

many studies, has the best precision, and is correlated with fracture risk. A WHO expert panel

defined osteoporosis as a BMD 

at the hip more than 2.5 standard

deviations (approximately 30 percent) below the

peak mean BMD achieved by normal young

adults.3 This same panel defined low bone mass

(osteopenia) as a BMD between 1 and 2.5 standard

deviations below the young adult peak bone density. The intent of these definitions was to enable

cross-cultural evaluation of bone mass, using culturally specific normal ranges. The definitions

have allowed a more rational estimation of the

numbers of people at risk for osteoporosis-related

fractures in different countries and with different

ethnicities. In some countries (especially the

United States) these definitions have become

accepted as diagnostic cut points. While this was

not the original intent, it has been a useful development in an environment where reimbursement 

is still aligned to diagnosis.

Using the WHO definitions of osteoporosis and

low bone mass, investigators have estimated that

osteoporosis poses a threat for 28 million people 

in the United States, 80 percent of whom are

women.4 Nationally representative BMD measurements would allow estimations of the prevalence

of osteoporosis and cost of osteoporotic fractures

in any country. It is important to recognize, however, that BMD is only one of a number of factors

that contribute to risk for fracture and that fracture

risk is the most important information for deciding

who needs treatment or intervention. Other factors

that contribute to risk for fracture include age, sex,

general nutritional status, genetic background, and

overall physical condition. The combination of

such factors and BMD measurement in risk assessment appear to be of powerful predictive value.5,6

2. EPIDEMIOLOGY AND ECONOMIC

COSTS OF FRACTURE

The clinical consequence of osteoporosis is bone

fracture. While most common sites of fracture are

the spine, hip, and wrist, most fractures increase in

frequency with age, with the exception of skull

fractures.7 In addition to increased mortality, acute

and chronic back pain, disability, loss of height,

decreased quality of life, and significant financial

and psychosocial costs are also associated with the

fractures.8 Estimates are from age 50 years onward

there is almost a 40-percent lifetime risk for any

Measurement of

BMD is the most

common clinical

diagnostic method

for assessing

skeletal status

and fracture risk.
183

fracture of the spine, hip, or distal forearm for

white women and a 13-percent risk for white men

in the United States.9 At least 90-percent of all hip

and spine fractures among elderly, white U.S.

women can be attributed to osteoporosis as well as

a significant proportion of all other fractures.10

Less is known about fracture risk in minority populations, although African-American women and

men have higher average bone mass values11 and

lower rates of fracture compared with white U.S.

women and men.11

Rates of fracture and even the male:female ratio of

fractures observed vary in different parts of the

world.12 In Europe, hip fracture shows an elevenfold

range in apparent incidence among women and a

sevenfold range among men between the various

countries in data from 17 countries.13 The highest

incidence was found in the northern part of Europe,

and the lowest was found in the Mediterranean

area. The overall lifetime risk for any fracture in

women older than 50 years in most European

countries is approximately 30–40 percent,14 similar

to that for white women in the United States,

despite the clear variability across cultures. In 

general, in Europe and elsewhere, the fracture rate

is greater in urban areas than in rural areas.15

Vertebral fractures are notoriously difficult to

detect and quantify. Lateral radiography of the

spine may be required to determine their presence.

Many fractures identified radiologically are

asymptomatic or, even if painful, are not brought

to medical attention. Only one-third of vertebral

fractures present as clinically apparent fracture

events.14 Symptoms and signs (back pain, height

loss, and kyphosis) are under recognized, in part

because they are nonspecific. Radiological definitions based on changes in the height of vertebrae,

used in clinical trials and in observational studies,

can yield widely different estimates of prevalence.16 In the United States, a prevalence of 25

percent in women over 50 years of age has been

estimated.17 The risk of vertebral fracture in U.S.18

and Australian19 women increases fifteenfold to

thirtyfold between ages 50 and 90 years. (The risk

increase for hip fracture across those years in

women is fiftyfold.) Spine fractures also predict

other fractures,20 in particular subsequent spine

fractures with the absolute risk of a second spine

fracture being approximately 20 percent in the first

year after the initial event.21 In addition, spine fractures are associated with an increase in all-cause

mortality rate.22,23

Medical expenditures for

the treatment of osteoporosis-related fractures

exceeded $13 billion in

1995, with the treatment of

white women accounting

for 75 percent of the

costs.24 As populations age

and health care costs

increase, the costs of

osteoporosis-related fractures will only escalate.

Projections based on population growth, particularly

the marked increase in the

elderly populations, suggest that fractures and their associated costs could

triple in the United States by 2040,25 and clearly

this is a worldwide problem.12 In many countries,

especially in Scandinavia, there is an upward trend

in fracture prevalence.26 In part, the trend is due to

the aging of the populations, with greater numbers

of old and very old people in many populations

across the world. However, clear age-specific

increases, particularly in hip fracture rate, have been

noted in the United States, the United Kingdom,

and Scandinavian countries. In the United States,

the increase appears to have plateaued.27 Assuming

no change in age- and sex-specific incidence, the

annual worldwide total of 1.26 million hip fractures in 1990 is expected to double by 2025 as

populations continue to grow older.28 The greatest

increases, due to demographic changes, are expected to be in Asia, in particular, in mainland China.28

The annual worldwide

total of 1.26 million hip

fractures in 1990 is

expected to double by

2025. The greatest

increases, due to 

demographic changes,

are expected to be in

Asia, in particular, in

mainland China.
184

3. PATHOGENESIS OF FRACTURE

Fracture is related to bone strength and to the force

exerted upon that bone. Because bone mass and

bone quality decline with age, less force is

required to cause a fracture as age increases.

Understanding the skeletal component of fractures

requires an understanding of the process of bone

remodeling. In addition, it is important to realize

that a number of factors can contribute to fracture

risk by increasing the likelihood of trauma and that

they can be independent of bone mass.

3.1 Bone Growth and Remodeling

During childhood, bone grows linearly and can be

reshaped to fit the stresses placed on it by the

process of modeling. At the cessation of growth,

modeling virtually ceases, and bone is continually

replaced, but not reshaped, by remodeling, although

modeling still occurs, for example, after a fracture,

when realignment is necessary. Remodeling29 can

be thought of as a preventive maintenance program

to ensure a strong, healthy skeleton, by old bone

removal—performed by osteoclasts—and new

bone deposition—performed by osteoblasts.

Osteoclastic activity also fulfills

the important role of calcium,

mobilization from the skeleton,

crucial which is to the maintenance of blood levels of calcium

especially when the nutritional

supply of calcium is insufficient.

In such situations, bone mass will

be lost in an attempt to provide

adequate calcium in conditions of

calcium deficiency.

Remodeling occurs in foci that are discrete in time

and place.29 It is a process initiated on the surface

of bone; therefore, any disturbance of remodeling

will preferentially affect sites with large surface

areas. Consequently, with increased osteoclastic

activity, bone is lost initially from the cancellous

(spongy bone) component, which forms only 20

percent of the skeletal mass but provides 80 percent of skeletal surface area. Because there is considerable cancellous bone in the spine and in the

ends of long bones, bone loss at those sites is

greatest. Excessive bone removal at these sites can

completely erode trabeculae, disrupting the architecture.29 Once trabeculae (and their surface area)

are lost, bone loss becomes more evident in cortical bone, especially consequently in later life.

During bone growth, bone mass is gradually

accrued in a process that is heavily dependent on

genetic factors.30 It is likely that many genes control so-called peak bone mass, that is, bone mass in

young adult life, including the genes that control

body size. The search for a specific gene that controls peak bone mass, bone loss, or osteoporosis

has been disappointing and will probably remain

so. Peak bone mass is also powerfully influenced

by factors affecting prenatal, and early childhood,

and adolescent growth, including diet and lifestyle.

Chronic illness, inadequate diet, or physical inactivity during childhood can reduce peak bone mass.

3.2 Impact of Menopause on Bone

After attainment of peak bone mass, bone density

is fairly stable in most healthy premenopausal

women. There may be some slow bone loss, particularly in the hip, but it is the gradual onset of

ovarian failure that heralds the most dramatic

changes in skeletal homeostasis. Bone loss accelerates markedly for a few years after natural

menopause or oophorectomy, and some loss continues for the remainder of life.31 Women with very

low endogenous estrogen concentrations after

menopause may be at particularly high risk for hip

and spine fractures.32 It has been proposed that

estrogen deficiency is the cause of both the early,

accelerated phase and, at least in part, the late,

slow phase of menopausal bone loss.33

The mechanism by which estrogen deficiency

causes bone loss is still not completely understood.

After menopause, there is increased bone turnover,

which by itself produces a transient, reversible loss

of some bone tissue.34 Irreversible bone loss is

The mechanism

by which estrogen

deficiency causes

bone loss is still

not completely

understood.
185

caused by an imbalance between the amount of

bone removed by osteoclasts and the amount of

new bone produced by osteoblasts within each

remodeling cycle. Considerable attention has

focused on the ways in which estrogen might modulate both turnover and remodeling imbalance.

Several possible potential second messengers for

estrogen’s effects have been proposed. Osteoblasts

or cells of the osteoblast lineage are thought to

control the remodeling process. Communication

between osteoclasts and osteoblasts may modify

the amount of bone removed by the former cells,

perhaps by controlling recruitment or the lifespan

of the osteoclast population. Candidates as messengers include the interleukins (especially interleukins 1, 6, and 11), prostaglandins, insulin-like

growth factors 1 and 2, TGF-β, and the rank/rankligand system.34,35 Rank ligand is secreted by

osteoblasts and mediates osteoclast recruitment and

activity through rank, its receptor expressed in

osteoclasts. Osteoblasts also secrete osteoprotegerin, a decoy receptor which mops up the ligand

and has potential as a mechanism to inhibit osteoclast function and thus prevent bone loss.

It is known that bone loss continues into and may

even accelerate in old age.36 There has been much

speculation on the role of estrogen deficiency in

mediating the process. It seems evident that estrogen deficiency, plays a role but that, increasingly

with age, other factors—including weight loss,

physical immobility and frailty, calcium and vitamin D deficiency and secondary hyperparathyroidism, and the effects of intercurrent disease—

come into play.

3.3 Falls and Bone Fragility

Multiple factors have been associated with an

increased likelihood of falling and consequent fracture.37 Age itself is a strong predictor for falls as

individuals become increasingly frail. Other factors

implicated with risk of hip fractures include cigarette smoking, low body weight (especially weight

loss, perhaps a marker of frailty), previous fracture,

and family history of hip fracture.5 Of particular

importance is a personal history of fracture as an

adult. A history of peripheral fracture is usually

easy to elicit, but determination of spine fracture

may require lateral radiography of the spine. Spine

fracture predicts risk for future hip fracture, independently of bone density.20 A single spine fracture

almost doubles the risk of hip fracture, and multiple spine fractures further increase the risk.

Prevalent spine fracture increases risk for further

spine fractures by a factor of 4 to 5. An incident

spine fracture (i.e., a newly occurring spine fracture) further increases the risk, such that 20 percent

of patients who present with a new spine fracture

may be expected to have a second spine fracture

within a year.21

4. CLINICAL ASSESSMENT

AND DIAGNOSIS

The initial approach to a patient

with osteoporosis or one who may

be at risk for osteoporosis is a

complete history and physical

examination. The physician should

determine the presence of any

underlying cause of osteoporosis,

including the use of any medication that might affect the skeleton,

such as thyroid hormone supplements or glucocorticoids. For women after

menopause, clinical evidence of osteoporosis

should be sought at every clinical evaluation. The

principal method for making the diagnosis of

osteoporosis is evaluation of the skeleton by a noninvasive measurement of bone density. In conjunction with the patient history and findings of the

physical examination, bone density evaluation will

determine whether the risk of fracture is sufficiently high to warrant pharmacological intervention.

Bone density measurement can also serve to monitor bone loss or the effects of therapy, although its

limited precision makes it somewhat less useful for

individual monitoring than for risk prediction.38

For women after

menopause, 

clinical evidence

of osteoporosis

should be sought

at every clinical

evaluation.
186

Diagnosis of osteoporosis according to BMD criteria is dependent upon the site assessed (hip, spine,

forearm, heel) and the methodology used.39,40

Measurement in the hip by DEXA is preferred

because it is less subject to the age-related artifacts

that affect the spine and is a better predictor of hip

fracture risk.41 Where that modality is not available, x-ray absorptiometry or computed tomography may be used to assess the spine, forearm,

tibia, or calcaneus. If these instruments are not

available ultrasound, can also be used to assess

fracture risk, but this modality has somewhat poorer precision and validation.42

At present, there are no internationally accepted

guidelines for the use of bone densitometry to

assess risk for osteoporosis. U.S. data, derived in

part from cost-effectiveness analysis in white

women, suggest that BMD should be measured in

the following patient groups:43

1. All women 65 years of age

or older, regardless of risk

factors.

2. All postmenopausal women

under 65 years of age who

have, in addition to

menopausal status, one or

more other risk factors (thinness, current smoking, family

history of osteoporosis-related fracture or a personal history of a fragility 

fracture).

3. Postmenopausal women who

present with fractures (to confirm the diagnosis

or determine the severity of disease).

4. Women who are considering therapy for osteoporosis, if the results of bone density evaluation

would facilitate the decision.

5. Women who have received HRT for prolonged

periods.

It would be cost-effective to be able to use a set of

clinical risk factors to select women for bone densitometry. A Canadian group recently reported an

assessment instrument based on only three factors—age, body weight, and current estrogen usage

(yes or no). This instrument showed high sensitivity for selecting women with low BMD according

to densitometry.44 The approach of improved targeting may reduce the number of women who

need densitometry for the identification of osteoporosis. In general, BMD measurement should not

be performed if the findings would not influence a

treatment decision. The presence of a disease

(hyperthyroidism) or the use of a drug increasing

the risk of osteoporosis (glucocorticoids, anticonvulsants) can also trigger referral for BMD measurement. More recently, an assessment tool for

the risk of hip fracture was developed using the

population from the study of osteoporotic fractures

and was validated against a European cohort. This

approach showed that clinical (and easily obtained)

risk factors could identify individuals at increased

risk of hip fracture and that the risk was amplified

when BMD testing was added. 6,7

5. AVAILABLE THERAPY

Efforts to reduce risk for osteoporosis should be

encouraged among all adults. For those who are

considered at high risk of fracture, pharmacological therapy may be required.

5.1 Nonpharmacologic Therapy

In general, risk factor reduction through nonpharmacologic means is considered sufficiently 

cost-effective that it should be instituted wherever 

possible in the general population.43

Avoidance of tobacco use and moderation in alcohol intake are obvious. All patients should also 

be encouraged to obtain an adequate calcium and

vitamin D intake and to undertake a reasonable

program of physical activity.

At present,

there are no

internationally

accepted guidelines for the

use of bone

densitometry to

assess risk for

osteoporosis.
187

5.1.1 Calcium

Controlled clinical trials indicate that among the

elderly, adequate calcium and vitamin D intake can

reduce bone loss and potentially the risk of fractures, especially vertebral fracture.45–47 In the only

large trial with a hip fracture endpoint, dietary supplementation with calcium and vitamin D for 36

months significantly reduced hip fractures in elderly women whose average age was 82.48 Calcium

should be obtained as a nutrient from the diet to

get the benefit of other components of food.

Although calcium-fortified foods are becoming

increasingly available, not all individuals will be

able to increase calcium intake in this way. For

those who cannot, supplementation should be

encouraged. In the United States, the DRI—the

recommended daily intake—for calcium is 1,200

mg for both women and men aged 51 years and

older.49 To achieve this goal, most menopausal

women would need to add 500–750 mg of calcium

to their usual intake. Selecting foods fortified with

calcium can easily achieve this.

5.1.2 Vitamin D

There may be widespread deficiency of vitamin D

in many populations, particularly the elderly,

housebound, and institutionalized.50,51 Inadequate

exposure to sunlight, poor diet, and a decrease

with age in the ability to absorb available vitamin

D all contribute.52 Because it is inexpensive to provide vitamin D and because many of the controlled

trials of calcium also used vitamin D supplementation, supplements of vitamin D are recommended

for at-risk populations. The recommended intake

of vitamin D is 15 μg (600 IU/day) for persons 

> 70 years in the United States.49

On the other hand, there is a potential for vitamin

D toxicity, and a dose of 2,000 IU or 50/lg per day

should not be exceeded, except under close monitoring. The toxic effects of vitamin D overdose,

mediated through hypercalcemia and hypercalciuria,

include irreversible renal and cardiovascular damage due to the deposition of calcium in soft tissues.

5.1.3 Physical Activity

Most clinical trials have shown fairly modest and

unsustained BMD responses to exercise in adults.

The type of exercise that promotes a bone response

may be different from the type recommended for

aerobic fitness; it appears that muscle-building,

weight-bearing resistance exercise is required to

alter bone density.53 For the frail elderly, exercise

to reduce the risk for a fall is an appropriate intervention as muscle weakness is an important cause

of falls. Muscle strength and neuromuscular performance can increase dramatically with proper

exercise, 54,55 even in the tenth decade of life.55

Consequently, where not

medically contraindicated,

increased physical activity

should be encouraged. The

most important feature of

exercise is the requirement

that it become a lifelong

habit. Thus, it is better to

recommend activities that

the individual will enjoy

than to provide rigid programs designed specifically to affect the skeleton.

5.2 Pharmacologic Therapy

A decade ago, estrogen and injectable calcitonin

were the only available pharmacologic therapies

for postmenopausal women with osteoporosis.

Now, new bone-specific drugs (e.g., bisphosphonates) and broad-spectrum drugs (e.g., SERMs)

that combat osteoporosis and may have beneficial

effects in other organ systems are available. PTH,

the hormone that controls the mobilization of calcium, is emerging as a treatment with potential to

add bone to an aging skeleton.

5.2.1 Estrogen Replacement Therapy

As discussed above (sec. 3.2), strong evidence

supports the concept that postmenopausal estrogen

deficiency precipitates bone loss. Controlled clinical trials have shown that ERT maintains bone

New bone-specific drugs

(e.g., bisphosphonates)

and broad-spectrum

drugs (e.g., SERMs) that

combat osteoporosis 

and may have beneficial

effects in other organ 

systems are available.
188

density and has a favorable effect on markers of

bone resorption.56 Data from observational studies

indicate that long-term use of estrogen reduces risk

for nonspine fracture57 and that discontinuation

allows bone loss and waning of fracture

protection.57,58 However, there are only a few clinical trials of estrogen’s effect on fracture, especially

vertebral fracture.59,60 One randomized, placebocontrolled trial in 464 early postmenopausal women

without osteoporosis found a reduction in nonspine

fractures over a mean period of 4.3 years in women

assigned to estrogen or estrogen plus vitamin D.61

However, in a trial of 2,763 women selected on the

basis of presence of CHD, no difference was found

in risks for nonspine fracture in women randomized to receive HRT compared with placebo.62 A

recent meta-analysis of the clinical trial data on the

effect of HRT on the prevention of nonspine fractures

showed an overall 27-percent decrease in nonspine

fractures in women randomized to receive HRT,

with the effect attenuated

in women over 60 years of

age.63 Since this effect is

so much less than expected

from observational studies,

it is possible that the

reduced fracture rates with

estrogen use reported in

observational studies

reflect the selective use of

hormones by healthier

women—women who, for

example, smoke less, exercise more, and have a

better diet. (See ch. 4 for bias.) Nevertheless, on

the basis of long clinical experience, positive effect

on BMD and bone turnover, limited fracture data,

putative other benefits, and fairly low cost, estrogen has been considered one of the major medical

options for menopausal osteoporosis prevention.

5.2.2 Selective Estrogen Receptor 

Modulator Therapy

SERMs are drugs that behave as estrogen agonists

in some tissues, including bone, but behave as

estrogen antagonists in other tissues, such as the

breast. (See ch. 6.) SERMs include tamoxifen and

raloxifene; the latter is the only SERM currently

marketed worldwide for osteoporosis. In placebocontrolled trials, raloxifene prevented bone loss in

healthy early postmenopausal women64 and reduced

risk for spine fracture in women with osteoporosis

(RR reduction about 40 percent) but did not reduce

risk for nonspine fractures in older women with

osteoporosis.65

5.2.3 Bisphosphonates

The bisphosphonates are analogues of pyrophosphate in which the oxygen has been replaced by a

carbon atom. They bind avidly to calcium hydroxyapatite in bone, with the potency of different bisphosphonates determined by the side chains on the

carbon. The first-generation bisphosphonate,

etidronate, was shown in a small, placebo-controlled trial to reduce risk for spine but not nonspine fractures.66 Recent studies of newer more

potent bisphosphonates have shown about a 45–50

percent reduced risk for spine fracture.67–69 A reduction in the risk of nonspine fractures has also been

demonstrated with both alendronate and risedronate.67–70 Risedronate has been shown to reduce

the risk of hip fractures in patients with osteoporosis in the only clinical study conducted thus far in

which hip fracture was the primary outcome.70

Alendronate and risedronate, but not etidronate, are

marketed in the United States for the treatment and

prevention of osteoporosis; etidronate is available

in a number of other countries.

5.2.4 Salmon Calcitonin

The peptide hormone calcitonin is approved in the

United States for the treatment of osteoporosis.

Some clinical trials have shown a reduction in

bone resorption and the preservation of bone

mass.71–74 In the major study completed thus far,

calcitonin nasal spray, 200 IU per day, compared

with placebo had modest but statistically significant effects on spinal bone mass and bone turnover

and reduced, by 33 percent, risk for new spine

The first-generation 

bisphosphonate,

etidronate, was shown 

in a small, placebocontrolled trial to reduce

risk for spine but not

nonspine fractures.
189

fracture in postmenopausal women with osteoporosis.74 This trial failed to show the effect of calcitonin on peripheral bone density or on the risk of

nonspine fracture, furthermore, the 400 IU dose

failed to show statistically significant reductions in

spine fracture. Although there are no conclusive

data on the effect of calcitonin on risk for nonspine

fracture, an analysis of pooled results from several

studies suggests that salmon calcitonin treatment

might provide benefit.75

5.3 Considerations in Selecting 

Pharmacologic Therapy

Which pharmacologic agent to select in a given

patient is a complex decision that must take into

account whether the need is for the prevention or

treatment of osteoporosis and for bone-specific or

broad-spectrum effects, as well as patient acceptability and tolerability and the cost of the drug

being prescribed.

5.3.1 Need for Prevention or Treatment

Theoretically, for maximum prevention of osteoporosis, drug therapy should probably be initiated

at menopause and continued lifelong. However,

there are as yet no data on the optimal duration of

use for nonestrogen formulations, and long-term

prevention is not easily achieved with estrogen

therapy, requiring its continuation for 20 to 25

years after menopause.57,76

An observational cohort study of 9,704 U.S.

women over 65 years of age showed a 71-percent

lower RR for hip and wrist fracture and a 50-percent lower RR for all nonspine fractures among

those who had started estrogen within 5 years of

menopause and who were still taking it.58 In this

same study, the use of estrogen for more than 10

years had little impact on later fracture risk for

elderly women who had stopped therapy. A crosssectional study of 740 white U.S. women aged 

60–98 years confirmed that 10 years of estrogen

use, begun soon after menopause but stopped, had

little effect on bone density many years later.58 This 

confirms prospective data, which demonstrate that

bone loss begins when estrogen is discontinued.77,78

In an observational study of 47,050 U.S. women,

Barrett-Connor and coworkers were able to separate duration of use from recency of use and found

both factors to be important for optimal preservation of bone density.79

Until recently, it was a popular belief that 6 or more years

after menopause was too late

to achieve fracture benefit

from any treatment. However,

data from the late 1980s had

shown that preservation of

bone mass could be achieved

among older women using

estrogen.80 Recent studies

have confirmed those data and have shown substantial reductions in risk for fracture when HRT was

initiated > 10 years after menopause.57,58,60 Several

large clinical trials have shown that antiresorptive

therapy with bisphosphonates67–70 or raloxifene65

given to elderly women can rapidly produce substantial reductions in risk for spine fracture (60–68

percent reductions in risk within the first year, and

41–46 percent reductions over 3–4 years). With such

excellent responses to treatment when started many

years after menopause, it is not surprising, therefore,

that the National Osteoporosis Foundation’s costeffectiveness analysis suggests that the ideal time,

from the viewpoint of use of medical resources, for

women to begin an osteoporosis drug is at age 60 to

65 years.43 Early postmenopausal prevention using

bone-specific drugs is not considered cost-effective

because, on average, the incidence of fracture

among women remains low until the age of 65 years

or more. (See “Cost-Effectiveness” below.) Drug

treatment with bone-specific agents may be most

effective in those who have osteoporosis, by BMD

criteria.76 Therapy begun after age 80 years in frail

individuals may not be effective in reducing hip fracture risk, and in the very elderly, interventions aimed

at reducing the impact of trauma, such as hip protectors, would be preferred.81

The ideal time, from

the viewpoint of use

of medical resources,

for women to begin an

osteoporosis drug is

at age 60 to 65 years.
190

How should this information be incorporated into

clinical practice? By targeting for treatment

women in whom clinical evidence of osteoporosis

has already appeared (height loss, fracture) or who

have very low BMD (more than 2.5 standard deviations below the mean value for young adults),

treating physicians can make the most efficient use

of limited medical resources. Because it appears

that bisphosphonates work

well to reduce fracture 

risk in patients with osteoporosis,68–70 bone density can

be used as an indicator for

treatment. It may also serve

as a patient-motivator;

acceptance of HRT was higher in women who had undergone BMD measure, regardless of the result, than in

those who had not,82 and

awareness of low bone density has been shown to

enhance acceptance of osteoporosis treatments.83,84

5.3.2 Need for Bone-Specific or BroadSpectrum Effects

Broad-spectrum therapies, such as estrogen and

raloxifene, are thought to act as “health packages”

that include improvement of the plasma lipid profile and, possibly, protection against other common

diseases of aging. In many instances, however,

trial data are not yet available to support the claims

for clinical endpoints. Although bone-specific

drugs, such as bisphosphonates, appear to provide

greater fracture risk reduction than broad-spectrum

drugs, especially for nonspine fractures, many

postmenopausal women want or need interventions

for other health concerns.

5.4 Acceptability and Tolerability

The reasons for women wanting or refusing to take

estrogen are complex. HRT is usually begun close

to menopause for symptom relief, and women will

often continue it for these tonic effects.85 Older

women, on the other hand, typically begin hormones and other treatments for health promotion,

particularly for prevention of osteoporosis-related

fractures.85

Long-term drug therapy requires a high degree of

patient acceptance—one that is predicated on the

patient’s perception that treatment benefits outweigh risks and that treatment is convenient, low

in cost, and free of side effects. Among U.S.

women > 60 years of age, it was found that 68 

percent and 48 percent who started estrogen or

raloxifene, respectively, had stopped within 24

months.86 A similarly high discontinuation rate was

found in U.S. women who had started

alendronate.87 Side effects are the main reason for

stopping antiosteoporosis drugs. Vaginal bleeding

and breast tenderness rank high among reasons

that older women give for stopping HRT.85

Gastrointestinal symptoms are the most common

reason for stopping alendronate, while vasomotor

symptoms are the reason cited by women for discontinuing raloxifene.65 There are as yet no data on

continuation of risedronate. Poor continuation is

not fully explained by side effects: nearly one-third

of relatively asymptomatic women who complied

with a HRT trial regimen for 3 years discontinued

the therapy within 2 years after the trial’s end.88 In

general, discontinuation rates in clinical settings

are several fold greater than those reported from

clinical trials; it is likely that patient selection plus

the education, motivation, and support provided to

participants by clinical trial staff account for some

of the differences.

Gastrointestinal side effects with alendronate are

more common in women over 70 years of age and

in those with active upper gastrointestinal problems, such as gastroesophageal reflux disease or

with current nonsteroidal anti-inflammatory drugs

(NSAIDs) use.89 These risks of developing gastrointestinal symptoms may be reduced if patients

adhere to dosing guidelines. In other patients who

exhibit upper gastrointestinal symptoms while takThe reasons for

women wanting or

refusing to take 

estrogen are complex.

HRT is usually begun

close to menopause

for symptom relief,

and women will often

continue it for these

tonic effects.
191

ing alendronate, administration of the medication

weekly may improve tolerability. Once-weekly

alendronate 70 mg yielded the same effects on

BMD and bone turnover as daily alendronate 10

mg.90 Risedronate may be less apt to cause gastrointestinal lesions.91

5.5 Cost Effectiveness

It is clear that greater treatment focus should be on

women aged 60 years and older, who are on average

10–15 years postmenopausal. On the basis of age

alone, they have a substantially higher risk for

fracture than younger women. They also are more

likely to have accumulated risk factors, including

spine or other osteoporotic fractures. Moreover,

older women may be more willing to begin and

continue osteoporosis treatment because they correctly perceive that their risk for fracture is more

immediate than the risk in younger women.

Osteoporosis drugs should be reserved for patients

at high proximate risk for fracture. By targeting

women over 65 years of age and who have multiple

risk factors or all women who have clinical evidence

of osteoporosis (height loss, fracture), treating

physicians can make more efficient use of limited

medical resources and can expose fewer women to

drugs whose long-term effects remain uncertain.

5.6 Clinical Perspective on Drug 

Selection Issues

If pharmacologic therapy is indicated for prevention of osteoporosis, estrogen is probably the best

choice for early postmenopausal women, because

it is low in cost, provides relief of climacteric

symptoms, and perhaps lowers risks for certain

other diseases of aging. For women at high risk of

fracture and in need of treatment—typically those

who are elderly with fractures—a bisphosphonate

might be considered more appropriate. For many

women between these two extremes, who have a

moderate risk of fracture (especially vertebral fractures) and who are also seeking other health benefits (reduced risk of breast cancer), raloxifene

might be preferred.

Now that a number of effective osteoporosis therapies have become available, two new questions

have arisen regarding their use: Should they be

combined? How long should they be continued?

The therapies in use today are all antiresorptive,

and their effects on bone turnover are additive to a

degree. For example, estrogen alone or alendronate

alone will suppress bone turnover 50–55 percent

on average; when added together, bone turnover is

suppressed 65–70 percent.92 The increment in bone

density achieved with combination therapy is

small, about 1–2 percent over the usual 5-percent

increment with either treatment used alone. There

are no data to show greater efficacy in fracture

reduction, and there is concern that oversuppression of bone turnover could contribute to greater

fracture risk by either causing hypermineralized,

brittle bone or by impairing bone repair and

renewal.93 The added cost, complexity, and potential side effects also are reasons to exercise caution

in the use of combination antiresorptive therapies.

However, future study of low dosages of two

antiresorptive therapies is warranted; this could

produce the desired bone and other effects with

lower cost and better tolerability and potentially

reduce the adverse effects of these drugs.

In the future, we are likely to see the use of osteoporosis drugs in sequence; for example, a bone

anabolic drug (see below) might be used for 1–2

years to stimulate new bone formation, and an

antiresorptive

drug would be

used subsequently

to consolidate

and maintain the

bone gains.

Choosing the right drug regimen for the right

woman involves assessment of short-term fracture

risk and other nonskeletal health issues. By understanding available regimens and customizing the

therapy to the needs of each woman, clinicians are

more likely to achieve clinical goals and optimize

the chances for long-term continuation. With the

Osteoporosis drugs should be

reserved for patients at high

proximate risk for fracture.
192

emergence of proved treatment alternatives, it is 

no longer acceptable to use a “one size fits all”

approach to the years after menopause.

6. NOVEL THERAPEUTIC OPTIONS

Options in development for the treatment of osteoporosis range from KyphoplastyTM (a method for

filling collapsed spine bodies with a cement) to hip

pads designed to reduce the

energy transmitted to the

hip during a fall. Some

potential pharmacologic

agents are variants of

available agents; others

seek to interfere with novel

targets in the osteoclast

population or to stimulate

new bone formation.94

One very promising

approach is the use of

PTH. Among menopausal

women with osteoporosis who were already

receiving HRT, the addition of daily subcutaneous

PTH markedly increased spine BMD during years

of treatment, compared with no significant change

in the group receiving HRT alone.95 Total-body

bone mineral was also increased, with no detrimental effect at any skeletal site, and the increased

bone mass was associated with a reduction in rate

of spine fracture. The findings were confirmed in a

larger study of 1,673 women with osteoporosis and

existing spine fractures.96 Compared to those

receiving placebo, those receiving 20 μg recombinant 1—34 PTH subcutaneously and daily, for an

average of 18 months, had marked reductions in

spine and nonspine fracture risk; a 65-percent

reduction was observed for spine fracture, and a

52-percent reduction was observed for nonspine

fractures. This very promising therapy, in addition

to increasing bone density, increases the area of

vertebra and the diameter of peripheral bones. The

early and profound fracture reduction may be due,

in part, to changes in bone geometry and integrity.

The development of many more therapeutic alternatives can be anticipated as understanding of the

genetics and pathophysiology of osteoporosis continues to grow.

7. ORAL BONE LOSS

Oral bone, like the rest of the skeleton, comprises

both trabecular and cortical bone and undergoes

formation and resorption throughout the lifespan.

Unlike the case of the postcranial skeleton, however, fracture rarely results when oral bone loss

exceeds gain. Generally, oral bone loss manifests

as either loss of tooth-anchoring support or as a

diminution of the remaining ridge in areas of partial or complete tooth loss. Residual ridge resorption refers to the loss of oral bone subsequent to

the natural loss or removal of teeth. Its rate and

extent are highly variable. Progressive residual

ridge resorption can interfere with the placement

of implants and can result in an inability to stabilize dentures.97

Given the chronic and progressive nature of oral

bone and attendant tooth loss and the fact that

symptoms often do not appear until advanced

stages of disease, painful and handicapping outcomes are highest among people in later stages of

life. Many older adults report changing the composition of meals, taking a long time to complete a

meal, being deterred from eating with others, and

feeling social discomfort in smiling, singing, or

kissing as a consequence of poor oral health.98 In

fact, the literature is replete with examples of not

only the physical but economic, social, and psychological consequences of oral diseases.

Options in development

for the treatment of

osteoporosis range 

from KyphoplastyTM ...

to hip pads designed 

to reduce the energy

transmitted to the 

hip during a fall.
193

7.1 Epidemiology

Analyses of U.S. data from the NHANES III indicate that, among women > 18 years of age, 63.8

percent have experienced loss of one or more teeth

excluding third molars and 67.1 percent have evidence of moderate periodontal disease, defined as

loss of bony tooth support of 2 mm or more.99

Furthermore, the prevalence of these conditions

increases with age in both sexes. Data from the

WHO’s Global Burden of Disease Study (GBDS)

provide a unique opportunity to examine the

prevalence of edentulism across eight global

regional groupings. Differences in disease definitions and methods prohibit direct comparisons

between NHANES and GBDS data, but the global

study provides evidence that the condition

accounts for significant morbidity worldwide. For

example, within the grouping identified as

Established Market Economies which includes

North America, Western Europe, and Australia, it

is estimated that 95 million people were edentulous in 1990.100 Epidemiologic data for residual

ridge resorption are lacking, but clinical impressions suggest that more women than men present

with severe residual ridge resorption requiring specialized treatment.

7.2 Etiology

The multifactorial nature of oral bone and tooth

loss make it difficult to unravel the roles of gender

biology, longevity, and health care utilization in

their pathogenesis. Women are reported to be more

inclined to self-care, more likely to visit a dentist,

and more likely to report symptoms such as

pain.101,102 The degree to which such behaviors

influence oral disease patterns and health statistics is

unknown. For instance, to what extent is tooth loss

the result of primary disease experience or dental

treatment? And do anecdotal reports of women’s

greater experiences with severe residual ridge

resorption reflect real differences in morbidity or

sex differences in longevity and illness behavior?

Despite these voids in understanding, there is a

growing body of literature that indicates that oral

bone and attending tooth loss are associated with

menopausal estrogen deficiency and osteoporosis.103–123 Not all studies in the topic area have yielded positive results, however.124–128 Differences in

study design—including in population, sample

size, approach to skeletal and oral bone assessments, definitions of outcomes, and adjustment 

for confounding variables—are likely reasons for

conflicting findings.

Still, data emerging from controlled clinical studies

provide evidence of a significant association

between oral bone status and skeletal status.129–131

These include preliminary findings of a 7-year 

longitudinal study of osteoporosis and oral bone

loss being conducted at the University of Alabama

at Birmingham in a subsample of participants 

(n = 457) enrolled in the observational component

of the WHI of the NIH.129,130 As part of the study

protocol, comprehensive medical history and

examination data from the core WHI, including 

hip BMD as determined by DEXA, are linked with

oral examination findings and oral bone density

measurements by the validated technique of digital

subtraction radiography. Analyses of cross-sectional

baseline data indicate a strong and significant 

correlation between hip BMD and lower jaw bone

density (r = 0.78, p < 0.001).129 Furthermore, 

preliminary analyses of longitudinal data from the

first 85 participants to return for their 3-year followup appointment indicate that the association is

clinically important.124

Among participants with

evidence of periodontal

bone loss at baseline, those

with hip BMD > 1 standard

deviation below the reference value for healthy young women had a significantly higher rate of progressive oral bone destruction than participants with hip BMDs within 1

standard deviation of normal (p < 0.05).

It is estimated that 95

million people were

edentulous in 1990.
194

Data on the relation between skeletal BMD and

tooth loss are not yet available from the described

WHI cohort, but other studies have examined this

issue. The Study for Osteoporotic Fractures

Research Group reported an association between

tooth loss and the rate of systemic bone loss

among 4,524 U.S. women age > 65 who reported

being dentate at baseline and who returned approximately 5.7 years later for a followup visit. On

adjustment for age, weight, use of estrogen, and

smoking status, it was found that women reporting

tooth loss had higher annual decreases in hip BMD

than women who did not lose teeth (0.68 percent

versus 0.54 percent, p < 0.0029).132

7.3 Approaches to Therapy

Bone regenerative procedures, such as guided tissue regeneration and grafting, have already

become commonplace for treatment of localized

oral bony defects, and their use is likely to expand.

State-of-the-art treatment for tooth loss focuses on

the placement of single or multiple teeth implants;

this approach, too, is

gaining wide acceptance. Long-term studies are underway to

evaluate the effect of

antibiotics on progressive oral bone loss.

Another promising

area of research is the use of NSAIDs133 and bisphosphonates134 to control host inflammatory

and/or bone resorptive responses.

Given the data relating oral bone loss and osteoporosis, it has been hypothesized that treatments

used to maintain or improve skeletal bone density

may favorably affect oral bone status and tooth

loss. Two large cohort studies have examined the

effect of HRT on reported tooth loss.135,136 Analysis

of data on 48,483 participants in the Nurses’

Health Study in the United States136 showed that

among women who reported regular dental visits

there was an inverse relation between current hormone use and loss of teeth after controlling for age

and cigarette smoking. Among the 3,921 women in

the Leisure World Cohort Study who provided

suitable data with which to assess tooth status,

estrogen users had significantly lower age-adjusted

tooth loss and edentulism rates compared with

nonusers.111 Studies of the effect of other boneenhancing agents on tooth loss have been limited,

but some trials have demonstrated positive findings. Data obtained from women with normal

spine densities enrolled in a randomized nutritional

intervention trial indicate that a smaller proportion

of women taking calcium supplements reported

tooth loss compared with those taking placebo.137 A

pilot trial has provided evidence of a lower RR for

progressive oral bone loss among alendronatetreated participants than in placebo controls.138

7.4 Clinical Perspective on Oral Bone Loss

There are several important clinical implications of

an association between oral status and skeletal status. On one side of the issue, it is possible that oral

examination and radiographic findings may be useful signs of extra-oral bone diminution. Although

preliminary studies along these lines have yielded

promising findings, it is too early to know the

value of routine dental visit information in signaling the need for skeletal bone evaluations.139 On

the other side, history of skeletal osteopenia may

impact the need for, and outcome of, a variety of

periodontal and prosthetic procedures including

guided tissue regeneration and tooth implantations.

If therapy for skeletal bone conditions is undertaken and is successful, the oral cavity may reap benefits as well.

A connection between menopausal estrogen deficiency and oral bone loss is biologically plausible,

and many research findings to date are consistent

with that link. More research is needed to contextualize the relation fully and to understand the

extent to which menopause increases a woman’s

oral health risks. Even as we await more detailed

information, women and their health care

providers are advised to incorporate oral health

into the menopausal conceptual milieu.

There are several important

clinical implications of an

association between oral

status and skeletal status.
195

8. FUTURENEEDS

• We must improve methods for identifying people at risk for fracture; develop inexpensive and

accurate machines to measure BMD and bone

structural integrity; develop simple clinical

means for determining risk of serious falls; and

validate algorithms that combine clinical risk

factors, bone density, and so forth, to accurately

predict an individual’s fracture risk in the next

5–10 years.

• Improve interventions; finding ways to enhance

long-term compliance with calcium, vitamin D,

and exercise; develop drugs that stimulate bone

formation, which will restore bone mass and

bone structural integrity; learn how to use drugs

in combination or in sequence; have a better

understanding of the optimal time to start drugs,

how long to use them, and effects of their withdrawal; and know more about the long-term

safety of drugs, that cumulate in bone, for

example, bisphosphonates.

• Understand skeletal factors responsible for

maintaining bone mass and bone strength, in

particularly bone cytokines and growth factors,

the effects of mineralization and hypermineralization on bone strength, and the way that bone

anabolic agents signal bone cells.

• Improve tests that monitor bone health, including densitometric, ultrasonographic, and biochemical tests. • Understand the relationship between oral bone

loss and loss in the rest of the skeleton.

• Find therapies that will reduce bone loss that

occurs early in life before osteoporosis becomes

a clinical problem.
196

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124 Elders PJM, Habets LL, Netelenbos JC, van der

Linden LW, van der Stelt PF. The relationship

between periodontitis and systemic bone mass in

women between 46 and 55 years of age. J Clin

Periodontol 1992;19(7):492–6.

125 Klemetti E, Vainio P, Lassila V, Alhava E. Trabecular

bone mineral density of mandible and alveolar

height in postmenopausal women. Scand J Dent

Res 1993;101(3):166–70.

126 May H, Reader R, Murphy S, Khaw KT. Self–reported tooth loss and bone mineral density in older

men and women. Age and Ageing

1995;24(3):217–21.

127 Mohajery M, Brooks SL. Oral radiographs in the

detection of early signs of osteoporosis. Oral Surg

Oral Med Oral Pathol 1992;73(1):112–7.

128 Norderyd OM, Grossi SG, Machtei EE, et al.

Periodontal status of women taking postmenopausal estrogen supplementation. J

Periodontol 1993;64(10):957–62.

129 Jeffcoat MK, Lewis CE, Reddy M, Wang CY,

Redford M. Post-menopausal bone loss and its 

relationship to oral bone loss. Periodontology

2000;23(1):94–102.
202

130 Jeffcoat MK, Lewis CE, Reddy M, Wang CY,

Redford M. From benchtop to clinic: osteoporosis

and oral bone loss. Proceedings of the IADR

Australian and New Zealand Division Meeting

2000b;abstract 402.

131 Wactawski-Wende J, Grossi SG, Hausmann E, et al.

The relationship of bone mineral density to oral

bone loss in postmenopausal women (abstract).

Osteoporos Int 2000;11:S200.

132 Kahn AJ, Stone K, Blackwell T, Duong T, Bird W,

Cummings SR. Study for Osteoporotic Fractures

Research Group. Tooth loss is significantly associated with the rate of non-oral bone loss in postmenopausal women: a prospective study. Bone

1998;23: abstract 1093.

133 Morton DJ, Barrett-Connor EL, Schneider DL.

Nonsteroidal anti-inflammatory drugs and bone

mineral density in older women: the Rancho

Bernardo Study. J Bone Miner Res

1998;13(12):1924–31.

134 Jeffcoat MK. Osteoporosis: a possible modifying 

factor in oral bone loss. Ann Periodontol

1998;3(1):312–21.

135 Grodstein, F, Colditz GA, Stampfer MJ. PostMenopausal hormone use and tooth loss. J Am

Dent Assoc 1996;127(3):370–7.

136 Paganini-Hill A. The benefits of estrogen replacement therapy on oral health – the Leisure World

cohort. Arch Intern Med 1995;155(21):2325–9.

137 Krall EA, Garcia RI, Dawson-Hughes B. Increased

risk of tooth loss is related to bone loss at the

whole body, hip, and spine. Calcif Tissue Int

1996;59(6):433–7.

138 Jeffcoat MK, Reddy M. Alveolar bone loss and

osteoporosis: Evidence for a common mode of

therapy using the bisphosphonate alendronate. In:

Davidovitch Z, ed. The biologic mechanism of

tooth resorption and replacement by implants.

Boston: Harvard Society for the Advancement of

Orthodontics, 1996:365–73.

139 Ruttimann UE, Webber RL, Hazelrig JB. Fractal

dimension from radiographs of periodontal alveolar

bone. A possible indicator of osteoporosis. Oral

Surg Oral Med Oral Pathol 1992;74(1):98–110.
203

CHAPTER 10: GYNECOLOGIC AND URINARY ASPECTS

OF MENOPAUSE

Piergiorgio Crosignani, M.D.;*† Susan Hendrix, D.O.;‡§ Vivian W. Pinn, M.D., Ph.D.** 

KEY POINTSa

* From the First Department of Obstetrics and Gynecology, University of Milan, Milan, Italy.

† Paragraphs 1 to 4.

§ From the Division of Gynecology, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Hutzel Hospital, Detroit, MI,

U.S.A.

‡ Paragraphs 5 to 7.

** From the Office of Research on Women’s Health, NIH, Bethesda, MD, U.S.A.

a Evidence categories are given in square brackets. A = randomized controlled trials (rich body of data); B = randomized controlled trials (limited data); 

C = nonrandomized trials and observational epidemiologic studies; D = panel expert judgement. (See also table 1–1.)

1. Changes in the menstrual cycle have been described in several clinical 

studies during the menopausal transition [C].

2. It is important to know how to diagnose endometrial cancer because it 

is a cause of abnormal uterine bleeding [C,D].

3. Management of uterine bleeding during HRT includes observation, surgery,

or specific modifications of the treatment regimen [C,D].

4. Vulvovaginal complaints in menopause are very common, and estrogen is

efficacious in their treatment [A,C,D].

5. (UI) is common with aging. The relationship between UI and menopause is not well understood [C,D].

6. Estrogen may benefit urge incontinence; however, it may exacerbate stress UI [A].

7. There are multiple new agents shown to be effective in the treatment of incontinence [A].

8. Some SERMs may increase risk for pelvic organ prolapse [B].

Changes in the menstrual

cycle have been described

in several clinical studies

during the menopausal

transition.
204

1. INTRODUCTION

Perimenopausal women request consultation for

gynecologic evaluation when cycle irregularities

begin or when hot flushes or other complaints

related to hypoestrogenemia occur. In some countries, the gynecologist is the only medical contact

for healthy women. Because they routinely perform breast examinations and Papanicolaou tests

(Pap smears), gynecologists are often responsible

for the management of perimenopausal health issues.

Moreover, irregular bleeding

and urogenital symptoms are

specific gynecologic aspects 

of menopause. In particular,

uterine bleeding is common in

menopausal transition women

and in women receiving HRT.

2. PERIMENOPAUSAL BLEEDING

Ovarian aging is the cause of menstrual changes

occurring before menopause.

2.1 Changes in the Menstrual Cycle

The median menstrual cycle is 29 days in the early

years after menarche but decreases to 26 days by

the age of 40. Studies carried out mostly in industrialized countries show that starting 8–10 years

before menopause there is greater variability in the

intermenstruum.1 Intermittent ovulation2 and long and

short cycles intermingled with oligomenorrhea occur

in the transition period. Evidence of (irregular) ovarian follicular growth and estradiol production may

be detected even after the last menstrual period.3

Mean menstrual flow volume is about 35 mL and

is usually stable over time. During the menopausal

transition, cycles can be abnormal in terms of 

frequency, duration, and volume according to the

following definitions:4

• Hypomenorrhea: bleeding occurring at regular

intervals but of low volume (< 20 mL).

• Oligomenorrhea: bleeding occurring at intervals

> 35 days.

• Spotting: intermenstrual bleeding not necessitating

sanitary protection.

• Metrorrhagia: intermenstrual bleeding necessitating sanitary protection.

• Menorrhagia (hypermenorrhea): bleeding occurring at regular intervals but excessive in quantity

(> 80 mL).

• Polymenorrhea: bleeding occurring at regular

intervals < 21 days.

• Menometrorrhagia: frequent and excessive

bleeding without any cyclic pattern.

Dysfunctional uterine bleeding is abnormal uterine

bleeding with no demonstrable organic cause. It is

a diagnosis of exclusion. Approximately one-half

of dysfunctional uterine bleeding occurs between

ages 40 and 50,5 caused by estrogen secretion sufficient to stimulate endometrial growth but insufficient to induce a midcycle surge of LH. In older

women, the capacity of follicles to secrete estradiol is diminished; progesterone secretion and the

length of the luteal phase subsequently decrease, 

at which time menstrual irregularities begin. (See

also ch. 2, sec. 4.)6 Decreases in progesterone

cause abnormal endometrial structure, which in

turn gives rise to uterine bleeding varying from

spotting to heavy bleeding.7

2.2 Endometrial Changes in the 

Transition Period

Histologic studies of the endometrium in the years

before and after menopause show important

interindividual and intraindividual variations.

Frequently, the endometrium appears out of phase

with endocrine events and appears autonomous. 

In many cases, the endometria are hyperplastic;

however, endometrial atrophy is the most common

histologic finding after menopause. Trevoux et al.

found the greatest degree of variability in endometrial appearance in the year before menopause,

when 42 percent of the endometria were atrophic

Gynecologists are

often responsible

for the management

of perimenopausal

health issues.
205

or hypotrophic, 24 percent were proliferative, 24

percent were secretory (30 percent of those showed

luteal delay), and 9 percent showed hyperplasia.8

Endometrial hyperplasia, a premalignant lesion,

may be simple or complex. Risk for transformation

to cancer is much greater when atypia is present

(table 10–1).9,10 Endometrial hyperplasia can revert

to normal with administration of a progestin. In a

study of 85 patients with endometrial hyperplasia,

long-term progestin treatment provided uniform

protection against malignant transformation in the

65 without cytological atypia; in the 20 with atypia,

however, endometrial cancer developed in 25 percent, even after 2–7 years of progestin treatment.11

Whereas hyperplasia is uncommon in young

women with normal menstrual cycles (1 percent),

it is frequently found in the transition period

women (6–13 percent)12 or in women presenting

with abnormal bleeding (4–30 percent).13

In patients with abnormal uterine bleeding, cancer

of the reproductive tract is found in < 10 percent of

those who are in the menopausal transition but in

about 25 percent of those who are postmenopausal.5

Although cancer is not the most common etiology,

perimenopausal bleeding should be considered secondary to malignancy until proved otherwise.

Risk for endometrial cancer increases with age

until menopause when it begins to decrease.14

Other risk factors include diabetes,15 chronic

anovulation, obesity, and estrogen-producing ovarian tumors. There are two types of

endometrial cancer. The more prevalent and less aggressive occurs in

obese, younger women with high

concentrations of circulating estrogen

and in postmenopausal women

receiving estrogen without progestin.

The second, more aggressive type

affects older women without signs of

hyperestrogenism. Use of unopposed

estrogen increases a postmenopausal

woman’s risk for adenocarcinoma of the

endometrium by twofold to ninefold, compared

with no estrogen use, and there is a clear association between the duration of replacement therapy

and risk.16–18 Although long-term use of unopposed

estrogen, even in very low dosages, in postmenopausal women is the single most important

modifiable risk factor for endometrial cancer after

obesity, cases of endometrial cancer have been

reported during long-term estrogen-progestin

replacement therapy,19 more frequently with cyclic

use of progestins18,19 than with continuous combinations. Menopausal women treated with tamoxifen

Endometrial

hyperplasia

can revert to

normal with

administration

of progestin.

TABLE 10–1

Probability That Untreated Endometrial Hyperplasia Will Progress 

to Carcinoma

Type of Hyperplasia Cytologic Atypia Progression to Carcinoma (percent) 

Simple Absent 1

Complex Absent 6

Simple Present 7

Complex Present 33

Sources: Data are from Kurman et al.9 and Baak et al.10
206

for breast cancer are at increased risk as well.20

As noted above, estrogen-induced endometrial 

carcinoma belongs to the less aggressive type.21

2.3 Bleeding During Hormone 

Replacement Therapy 

The use of sex steroid hormones for therapeutic or preventive purposes has introduced a new cause of uterine

bleeding, which should be

clearly differentiated from

organic conditions.

Uterine bleeding due to HRT is

a cause of patient concern,22

inconvenience,23,24 and discontinuation of use.25,26 Clinical

aspects of the bleeding differ

according to the treatment 

regimen. Nonhysterectomized

patients taking unopposed

estrogen often have vaginal

bleeding;27 however, the administration of unopposed estrogen should be limited to hysterectomized women. A progestin should be added in

all other cases, because sequential addition of a

progestin for 10–14 days will in the short-term

prevent estrogen-induced hyperplasia.27

Nevertheless, there is a modest increase in risk for

endometrial cancer after 3 years of sequential

progestin use.28,29 Progestin decreases mitotic activity of endometrial cells by secretory conversion 

of estrogen–primed glandular cells and decidual

changes of stromal fibroblasts. In addition, 

progestin inhibits synthesis of ERs.30

Bleeding during HRT may be related to the 

specific regimen. Other causes of bleeding during

hormone replacement are failure of compliance

(missed tablets, failure to change patch), absorption problems (intestinal problems, change in diet,

use of antibiotics, defective patch compliance, skin

problems), endometrial pathology (atrophy, polyps,

submucosal leiomyoma, hyperplasia, adenocarcinoma), myometrial pathology, and drug use (anticoagulants, steroids, barbiturates, chemotherapy).

2.3.1 Sequential Estrogen-Progestin

Replacement Therapy 

About 95 percent of women receiving sequential

combined HRT will experience withdrawal bleeding after the progestin phase. About 6 percent will

not bleed at all; the likelihood of no bleeding is

higher in older age.31 The absence of withdrawal

bleeding may also be due to pregnancy which

should be excluded in perimenopausal women, too

little estrogen in the preparation used, or cervical

stenosis. The most common forms of irregular

bleeding during sequential estrogen-progestin

replacement therapy11 are—

• Bleeding during the estrogen-only phase, which

is more likely associated with endometrial

pathology than bleeding during the progestin

phase.

• Bleeding before day 11 of progestin treatment, a

result of incomplete shedding and correctable

by a higher progestin dose.

• Prolonged, heavy cyclic bleeding, which may

be due to too much estrogen or insufficient

progestin in the preparation used, may be due to

endometrial pathology, or may represent an

abnormal response to replacement therapy.

• Breakthrough bleeding, which is often caused

by benign hyperplasia but may be due to an

atrophic endometrium associated with an insufficient estrogen dosage.

2.3.2 Continuous Estrogen-Progestin

Replacement Therapy 

Continuous administration of a progestin in combination with estrogen has been suggested to prevent

the cyclic withdrawal bleeding associated with

HRT.32 Nevertheless, a high incidence of episodes

of irregular bleeding (50 percent) has been

observed, particularly during the first months.33,34

Bleeding is usually slight, and the incidence of

episodes decreases rapidly with time. Bleeding

The use of sex

steroid hormones 

for therapeutic or 

preventive purposes

has introduced a

new cause of uterine

bleeding, which

should be clearly 

differentiated from

organic conditions.
207

usually disappears within 1 year.34 Because

endometrial cancer has been reported during continuous combined regimens, evaluation is needed

if bleeding persists.18

2.4 Diagnosis and Management of Abnormal

Uterine Bleeding 

Incidence of bleeding episodes without HRT

decreases with the time since menopause. In addition to the use of HRT, the differential diagnosis

for dysfunctional peri-postmenopausal uterine

bleeding includes reproductive tract disorders, 

systemic disorders, and iatrogenic causes (table

10–2). Complaints of excessive uterine bleeding

immediately suggest a genital source; however,

bleeding can originate in the urinary or gastrointestinal tract, a confusion more common in elderly

patients. It must be reemphasized that perimenopausal uterine bleeding in women not receiving HRT should be considered endometrial cancer

until proved otherwise.

Measurement of endometrial thickness is a noninvasive clinical indicator of endometrial normality.

Studies comparing ultrasonographic measurement

of endometrial thickness with histopathologic 

TABLE 10–2

Differential Diagnosis of Abnormal Uterine Bleeding at Any Age

Disorders of the Genital Tract 

• Complications of early pregnancy 

• Benign pelvic lesions 

• Cervicitis 

Uterine leiomyoma 

Polyps 

Adenomyosis 

Endometritis 

Traumatic 

• Malignant pelvic lesions 

Cervix, endometrium, fallopian tube, ovary, vulva 

Endometrial hyperplasia 

Systemic Disorders

• Coagulation disorders

• Liver diseases 

• Renal failure 

Iatrogenic Causes 

• Steroids 

• Anticoagulants 

• Hemodialysis 

• Intrauterine contraceptive device (IUD)
208

findings on biopsy in women with and without use

of HRT showed endometrial thickness < 4 mm to

correlate with atrophic endometrium and thickness

> 4–7 mm to correlate with increased incidence of

endometrial pathology in both groups.35–39 Endometrial

cancer is rarely found when endometrial thickness

is < 4 mm (double layer).40 Ultrasound scanning

cannot replace histopathologic assessment in

women receiving HRT.40–43 In women receiving

hormones, the endometrium is often thicker than in

untreated menopausal women. With sequential

estrogen-progestin regimens, endometrial thickness

can vary depending on the treatment phase.

Sonography can accurately assess endometrial

thickness in the proliferative or postmenopausal

phase. Hysteroscopy, however, can easily detect

endometrial pathology at any time and allows

biopsy under direct vision when a lesion is identified. Thus, several groups consider hysteroscopy 

to be the gold standard.5

More recently, sonohysterography, which is less

invasive and less expensive than hysteroscopy,

has been proposed as a

better method for the

morphologic evaluation

of the endometrium.44

Clinical management of abnormal uterine bleeding

in perimenopausal patients is addressed according

to the diagnosis, observation, surgery, or specific

changes in the treatment regimen. For example, in

patients with bleeding during the progestin phase

of sequential combined HRT, increasing the progestin potency should be beneficial. A drug-free

interval of 3 to 7 days can also improve the bleeding pattern. In patients with bleeding during continuous combined HRT, lowering the estrogen and

progestin doses can be the answer. In difficult

cases, a very weak estrogen (estriol), tibolone, or

local therapy for the treatment of vulvovaginal

atrophy may be suggested since this therapy is

almost always associated with amenorrhea.45

3. GENITAL ATROPHY AND

VULVOVAGINAL COMPLAINTS

The inner layer of the vagina is stratified squamous epithelium, the middle layer is muscular, 

and the outer layer is fibrous.46 The epithelial cells

contain the highest number of nuclear estrogen

binding sites of any genital structure. Even higher

numbers are noted in the postmenopausal vagina.47,48 Because estrogen is progressively depleted

during postmenopausal years, the percentage of

superficial cells decreases. Vaginal secretions,

made up mainly of vaginal wall transudate and

cervical mucus, also decrease because their production is estrogen-dependent and largely mediated

by blood flow.49,50

In the atrophic vagina, lubrication with sexual

stimulation decreases. The vaginal surface becomes

fragile, and petechiae and bleeding often occur

after minimal trauma. Because estrogen is also

responsible for deposition of glycogen in the vaginal epithelium, the absence of glycogen-containing

superficial cells results in decreased production of

lactic and acetic acids. This causes abnormally low

vaginal pH (3.8 to 4.2) and creates a milieu that

favors infection.

Vulvovaginal complaints are very common in

postmenopausal women.51 The most common local 

complaint is vaginal dryness. The loss of lubrication

leads directly to vaginitis, vaginismus, and dyspareunia. Estrogen is efficacious in treatment, and local

estrogens are as effective as systemic in the therapy

of genital atrophy.52 Atrophic vaginitis is the most

common cause of benign postmenopausal bleeding.

4. PELVIC FLOOR AND URINARY TRACT

With estrogen loss, relaxation of vaginal tissue and

decreased perineal muscle tone occur, a situation

associated with decreased sexual response as well

as urinary and bowel dysfunction.53 Kegel (pelvic

floor) exercises are often prescribed in the therapy

of vaginismus and stress incontinence.

Estrogen is efficacious 

in treatment, and local

estrogens are as effective

as systemic in the therapy

of genital atrophy.
209

Estrogen deficiency causes atrophic changes of the

urethral epithelium and the submucosa. This may

lead to incomplete urethral closure and an abnormal urinary flow pattern. In addition, urethral atrophy predisposes to ascending infections and urogenital infections, which constitute a major problem in elderly women.54,55 It is important to identify

patients with recurrent infections because of the

significant morbidity, which includes risk for renal

impairment. Urinary tract infections are usually

secondary to stepwise colonization of the vaginal

introitus and urethral mucosa by organisms from

the rectal flora. ERT reduces urinary tract infections

in postmenopausal years probably by its support of

normal vaginal flora.56

To ensure continence, urethral pressure must

exceed bladder pressure except during micturition.

Positive urethral closure pressure is produced by the

urethra. All four functional layers of the urethra—

epithelium, connective tissue, vascular tissue, 

and muscle—are affected by estrogen status. In

particular, the connective tissue is an important

component; collagen is its most abundant structural

protein.57 ERT enhances collagen production by

fibroblasts.58

5. URINARY INCONTINENCE

UI is a common but poorly understood problem.

The International Continence Society defines

incontinence as involuntary loss of urine that is

objectively demonstrable and is a social or hygienic problem.59 In 1998, a review of published population-based studies of prevalence to determine the

estimated prevalence of incontinence stratified by

frequency, age, and gender reported rates that varied from 14–35 percent.60 The Agency for Health

Care Policy and Research (AHCPR) estimates that

13 million Americans are incontinent; 11 million

are women.61

The economic costs can be substantial with direct

costs from diagnosis, treatment, and continuing

care, including purchase of products for protection,

as well as indirect costs from loss of freedom and

independent living. A report of incontinence in

individuals aged 65 and older in the United States

in 1995 revealed a cost of $24.3 billion dollars or

$3,565 per individual with incontinence.62 The

Agency for Healthcare Research and Quality

(AHRQ) calculates for the United States $16.4 

billion is spent every year on incontinence-related

care: $11.2 billion for community-based programs

and at home, and $5.2 billion in long-term care

facilities. Furthermore, $1.1 billion is spent every

year on disposable products for adults.

The relationship between menopause and UI is

unknown and not well studied. Although many

experts quote menopause as a major risk factor for

both stress and urge incontinence, there has been

limited data to support this. It is theorized the lack

of estrogen in menopause can result in thinning of

the lining of the urethra, which causes improper

closure. Estrogen deficiency also makes the bladder muscles weaken. The combination of a thin,

injury-prone urinary tract and weak bladder 

muscles can cause the

urethra to open unexpectedly during physical

activity, leading to stress

incontinence.

5.1 Types and Causes of Urinary Incontinence

Established UI can usually be divided into one of

four major types: stress incontinence, urge incontinence (detrusor overactivity or instability), mixed

incontinence, and overflow incontinence. These

disorders often have classic histories or typical

physical findings. Neurogenic incontinence may be

related to defects in the nervous system, which

conducts urination signals between the bladder and

the brain. As it is not related to menopause, it will

not be discussed.

Stress Incontinence: It is diagnosed when, in the

absence of a detrusor contraction, the pressure

inside the bladder exceeds the pressure in the ureUI is a common but poorly

understood problem. 
210

thra. Patients typically describe losses of small

volumes of urine with activities resulting in transiently increased intra-abdominal pressure (coughing, sneezing, running, laughing). It is thought that

these changes become more pronounced following

menopause as estrogen deficiency allows atrophy

of the genitourinary tissues; however, there is no

real evidence that this is the case. Physical examination may reveal evidence of pelvic relaxation,

such as cystocele, rectocele, and/or uterine prolapse. Urine loss can usually be demonstrated with

coughing while the patient is in the supine position.

Urge Incontinence: It is diagnosed when the

detrusor muscle contracts, spontaneously or on

provocation, during the filling phase of the bladder

while the woman is attempting to inhibit micturition.59 Urge incontinence is more common in older

adults. This type of incontinence is also known as

detrusor overactivity, detrusor instability, detrusor

hyper-reflexia, or uninhibited bladder. Patients

with detrusor overactivity have early, forceful

detrusor contractions, well before the bladder is

full. This creates a sensation of urinary urgency

and frequency. Patients with detrusor overactivity

tend to lose small to moderate volumes of urine. If

the detrusor contraction is strong enough to overcome the urethral resistance, incontinence occurs.

The diagnosis of detrusor overactivity is made primarily by history and confirmed with urodynamic

testing. There are no pathognomonic findings on

physical examination, although a careful pelvic

and rectal examination and neurologic screening

can occasionally reveal anatomic abnormalities

(e.g., uterine prolapse, fecal impaction) or evidence of neurologic disease.

Mixed Incontinence: It is a combination of both

stress and urge incontinence and is most common

in older women.

Overflow Incontinence: In overflow incontinence,

the bladder becomes too full because it can’t be

fully emptied. This condition is rare and is the

result of bladder obstruction or injury. Those with

overflow incontinence commonly present with

symptoms of markedly reduced urinary stream,

incomplete or unsuccessful voiding, and frequent

or even continuous urinary dribbling. Overflow

incontinence is generally due to bladder contractile

dysfunction (hypotonic/atonic bladder) or vesicles

obstructing urinary outflow. In either case, large

bladder volumes result in the intravesicular pressure

exceeding intraurethral resistance, and symptoms

of urinary dribbling. Physical examination often

reveals a distended bladder, and measurement of

urine volume after voiding reveals an elevated

postvoid residual volume. Patients also demonstrate low urinary flow rates on urodynamic tests.

Other factors can cause incontinence, such as

decreased mobility, cognitive impairment, or 

medications (table 10–3).

5.2 Evaluation

Evaluation and treatment for incontinence is

dependent on the type of incontinence and the person’s age, medical history, and desire for therapy.

The assessment for incontinence should include a

history; physical examination; and mental, functional, and environmental assessments.

The characteristics of the incontinence are noted,

including the onset, frequency, and severity as

determined through the person’s description of the

problem and the pattern of incontinence behavior.

Urinary symptoms provide clues to possible causes

of the problem and, when combined with the information obtained from a history and physical examination, a provisional diagnosis can often be made.

The patient should be thoroughly questioned about

related urinary symptoms and habits. Symptoms

can be classified as obstructive or irritative.

Obstructive symptoms include hesitancy, dribbling,

intermittency, impaired trajectory, and sensation of

incomplete emptying. Irritative symptoms include

nocturia, frequency, urgency, and dysuria.

Obstructive symptoms often require referral to a

specialist, whereas irritative symptoms can often

be controlled by behavioral interventions.
211

Obtaining a recent medical history can identify

acute or reversible causes. Significant past medical

history includes the number of births, recurrent

urinary tract infections, bladder repair surgeries,

and pelvic radiation. The history should include an

assessment of memory impairment and environmental barriers. A mental status assessment should

be performed if the person has memory loss.

Certain environmental barriers, such as the location of the toilet, may be contributing to the incontinence. This is especially true in older persons. In

these cases, incontinence may improve with the

use of catheters or other urine assistive or collective devices.

5.3 Urodynamics

Urodynamic assessment includes a group of tests

that measure bladder function. Multichannel urodynamic studies include uroflow, cystometrogram,

urethral pressure profiles, and electromyogram.

Today, multichannel urodynamic studies to document bladder pressure and capacity, muscle contractibility, urethral length, and sphincter control

are performed under the auspice of a gynecologist

specializing in disorders of the pelvic floor or an

urologist. These studies should be done if surgery

on the pelvic floor is being considered for UI.

5.4 Treatment

Treatment for incontinence depends on the type of

incontinence, its causes, and the capabilities of the

patient. The evidence on the effects of clinical

interventions will be reviewed below.

5.4.1 Pelvic Muscle Rehabilitation (To Improve

Pelvic Muscle Tone and Prevent Leakage)

Pelvic Floor Muscle Exercises

Kegel Exercises. Regular, daily exercising of

pelvic muscles can improve, and even prevent, 

urinary incontinence. This is particularly helpful

for younger women. Kegel exercises should be

performed 30–80 times daily for at least 8 weeks.

TABLE 10–3

Other Factors Causing Incontinence

Drug Side Effect 

Antidepressants, antipsychotics, sedatives/hypnotics Sedation, retention (overflow) 

Diuretics Frequency, urgency (OAB)

Caffeine Frequency, urgency (OAB)

Anticholinergics Retention (overflow)

Alcohol Sedation, frequency (OAB)

Narcotics Retention, constipation, sedation (OAB and overflow)

Alpha-adrenergic blockers Decreased urethral tone (stress incontinence)

Alpha-adrenergic agonists Increased urethral tone, retention (overflow)

Beta-adrenergic agonists Inhibited detrusor function, retention (overflow)

Calcium channel blockers Retention (overflow)

ACE inhibitors Cough (stress incontinence)

OAB = Overactive Bladder
212

Biofeedback: Used in conjunction with Kegel

exercises, biofeedback helps people gain awareness and control of their pelvic muscles.

One review identified 15 RCTs, 8 of

sufficient quality for conclusion in a

further analysis.63 Women performing pelvic floor muscle exercises in

comparison with no treatment were

more likely to be dry or mildly

incontinent than the no treatment

group (61 percent versus 3 percent).

After 3 months, incontinent episodes

were significantly reduced in the

treatment group. There was a

greater rate of “cure or almost cure” for high intensity home-based pelvic floor muscle exercise versus low intensity (60 percent versus 17 percent).

There were five randomized clinical trials comparing biofeedback versus pelvic floor muscle exercise.

One trial found biofeedback significantly improved

UI, while the other four found no difference.

In a meta-analysis of the five trials identified in the

systematic review, the odds ratio (OR) for biofeedback combined with pelvic floor muscle exercises

alone, leading to cure was 2.1 (95 percent confidence interval (CI) 0.99–4.4).64 The authors concluded that biofeedback might be an important

adjunct to pelvic floor muscle exercises alone in

the treatment of female genuine stress UI. A quantitative statistical analysis of the studies identified

leads to different conclusions from those in the

systematic review. One randomized clinical trials

compared pelvic floor muscle training with bladder

training or the two treatments combined.65

Combination of therapy had the greatest immediate

satisfaction in the management of female UI

regardless of urodynamic diagnosis. However,

each of the three interventions had similar effects 3

months after treatment.

Vaginal Weight Training

Small weights are held within the vagina by tightening the vaginal muscles. Vaginal weight training

should be performed for 15 minutes, twice daily,

for 4 to 6 weeks.

The systematic review described above identified

three randomized clinical trials comparing pelvic

floor muscle exercise alone or in combination with

an intravaginal resistance device (one clinical trial)

or biofeedback (two clinical trials).63 There was no

significant difference in the frequency of incontinent episodes per week. One randomized clinical

trials compared pelvic floor exercises, electrical

stimulation, vaginal cones, and no treatment for

genuine stress incontinence. Training of the pelvic

floor muscles was superior to electrical stimulation

and vaginal cones in the treatment of genuine

stress incontinence.66

Pelvic Floor Electrical Stimulation

Mild electrical pulses stimulate muscle contractions. Pelvic floor electrical stimulation should be

performed in conjunction with Kegel exercises.

Two systematic reviews of randomized clinical 

trials found conflicting evidence on the effects of

electrical stimulation of the pelvic floor in women

with stress incontinence.63,65 randomized clinical 

trials have found it less effective than pelvic floor

muscle exercises.

5.4.2 Behavioral Therapies (To Assist In 

Regaining Control of Bladder Function)

Bladder Training: It teaches people to resist the

urge to void and to gradually expand the intervals

between voiding. Biofeedback and muscle conditioning, known as bladder training, can alter the

bladder’s schedule for storing and emptying urine.

These techniques are effective for urge and overflow incontinence. The evidence on biofeedback is

reviewed above.

Toileting Assistance: Toileting assistance uses

routine or scheduled toileting, habit training schedules, and prompted voiding to empty the bladder

Regular, daily

exercising of

pelvic muscles

can improve,

and even 

prevent, UI. 
213

regularly to prevent leaking. Timed voiding (urinating) and bladder training are techniques that use

biofeedback. In timed voiding, individuals fill in a

chart of voiding and leaking. From the patterns

that appear in their chart, they can plan to empty

their bladder before they would otherwise leak.

5.4.3 Pharmacologic Therapies

Alpha-Adrenergic Agonists

Alpha-adrenergic agonist drugs may improve the

micturition of patients suffering from forms of

incontinence requiring increased muscle tone and

urethral resistance. Phenylpropanolamine

hydrochloride, the prototype agent in this class, is

an independent risk factor for hemorrhagic stroke

in women.67 One systematic review identified one

randomized clinical trial on phenylpropanolamine.63

There was no significant difference between pelvic

floor muscle exercise and phenylpropanolamine. New

alpha-adrenergic agonists with tissue selectivity are

in development—oxymetazoline and methoxamine.

Muscarinic Receptor Antagonists

Tolterodine tartrate (Detrol, Pharmacia

Corporation, Peapack, NJ) is classified as a muscarinic receptor antagonist: it blocks nerve receptors that respond to the chemical muscarine. Both

bladder contraction and salivation (formation of

saliva) are controlled by muscarinic receptors. By

blocking muscarinic nerve receptors, tolterodine

tartrate can reduce symptoms of urinary frequency

or urgency and can treat bladder overactivity and

urge incontinence.

Two randomized clinical trials showed tolterodine

administration resulted in a significant decrease in

the frequency of voiding and improved voided volume with few troublesome or severe side

effects.68,69 Two other RCTs compared tolterodine

and oxybutinin. One study compared the efficacy

and safety of tolterodine given at 1 or 2 mg b.i.d.

versus placebo.70 At week 4, a statistically significant increase in the volume at first contraction (p =

0.030) and maximal cystometric capacity 

(p = 0.034) occurred only in the tolterodine 2 mg

b.i.d. group. The other studied the clinical efficacy

(determined from micturition diaries) and safety of

12 weeks’ treatment with either tolterodine 2 mg

twice daily, oxybutinin 5 mg three times daily, or

placebo in 277 patients with an overactive bladder.71 Both tolterodine and oxybutinin significantly

increased volume voided/micturition compared to

placebo. Both treatment groups evoked greater

decreases in micturition per 24 hours and incontinence episodes per 24 hours compared to placebo;

however, only tolterodine was significantly better

than placebo in reducing micturition frequency.

Anticholinergic Medications 

Oxybutynin (brand name Ditropan,

Alza Pharmaceuticals, Kalamazoo,

MI) prevents urge incontinence by

relaxing detrusor muscle. One RCT

shows the benefit of oxybutynin in

reducing the episodes of incontinence.72 A once-daily formulation

(Ditropan XL) reduced the number

of incontinence episodes with less

side effects than the short-acting

formulation.73–75 Oxybutinin and

tolterodine are equivalent in their

effectiveness. A recent RCT of

biofeedback, medication, and placebo showed behavioral treatment was significantly

more effective than drug treatment and both were

more effective than the placebo control condition.76

Estrogen Replacement Therapy

Estrogen, oral or vaginal, until recently has been

thought to improve incontinent episodes, either

alone or in conjunction with other treatments, for

postmenopausal women with incontinence. Both

the urethra and trigone of the bladder are covered

by non-keratinized squamous epithelium similar to

the vagina.77 These tissues contain ERs78,79 and

respond to estrogen.80,81 In the baboon model, ERT

increased urethral closure pressures, suggesting that

ERT might be effective treatment for incontinence.82

Tolterodine

administration

resulted in a

significant

decrease in the

frequency of

voiding and

improved 

voided volume.
214

There has been one systematic review and 17

uncontrolled trials of estrogen for the treatment of

incontinence in women.83 Although the uncontrolled trials showed subjective improvement of

incontinence, three randomized clinical trials

found no objective improvement in measures of

urine loss. Two subsequent RCTs found no significant difference between treatment and control

groups in the number of incontinent episodes at 3

and 6 months of followup.84,85 Several large observational studies have shown an increased risk of

UI in older women on HRT.86–88 There are no data

on the use of vaginal estrogen creams or the estrogen ring for the treatment of incontinence. A randomized clinical trial (HERS) found HRT to be

associated with worsening of UI.89

Combined Estrogen/Alpha-Adrenergic 

Agonist Therapy

Since ERT appears to heighten the response of

nerve receptors in the urethra (the alpha-adrenergic

receptors, which increase the tone of striated and

smooth muscle), a combination of estrogen and

alpha-adrenergic agonists may be beneficial in

postmenopausal women who lose bladder control

because of insufficiency (malfunction) of the urinary sphincter muscles. Two trials of combination

therapy concluded that frequency and nocturia

improved more with combined treatment than with

estrogen alone.76 Newer

agents in development

may offer promise in combination with estrogen.

Phenylpropanolamine

should no longer be used

for the treatment of UI.

5.4.4 Bulking Injections (Such as Collagen)

An RCT on periurethral injection of collagen in

women with genuine stress incontinence followed

for 5 or more years found no evidence to support

the use of periurethral collagen injections in

women with intrinsic sphincter deficiency.90 A

recent case series of 63 consecutive women who

had sphincteric incontinence confirmed by urodynamics and who underwent a total of 131

transurethral collagen injections showed a low

short-term cure rate.91

5.4.5 Surgical Treatment 

Surgical treatment can be very effective in improving or curing stress incontinence.

5.5 Treatment Recommendations for the

Chronically Incontinent

Although many people will improve their continence through treatment, some will never become

completely dry. They may need to take medications that cause incontinent episodes or have cognitive or physical impairments that keep them from

being able to perform pelvic muscle exercises or

retrain their bladders. Many will be cared for in

long-term care facilities or at home. The AHRQ

guideline update makes the following recommendations to help caregivers keep the chronically

incontinent drier and reduce their cost of care:

• Scheduled toileting. Take people to the 

toilet every 2 to 4 hours or according to their

toilet habits. 

• Prompted voiding. Check for dryness, and

encourage use of the toilet.

• Improved access to toilets. Use equipment

such as canes, walkers, wheelchairs, and

devices that raise the seating level of toilets 

to make toileting easier.

• Managing fluids and diet. Eliminate dietary

caffeine (for those with urge incontinence), 

and encourage adequate fiber in the diet.

• Disposable absorbent garments. Use to keep

people dry.

• Education

The AHRQ guideline recommends that patients

and professionals learn about the different treatment options for incontinence. Patients and their

families should know that incontinence is not

Surgical treatment can

be very effective in

improving or curing

stress incontinence.
215

inevitable or shameful but is treatable or at least

manageable. All management alternatives should

be explained. Professional education about incontinence evaluation and treatment should be included

in the basic curricula of undergraduate and graduate training programs of all health care providers,

as well as continuing education programs.

6. URINARY TRACT INFECTIONS

Estrogens may increase alpha receptor sensitivity

in urethral smooth muscle.92 In addition, estrogen

treatment increases numbers of epithelial cells in

the urethra and bladder. Through those mechanisms, estrogen may reduce urinary tract infections.

7. PELVIC ORGAN PROLAPSE

SERMs may increase risk for pelvic organ prolapse.93 The possible risk for pelvic organ prolapse

with SERMs was first identified in the clinical trials of levormeloxifene. Subsequently, the development of this pharmaceutical was discontinued, primarily for endometrial concerns. However, pelvic

organ prolapse was reported to the Food and Drug

Administration (FDA) as an adverse event associated with the drug.

Idoxifene was the second SERM in which a preponderance of prolapse cases was observed in

treated versus untreated women. Of the 1,436 nonhysterectomized women enrolled in two clinical

trial groups, there were 9 uterine prolapses, 3 cystoceles (bladder prolapse), and 3 cystocele/rectocele (bladder/rectal prolapse) combinations; all

were identified in the treated group (there were 14

cases total; 1 subject had uterine prolapse and cystocele/rectocele), and 0 cases were identified in the

untreated group (B. MacDonald, personal communication). The cohorts were evenly matched for

BMI (a stratification variable) and age. This difference between groups was statistically significant

by Fisher’s exact test, p < 0.0001. Heavy cigarette

smoking was an exclusion criterion, and data on

parity were not collected. As mentioned earlier,

this drug has also been discontinued from development for concerns both with the endometrium and

pelvic organ prolapse.

In the phase 2 studies of droloxifene,

the prevalence of all prolapse disorders at baseline in over 1,000 women

was 10 percent, the same in both

groups (A. Lee, personal communication). In the phase 3 studies, 300

osteoporotic women on 4 different doses, the incidence of prolapse was the same between groups.

Clinical trials with this drug have been closed

because of endometrial stimulation. To this

author’s knowledge, no increase in incidence has

been reported with raloxifene94 or tamoxifen.95

While only levormeloxifene and idoxifene showed

a problem with prolapse, all SERMs must be evaluated for this adverse effect. Although the predominance of pelvic organ prolapse was higher in the

group treated with idoxifene, the overall incidence

was lower than that commonly reported in the general population. While confounding factors, such

as age, parity, obesity, and cigarette smoking, were

not established as equal between groups, the obvious imbalance of prolapse in the treated group

should not be ignored.

There are many inconsistencies in the adverse

events between groups in the clinical trials on

these drugs that cause us to examine the results

more carefully. The incidence of prolapse was

extraordinarily low in the idoxifene study (0 percent in the untreated group and 1.5 percent in the

treated group). Although pelvic organ prolapse is

one of the most common indications for gynecologic surgery, there is little epidemiologic information regarding the condition. In one report from

Quebec, it accounted for 13 percent of all hysterectomies in all age groups.96 The idoxifene groups

were not necessarily similar for confounding factors, such as age, parity, obesity, cigarette smoking,

and other risk factors for pelvic organ prolapse. A

difference between groups could explain the differEstrogen may

reduce urinary

tract infections.
216

ence in pelvic organ prolapse. The majority of the

case reports on idoxifene occurred after rumors

surfaced of problems with pelvic organ prolapse in

the levormeloxifene phase 3 trial. The investigators

may have become sensitized to looking for prolapse after the reports on levormeloxifene.

8. FUTURE NEEDS

• More data are needed on the determinants of

endometrial function and on the specific effect

of ovarian hormones on skin and different 

urogenital mucosae.

• New ERβ and ERα agonists and antagonists as

well as new progestins are needed.

• There is a need for sensitive methods for early

diagnosis at the molecular level of estrogen

defects in various tissues, additional noninvasive methods of endometrial testing, and reliable diagnostic indexes for pelvic floor and urogenital syndromes, to improve clinical testing.

• Future clinical trials need to assess the relationship between SERMs and pelvic organ prolapse; future preclinical studies need to investigate whether some SERMs modify or otherwise

affect collagen, increasing the elasticity of the

pelvic floor tissues and increasing the risk for

pelvic organ prolapse.

• Future clinical trial research should include the

use of a standardized pelvic exam administered

by gynecologists or other clinicians trained in a

uniform approach, and consideration should be

given to excluding those women with moderate

to severe prolapse until the effect of SERMs on

the risk of prolapse is better known.
217

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North Am 1997;26(2):347–60.

78 Iosif CS, Batra S, Ek A, Astedt B. Estrogen receptors

in the human female lower uninary tract. Am J

Obstet Gynecol 1981;141(7):817–20.

79 Ingelman-Sundberg A, Rosen J, Gustafsson SA,

Carlstrom K. Cytosol estrogen receptors in the 

urogenital tissues in stress-incontinent women.

Acta Obstet Gynecol Scand 1981;60(6):585–6.

80 Bergman A, Karram MM, Bhatia NN. Changes in

urethral cytology following estrogen administration. Gynecol Obstet Invest 1990;29(3):211–13.

81 van der Linden MC, Gerretsen G, Brandhorst MS,

Ooms EC, Kremer CM, Doesburg WH. The effect

of estriol on the cytology of urethra and vagina 

in postmenopausal women with genito–urinary

symptoms. Eur J Obstet Gynecol Reprod Biol

1993;51(1):29–33.

82 Bump RC, Friedman CI. Intraluminal urethral 

pressure measurements in the female baboon:

effects of hormonal manipulation. J Urol

1986;136(2):508–11.

83 Cardozo LD, Kelleher CJ. Sex hormones, the

menopause and urinary problems (review). Gynecol

Endocrinol 1995;9(1):75–84.

84 Fantl JA, Bump RC, Robinson D, McClish DK,

Wyman JF. Efficacy of estrogen supplementation 

in the treatment of urinary incontinence. The

Continence Program for Women Research Group.

Obstet Gynecol 1996;88(5):745–9.

85 Jackson S, Shepherd A, Brookes S, Abrams P. The

effect of oestrogen supplementation on postmenopausal urinary stress incontinence: a doubleblind placebo–controlled trial. Br J Obstet

Gynaecol 1999;106(7):711–18.
221

86 Brown JS, Seeley DG, Fong J, Black DM, Ensrud

KE, Grady D. Urinary incontinence in older

women: who is at risk? Study of Osteoporotic

Fractures Research Group. Obstet Gynecol

1996;87(5 Pt 1):715–21.

87 Thom DH, van den Eeden SK, Brown JS. Evaluation

of parturition and other reproductive variables as

risk factors for urinary incontinence in later life.

Obstet Gynecol 1997;90(6):983–9.

88 Diokno AC, Brock BM, Herzog AR, Bromberg J.

Medical correlates of urinary incontinence in the

elderly. Urology 1990;36(2):129–38.

89 Grady D, Brown JS, Vittinghoff E, Applegate W,

Varner E, Snyder T. Postmenopausal hormones and

incontinence: the Heart and Estrogen/Progestin

Replacement Study. Obstet Gynecol

2001;97(1):116–20.

90 Gorton E, Stanton S, Monga A, Wiskind AK, Lentz

GM, Bland DR. Periurethral collagen injection: a

long–term follow-up study. BJU Int

1999;84(9):966–71.

91 Groutz A, Blaivas JG, Kesler SS, Weiss JP, Chaikin

DC. Outcome results of transurethral collagen

injection for female stress incontinence: 

assessment by urinary incontinence score. 

J Urol 2000;164(6):2006–9.

92 Formosa M, Brincat MP, Cardozo LD, Studd JWW.

Collagen: the significance in skin, bones, and 

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New York: Raven Press, 1994:143–51.

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Selective Estrogen Receptor Modulators (SERMs),

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94 Goldstein SR, Neven P, Zhou L, Taylor YL, Ciaccia

AV, Plouffe L. Raloxifene effect on frequency of

surgery for pelvic floor relaxation. Obstet Gynecol

2001;98(1):91–6.

95 Fisher B, Constantino JP, Wickerham DL, et al.

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of the National Surgical Adjuvant Breast and

Bowel Project P-1 study. J Natl Cancer Inst

1998;90(18):1371–88.

96 Allard P, Rochette L. The descriptive epidemiology of

hysterectomy, Province of Quebec, 1981–1988.

Ann Epidemiol 1991;1(6):541–9.
222
223

CHAPTER 11: HORMONE REPLACEMENT THERAPY, RELATED

THERAPIES, AND CANCER EPIDEMIOLOGY

1. There is no appreciable association between short-term (i.e., < 5 years) use 

of HRT and breast cancer risk. Longer use is associated with a moderate 

excess breast cancer risk for current users but not former users. Combined 

HRT may be associated with higher breast cancer risk compared with 

unopposed estrogen.

2. Combined HRT is not related to a major excess of endometrial cancer, if 

progestins are given for more than 10–14 days per cycle.

3. The evidence for HRT and ovarian cancer risk is less consistent than that for

endometrial and breast cancer, but available data include the possibility that HRT

increases ovarian cancer risk.

4. HRT may reduce colorectal cancer risk, but further research is required to confirm and quantify a favorable

effect of HRT on colorectal cancer.

5. There is no consistent association between HRT use and liver cancer, other gastrointestinal neoplasms, or

melanoma.

6. SERMs may have a favorable effect on breast cancer, CVDs, and bone. Research studies examining these

issues with raloxifene therapy are in progress.

Carlo La Vecchia, M.D.;* Louise A. Brinton, Ph.D.;† and Anne McTiernan, M.D., Ph.D.‡

KEY POINTSa

* From the Laboratory of Epidemiology, Mario Negri Institute for Pharmacological Research, Professor of Epidemiology, University of Milan, Milan,

Italy.

† From the Environmental Epidemiology Branch, National Cancer Institute, NIH, Bethesda, MD, U.S.A. 

‡ From the Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Research Associate Professor, Department of Epidemiology,

University of Washington Schools of Medicine and Public Health and Community Medicine, Seattle, WA, U.S.A.

a Evidence categories are given in square brackets. A = randomized controlled trials (rich body of data); B = randomized controlled trials (limited data); 

C = nonrandomized trials and observational epidemiologic studies; D = Panel expert judgement. (See also table 1–1.) All findings in this chapter belong

to evidence category C, as they address side effects rather than interventions. This should not weaken the significance of the results.

There is no appreciable

association between

short-term (i.e., < 5

years) use of HRT and

breast cancer risk.
224

1. INTRODUCTION

Worldwide, breast cancer is by far the most frequent cancer in women and the leading cause of

death, accounting for more than 300,000 deaths

each years as estimated from 1999 statistics.1,2

Ovarian cancer adds another 100,000 deaths each

year and cancer of the uterus adds 40,000. In the

United States, breast cancer (the second leading

cause of cancer death in women, after lung or

bronchial cancers) and cancers of the ovary and

uterus account for 23 percent of cancer deaths in

women as estimated for 2000.3

Menopause and age at menopause

have a profound effect on the risk

of cancer in women, including

breast, endometrium, ovary, and

other less common cancers.

Although the incidence rises with

age, the rate slows around the

time of menopause for most cancers, which does not occur with

hormone-independent adult cancers, such as lung cancer.4

Age at menopause is a recognized risk factor for

breast cancer, with risk increasing with later age at

menopause.5–7 It is unclear whether latency effects

are involved or whether the association between

menopause and breast cancer risk varies by different ages at breast cancer diagnosis.7–9 The most

precise and reliable estimate of the influence of

age at menopause on breast cancer risk is given by

the collaborative reanalysis of individual data from

51 epidemiologic studies, most conducted in North

America or Europe, of 52,705 women with breast

cancer.10 The Collaborative Group believed these

studied represented > 90 percent of the observational data available at that time. Thirty-three percent of women had received HRT at some time.

Among never users, an increased risk of 2.8 percent per year of delayed menopause was estimated.

Difficulties also exist in understanding and in 

disentangling the potential effects of type of

menopause. Trends similar to those observed for

all menopausal types were detected in women

experiencing surgical menopause in some studies,7,11 while they differed in others.9,12 This is probably attributable to varying definitions of surgical

menopause, with some studies including only

women with a hysterectomy alone and others also

including those with unilateral or bilateral

oophorectomy. Inclusion of women with simple

hysterectomy leads to an underestimation of the

effect of age at menopause, as well as of exogenous hormones, on breast cancer risk.13

Pooled data from two case-control studies conducted between 1983 and 1994 in Italy14 on 3,576

menopausal women with incident, histologically

confirmed breast cancer and 3,578 menopausal

control subjects admitted to hospital for acute,

nonneoplastic, nonhormonal, nongynecological

conditions provided information on the role of 

age and type of menopause. When all types of

menopause were considered together, the floating

absolute risks (FARs) (which avoid the definition

of an arbitrary reference category)15 were 0.49 for

< 35 years, 0.81 for 35–39 years, 0.82 for 40–44

years, 0.88 for 45–47 years, 1.02 for 48–50 years,

1.23 for 51–53 years, and 1.24 for 54–56 years,

with a significant linear trend in risk. A stronger

association was observed in women reporting natural menopause, with FARs of 0.14 for women

with menopause < 35 years versus 1.20 for those

with menopause at 54–56 years (ratio between the

two extreme FAR estimates = 8.6). No trend with

age at menopause was seen among the overall surgical menopause group, or among groups defined

by hysterectomy alone, hysterectomy with unilateral oophorectomy, or bilateral oophorectomy.

When only women reporting bilateral oophorectomy were considered, a strong linear trend in risk

was observed. No heterogeneity emerged when

risks were evaluated in separate strata of age at

diagnosis/interview.

Later menopause has also been associated with

increased risks of ovarian16 and endometrial canWorldwide, breast

cancer is by far

the most frequent 

cancer in women

and the leading

cause of cancer

death in women.
225

cers,17 and perhaps with a reduced risk of colorectal

cancer,18 although this issue is still open to discussion.

Of major concern is the effect on cancer risk of

HRT.19,20 HRT reduces climacteric symptoms (see

ch. 3) and has favorable effects on bone metabolism

and osteoporosis (see ch. 9) and possibly on coronary heart disease and other CVDs (see ch. 8).21–23

It may also reduce the risk of colorectal cancer.24

Total mortality among women who use HRT is

lower than among nonusers, which probably to a

large extent reflects favorable health characteristics

of women who decide and continue to use HRT.25

HRT has also a number of adverse effects, the

main ones being a promotional effect on endometrial cancer, and some elevation in the risk of

breast and, possibly, ovarian cancers.20,26,27 These

hormonal effects on risk of various neoplasms are

considered in the present review.

2. BREAST CANCER

A summary tabulation of the

main risk factors for breast 

cancer is given in table 11–1.

Breast cancer incidence varies

markedly among countries. It is highest in the

United States and Northern Europe and lowest in

Asia.28 Numerous observational epidemiologic

studies have examined the relationship between

HRT and breast cancer, providing answers often

Breast cancer 

incidence varies

markedly among

countries.

TABLE 11–1

Summary Tabulation of Risk Factors for Breast Cancer

Factors Influencing Risk Estimated Relative Risk*

Residency in North America or Europe versus Asia 4–5

Residency in urban areas 1.5

White race 2

Higher levels of education or income 1.5

Mother or sister with breast cancer 2–3

Nulliparity or late ages at first birth (> 30 versus < 20 yr) 2–3

Absence of breastfeeding for long durations 1.5

Early ages at menarche (< 3 versus > 15 yr) 1.5

Late ages at natural menopause (> 55 versus < 45) 2

Recent use of estrogens or combined estrogen-progestin replacement therapy 1.4–1.8

Use of oral contraceptives (premenopausal risk only) 1.2

High cumulative doses of tamoxifen 0.5

Biopsy confirmed proliferative breast disease or dense mammographic patterns 2–5

Overweight (postmenopausal risk only) (BMI > 28 versus < 22) 2

Radiation to chest in moderate to high doses 1.5–2

History of breast cancer in one breast 2–4

History of primary cancer in endometrium, ovary 1.5–2

*Relative risks depend on the population under investigation and reference group employed.
226

difficult to compare because of complex methodological issues, statistical power. and potential confounding variables.

2.1 Hormone Replacement Therapy and 

Breast Cancer 

As with age at menopause, most

information on HRT and breast

cancer derives from a reanalysis

of individual data from 51 epidemiologic studies, conducted in

21 countries and including 52,705

women with breast cancer and

108,411 controls.10 This showed a

2.3 percent (95 percent CI, 1.1 to

3.6 percent) increase in the RR of

breast cancer for each year of

HRT use among current or recent

users (who stopped use 1 to 4 years previously).

This corresponds to an RR of 1.35 (95 percent CI

1.20 to 1.49) for those who had used HRT for 5

years or more and to a cumulative excess for women

who began use of HRT at age 50 of approximately

2 cases/1,000 women for 5-year users, 6 cases/1,000

women for 10-year users, and 12 cases/1,000

women for 15-year users compared with never users.

This increase was comparable with the effect of

later menopause on breast cancer. This elevated risk,

however, leveled off after stopping HRT use, with

no significant excess risk observed at 5 or more

years after stopping, as compared to never users.

The use of HRT for a short time (i.e., < 5 years) to

control menopausal symptoms is not related to any

material increase in the risk of breast cancer, whereas

long-term use increases breast cancer risk in current

users.10,21,29 The biologic mechanism underlying this

association remains unclear. Changes in the composition of the breast tissue have been documented,

with greater mammographic density (an established risk factor for breast cancer) noted following

hormone use.30,31 Also of interest is whether genetic

factors, including polymorphisms in hormonemetabolizing genes, might be etiologically involved.

Further research in this area is critically needed. 

Another open question is the impact on breast cancer risk of the combination of estrogen and progestin, a replacement therapy effective in reducing

the excess endometrial cancer risk associated with

estrogen use alone.32 There are biologic reasons to

suspect an unfavorable effect of added progestin

on breast carcinogenesis, since ovulatory cycles

are related to breast cancer risk and breast mitotic

activity is higher during the luteal phase of the

cycle (when progesterone levels are at their highest).33,34 An early report of a Swedish cohort study35

suggested that combined HRT may be more

strongly related to breast cancer risk than estrogen

alone, with a nonsignificantly elevated RR of 1.2

for ever use and of 4.4 for more than 6 years use

of combined HRT (95 percent CI 0.9 to 22.4),

based on 10 cases (hence a wide CI); the RR was

1.8 (1.0 to 3.1) for > 9 year use of estrogen alone,

on the basis of data on 23 cases). An update of the

same study36 confirmed these findings, showing

RRs of 1.4 (95 percent CI 0.9 to 2.3) after 1 to 6

years and 1.7 (95 percent CI 1.1 to 2.6) after more

than 6 years of use of combined HRT. The excess

risk, however, appeared confined to recent users.

No excess risk relative to short-term users was

shown for users of estrogen alone. Three other

studies from Britain,37 Denmark,38 and Sweden 39

showed an association between combined HRT

and breast cancer. A report from the American

Nurses’ Health Study cohort40 confirmed some

excess breast cancer risk among current long-term

HRT users versus never users: the RRs were 1.3

(95 percent CI 1.1 to 1.5) for conjugated estrogen

users, 1.3 (95 percent CI 1.0 to 1.7) for other estrogen users, and 1.4 (95 percent CI 1.2 to 1.7) for

estrogen plus progestin. A large case-control study

(N = 3,345 and 3,454) in Sweden risk showed a

significant increasing risk with duration of different types of combined estrogen-progestin use (OR

of 3.0 for women treated for more than 10 years).41

A recent report of 46,355 participants followed for

a mean of 10.2 years in the Breast Cancer

Detection and Demonstration Project (BCDDP)

There are no

available data

from clinical trials

investigating the 

relationship

between HRT and

breast cancer.
227

showed that women who had used combined estrogen and progesterone had a 40-percent increased

incidence rate (RR 1.4, 95 percent CI, 1.1 to 1.8)

of developing breast cancer compared with never

users.42 Furthermore, the risk from combined HRT

was greater than with unopposed estrogen (RR 1.2,

95 percent CI 1.0 to 1.4), compared to cases in which

HRT had never been used. The increased risk was

limited to recent use of hormones (current use or

use within previous 4 years). The increased risk

was also largely confined to women with a BMIs ≤

24.4 or less, which indicates that there could be a

threshold effect of HRT since heavier women are

likely to have a higher average level of endogenous

estrogen that in itself increases risk. After menopause,

adipose tissue is the major source of endogenous

estrogen, which may account for the continued slow

rise in incidence of hormone-dependent cancers 

in postmenopausal women in countries with a high

prevalence of overweight and obesity.4,17

Likewise, a population-based case-control study

(N = 1,897 and 1,637) conducted among postmenopausal women from Los Angeles County43

found an OR of 1.1 (95 percent CI 0.97 to 1.15)

for each 5 years of ERT use, but of 1.2 (95 percent

CI 1.07 to 1.45) for each 5 years of combined

estrogen-progestin treatment, suggesting that the

addition of a progestin to HRT enhances the risk 

of breast cancer relative to estrogen use alone.

The reanalysis of individual data from 51 studies,10

however, found a similar excess breast cancer risk

for women using estrogen alone and combined

estrogen-progestin replacement treatment, and no

marked differences in relation to hormone types or

doses of HRT preparations, although little information was available about long duration of use of any

specific preparation. The issue, therefore, remains

open to discussion and further quantification.44

A case-control study from Washington State45 suggested that combined HRT increases the risk of

lobular but not ductal breast carcinoma, but the

findings are inconclusive due to the small number

of exposed cases.

There are no available data from clinical trials

investigating the relationship between HRT and

breast cancer, but the PEPI trial reported that

increased mammographic density was observed in

3.5 percent of the estrogen-only group and in 16 to

23 percent of the different estrogen/progestin regimens.46 Some studies have suggested that mammographic parenchymal density may adversely affect

diagnostic accuracy.

Another major issue is the time-risk relationship

after stopping HRT. The effect of steroid hormones

is thought to be on the later stages of carcinogenesis (i.e., they are promoters);47 consequently, the

increased breast cancer risk associated with HRT

should decline within a few years after stopping use.

Although the absence of a long-term cumulative

risk is clearly reassuring,48 a 20- to 30-percent

excess risk of breast cancer in women aged 50 to

65 years—when HRT use is most frequent—has to

be weighed against the benefits of HRT on the

bone and perhaps on the cardiovascular system,

since the incidence of breast cancer is high in the

sixth decade of life.49–51

Another open question is

whether the relation

between HRT and breast

cancer risk differs at various ages. Since there are

indications that it is influenced by age at diagnosis, with a higher RR in

older women,40,52 any

risk-benefit ratio is particularly critical and must be carefully and individually assessed for elderly women using HRT after

menopause.53,50 However, in reanalysis of individual data from the 51 studies, no significant interaction was observed between the RR for HRT use

and age,10 although elderly women were at a

greater absolute risk of breast cancer given

increasing incidence trends with age.

In conclusion, evidence

from observational 

epidemiologic studies

indicates that the risk of

breast cancer is elevated

among women using HRT.
228

Although HRT has been related to an increased

incidence of breast cancer, use appears to lead to

lower mortality from breast cancer or to improved

prognosis in some,53–60 although not all,25,61 studies.

Although some of these effects may be due to

increased medical surveillance and detection of

early-stage tumors among hormone users,57 a

favorable effect of hormone use on the characteristics of breast tumors cannot be 

dismissed.62

Although a diagnosis of

breast cancer has been

conventionally viewed

as a contraindication for

subsequent HRT use, as

breast cancer patients

remain at risk for recurrence of their cancers

for many years,63 this

notion is being questioned;4 recent data show

favorable effects of HRT on breast cancer prognosis.

Although the few studies that have addressed this

issue seem to indicate no adverse effects of HRT

use among breast cancer survivors, sample sizes

have been limited.65 Additional studies are needed.66

In conclusion, evidence from observational epidemiologic studies indicates that the risk of breast

cancer is elevated among women using HRT,

increases with longer duration of use is reduced

after cessation of use and levels off about 5 years

after stopping use. Recommendations for prolonged HRT use must be considered on an individual basis, taking into account the presence of other

risk factors for breast cancer, such as family history

of breast cancer or a personal history of benign

breast disease.

3. ENDOMETRIAL CANCER

A summary tabulation of the main risk factors for

endometrial cancer is given in table 11–2.

The possibility that HRT could increase endometrial

cancer risk was suggested on the basis of a substantial rise in the incidence of endometrial cancer

in the United States (particularly in California) in

the early 1970s, following widespread unopposed

HRT use.17 Two case-control studies, published 

in 1975 in the same issue of the New England

Journal of Medicine, confirmed this observation.67,68 The possibility that this relationship might

merely reflect a detection bias was raised, either

through increased medical surveillance of HRT

users or because estrogens caused bleeding of

existing tumors, prompting the diagnosis of endometrial cancer. The presence of more differentiated

neoplasms, and, hence, better survival rates after

cancer diagnosis in HRT users, was also reported.69

Epidemiologic evidence now confirms the existence of a relationship between estrogen use and

endometrial cancer and confirms the persistence of

elevated risk several years after cessation of use.70

The risk is about two to three times greater in ever

than in never users of estrogen, with a summary

the RR from a meta-analysis of published studies

of 2.3 (95 percent CI 2.1 to 2.5);71 the risk estimates were similar for cohort (RR 1.7) and casecontrol studies using hospital (OR 2.2) or population (OR 2.4) controls. The summary risk was

directly related to duration of use: the RR was 1.4

(95 percent CI 1.0–1.8) for use < 1 year, 2.8 (95

percent CI 2.3–3.5) for 1–5 years, 5.9 (95 percent

CI 4.7–7.5) for 5–9 years, and 9.5 (95 percent CI

7.4–12.3) for > 10 years; the RR was inversely

related to time elapsed since last use,71 suggesting

that estrogen has a late-stage effect in endometrial47,72 as well as in breast carcinogenesis. 

Similarly to breast cancer, estrogen-associated

risks for endometrial cancer tend to be higher in

leaner than overweight women, who have higher

endogenous estrogen levels and availability. The

Epidemiologic evidence

now confirms the 

existence of a relationship

between estrogen use 

and endometrial cancer.
229

combined effect of exogenous and endogenous

estrogens is additive rather than multiplicative,

suggesting that exogenous estrogens and obesity

act through similar biologic mechanisms on the

risk of the disease.73 Estrogens and obesity appear,

therefore, to have an additive rather than a multiplicative interaction, which suggests either an

upper risk threshold and/or some limiting factor

(e.g., sex hormone receptors), which stops the

estrogen-raising effect of obesity and exogenous

estrogen accumulating beyond a certain level.73

Some studies suggest a greater excess risk of HRT

among smokers,74 who tend to have lower estrogen

availability,75 and a lower HRT-related risk among

women who had a history of use of combined

OCs.74,76 Others77 failed to delineate a subgroup that

is exempt from the increased risk of endometrial

cancer associated with use of unopposed estrogen.

Data on the type, dose, or regimen of estrogen use

do not provide a clear assessment of risk, and in

general, there appears to be no clear relationship

with type of preparation, its potency and bioavailability, dose and duration, although users of highdose preparations tend to have a higher risk.74,78 In

the meta-analysis by Grady et al.,71 the RR was 3.9

(95 percent CI 1.6 to 9.5) for users of 0.3 mg conjugated estrogens, 3.4 (95 percent CI 2.0 to 5.6)

for users of 0.625 mg, and 5.8 (95 percent CI

4.5–7.5) for users of > 1.25 mg; it is not clear

whether duration and other time factors could be

adequately controlled in these analyses. The RR

was 2.5 (95 percent CI 2.1 to 2.9) for users of conjugated estrogens and 1.3 (95 percent CI 1.1 to

1.6) for users of synthetic estrogens. With reference to pattern or regimen of use, the RR was 3.0

(95 percent CI 2.4 to 3.8) for intermittent and

TABLE 11–2

Summary Tabulation of Risk Factors for Endometrial Cancer

Factors Influencing Risk Estimated Relative Risk*

Residency in North America or Europe versus Asia 4–5

White race 1.5–2

Higher levels of education or income 1.5–2

Nulliparity 3

History of infertility 2–3

Menstrual irregularities 1.5

Early ages at menarche (< 13 versus > 15 yr) 1.5–2

Late age at natural menopause (> 55 versus < 45 yr) 2

Long-term use of ERT 5–10

Use of oral contraceptives 0.3–0.5

High cumulative doses of tamoxifen 3–7

Overweight (BMI > 28 versus < 22) 2–5

Stein-Leventhal disease or estrogen-producing tumors > 5

Histories of diabetes, hypertension, gallbladder disease, or thyroid disease 1.3–3

Cigarette smoking 0.5

*Relative risks depend on the population under investigation and reference group employed.
230

cyclic use and 2.9 (95 percent CI 2.2 to 3.8) for

continuous regimens.71 It is not clear whether differences in the baseline characteristics of women

using the various preparations may explain these

apparent differences in RR.

In terms of population attributable risks, it has

been estimated that unopposed estrogen treatment

was related to more than 50 percent of cases of

endometrial cancer in North America in the late

1970s70 and 10–25 percent of cases in selected

European countries in the 1980s.76,79

The cyclic addition of progestin to estrogen (for at

least 7 days in each treatment cycle) protects

against endometrial hyperplasia, which is considered an endometrial cancer precursor, as shown by

a multicenter randomized clinical trial.32 However,

data on long-term consequences are not completely

reassuring, since of 41 patients treated for a mean

duration of 8 years, 6 patients experienced breakthrough bleeding and 2 had adenocarcinoma of the

endometrium.80

The summary RR from a metaanalysis71 of endometrial cancer 

in women using cyclic combined HRT was 0.8 (95 percent

CI 0.6 to 2.2). However, the

results from cohort and casecontrol studies were inconsistent, with the pooled RR being

0.4 for the cohort studies and

1.8 for the case-control studies.

The number of days per month of progestin addition is an important determinant of risk. One

study81 suggested that the RR was reduced from

2.4 for women using progestins for less than 10

days per month to 1.1 for women using them for

ten days or more per month. In a population-based

case-control study (N = 832 cases and 1,114 controls),82 the RR for ever users was 3.1 (95 percent

CI 1.7 to 5.7) for women with fewer than 10 days

of added progestin per month and 1.3 (95 percent

CI 0.8 to 2.2) for those with 10 to 21 days of

added progestin. Another study of 833 cases and

791 population controls from Los Angeles

County83 showed RRs per 5 years of use of 2.2 (95

percent CI 2.0 to 2.5) for unopposed estrogen, 1.9

(95 percent CI 1.3 to 2.6) for estrogen plus progestin for less than 10 days per month, and 1.1 (95

percent CI 0.8 to 1.4) when progestin was given

for 10 days or more. 

A case-control (N = 709 and 3,368) study conducted

in Sweden on endometrial cancer in menopausal

women84 confirmed a strong association with unopposed estrogen (OR = 6.2 for estradiol and 6.6 for

conjugated estrogens for 5 or more years of use).

The association was considerably less strong for

the combination of estrogen and progestin (OR =

1.6, 95 percent CI 1.1 to 2.4), and the excess risk

was restricted to cyclic progestin usage. The risk

was below unity for continuous use of progestin

(OR = 0.2, 95 percent CI 0.1 to 0.8 for use lasting

5 years or longer).

A record linkage study conducted in Sweden on a

cohort of 8,438 women at risk of endometrial cancer36 has shown—on the basis of 66 observed cases

versus 34.8 expected—an RR of 4.2 (95 percent CI

2.5–8.4) for 6 years or more of use of unopposed

estrogen and of 1.4 (95 percent CI 0.6–3.3) for combined estrogen and progestin replacement therapy.

In a case-control study conducted between 1994

and 1998 in Ontario, Canada (521 cases and 513

controls), the RR was 4.1 (95 percent CI 2.2–7.7)

for use of > 5 years unopposed HRT, and around

1.5 (of borderline significance) for various types 

of combined replacement therapies, although the

numbers of subjects were small in most subgroups.85

Thus, although the use of estrogen alone may

increase endometrial cancer risk, several studies

indicate that combined replacement therapy is not

related to a major excess of endometrial cancer, if

progestin is given for more than 10 or 14 days in

each cycle.86

Descriptive studies

are consistent with

the absence of a

major effect of HRT

on ovarian 

carcinogenesis.
231

4. OVARIAN CANCER

Descriptive studies are consistent with the absence

of a major effect of HRT on ovarian carcinogenesis.87

Major findings of cohort and case-control studies

and reanalyses of individual data on HRT and

ovarian cancer risk are shown in table 11–3.88–106

Two cohort studies have shown no relationship

between use of HRT and ovarian cancer risk. They

are the Walnut Creek Study on Contraception,88

based on 16,638 women followed for 13 years 

(RR = 1.0), and a Swedish cohort study,91 based on

23,246 women followed for an average of 8.6

years (RR 0.99, 95 percent CI 0.76–1.27). In contrast, in the American Cancer Society Cancer

Prevention Study II (CPS-II),89 based on mortality

data of 240,073 women followed for 7 years, the

RR was 1.4 (95 percent CI 0.9–2.1) for 6–10 years

of use and 1.7 (95 percent CI 1.1–2.8) for ≥ 11

years of use of HRT; this elevated risk was not

explained by other known or likely risk factors for

ovarian cancer. The 14-year followup of the same

CPS-II study93 confirmed the relationship between

HRT and ovarian cancer. The RR was 1.5 (95 percent CI 1.1–2.0) for ever use and 2.2 (95 percent

CI 1.5–3.2) for baseline users (i.e., current users at

interview). Among former users, the RR decreased

with time since last use.

At least 12 case-control studies (see table 11–3) and

a reanalysis of individual data of 12 U.S. case control studies have provided data on HRT and ovarian cancer risk. Of these, seven studies—including

two from the United States,94,98 one populationbased case-control investigation from Canada,103

and four European studies, from the United

Kingdom,99 Greece,96,100 and Italy101—reported an

increased RR (i.e., between 1.2 and 1.6) when

compared to control subjects. In some, and particularly in the largest European studies,99,101 the elevated risk estimates were significant. Other case-control studies published since 1980, including three in

the United States,92,97,104 one in Italy,95 and two in

Australia,102,107 found no clear relationship between

ever use of HRT and ovarian cancer risk.

The combined analysis of individual data from 12

United States case-control studies, based on 2,197

white women with invasive epithelial ovarian cancer

and 8,893 white controls,105 found a pooled multivariate RR of invasive ovarian cancer for ever HRT

use of 0.9 (95 percent CI 0.7–1.3) in hospital-based

and 1.1 (95 percent CI 0.9–1.4)

in population-based studies; the

analysis found no consistent

duration-risk relation, after

allowance for age, study, parity,

and OC use. The overall RR

per year of use was 0.98 for

hospital-based and 1.02 for population-based studies; neither

estimate was significant. The

RR for ever HRT use was 1.1

(95 percent CI 0.7–1.9) in a

reanalysis of original data considering 327 cases of borderline

epithelial ovarian cancers.106

A collaborative reanalysis of four European studies

from the United Kingdom, Italy, and Greece, based

on 1,470 ovarian cancer patients and 3,271 hospital

controls found an OR of 1.71 (95 percent CI

1.30–2.25) for ever HRT use, a weak direct positive

relationship with duration of use, and some indication that the excess RR for ovarian cancer declined

with time since last use.108 The overall RR estimate

from a meta-analysis of all published data was 

1.15 (95 percent CI 1.0–1.3) for ever use and 1.27

(95 percent CI 1.0–1.6) for > 10 years of use.109

It is not clear whether HRT is related to any specific histologic type of ovarian cancer. A Canadian

study103 found ORs of 1.4 for serous, 1.9 for

endometrioid, and 0.7 for mucinous tumors, with

significant trends in risk with duration of use for

serous and endometrioid tumors. Purdie et al.107 also

found an elevated risk of endometrioid and clear

cell ovarian cancers associated with unopposed

estrogen use (RR 2.6, 95 percent CI 1.3–4.9).

Thus, the evidence 

on HRT and ovarian 

cancer is less 

consistent than that

for endometrial 

and breast cancer,

but a moderate 

association remains

open to debate.
232

TABLE 11–3

Selected Studies on Hormone Replacement Therapy in Menopause and

Ovarian Cancer Risk, 1980–1997

Relative Risks

for Ever HRT Use

1.0

1.2

1.0

1.0

Relative Risks

for Ever HRT Use

0.9

1.3

1.0

1.6

Cohort Studies

Reference

Petitti et al.,88 1987, U.S.A.

Rodriguez et al.,89 1995,

U.S.A.

Adami et al.,90 1989,

Sweden

Schairer et al.,91 1997,

Sweden

Reference

Hildreth et al.,92 1981,

U.S.A.

Weiss et al.,94 1982, 

U.S.A.

Franceschi et al.,95 1982,

Italy

Tzonou et al.,96 1984,

Greece

Outcome

Mortality

Mortality

Incidence

Mortality

Study Design

Hospital-based

Population-based

Hospital-based

Hospital-based

No. of Cases

(Age Group)

6

436

64

52

No. of Cases

(Age Group)

62

(65–74)

112

(36–55)

161

(19–69)

112

(postmenopause)

Observations

13-year mortality 

followup of the Walnut

Creek Study on

Contraception.

Direct relationship with

duration. The RR was

1.4 for 6–10 years and

1.7 for ≥ 11 years of use.

Cohort of 23,246 women

prescribed HRT, 

followed for an average

of 6.7 years.

As above, followup for

mortality 8.6 years.

Observations

Nonsignificant 

(95% CI 0.5–1.6).

No consistent durationrisk relationship.

Stronger association for

endometrioid neoplasms.

Adjusted for age, area 

of residence, and 

hysterectomy.

Nonsignificant.

Case-Control Studies
233

TABLE 11–3 (continued)

Relative Risks

for Ever HRT Use

0.9

1.2

1.5

1.4

1.6

1.0

1.3

0.9

Reference

Harlow et al.,97 1988,

U.S.A.

Kaufman et al.,98 1989,

U.S.A.

Booth et al.,99 1989, UK

Polychronopoulou et al.,100

1993, Greece

Parazzini et al.,101 1994,

Italy

Purdie et al.,102 1995,

Australia

Risch et al.,103 1996,

Ontario, Canada

Hempling et al.,104 1997,

U.S.A.

Study Design

Hospital-based

Hospital-based

Hospital-based

Hospital-based

Hospital-based

Population-based

Population-based

Hospital-based

No. of Cases

(Age Group)

116

(20–59)

377

(18–69)

158

(< 65)

152

(30–64)

953

(23–74)

824

(18–79)

367

491

Observations

Borderline ovarian neoplasms. No consistent

duration-risk relationship.

Unopposed estrogen

only. No association

with combined treatment

(OR 0.7) or with specific

histotypes. Some duration-risk relationship.

Nonsignificant 

(95% CI 0.9–2.6). 

No association with 

specific histotypes.

Nonsignificant 

(95% CI 0.4–4.9).

Adjusted for major

covariates, including

oral contraceptive use.

95% CI 1.2–2.3. 

Modest duration-risk

relationship.

Multivariate OR, 95%

CI 0.8–1.3.

Multivariate OR 2.0 

for serous and 2.8 for

mucinous for ≥ 4 years

of use. No association

with mucinous tumours.

Other cancers as controls. No duration-risk

relationship.

Case-Control Studies (continued)
234

Thus, a strong association between HRT and invasive or borderline malignant epithelial ovarian neoplasms can be excluded, although relationships

with histological subtypes may exist. However, it

is possible that ovarian cancers in women who had

used HRT are more often classified as endometrioid tumors, and there is a lack of clear understanding of the biologic meaning of histologic type.

Very little information is available on the addition

of progestin to estrogen preparations. In a cohort of

4,544 women, recruited since 1978 from 21 menopause clinics in Britain and followed to 1988,55

HRT use could not be related to ovarian cancer risk

increase (RR = 0.63); similarly, in a multicenter

case-control study (N = 377 cases and 2,030 controls) conducted between 1976 and 1985 in various

United States areas (Kaufman et al., 1989),98 only

2 percent of cases and controls had ever used combination HRT, and the multivariate RR was 0.7 (95

percent CI 0.2–1.8).

Thus, the evidence on HRT and ovarian cancer is less

consistent than that for endometrial and breast cancer,

but a moderate association remains open to debate.

5. COLORECTAL CANCER

Colorectal cancer is the most frequent cancer in

nonsmokers of both sexes combined in Western

countries.87,110 Similar incidences between the two

sexes are seen for colon cancer, while a male 

predominance is found for rectal cancer.

During the last two decades, mortality rates from

colorectal cancer in many developed countries

have declined in women but not in men.24,87 A role

of exogenous female hormones (i.e., OCs, and

HRT) on these trends is possible.

Eight cohort studies (see table 11–4) reported

information on HRT use and colorectal cancer risk,

for a total of over 2,400 cases. Most studies

showed RRs around or below unity. A significant

inverse relation was found in two cohort investigations, including the largest one focusing on fatal

colon cancers (table 11–4).56,90,111–119 Findings from a

recent study also suggested that HRT use may

improve short-term survival after a diagnosis of

colon cancer.120

TABLE 11–3 (continued)

Relative Risks

for Ever HRT Use

0.9/1.1

0.9/1.1

Overviews

Reference

Whittemore et al.,105 1992,

U.S.A.

Harris et al.,106 1992,

U.S.A.

Study Design

Pooled analysis of

12 U.S. hospitaland populationbased case-control

studies

As above

No. of Cases

(Age Group)

2,197

(all ages)

327

(all ages)

Observations

Invasive cancers. 

No duration-risk 

relationship.

Borderline ovarian 

neoplasms. Hospitalbased/population-based

studies. No duration-risk

relationship.
235

Of 12 case-control studies (see table 11–5)18,121–134

for a total of over 5,000 cases, five reported 20–40

percent significant risk reductions among ever users

of HRT. Two additional investigations showed

moderate, nonsignificant inverse relationships. 

Studies showing an inverse relationship between

HRT use and colorectal cancer were among the

largest and best controlled ones. The apparent protection tended to be stronger among recent users.

Differences in RRs by duration of HRT use and

anatomic subsite were not consistent, but the protective effect seemed stronger in most recent publications. Available studies support the possibility of

an inverse relationship between colorectal cancer

and HRT, but prevention and surveillance bias cannot be ruled out.135

Very few studies have allowed distinguishing

unopposed from opposed estrogen, and all included few subjects exposed to opposed estrogen only.

Among these, one cohort study56 and one case-control investigation132 suggested an inverse relationship of opposed estrogen with cancer of the colon,

as for HRT of any type. Differences in RRs by

anatomic subsite were not consistent, but the data

for rectal cancer are scantier than for colon cancer.

Finally, risk reduction has appeared stronger in

more recent publications.

A meta-analysis of 20 studies published up to

December 1996136 found an overall RR for ever

HRT use of 0.85 (95 percent CI 0.7–0.9). The protection was greater for current or recent users (RR

0.69, 95 percent CI 0.5–0.9) and users of more

than 5 years (RR 0.73, 95 percent CI 0.5–1.0). 

Taken together, available data suggest the possibility of a real inverse association between colon cancer and HRT. A causal interpretation of the above

findings is, however, hampered by (1) the timerelated risk pattern observed; (2) the potential for

prevention bias (i.e., a more favourable pattern of

risk factor exposure)137 or surveillance bias in

women taking HRT;8 and (3) lack of clear understanding of the possible mechanisms of action of

HRT on colorectal mucosa. Postmenopausal

women treated with HRT tend to be of higher

social class and more educated.137,139 This selection

may imply a healthier lifestyle (e.g., more frequent

consumption of vegetables, higher levels of physical activity, and lower prevalence of being overweight). In addition, long-term HRT users are, by

definition, compliant, which is, per se, a favorable

health indicator.137 (See also ch. 4.)

The inverse relation between colorectal cancer risk

and HRT tends to emerge soon after first exposure

113,127 and seems to level off 5–10 years after cessation. The apparent protection increases with duration in some116,127 but not all113,132 studies. Such a pattern of risk seems compatible with the possibility

that HRT acts as a promoting agent.140 Of the few

studies on precursors for colorectal cancer, a large

prospective investigation127 found a decreased risk

for large colorectal adenomas but no effect on risk

for small adenomas. Of concern is the possibility

that women may discontinue HRT when symptoms

of disease develop,138 leaving mainly healthy

women in the category of current users. However,

no difference in risk was found between current

users and recent users (i.e., those who had stopped

HRT in the past 5 years).113

Sex hormones modify hepatic

cholesterol production and alter

bile acid concentration.141

Secondary bile acids are believed

to favor malignant changes in the

colonic epithelium, and exogenous estrogens, which decrease

secondary bile acid production

and can alter intestinal microflora, could, therefore, protect

against colorectal cancer. Issa et

al.142 suggested that methylation-associated inactivation of the ER gene in ageing colorectal mucosa

could predispose to colorectal tumorigenesis.

Exogenous estrogen may thus counteract the natural

decline of circulating estrogen in postmenopausal

women. However, data on reproductive and menColorectal cancer

is the most 

frequent cancer 

in nonsmokers 

of both sexes

combined in

Western countries.
236TABLE 11–4

Cohort Studies on Hormone Replacement Therapy and Colorectal Cancer

HRTEstriol Opposed HRTAny typeCurrent usersPast usersFormer usersCurrent users

ReferenceWu et al.,1111987Adami et al.,901989 andPersson et al.561996 Chute et al.,1121991 andGrodstein etal.,113 1998

Bostick et al.,114

1994 andFolsom et al.,1151995

CountryCalifornia,U.S.A.SwedenU.S.A.,Nurses’Health StudyIowa, U.S.A.

Population(Followup)No Cancer7,345(4 years)6822,597(13 years)23362 deaths59,002(14 years)47041,837(6 years)293

Duration of UseNo effect(RR = 1.02, 0.6–1.8, for ≥ 8-year use)

No effectNo effect(RR = 0.7, 0.5–1.0,for ≥ 5 year use)

Inverse trend(RR = 0.31 for ≤ 5

year use)

Recency of UseNot shownNot shownNo risk reductionafter 5 years ofdiscontinuation(RR = 0.9, 0.8–1.2)No effect

Adjustment CommentsAge.Age.RR for colonmortality = 0.6, 0.4–0.9.Age, BMI, OC use, cancer family history,diet, alcohol, smoking, and age at menopause.Age, BMI, W/H ratio,alcohol, exercise, andmedical history.

ColonRectum1.00(n. s.)——0.7(0.5–0.8)0.8(0.7–1.1)

Colon—0.9(0.7–1.1)1.0(0.8–1.3)0.6(0.4–1.0)0.9(0.7–1.2)0.6(0.5–0.9)0.7(0.7–1.1)0.8(0.6–1.1)0.7(0.5–1.1)

Rectum—0.9(0.7–1.2)0.8(0.5–1.2)0.8(0.4–1.3)0.9(0.7–1.1)0.7(0.4–1.1)0.8(0.5–1.2)—

RR (95% Confidence Interval)

(Ever versus Never Users)
237 BCDDP = Breast Cancer Detection Demonstration Project, BMI = Body Mass Index, W/H Ratio = Waist/Hip Ratio, OC = Oral Contraceptives. + = Recent users (≤ 1 year)

—Unopposed HRTOpposed HRTAny HRT

ReferenceCalle et al.,1161995Risch andHowe,1171995Troisi et al.,1181997Paganini-Hill,1191999

CountryU.S.A.,CPS-IICanadaU.S.A.,BCDDPU.S.A.,LeisureWorldCohort

Population(Followup)No Cancer422,373(7 years)897 deaths32,973(14 years)23033,779(7.7 years)3137,701(14.5 years)249

Duration of UseSignificant trend(RR = 0.5, 0.4–0.8, for > 11 year use)RR = 0.7(0.2–2.6for ≥ 5 years)

No effectRR = 0.75For ≥ 15 years

Recency of UseStronger effectamong current users(RR = 0.5, 0.4–0.8)Not shownRR for recent use= 0.78(0.55–1.1)0.66(0.44–0.98)

Adjustment CommentsAge.Linkage study.Age (but unaltered byeducation, BMI, parityand OC use).Age.Significant trend withrecency of use.

ColonRectum1.0(0.7–1.5)—0.99(0.79–1.2)0.81(0.63–1.04)

Colon0.7(0.6–0.8)1.3(0.9–1.9)1.1(0.7–1.5)1.4(0.7–2.5)1.1(0.81–1.6)0.70+(0.45–1.09)

Rectum—0.6(0.3–1.2)1.2(0.7–2.3)—1.1(0.59–1.9)0.52+(0.21–1.31)

RR (95% Confidence Interval)

(Ever versus Never Users)

TABLE 11–4 (continued)
238TABLE 11–5

Case-Control Studies on Hormone Replacement Therapy and Colorectal Cancer

Current users:Former users:

ReferenceWeiss et al.,1211981Potter andMcMichael,1221983Davis et al.,1231989Furner et al.,1241989Negri et al.,181989;Fernandez etal.,125 1996;

Talamini etal.,126 1998;Fernandez etal.,127 1998

CountryWashington,U.S.A.Adelaide,AustraliaCanadaChicago,U.S.A.Italy

Case:Control(Type ofControls)143:707 (population)155:311 (population)720:349 (cancerpatients)90:208(spouses)1,536:3,110(hospital)

Duration of UseNo trendNo trendNo trendSignificant(RR for ≥ 2 yr use = 0.5, 0.3–0.8)

Recency of UseNot shownNot shownNot shownRR ≥ 10 yrsince last use:0.5 (0.3–1.0)

AdjustmentCommentsAge.Reproductive variables(diet was uninfluent).Age and parity. No distinction was possible between HRT and OC use.Age, parity, and hysterectomy.Age, education, cancerfamily history, BMI,parity, menopause, OC,and energy intake.

ColonRectum≤ 5 yr: 1.1(0.7–1.9)≥ 6 yr: 1.0(0.6–1.6)—1.5(0.8–2.7)1.1(0.7–1.9)0.5(0.3–0.9)0.6(0.4–0.8)

Colon—0.8(0.4–1.5)——0.6(0.5–0.9)

Rectum—1.5(0.8–3.0)—0.2(0.0–0.8)0.5(0.3–0.7)

RR (95% Confidence Interval)

(Ever versus Never Users)
239

North AmericaChinaUnopposedHRTOpposed HRTAny HRT(recent use)

ReferencePeters et al.,1281990Wu-Williams etal.,129 1991

Gerhardsson deVerdier andLondon,130 1992

Jacobs et al.,131

1994Newcomb andStorer,132 1995

CountryLos Angeles,U.S.A.NorthAmerica andChinaSwedenSeattle,U.S.A.Wisconsin,U.S.A.

PopulationFollowup327:327(neighbours)189:494(neighbours)206:618(neighbours)299:276(population)148:138(population)694:1,622(population)

Duration of UseNo effectNot shownMostly short duration useNo trendSignificant trend(RR ≥ 5 yr use =

0.5, 0.2–0.9)Significant trend(p = 0.002)

Recency of UseNot shownNot shownNot shownRR in current users= 0.5, (0.3–1.0)Lower RR for< 10 yr since lastuse = 0.5,(0.4–0.8) for colon

Adjustment CommentsCancer family history,parity, menopause,exercise, fat, alcohol,and calcium intake.Unadjusted (but unaltered by exercise, saturated fat intake, andyears in the U.S.A.).Artificial menopause wasa risk factor in China.Age. Hormone use includedboth HRT and OC, butmostly HRT.Age, vitamin intakeand hysterectomy.Greater protection inmultiparous women.Age, alcohol, BMI,cancer family history,and, sigmoidoscopy.

ColonRectum< 5 yr5–14 yr≥ 15 yr——

Colon1.3(0.9–2.0)1.1(0.6–1.8)1.1(0.6–1.9)2.1p = 0.14—p = 0.010.6(0.4–1.0)0.6(0.4–1.0)0.5(0.3–0.9)0.5(0.3–1.1)0.7(0.6–0.9)

Rectum—0.5p = 0.23p = 0.560.7(0.4–1.3)—0.90(0.46–1.76)1.1(0.5–2.5)1.2(0.8–1.6)

RR (95% Confidence Interval)

(Ever versus Never Users)

TABLE 11–5 (continued)
240TABLE 11–5 (continued)

Current usePast use

ReferenceKampman etal.,133 1997

Yood et al.,134

1998

CountryU.S.A.,KPMCDetroit,U.S.A.

Case:Control (Typeof Controls -Ever vs.Never Users)815:1,019(KPMC members)60:143(HMO members)

Duration of UseNo trendNot shown

Recency of UseRR for recent use= 0.71(0.56–0.89)Not shown

Adjustment CommentsAge, cancer family history, aspirin andenergy intake, OC, and exercise.Age, race, reproductive variables,dietary habits, andcolonoscopy.

ColonRectum—0.3(0.1–1.0)0.4(0.1–1.4)

Colon0.8(0.7–1.0)

Rectum——

RR (95% Confidence Interval)

(Ever versus Never Users)

BMI = Body Mass Index, HMO = Health Maintenance Organization, KPMC = Kaiser Permanente Medical Care, OC = Oral Contraceptives
241

strual correlates of colorectal cancer risk are inconclusive. Moderate inverse associations with parity

and OC use have been reported, but a favorable

role of later age at menopause is still

unclear.131,143,144

Additional research is needed to confirm a potentially favorable effect of HRT on colorectal cancer.

In Western countries, the numbers of deaths from

colorectal and breast cancers in women aged 55 or

older are similar (27,000 and 34,000, respectively,

in 1994 in the United States).145 Thus, a decrease in

incidence or mortality from colorectal cancer could

greatly affect the balance of risks and benefits

associated with the use of HRT.

6. OTHER NEOPLASMS

A cohort study in Sweden of 23,244 women followed for 6.7 years suggested a slight excess risk

of lung cancer related to the use of estrogen (RR =

1.3, 95 percent CI 0.9–1.7).90 No information was

available on the duration of use or any other risk

factors. Two case-control studies in the United

States have also examined the relationship between

HRT use and risk of adenocarcinoma of the lung.

One study of 181 cases found a 70-percent excess

risk among HRT users, with the risk increasing to

a twofold risk for users who had started treatment

25 or more months previously.146 In another casecontrol study (N = 336 and 336), no substantial

relationship was found between HRT use and risk.147

In the Swedish cohort study mentioned above,90 a

total of 13 cases of biliary tract and liver cancers

were observed versus 31.7 expected, corresponding

to a RR of 0.4 (95 percent CI 0.2–0.7). In an

Italian case-control study, based on 82 histologically

confirmed cases of primary liver cancer and 368

control subjects, a decrease in risk related to HRT

was also noted (OR = 0.2, 95 percent CI 0.03–1.5).148

However, no relationship between conjugated

estrogen and other estrogen use and hepatocellular

carcinoma was observed in another population

case-control study involving 74 cases and 162 population controls from Los Angeles County;149 the

RR was 1.1 for ever use, and 1.0 for > 5 years of

use. These data are not consistent with an adverse

effect of HRT on hepatocellular carcinoma.

Effects of HRT on other cancers, including stomach,

pancreas, and skin melanoma, are inconsistent.20 A

suggestion of an inverse relation between HRT use

and cervical cancer150 requires confirmation.

7. OTHER THERAPEUTIC APPROACHES

Given the recognized adverse effects of HRT,

much recent attention has focused on assessing

alternative approaches to treating the menopause,

including use of tamoxifen and other SERMs.

These agents (see also ch.7) are recognized estrogen antagonists at selected target sites, such as

breast, while they behave as estrogen agonists in

different organ systems (e.g., bone). This may

offer many of the same advantages as HRT, while

eliminating some of the disadvantages (e.g.,

increase in the risk of breast cancer), which, in

fact, seem to be substantially reduced based on

available data.

In the National Surgical Adjuvant Breast and

Bowel Project (NSABP), a total of 13,388 U.S.

women who were 60 years of age or older or who

had a 5-year risk of 1.66 percent or more of developing breast cancer or who had a history of lobular

carcinoma in situ were randomly assigned to

receive 20 mg daily of tamoxifen or placebo for 5

years.151 After 69 months of followup, women

receiving tamoxifen had a 49 percent lower risk of

invasive breast cancer than placebo-treated

women. This beneficial effect of tamoxifen applied

to women of all ages and was particularly evident

in women with a history of lobular carcinoma in

situ or atypical hyperplasia. The reduction in risk

was limited to ER-positive tumors. Adverse effects

of tamoxifen, however, included excess risks of

endometrial cancer, stroke, pulmonary embolism,

and deep-vein thrombosis, events that occurred

more frequently in women aged 50 years or older.
242

When the same women in NSABP were rerandomized to receive either placebo or more prolonged

tamoxifen treatment, no additional advantage was

obtained through 7 years of followup after rerandomization from tamoxifen administered beyond 

5 years.152

Two other clinical trials of tamoxifen in breast

cancer prevention have presented interim results.

In a British trial, 2,494 women aged 30 to 70 years

with a family history of breast cancer were randomly assigned to tamoxifen or placebo and followed for up to 8 years.153 The risk of invasive or

in situ breast cancer was 1.06 in the group given

tamoxifen compared to the group given placebo.

One difference between this and the U.S. trial

study was that the British women were allowed to

use HRT during the trial (about one-third of study

participants were users). In a trial conducted in

Italy, 5,408 women who had a hysterectomy were

randomized to 5 years of tamoxifen or placebo.154

The study was stopped prematurely because of

patient drop-out. After a median of 46 months of

followup, there was no difference in breast cancer

incidence by treatment arm. Despite the inconsistent trial results, the U.S. F.D.A. has approved the

use of tamoxifen for breast cancer risk reduction in

high-risk women.155

Less information is available

for other SERMs. In the

Multiple Outcomes of

Raloxifene Evaluation

(MORE) trial of 7,705 postmenopausal osteoporotic

women under age 81, 60 or

120 mg of raloxifene daily

decreased breast cancer risk

by 76 percent (RR = 0.24, 95

percent CI, 0.1–0.4) as compared to nonusers.156 Risk for thromboembolic disease was increased threefold, but there was no

increased risk for endometrial cancer in raloxifenetreated compared with placebo-treated women. The

U.S. National Cancer Institute and the NSABP are

now conducting a large, multicenter study to test

tamoxifen versus raloxifene to determine whether

raloxifene shows the same risk reduction as tamoxifen and to determine whether the risk for adverse

events differs.

In a 5-year osteoporosis prevention trial, mammographic density decreased significantly in women

receiving raloxifene and placebo and showed a

nonsignificant increase in women receiving ERT.157

Consequently, raloxifene should not interfere with

mammographic detection of breast cancer.

Risk for invasive breast cancer is also being evaluated in 10,101 postmenopausal women with CHD

or at high risk for its occurrence randomized to

raloxifene or placebo in the RUTH trial.

Research is also beginning to focus on whether

more natural approaches to treating the menopause

should be recommended. Although there is a growing enthusiasm for use of phytoestrogens, termed

by some as natural SERMs,158 their effects on cancer risk remain unresolved.

8. CONCLUSIONS

Most potential favorable and adverse effects on

cancer risk of HRT are restricted to current users.

On the basis of observational epidemiologic data,

the RR of breast cancer is moderately elevated in

current and recent HRT users, and increases by

approximately 2.3 percent per year with longer

duration of use, but the effect decreases after cessation and largely, if not totally, disappears after

about 5 years.

Unopposed estrogen use is strongly related to

endometrial cancer risk, but cyclic combined estrogen-progestin treatment appears to largely or totally reduce this side effect if progestin is used for

more than 10 days per cycle. However, combined

HRT may be related to higher risk of breast cancer

as compared to unopposed estrogen.

In most studies, HRT

has been related to

increased ovarian and

decreased colorectal

cancer risk, but these

issues await further

investigation.
243

In most studies, HRT has been related to increased

ovarian and decreased colorectal cancer risk, but

these issues await further investigation.

Based on the available evidence, no strong or consistent relationship is present between HRT and

liver or other gastrointestinal neoplasms, or

melanoma.

9. FUTURE NEEDS

• The breast cancer risk of the combination of

estrogen and progestin should be further quantified: there are biological reasons to suspect an

unfavorable effect of added progestin on breast

carcinogenesis, and some epidemiological studies have suggested an excess risk.

• Research is needed to determine whether the

relation between HRT and breast cancer risk

differs at various ages. Any risk-benefit ratio is

particularly critical and must be carefully and

individually assessed for elderly women using

HRT after menopause in terms of relative and

absolute risk.

• In consideration of the better prognosis of

breast cancer in HRT users, future research

should further investigate a potentially favorable effect of hormone use on the biologic characteristics of breast tumors.

• Additional studies are needed on HRT use in

women with a diagnosis of breast cancer.

• Although use of estrogen alone increases

endometrial cancer risk, several studies indicate

that combined HRT is not related to a major

excess of endometrial cancer if progestin is

given more than 10 or 14 days in each cycle.

This should be better quantified to provide

information for prescription.

• The evidence on HRT and epithelial ovarian

cancer risk is less consistent than that for

endometrial and breast cancer, though available

data suggest a positive relationship.

• Additional research is needed to confirm a

potentially favorable effect of HRT on colorectal cancer. In western countries, the number of

deaths from colorectal cancers in women aged

55 or older are similar. Thus, a decrease in incidence or mortality from colorectal cancer could

greatly affect the balance of risks and benefits

associated with the use of HRT.

• Further data on lung and liver cancer would

also be useful.

• Research is required on the use of tamoxifen

and other SERMs and perhaps more natural

approaches to treating the menopause. Although

there is growing enthusiasm for use of phytoestrogens, termed by some as “natural” SERMs,

their effects on cancer risk, if any, should be

better understood. 
244

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251

1. Menopausal ERT appears to help preserve certain cognitive skills immediately after

induced menopause [B] and during normal aging [C].

2. Estrogen therapy begun after menopause may reduce risk of Alzheimer’s disease

[C]. In contrast, limited data from RCTs indicate that estrogen alone begun after 

the onset of dementia does not seem to improve Alzheimer symptoms [B].

3. In observational studies, ERT does not modify stroke risk in older healthy 

women [C].

4. For many neurologic disorders (epilepsy, migraine, multiple sclerosis, and

Parkinson’s disease), observational study findings do not indicate an overall 

positive or negative impact of menopause or HRT on neurologic symptoms or 

disability [C]. Some sleep disturbances that occur during the climacteric may 

benefit from ERT [C].

5. Hormonal changes associated with menopause have shown little direct impact on mood [C]. Although 

clinical implications are uncertain, limited data suggest a beneficial effect of estrogen on mood [B].

6. There is little evidence that HRT alters risk for age-related maculopathy, cataract, or dry eye [C].

7. Few clinical characteristics or diagnostic procedures identify subgroups of women particularly likely to 

benefit from HRT for the prevention or treatment of disorders of neurologic function, mental health, or the

eye [D]. Despite a strong biologic rationale, clinical data are sparse. Thus, recommendations regarding 

HRT to prevent or ameliorate those disorders are limited. Well-characterized benefits and risks of HRT for

other organ systems override considerations of potential benefit for the brain and eye [D].

CHAPTER 12: MENOPAUSE AND DISORDERS OF NEUROLOGIC

FUNCTION, MENTAL HEALTH, AND THE EYE

Victor W. Henderson, M.D., M.S.;* Barbara E. K. Klein, M.D., M.P.H.;† and Susan M. Resnick, Ph.D.‡

KEY POINTSa

* From the Donald W. Reynolds Center on Aging, University of Arkansas for Medical Sciences, Little Rock, AK, U.S.A.

† From the University of Wisconsin-Madison, Ocular Epidemiology, Madison, WI, U.S.A.

‡ From the Cognition Section, Laboratory of Personality and Cognition, National Institute on Aging, NIH, Bethesda, MD, U.S.A.

a Evidence categories are given in square brackets. A = randomized controlled trials (rich body of data); B = randomized controlled trials (limited data); 

C = nonrandomized trials and observational epidemiologic studies; D = Panel expert judgement. (See also table 12–1).

Menopausal ERT

appears to help 

preserve certain 

cognitive skills

immediately after

induced menopause

and during 

normal aging.
252

1. INTRODUCTION

Menopause is associated with sharp declines in

concentrations of circulating estrogen and other

alterations in the hormonal milieu.1 The hormonal

changes affect a variety of reproductive and nonreproductive tissues, including the CNS eye; HRT

with estrogen or other sex steroids may influence

brain and eye functions (table 12–1).2

In the brain and eye,3,4 as in

other target organ systems,

estrogen interacts with specific intranuclear receptors to

regulate protein synthesis.

Within the CNS system, individual neurons can express ERα, the ERβ, neither

receptor, or occasionally both receptor types. (See

ch. 5.)3 Androgen and PRs are found in populations of neurons. Within the brain, some estrogen

actions occur within a matter of seconds or minutes, too rapidly to involve genomic activation.

Those rapid estrogen effects are believed to

involve receptors located in the cell membrane.5

Finally, estrogen can influence brain and eye functions indirectly, through effects on nonneural and

nonocular tissues, including the vasculature and

the immune system.

Despite a strong biologic rationale, there is no

strong evidence based on consistent findings from

well-designed RCTs, controlled trials regarding the

clinical importance of HRT for the central nervous

system and the eye. Relevant preclinical and clinical data are beginning to emerge for several disorders. In some areas, a developing consensus may

help guide clinical decisions on prevention and

treatment.

Age-associated cognitive decline is considered in

this chapter, as are dementia, stroke, epilepsy,

migraine, multiple sclerosis, Parkinson’s disease,

and sleep disorders. With regard to mental health,

there are data on mood and schizophrenia. Eye disorders of interest include age-related maculopathy,

cataract, and dry eye.

2. AGE-ASSOCIATED COGNITIVE

DECLINE AND NEUROLOGIC DISORDERS

Clinical data exist for age-associated cognitive

decline in healthy women and for a number of

neurologic conditions. Some topics have been

reviewed.6

2.1 Age-Associated Cognitive Decline

Memory and other cognitive abilities change over

time during adult life. Changes that represent usual

or normal accompaniments of aging are not viewed

as pathologic. Modest cognitive decrements initially

detectable in middle age are accentuated at elderly

age. In general, cognitive tasks that depend on 

previously learned knowledge are more resistant 

to decline than tasks involving new information 

or requiring the manipulation of old information.

2.1.1 Effects of Estrogen

Considerable data indicate that sex hormones 

measurably influence brain functioning throughout

life. Higher cognitive scores in childhood are 

associated with a later age at menopause.7 There 

is little evidence that menopause per se initiates

cognitive deterioration.

As inferred from in vitro and animal studies, 

estrogen has the potential to modulate cognitive

processes.6 Within the brain, estrogen affects a

number of neurotransmitter systems, including

cholinergic, noradrenergic, serotoninergic, and

dopaminergic pathways,6 which are involved in

aspects of memory and attention. In ovariectomized rodents, estrogen improves memory 

performance on a variety of behavioral tasks.8–10

Estrogen interacts with NGF and other neurotrophins,11 promotes the growth of nerve

processes,12,13 and enhances synaptic plasticity.14

Estrogen protects neurons from a variety of

endogenous and exogenous insults.15,16 In animal

studies, estrogen augments glucose transport into

the brain and increases cerebral metabolism.17,18

In human studies, estrogen influences the pattern

of brain activation during the performance of cogLimited data suggest

a beneficial effect of

estrogen on mood.
253

nitive tasks, as inferred from measures of cerebral

blood flow.19–21 Chronic estrogen use is associated

with greater increases in relative blood flow in

regions of the temporal lobe.22 As described below,

effects of estrogen on cognitive abilities of healthy

adult women have been studied in various clinical

settings; the findings have been inconsistent but

often positive.

Primary prevention: The possibility that estrogen

might help preserve cognitive function during normal aging has been examined in observational

studies.23 Serum estrogen concentration in postmenopausal women does not appear to be closely

related to cognitive skills,24 although one study

reported a positive relationship between levels of

bioavailable estradiol and verbal memory but an

TABLE 12–1

Estrogen Actions Potentially Germane to Disorders of the Brain and Eye*

Effects on neurotransmitter systems

Acetylcholine

Noradrenaline

Serotonin

Dopamine

Others 

Neurotrophic actions

Interactions with neurotrophins

Neurite extension

Synapse formation and synaptic plasticity 

Protective actions

Augmentation of blood flow

Enhancement of glucose transport into the brain

Protection against apoptosis

Antioxidant properties

Anti-inflammatory properties 

Effects on proteins involved in Alzheimer's disease

Apolipoprotein E

Amyloid precursor protein 

Effects on ocular tissues 

Effects on light transmission through the crystalline lens 

* Modified from Henderson VW, 1997.2
254

inverse relation with nonverbal memory.25 Healthy,

community-dwelling older women who use ERT,

with or without a progestin, appear to perform better on cognitive tasks.26,27 In one well-characterized,

longitudinally assessed American cohort, postmenopausal women receiving estrogen performed

significantly better on measures of nonverbal and

verbal learning and memory than menopausal

women who had never used estrogen.28,29 In other

American cohorts estrogen users scored better on

specific tests of verbal memory, naming, and

abstract reasoning30 or on cognitive screening

tasks.31,32 In Austria, a population-based study

found that postmenopausal women currently using

estrogen performed better than nonusers on several

psychometric measures; the greatest differences

were seen in complex problem-solving tasks and

psychomotor speed.33 In a Dutch patient registry,

women receiving HRT performed significantly better on a composite measure of psychomotor speed

but did not differ significantly from nonusers on

measures of memory or cognitive flexibility.34

Analyses in two large American cohorts, did not

show appreciable differences in a variety of cognitive measures between users and

nonusers of postmenopausal

estrogen.35,36 Longitudinal

observations imply that estrogen may help preserve cognitive30 or functional37 abilities,

although current estrogen use

failed to protect against cognitive decline on a brief psychometric instrument in another

observational study.31

Treatment of symptoms: Several randomized,

controlled clinical trials have examined cognitive

effects of estrogen after natural or surgical

menopause. Treatment was up to 3 months in duration. Women given estrogen outperformed women

given placebo on a variety of psychometric measures.38,39 On long-term memory tasks, improvement was more apparent when verbal, as opposed

to nonverbal, memory was assessed.38–40 Verbal

memory enhancement was also described in a

placebo-controlled study of younger women whose

ovarian function had been suppressed with a

GnRH agonist before “add-back” treatment with

estrogen.41 Positive findings generally occurred in

acute studies of relatively younger women after

ovarian function was abruptly suppressed;38,39,41 few

clinical trials considered ERT initiated at a later

point after natural menopause. In contrast to these

generally positive findings, a randomized,

placebo-controlled trial of estrogen in 62 women

who had previously undergone hysterectomy, conducted by Finnish investigators, detected no benefit of estrogen on measures of psychomotor speed,

attention, working memory, or visual memory.42

2.1.2 Recommendations for Age-Associated

Cognitive Decline

Recommendations for the primary prevention of

age-associated cognitive decline and for the

improvement of cognitive skills in otherwise

healthy women are derived primarily from inconsistent findings of observational studies and uncontrolled trials and from a limited number of

short-term RCTs. In observational studies, women

who choose to use estrogen differ in a number of

ways from women who do not,43 and positive findings in such studies may reflect unrecognized bias

or confounding.44 Evidence that estrogen use after

menopause is associated with better cognitive

skills remains weak. The evidence is somewhat

better in short-term studies of younger women

with induced menopause. On the basis of available

information, the desire to protect against age-associated cognitive decline should not generally affect

decisions about whether to use ERT, except possibly in women undergoing surgical menopause.

2.2 Dementia

Dementia represents a decline in memory and

other cognitive abilities severe enough to have a

deleterious effect on daily function. In many

regions, Alzheimer’s disease is the commonest

Healthy, communitydwelling older

women who use

ERT, with or without

a progestin, appear

to perform better on

cognitive tasks.
255

cause of dementia;45 whether its occurrence or progression is affected by estrogen has been of

research interest. Very few data directly address

whether estrogen might influence dementia due to

disorders other than Alzheimer’s disease. 

2.2.1 Alzheimer’s Disease

As an age-associated disorder, Alzheimer’s disease

rarely appears before menopause, but its prevalence increases exponentially between the 6th and

10th decades of life.46 During the first half of the

21st century, it is expected that current trends of an

increasing proportion of elderly people in the population will continue for both developed and developing countries, and that the burden of

Alzheimer’s disease will expand accordingly.

Alzheimer’s disease is 1.5 to 3 times more common among women than men,46 in part because of

sex differences in longevity.

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by the insidious onset

of memory loss and other cognitive symptoms that

relentlessly worsen over a period of years.

Pathologic features include intracellular neurofibrillary tangles and extracellular neuritic plaques.

The latter are associated with inflammatory proteins and typically contain a central core composed

of β-amyloid. There is evidence that oxidative

damage contributes to Alzheimer pathology.

Both genetic and nongenetic factors are implicated

in Alzheimer pathogenesis. Autosomal dominant

mutations are important causes of early-onset, but

not late-onset, illness. For the common, late-onset

form of Alzheimer’s disease, several genes may

modify susceptibility. The best-recognized susceptibility gene encodes the lipid transport protein

apolipoprotein E, which is involved in neuronal

repair processes. Increased Alzheimer susceptibility is conferred by the apolipoprotein E ε4 allele,47

which is associated with reduced neuronal sprouting compared with the more common ε3 allele.48

Sex appears to modify risk: the ε4 allele increases

risk more for women than men.49,50

Of theoretical benefit in Alzheimer’s disease are

neurotrophic and neuroprotective effects of estrogen, as well as effects on cholinergic and other

neurotransmitter systems. In the laboratory, protective effects against programmed neuronal death

(apoptosis),51 inflammation,52 and

oxidative damage15,16 appear particularly relevant to Alzheimer

pathogenesis. Finally, estrogen

increases the expression of

apolipoprotein E within select

brain regions53 and inhibits the

formation of β-amyloid from its

precursor protein.54 For these reasons, investigators have inquired

whether ERT might have roles in

preventing or treating

Alzheimer’s disease.

Primary Prevention: In the early 1990s, cross-sectional analyses compared current estrogen use in

women with Alzheimer’s disease and women in the

same age group without dementia.55–57 Although

subject to important bias, results implied that ERT

may reduce Alzheimer risk. Several earlier casecontrol studies had failed to document a link

between estrogen use and Alzheimer risk, but since

1994 nine additional studies have assessed the relation between ERT and Alzheimer’s disease.57–66

Most analyses were based on data for estrogen use

collected prior to the onset of dementia symptoms,56–61,63,64 and most, but not all,59 found an association between the use of estrogen after menopause

and protection against Alzheimer’s disease. In these

case-control and cohort studies, estimates of total

reduction in RR are about 50 percent.60 Estrogen

effects were reported for women with and without

the ε4 allele of apolipoprotein E.61

If ERT reduces Alzheimer risk, it might be expected that greater estrogen exposure would be associated with greater risk reduction. Several studies of

estrogen exposure assessed by dosage or duration

of use support that contention. In the Leisure

World Study, risk estimates for Alzheimer’s disVery few data

directly address

whether estrogen

might influence

dementia due to

disorders other

than Alzheimer’s

disease.
256

ease decreased significantly with increasing dose

of the longest used oral estrogen preparation.60

Significant associations between the duration of

estrogen use and the degree of risk reduction were

found in analyses from Leisure World,60 New York

City,61 and Rochester, MN.66 However, in a longitudinally followed cohort in Baltimore, MD, there

was no significant link between duration of use

and the magnitude of risk reduction.63 No data

address whether there may be a critical period during which ERT exerts its putative beneficial effects

(e.g., the early menopausal period versus the senium). There are no clinical studies on possible beneficial or deleterious effects of dietary estrogens on

Alzheimer risk in women, although one study

reported a link between higher midlife consumption of tofu, a rich source of isoflavone phytoestrogens, and poor cognitive test performance in men.67

Treatment of Symptoms: Cholinergic systems of

the brain are markedly impaired by pathologic

changes of Alzheimer’s disease, and medications

that increase cholinergic activity by inhibiting the

breakdown of acetylcholine are of modest benefit.68–70 Antioxidants may slow disease progression

(e.g., vitamin E)71 or modestly improve symptoms

(e.g., gingko biloba).72 In observational studies of

women with Alzheimer’s disease, HRT is associated with milder cognitive deficits,73,74 although most

estrogen use is of long-standing duration. Results

from relatively short-term randomized clinical trials

of estrogen use are less supportive. Positive results

in a 3-week study of conjugated estrogens in 14

women with Alzheimer’s disease75 and suggestive

results in an 8-week study of

transdermal estradiol in 12

women76 are offset by decidedly

negative findings in two larger

trials of conjugated estrogens.

One randomized trial in 

42 menopausal women with mild to moderate

Alzheimer’s dementia showed no difference

between the estrogen and the placebo group after

16 weeks on the primary cognitive outcome measure or on secondary measures of global change

and functional status.77 Women with mild to moderate Alzheimer symptoms who had undergone

hysterectomy were randomized in a second trial to

one of two treatment arms using different estrogen

dosages (N = 42 and 39) or to placebo (N = 39).

At 12 months, there was no benefit of estrogen on

measures of global change, cognition, or function.78 Preliminary observational analysis of concomitant estrogen use in a large, multicenter trial

of tacrine raises the possibility that estrogen given

in combination with a cholinergic drug may be

useful; greatest improvement was observed in the

subgroup taking ERT at the time of initial randomization to tacrine.79

2.2.2 Vascular Dementia

Another common cause of dementia is ischemic

vascular disease of the brain, particularly multiple

strokes, that is, multi-infarct dementia.45 In some

Asian countries, the prevalence of vascular dementia may exceed that of Alzheimer’s disease.80

Symptoms of multi-infarct dementia often begin

abruptly, and cognitive decline may occur in a

stepwise manner. Neurologic examination typically

finds signs of focal brain damage, and radiologic

studies, such as MRI usually confirm cerebral

infarction. Neuroprotective effects of estrogen

could be important. In experimental models of

acute cerebral ischemia, estrogen reduces ischemic

damage.81–83 In one observational study, women

with vascular dementia were less likely than

healthy women to use HRT.57 Stroke incidence,

however, is not closely associated with the use of

HRT (see below), and there is no defined role for

menopausal estrogen in women with vascular

dementia.

2.2.3 Recommendations for Dementia

Evidence from an increasing number of case-control and cohort studies provides substantial—but

not compelling—evidence that use of estrogen

after menopause reduces women’s risk for

Alzheimer’s disease. A woman at high risk for

Results implied that

ERT may reduce

Alzheimer risk.
257

Alzheimer’s disease from, for example, genetic

predisposition or a strong family history in firstdegree relatives, may wish to consider ERT if

other potential benefits of treatment are not exceeded by well-recognized potential risks. Decisions

concerning estrogen dosage, timing, and treatment

duration should be guided by other medical considerations; the literature on Alzheimer’s disease

allows no consistent guidance. On the basis of data

from a small number of RCTs,77,78 estrogen

monotherapy is not useful for the treatment of

dementia in women diagnosed with Alzheimer’s

disease. Short-term side effects, including venous

thrombosis,75 breast tenderness, and withdrawal

bleeding, are particularly worrisome in that population. Few data address estrogen effects in forms

of dementia other than Alzheimer’s disease.

2.3 Other Neurologic Disorders

2.3.1 Stroke

Stroke refers to brain disease caused by ischemic

or hemorrhagic abnormalities in the vascular supply

to the brain. (See ch. 8, sec. 7.) The incidence of

stroke varies widely from country to country.84 Its

incidence rises dramatically with age, and worldwide, stroke is the second leading cause of death.85

In the Framingham Study in the United States,

rates for ischemic stroke are lower in women than

men.84 Atherosclerosis in arteries that supply blood

to the brain predisposes to cerebral infarction.86

Estrogen may reduce these atherosclerotic

changes, perhaps due to favorable effects on the

serum lipid profile and vascular endothelial function. (See ch. 8, sec. 3.2 and sec. 4.1.1).87,88

Estrogen increases cerebral blood flow in humans.89

In rats, estrogen reduces the extent of brain damage

caused by acute infarction.81–83

In a number of observational studies, HRT is associated with reductions in risk for stroke death of

20–60 percent.90 However, even in analyses

restricted to ischemic stroke, HRT does not appear

to reduce stroke incidence.91,92 This conclusion is

supported by secondary analyses in a large clinical

trial among postmenopausal women with CHD;

after a mean followup of 4 years, HRT had no

effect on stroke risk.93

Among relatively younger women in the Nurses’

Health Study, current hormone use was associated

with higher risk of ischemic stroke.91 There is good

evidence that treatment of hypertension, the use of

statins after MI, and carotid endarterectomy in

patients with severe stenosis can reduce the risk of

a first ischemic stroke due to atherothrombotic 

disease.94 Because ERT may increase short-term

cardiovascular risk,93 there is a need for caution in

beginning estrogen after recent ischemic stroke.

2.3.2 Epilepsy

Epilepsy is a CNS disorder

characterized by recurrent

seizures. Epilepsy often begins

in early life but can start at any

age. Causes are legion. In rats,

estrogen increases the excitability of hippocampal neurons95

and exacerbates epilepsy by lowering the seizure

threshold;96 epileptogenic effects may be opposed

by progesterone.96 In women with so-called catamenial epilepsy, seizures tend to recur immediately

preceding or during menstruation and are thought

to be triggered by fluctuations in concentrations of

ovarian hormones.97 Catamenial seizures can occur

during other phases of the menstrual cycle as

well.98 The use of estrogen-containing OCs does

not increase seizure frequency.99 Effects of

menopause on epilepsy have not been well studied.

Based on limited questionnaire data, epileptic

women probably would not experience a change in

seizure frequency or severity with menopause, but

HRT may increase seizure frequency.100,101

2.3.3 Migraine

Migraine is a common disorder characterized by

recurrent attacks of throbbing headache. Pain is

often unilateral and is sometimes preceded by

focal neurologic symptoms and accompanied by

gastrointestinal symptoms. A questionnaire study

Stroke incidence,

however, is not

closely associated

with the use of HRT.
258

of households selected to be representative of the

U.S. population found migraine prevalence to be

greatest between ages 35 and 45 years and women

to be affected three times as often as men.102

Headache frequency is influenced by the menstrual

cycle and pregnancy. Migraine attacks occur less

often during middle age and

beyond.102,103 Menopause per se has

been reported to have either little

effect104 or a beneficial effect105 on

migraine frequency. For women

undergoing surgical menopause,

migraine symptoms may worsen, and

occasionally migraine first appears

after menopause.105 Effects of ERT

on migraine have not been extensively studied, but estrogen treatment

may reduce headache frequency.106

2.3.4 Multiple Sclerosis

Multiple sclerosis, a chronic immunologic disorder

of the CNS system, affects women more often than

men. Disease incidence is greater among whites

and with increasing latitude in temperate regions

of the northern and southern hemisphere.107

Pathologic changes of multiple sclerosis are mediated by T-cell lymphocytes directed against white

matter antigens. Neurologic symptoms, which

often first appear in early adulthood, depend on the

focal distribution of pathologic changes.

Exacerbations and remissions are common.

Estrogen influences cell-mediated immunity,108 but

the clinical relevance of estrogen to multiple sclerosis is not well established. Incidence is not

increased by the use of OC medications.109 Among

women with multiple sclerosis, pregnancy does not

increase long-term disability,110 even though neurologic relapse often occurs during the postpartum

period.111 Some women experience a worsening of

neurologic symptoms immediately prior to or during menstruation.112,113 Effects of menopause or

HRT on the neurologic symptoms or long-term

course of multiple sclerosis are unknown.114

2.3.5 Parkinson’s Disease

Parkinson’s disease is a common, progressive 

neurodegenerative disorder of the basal ganglia.

Symptoms include tremor, rigidity, and reduced

movement (bradykinesia). Catecholamine neurotransmitters are characteristically reduced in

Parkinson’s disease, and most symptoms are attributed to the prominent loss of dopamine-containing

neurons in the substantia nigra. Although the substantia nigra does not appear to contain large numbers of ERs in the adult brain,115 estrogen affects

dopamine receptors, the activity of dopaminergic

neurons, and motor behaviors mediated by

dopamine.116–118

There are a few studies of ERT and Parkinson’s

disease. For postmenopausal women with early

Parkinson’s disease, a retrospective chart review

found estrogen use to be associated with milder

Parkinsonian symptoms,119 and results of a small

crossover trial suggested that estrogen may

enhance the response to dopaminergic therapy.120

An American cohort study that compared women

with idiopathic Parkinson’s disease and women

without stroke or dementia found no association

between ERT and a Parkinson diagnosis.121 For

women in the cohort who had dementia as well as

Parkinson’s disease, estrogen use was linked to a

significantly reduced likelihood of dual symptoms.

2.3.6 Sleep Disorders

A common symptom of the climacteric is the hot

flush, characterized by an increase in core body

temperature followed by cutaneous vasodilation,

diaphoresis, tachycardia, and the transient sensation of heat. Troubled sleeping can be caused by

hot flushes. Thermoregulatory disturbances in part

reflect increased noradrenergic activity,122 probably

at the level of the hypothalamus, which in turn

may be modulated by sex steroids. (See ch. 3, sec.

4.) Data from observational studies suggest that

menopause is associated with increased sleep disturbances.123,124 Nocturnal hot flushes are known to

disrupt normal sleep patterns;125,126 sleep disruption

In a number of

observational

studies, HRT is

associated with

reductions in

risk for stroke

death of 20–60

percent.
259

is alleviated by estrogen treatment.123,127 In a small

pilot study, ERT ameliorated sleep apnea syndrome

in menopausal women.128

2.3.7 Recommendations for Other 

Neurologic Disorders

Data from observational studies suggest that ERT

does not protect healthy women from the occurrence of stroke. For epilepsy, migraine, multiple

sclerosis, and Parkinson’s disease, no compelling

data indicate that ERT after menopause has substantial effects. Sleep disturbances, particularly

during the climacteric and particularly when associated with hot flushes, may improve with ERT,

although evidence from RCTs is lacking.

3. DISORDERS OF MENTAL HEALTH

3.1 Mood

Women of all ages have higher rates of depression

than men.129,130 Geriatric depression is an important

public health concern.131 Hot flushes and other

menopausal symptoms may affect the quality of a

woman’s life.132 The menopausal transition does

not appear to represent a time of heightened vulnerability to affective disorders.133

A number of antidepressant drugs increase CNS

levels of noradrenaline and serotonin, suggesting

the importance of monoaminergic neurotransmitter

systems in regulating mood. Estrogen influences

noradrenalin and serotonin. Research findings on

women with premenstrual dysphoric disorder or

with major depression beginning in the postpartum

period point toward the importance of sex hormones.

Several short-term studies indicate that ERT given

during the perimenopausal or menopausal period

can diminish anxiety or enhance mood and subjective sense of well-being.134–136

Limited data suggest that severe depression in certain clinical populations is occasionally improved

by ERT. Recent clinical experimental studies of

postpartum depression indicate that reproductive

hormones can be involved in the development of

the disorder137 and that estrogen can be effective in

a major depressive episode with postpartum

onset.138 For women with a major depressive disorder, an older randomized, placebo-controlled trial

of high-dosage estrogen showed significant amelioration of affective symptoms.139 Among women

with major depression treated with a selective

SSRI, retrospective analyses do not strongly suggest important additive effects of concomitant

ERT.140,141

Older postmenopausal women who use estrogen

typically report fewer depressive symptoms than

nonusers.142 In RCTs in postmenopausal women

without a diagnosis of depression, ERT has been

reported to reduce scores on measures of depressive symptoms134–136 and to have no effect on

mood.42,43 Apparent beneficial effects of estrogen

on mood may be diminished by the concomitant

administration of a progestin.143

3.2 Schizophrenia

Schizophrenia is a chronic psychotic disorder

characterized by delusions, auditory hallucinations, disorganized

thought processes, affective blunting, and difficulty in sustaining

goal-directed activity. Frequency does not significantly vary according to sex. Symptoms typically

appear in the third decade of life, but onset occurs

on average 3–5 years later for women than

men.144,145 Late-onset schizophrenia is more common in women,146 although menopause does not

appear to heighten risk.145 Estrogen effects on

dopaminergic or serotonergic systems of the brain

could influence schizophrenic symptoms. Among

ovulating women, a higher serum estrogen 

concentration has been associated with milder 

psychopathology.147 In a small, open-label trial in

women with schizophrenia, estrogen added to 

Data from observational

studies suggest that

menopause is associated

with increased sleep 

disturbances.
260

standard antipsychotic drugs increased the speed

with which psychotic symptoms improved,

although the difference was not sustained.148

3.3 Recommendations for Mood Disorders 

and Schizophrenia

Possible estrogen effects on schizophrenia are inadequately addressed in

the literature, and estrogen should

probably not be considered as treatment for a major depressive episode or

schizophrenia. There are weak data that

estrogen might be considered for mild

depressive symptoms attributed to hot

flushes, sleep disturbances, or other climacteric symptoms. No data exist whether estrogen could be used as adjunct therapy for other

depressive disorders during the menopausal transition or postmenopausal period.

4. DISORDERS OF THE EYE

Increasing age is often accompanied by visual loss

or blindness, and among older people diminished

visual acuity affects women more often than

men.149 Two of the most important causes of visual

loss in older adults are age-related maculopathy

and cataract. Another common problem among

older adults is dry eye syndrome; symptoms, while

usually not disabling, can be distressing and difficult to eradicate.

Because clinical data on estrogen and eye disorders are limited, visual considerations should not

influence practice decisions on the use of HRT.

4.1 Age-Related Maculopathy

Maculopathy, which is most severely manifest as

macular degeneration, is characterized by atrophy

and neovascularization of the central portion of the

retina. Age-related maculopathy affects women

somewhat more often than men.150 Although pathophysiologic mechanisms for the condition are 

unknown, several studies have evaluated possible

effects of reproductive events and exogenous hormone use.

A case-control study from Rotterdam found that

women with early surgical menopause were more

likely to have macular degeneration than those

with late surgical menopause.151 Early spontaneous

menopause was not associated with increased risk.

In a cohort from the Blue Mountains region of

Australia, increasing years from menarche to

menopause, a measure of endogenous estrogen

exposure, was associated with reduced odds of

early changes of age-related maculopathy.150

In a U.S. multicenter case-control study, the use of

HRT was associated with decreased risk for neovascular age-related macular degeneration,152 the

form of macular degeneration most commonly

associated with severe visual loss. In a

population-based cohort in Beaver Dam, WI, there

was an inverse relation of borderline significance

between the number of years of ERT and maculopathy, although there was no association between

ever-use of estrogen and occurrence of maculopathy.153 Analysis of pooled data from Rotterdam,

Blue Mountains, and Beaver Dam failed to confirm an association between the use of menopausal

estrogen and age-related maculopathy.150 Similarly, the U.S.

NHANES III found that current, but not past, use of HRT

is associated with a lower

prevalence of age-related maculopathy.154 In an analysis of

data from the Beaver Dam Eye

Study, there was no evidence

of a relationship between HRT

and 5-year incidence of agerelated maculopathy.155

Maculopathy is among the most serious of the eye

disorders, but evidence of estrogen benefit remains

tenuous. No data address effects of HRT once

maculopathy is evident.

Symptoms of 

dry eye improved 

significantly in an

RCT of estrogen

eye drops in 

postmenopausal

women.

Women of all

ages have

higher rates 

of depression

than men.
261

4.2 Cataract

Cataract refers to a loss of transparency within the

crystalline lens of the eye, which interferes with the

transmission of light to the retina. The generic term

encompasses different kinds of opacity, including

opacities located in the nuclear, cortical, and posterior

subcapsular portions of the lens. About 50 percent

of the world’s blind have cataract. Epidemiologic

studies from Australia,156 Asia,157 Europe,158 and

North America159–161 indicate that cataract affects

elderly women more often than elderly men. In

studies that discriminated among types of cataract,

female sex was positively associated with both

nuclear156,161 and cortical160,161 cataracts.

The relation of cataract formation to menopause or

estrogen use has been considered in several observational epidemiologic studies. Early menopause

was associated with cataract formation in reports

from Beaver Dam and the Nato area of Japan162,163

but not in a report from Blue Mountains.164 In

Beaver Dam, cortical cataract was more prevalent

among older women; premenopausal women in the

sixth decade of life had fewer nuclear cataracts

than perimenopausal or postmenopausal women of

the same age.162 Transmission of light through the

crystalline lens was greater in postmenopausal

women receiving ERT than in women not taking

estrogen or in men of similar age. The prevalence

of cortical cataract was reduced among current

estrogen users in the Blue Mountains Eye 

Study,164 165 as was the severity of nuclear sclerosis

in the Beaver Dam Eye Study.162 Neither study,

however, found an association between cataract

and ever-use of menopausal hormones.162,164 In the

Blue Mountains data, but not Beaver Dam, posterior subcapsular opacity was more prevalent among

older subjects who were current users of estrogenprogestin replacement therapy.162,164 In the Beaver

Dam Eye Study, there was no evidence of a relationship between HRT and the 5-year incidence of

any type of age-related cataract.155

Estrogen effect on cataract has not been studied in

randomized controlled studies.

4.3 Dry Eye

Dry eye, or keratoconjunctivitis sicca, is a common complaint among older adults.166–168 Symptoms

localized to the ocular surface include irritability,

burning, itching, and sensations of

dryness or the presence of a foreign body. Visual disturbances

can occur, and severe manifestations occasionally threaten vision.

Dry eye syndrome is pathogenetically heterogeneous and is caused

by both decreased tear production

and increased evaporative loss of

the aqueous component of tears.

Dry eye is associated with

Sjögren’s syndrome and other

autoimmune diseases but frequently occurs in the absence of

associated systemic illnesses.

Little evidence links estrogen to dry eye. Women

are more likely to report symptoms of dry eye than

men;167–169 not all studies support the finding.166 In

the Beaver Dam Eye Study, the age-adjusted

prevalence was 11 percent in men and 17 percent in

women.169 Menstrual status, history of hysterectomy,

and use of HRT were not associated with dry eye.169

Gonadal steroids are important in the production of

different tear components. Androgens may be the

most important in the process.170–172 It is hypothesized that the decline in androgen production after

menopause, rather than the menopausal loss of

estrogen, contributes to dry eye symptoms in older

women.170 Symptoms of dry eye improved significantly in an RCT of estrogen eye drops in postmenopausal women.173 Clarification of the roles of

hormones and of potential treatment possibilities

awaits further investigation.

Because clinical

data on estrogen

and eye disorders

are limited, visual

considerations

should not 

influence practice

decisions on the

use of HRT.
262

5. FUTURE NEEDS

• Explore the possibility that SERMs may act as

estrogen antagonists in the brain or eye.

• Evaluate in long-term RCTs the potential effects

of HRT on age-associated cognitive decline.

• Evaluate in long-term RCTs the potential effects

of HRT on primary prevention of Alzheimer’s

disease and vascular dementia.

• Evaluate the effectiveness of combination therapy with estrogen plus a cholinomimetic drug in

RCTs for women with Alzheimer symptoms.

• Evaluate in RCTs the potential effects of HRT

on primary prevention of Parkinson’s disease

and on symptoms of Parkinson’s disease.

• Determine in RCTs whether estrogen combined

with antidepressants or antipsychotic drugs

might enhance the effects of these medications

in depressive disorders and schizophrenia,

respectively.

• Determine in long-term RCTs whether HRT

might reduce incidence of age-associated maculopathy, cataract, or dry eye.

• If estrogen proves beneficial for disorders of

neurologic function, mental health, or eye, the

timing of therapy and the duration of usage for

optimal benefit have to be resolved.

• If estrogen proves beneficial for disorders of

neurologic function, mental health, or eye, the

possibility that benefit may be altered by a

progestin has to be resolved.
263

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271

CHAPTER 13: BEST CLINICAL PRACTICES: 

A COMPREHENSIVE APPROACH

The proportion of women living past the age of

menopause has tripled during the past century, and

is expected to increase steadily in the foreseeable

future. If adulthood is defined as beginning at age 21,

the average age at menopause as age 51, and the

average life expectancy as age 81, women in the

United States, in Europe, and in much of the developed world will live one-half their adult lives in the

years after menopause, a time of relative estrogen

deficiency compared to their reproductive years.

In recent years, the aging of the female population,

together with the availability of “replacement” 

hormones, led to numerous studies of the menopause. Most of these studies were of middle-class

white women living in the United States and

Western Europe, with results that may not be relevant to other women. In addition, many studies

were clinical or epidemiological observations of

associations—less satisfactory for evidence-based

medicine than randomized, placebo-controlled,

double-blind clinical trials. Results from recent

clinical trials studying the benefits of HRT have

differed from observational studies. Results from

additional large clinical trials, expected in the next

5 years, may further change thinking about the

optimal management for the menopausal woman.

The menopause offers the health care provider an

opportunity to assess each woman’s health, her

concerns, and the need for health promotion and

disease prevention measures. Today’s health care

provider has to consider a bewildering array of

changing “facts” and sees increasingly informed

Elizabeth Barrett-Connor, M.D.;* Susan Hendrix, D.O.;† Bruce Ettinger, M.D.‡

Nanette K. Wenger, M.D. Chair; Rodolfo Paoletti, M.D., Cochair; Claude J. M. Lenfant, M.D., Cochair; Vivian W. Pinn,

M.D., Cochair

Panel: Martin H. Birkhäuser, M.D.; Louise A. Brinton, Ph.D.; Aila Collins, Ph.D.; Peter Collins, M.D.; Pier Giorgio

Crosignani, M.D.; Lorraine Dennerstein, A.O., M.B.B.S., Ph.D., D.P.M., F.R.A.N.Z.C.P.; Jan-Åke Gustafsson, M.D., Ph.D.;

Victor W. Henderson, M.D., M.S.; Carlo La Vecchia, M.D.; Robert Lindsay, Ph.D.; Adriana Maggi, Ph.D.; Joan A.

McGowan, Ph.D.; Anne McTiernan, M.D., Ph.D.; Maryann Redford, D.D.S., M.P.H.; Susan M. Resnick, Ph.D.; Jacques E.

Rossouw, M.D.; Sherry Sherman, Ph.D. 

1. INTRODUCTION

* From the Division of Epidemiology, Department of Family and Preventive Medicine, UCSD School of Medicine, La Jolla, CA, U.S.A.

† From the Division of Gynecology, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Hutzel Hospital, Detroit, 

MI, U.S.A.

‡ From the Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA, U.S.A.
272

patients with strong personal convictions about the

menopause and their need for medication. The

provider must be prepared to discuss a variety of

menopause or age-related topics, and decide what

to recommend for a specific woman—often in less

time than ever before.

Recommendations should

be specific to each woman

and her background. There

are country-specific and

cultural variations in

menopause symptoms, the

frequency of different

postmenopausal diseases,

clinical practice, health

care resources, and affordable interventions.

Country- and culture-specific practice will therefore

vary, and appropriately so.

Recent research findings include:

• Increasing recognition of the need to address

health promotion beyond the perimenopausal

years, and in women with and without

menopausal symptoms.

• The risks and benefits of lifestyle, pharmacological, and surgical interventions may change as

women age.

• The tailoring of menopausal treatment to the

individual woman should be based on her individual clinical profile and concerns.

• For the treatment of the climacteric syndrome,

HRT remains the most effective pharmacologic

intervention.

• The long-term benefits and risks of HRT

continue to be assessed.

• HRT for long-term health promotion, as for

osteoporosis, usually requires its continued use.

• New nonhormone therapies offer more options

for prevention of common menopausal conditions, to be tested fully in clinical trials.

• Preventive drug therapy can start many years

after menopause, particularly with respect to

osteoporosis. This, however, may not be optimal.

• The risk for many disease outcomes can be

reduced even in old age.

Research results are teaching us to be cautious

before assuming that current practice is best. For

example, although HRT remains the gold standard

for the treatment of vasomotor and urogenital

symptoms, as well as for the prevention of bone

loss, recent clinical trial results have failed to show

benefit for other menopausal conditions, such as

incontinence.

Past perceptions about

appropriate indications for

the use of HRT were based

almost entirely on clinical

experience and observational data. These perceptions are being questioned

as new knowledge emerges

from clinical trials. Some

examples follow:

Perception: HRT protects against coronary 

heart disease.

Evidence: The prospective randomized clinical

trials reported so far have not shown

benefit for reducing coronary events

in secondary prevention.

The menopause offers

the health care provider

an opportunity to

assess each woman’s

health, her concerns,

and the need for health

promotion and disease

prevention measures.

The long-term

benefits and

risks of HRT

continue to 

be assessed.
273

Perception: Estrogen prevents memory loss and

retards the progression of

Alzheimer’s disease.

Evidence: Clinical trials have not shown that

ERT retards progression of early

Alzheimer’s disease. Clinical trials

of the effects of ERT on memory

loss are still ongoing.

Perception: Estrogen improves symptoms of

depression.

Evidence: Clinical trial data have shown that

ERT improves mood and well-being

only in women with vasomotor

symptoms and sleep disturbance. No

convincing clinical trial data indicate

that estrogen therapy in postmenopausal women is an effective

treatment for major depression.

Perception: Estrogen improves urinary incontinence.

Evidence: Clinical trials have shown no benefit.

Perception: HRT, unlike oral contraceptives,

does not increase the risk of venous 

thromboembolism.

Evidence: Clinical trials confirm a threefold

increased risk of venous thromboembolism with oral ERT.

Perception: HRT during the first 5–10 years after

the menopause is sufficient to prevent osteoporosis in later life.

Evidence: Bone loss resumes after stopping

HRT, leaving women vulnerable to

osteoporosis in later life. Whether

estrogen is started early or late, it

must be continued into old age to

maintain skeletal health.

Although many clinically relevant questions

remain unanswered, women seeking advice about

the menopause now have more information about

and more options for healthy postmenopausal

years than ever before. New trial results and new

medications may further change recommendations

for the assessment and management of the postmenopausal woman.

We make the following

recommendations concerning HRT based on

results from clinical trials.

Where evidence from

clinical trials is not available, we make recommendations based on observational studies. These recommendations are intended as guidelines, not mandates. All interventions

should be individualized—tailored to the specific

needs and concerns of each woman and designed

to provide an optimal quality of life.

2. THE MENOPAUSE TRANSITION

2.1 Assessment

Some women sail through the menopause transition with no complaints, others are miserable, and

the majority have symptoms that are somewhat

bothersome. There is still controversy as to which

symptoms are related to menopause and which are

associated with or exacerbated by other factors.

Clearly not all symptoms that occur during the

menopause transition are due to hormonal changes.

Only vasomotor, sleep, and some vulvovaginal

symptoms have shown more favorable relief after

HRT than placebo, and can therefore be convincingly attributed to changing hormone levels and

menopause. At least 25 percent of women in clinical trials report significant improvement in their

vasomotor symptoms when taking placebo. 

New nonhormone 

therapies offer more

options for prevention

of common menopausal

conditions, to be tested

fully in clinical trials.
274

Therefore, convincing evidence of treatment benefit requires a placebo-controlled clinical trial.

Women may visit the physician because they have

symptoms they suspect are related to menopause

or because they want information about the

menopause. In either case, assessment for symptoms provides an opportunity to discuss issues that

might otherwise remain unaddressed.

Symptoms directly or indirectly related to the

menopause transition include:

• Vasomotor symptoms (hot flushes and 

night sweats)

• Sleep-related symptoms

• Mood changes

• Sexual dysfunction

• Problems with concentration and memory

• Urogenital symptoms

Symptoms can be queried by using a questionnaire

or symptom checklist during the interview. Some

find that asking about sexual satisfaction is facilitated by the use of a checklist. When a checklist is

used, it is important to go beyond the list to assess

the severity and duration of

reported symptoms and the

degree to which they interfere with the woman’s life.

For example, hot flushes

that are not bothersome 

do not require treatment.

When asking about 

symptoms, the clinician

should be sensitive to 

each woman’s:

• Beliefs and attitudes about menopause, including her medical vs. nonmedical treatment 

preferences, anxieties, and coping style

• Sociocultural and ethnic background that may

affect her concerns and choices

• Work situation, job satisfaction, and stress

• Other life stressors, particularly with personal

relationships

• Social supports

• Overall quality of life

• Current use of nonprescription herbal, nutriceutical (a nutritional supplement designed for a

specific clinical purpose), or phytoestrogen

remedies.

It is important to have a dialogue with the patient.

Failure to listen and discuss may explain why many

women prescribed HRT do not fill the prescription.

2.2 Symptom Prevention and Treatment.

Vasomotor Symptoms: Hot Flushes and 

Night Sweats

2.2.1 Lifestyle

• Wear layered clothing that can be removed or

added as necessary.

• There is conflicting evidence as to whether

exercise improves menopause vasomotor 

symptoms.

2.2.2 Diet

• Avoid hot spicy foods and beverages, and

reduce caffeine.

• Avoid alcohol beverages (excess can cause

flushing).

2.2.3 Pharmacotherapy

• In a systematic review of more than 40 randomized controlled clinical trials, oral and transdermal estrogen each reduced the severity of vasomotor symptoms, and estrogen was effective in

doses lower than the usual 0.625 mg of equine

estrogens or equivalent.

• Transdermal estradiol and intranasal 

17β-estradiol spray are as effective as oral

estrogen in reducing hot flushes.

It is important to have 

a dialogue with the

patient. Failure to listen

and discuss may explain

why many women 

prescribed HRT do not

fill the prescription.
275

• Oral tibolone is as effective as other forms of

HRT such as estradiol valerate or conjugated

estrogens in reducing hot flushes.

• Selective ER modulators can increase hot flushes. In clinical trials, approximately 20 percent

of women at least 2 years after menopause less

than 60 years of age and 10 percent of older

women developed hot flushes on raloxifene.

Vasomotor symptoms were mild and rarely led

to discontinuation of therapy.

• The selective serotonin reuptake inhibitors

(SSRIs) venlafaxine and paroxetine have been

shown to substantially reduce hot flushes in

clinical trials.

• Progestogens in high daily doses (medroxyprogesterone acetate 20 mg per day or megestrol

acetate 40 mg per day) also reduced vasomotor

symptoms.

• Veralipride (100 mg per day) reduces hot flushes in patients treated with GnRH agonists.

• Propranolol is no more effective than placebo

for the reduction of hot flushes, whereas evidence for clonidine’s benefit is inconsistent.

2.2.4 Complementary and Alternative Therapies

• Phytoestrogens have not been shown in most

clinical trials to decrease vasomotor symptoms

significantly better than placebo. Different

results may relate to differences in women (not

all of them absorb phytoestrogens equally well)

or differences in the products tested. The best

single dietary source of phytoestrogens is soy.

The U.S. Food and Drug Administration has

approved a statement that soy protein at a dose

of 25 gm/day may reduce the risk of CVD,

based on a modest reduction in total cholesterol

level.

• Dong quai has been shown in a clinical trial not

to be more effective than placebo for the treatment of hot flushes.

• Evening primrose oil (gamma-linolenic acid) is

not more effective than placebo for the reduction of hot flushes.

2.3 Symptom Prevention and Treatment.

Urogenital Symptoms

• At least nine RCTs have shown that estrogen

improves urogenital symptoms; this is true for

oral and transdermal estrogen and for a silicone

estradiol-releasing vaginal ring. Vaginal dryness

and dyspareunia can be treated with a topical

estrogen cream, tablet, or vaginal ring, or with

nonhormone moisturizing or lubrication products. In clinical trials, topical estrogen appears

to be better than systemic estrogen for relieving

these symptoms, and avoids high levels of circulating estrogen.

• In one clinical trial, an estradiol-releasing silicone vaginal ring was also found to reduce the

incidence of urinary tract infection.

• Systemic estrogen alone or with a progestin does

not reduce incontinence, and in one large clinical trial, HERS, actually increased incontinence.

3. FRACTURES

3.1 Assessment

When discussing osteoporosis,

it is important to be sure that

the provider and the patient are

using the same language. Some

patients confuse osteoporosis

(fragile bones) with osteoarthritis (painful joints). Other

women (and some doctors)

mistakenly believe that a diagnosis of osteoporosis means

they should not exercise.

Many factors are 

associated with an

increased fracture

risk in women,

which may differ 

by fracture site.
276

3.1.1 Risk Factors

Many factors are associated with an increased fracture risk in women, which may differ by fracture

site. Most available data are on risk factors for

spine or hip fractures in Caucasian women aged 65

and older. Predicting risk in younger women and

other ethnic groups is less accurate.

Nonmodifiable risk factors for fractures:

• Age—there is an approximate doubling of 

fracture risk every 7 years

• Family history—history of osteoporotic fracture,

especially hip fracture, in either parent or sibling

approximately doubles the risk

• Personal history of osteoporotic fracture

increases the risk twofold to fivefold

• Early menopause increases risk

Modifiable risk factors:

• Weight—there is an increased risk if thin, and 

a decreased risk if overweight

• Excessive weight loss is a powerful risk factor

for bone loss and fracture

• Current smoking—increases the risk of all

fractures

• Low calcium intake—increases the risk of hip

fracture

• Vitamin D deficiency—can cause secondary

hyperparathyroidism and osteoporosis

• Inadequate physical activity

• Factors associated with falls, some of which are

modifiable:

• Limited vision

• Impaired cognition

• Balance problems

• Alcohol excess

• Poor health, frailty, muscle weakness

• Medications, particularly sedatives

• Environmental hazards, such as poor lighting

and loose area rugs

• Low bone density is a risk factor for fracture

(fracture risk doubles for every 10 –12 percent

decrease in bone mineral density, a deviation 

of approximately—1 t-score or—1 z-score

(measured by dual energy x ray absorptiometry

[DEXA]).

3.1.2 Case Finding

Bone density testing is recommended in the United

States for all women aged 65 years or older.

• DEXA of the hip is currently the gold standard

for bone density measurements.

• Bone density results should be used in conjunction with information obtained in clinical risk

assessment.

3.2 Prevention and Treatment

Better bones in old age are a function of peak bone

mass (usually achieved around age 25), and subsequent rate of bone loss. Peak bone mass is maximized by an adequate calcium intake, physical

activity, and not smoking. Lifestyle changes have

been shown to improve bone density in young

women and to prevent fractures in older women.

They are low-cost, safe, and can be recommended

widely.

3.2.1 Lifestyle

• Stop smoking

• Avoid extreme weight loss

• Add weight-bearing, muscle-building, and 

balance exercises

• Avoid sedatives

• Avoid excess alcohol

• Correct visual impairment

• Fallproof the home
277

3.2.2 Diet

• Correct calcium deficiency. A diet devoid of

dairy products rarely provides more than 200 –

250 mg of calcium per day, which does not balance obligatory calcium loss and is associated

with increased bone loss. Much of the bone loss

can be attenuated by increasing calcium intake.

Ideally, the combined diet and supplement

intake should be 1,200 mg of calcium each day.

• In correcting dietary calcium deficiency, the

first step is to increase calcium-rich foods; each

dairy portion contains approximately 300 mg.

Calcium-supplemented orange juice or mineral

water rich in calcium are useful for women with

lactose intolerance.

• If adequate dietary calcium is not likely, calcium supplements should be recommended.

Calcium supplementation should be given concomitantly with Vitamin D. Clinical trials have

shown that calcium with vitamin D can reduce

fracture risk; no clinical trials have shown that

vitamin D without calcium significantly reduces

fracture risk. Clinical trials consistently show

better bone preservation in women who take

calcium with estrogen than estrogen alone.

• Supplement vitamin D intake for women 65 and

older; 600–800 IU/day together with adequate

calcium intake can reduce the risk of fracture in

elderly women by about 25 percent.

3.2.3 Pharmacotherapy

With growing evidence for efficacy of osteoporosis

treatments and with growing concern about drug

costs, policymakers have recommended that

expensive drugs not be used for osteoporosis prevention. In addition, all medications have risks and

side effects. Therefore, aggressive pharmacotherapy should be reserved for women who are at high

risk of fracture in the near future.

Practitioners in discussion with their patients must

decide between therapy with bone-specific drugs

or broad-spectrum drugs (HRT, SERMs).

• Drugs shown in clinical trials to prevent bone

loss, that is, to be effective in prevention of

osteoporosis, include estrogen, tibolone, raloxifene, alendronate, and risedronate.

• Drugs shown in clinical trials

to prevent fractures include

raloxifene, alendronate, and

risedronate. These clinical trials were conducted in women

at increased risk of fracture.

Similar large trials have not

been conducted using estrogen or tibolone. HERS found

no difference in clinical fracture rate or height loss (a

marker for vertebral fractures) in women assigned to HRT vs. placebo.

Fracture was a preset secondary endpoint in

HERS, but women in this trial were not at high

risk for fracture.

Estrogen therapy

• Bone loss is accelerated during the first 5–10

years following menopause, and postmenopausal

estrogen therapy is effective in preserving 

existing bone, whether begun in old age or at

the time of the menopause. Results are similar

with estrogen alone or when estrogen is used

with a nonandrogenic progestin such as

medroxyprogesterone acetate or progesterone.

Androgenic progestins such as norethisteroneacetate have a synergistic activity when combined with 17β-estradiol.

• Clinical trials have shown that doses of 0.3 mg

per day of conjugated equine estrogen (lower

than the previously recommended 0.625 mg per

day), 0.5 mg of oral 17β-estradiol, or 25 micrograms of transdermal 17β-estradiol maintain

bone in most women when taken with adequate

calcium. Smaller doses were better tolerated

with regard to fewer episodes of uterine bleeding and less breast tenderness, two major reasons why women discontinue estrogen. Whether

Lifestyle changes

have been shown

to improve bone

density in young

women and to 

prevent fractures

in older women. 
278

lower dosages of estrogen will be safer (lower

rates of venous thomboembolism, breast cancer)

remains to be proven.

When medication is indicated, based on a combination of clinical risk factors and low bone mineral

density, the choice varies with the age of the

patient and the severity of osteoporosis.

• Estrogen must be used continuously to preserve

bone. Observational data suggest that bone density in older women who have never received

estrogen is similar to bone density in women

who used estrogen for 10 years and then discontinued it for another 10 years.

• Hormone treatment of women soon after

menopause should be reserved for management

of postmenopausal symptoms, but it will preserve bone in most women.

Non-estrogen therapy

Asymptomatic women 10 or

more years postmenopause,

without severe osteoporosis,

may prefer tibolone or

raloxifene. For women aged

60 or older who have osteoporosis but are not at high

risk for nonspine fracture,

raloxifene can be used to

reduce the risk of spine fractures and for its possible other health benefits.

Older women, particularly those with severe osteoporosis and prior fracture(s), may prefer alendronate or risedronate for their rapid acting bonespecific effects and reductions in nonspine as well

as spine fractures.

Parathyroid hormone treatment by daily injection

promises to be particularly effective for women

with very severe osteoporosis who need to gain

substantial amounts of bone.

The way medications are prescribed influences

patient adherence. Beginning with a low dose for

women prescribed estrogen helps reduce breast

pain and slowly increasing dosage of raloxifene is

useful in overcoming the hot flush side effect.

Women who cannot tolerate the first medication

often tolerate one of the other bone-sparing medications. A few trials have shown improved bone

density over single therapy when a bisphosphonate

is combined with estrogen or raloxifene, but there

are no fracture data in women using these combinations (and the cost of combination therapy precludes routine use).

• Statins have been inconsistently associated with

higher bone density. Statins have not been consistent in reducing bone loss or fracture risk,

and these skeletal benefits have not been

assessed in clinical trials.

• Clinical trial data show that a thiazide diuretic

reduces but does not prevent bone loss.

• Observational studies suggest that people using

thiazides are less likely to have fractures.

3.2.4 Complementary and Alternative Therapies

• Soy food (soy protein isolate) has been shown

in clinical trials to have little or no benefit 

for the skeleton when ingested in the usually

recommended amounts (20–25 grams of soy

protein per day).

• Ipriflavone, a synthetic isoflavone, has been

shown in preliminary studies to reduce bone

loss but failed to improve bone density or

reduce fracture risk in a large clinical study 

of women with osteoporosis.

4. CARDIOVASCULAR DISEASE

4.1 Assessment

When assessing a woman’s knowledge about heart

disease and stroke prevention, it is important to note

that cardiovascular disease is a more common cause

of morbidity and mortality for women in most of

the world than osteoporosis and cancer combined.

Aggressive pharmacotherapy should 

be reserved for

women who are at

high risk of fracture

in the near future.
279

4.1.1 Risk Factors

The main risk factors for coronary heart disease

are: high blood cholesterol, high blood pressure,

diabetes, and cigarette smoking. These same factors also apply to stroke and peripheral arterial disease, but the order of importance differs. High

blood pressure is the most important risk 

factor for stroke, while smoking has been consistently associated with peripheral arterial disease,

and high blood cholesterol with CHD.

Nonmodifiable risk factors

• Age. For every 10-year increase in age, the risk

for heart disease increases about threefold.

• The presence of CHD or other evidence of 

atherosclerotic arterial disease including stroke

or lower extremity arterial disease increases 

the risk for myocardial infarction (MI) about

fivefold. Atrial fibrillation, aortic stenosis, 

and narrowing of the coronary arteries are also

risk factors for stroke.

• Family history of premature CHD (MI before

age 55 in men, 65 in women) increases the risk

for MI about twofold.

• The importance of a positive family history is

amplified in women who smoke cigarettes.

Modifiable risk factors

• Cigarette smoking: Compared to smokers, 

nonsmokers or women who stop smoking 

have one-third the risk for MI.

• Physical activity: Women who walk briskly for

3 hours per week have a one-third lower risk for

MI compared to women who do little exercise.

• Nutrition: Women whose usual diet is low in

saturated and trans fats, and relatively high in

unsaturated fats (including monounsaturated

fats and fish oils), and high in cereal fiber,

fruits, and vegetables, have half the risk for 

MI compared to women who do not have this

healthy eating pattern.

• Weight: Lean women (body mass index below

25) have one-quarter less risk than overweight

women, and less than one-half the risk of obese

women (body mass index above 30).

• Fat distribution: Women with

a waist circumference of less

than 28 inches (71 cm) have

one-third the risk for MI compared to women with a waist

circumference of more than 38

inches (96.5 cm). Weight and

weight distribution associated

risks are not the same in all

populations. For example,

overweight and central obesity

seem to be less important risk

factors in African American

women than in women of northern European

ancestry and Asian American women who seem

to be at increased risk at lower weights.

• Psychosocial factors: Life stress situations,

depression, and social isolation have been

linked to increased risk for MI in women.

• Blood pressure: Women with a systolic blood

pressure below 140 mmHg have a risk for MI

one-half that of women with a level above 

180 mmHg.

• Blood cholesterol: Women with a LDL cholesterol below 130 mg/dL (3.4 mmol/L) have a

risk for MI one-half that of women with levels

above 190 mg/dL (4.9 mmol/L).

• HDL cholesterol: Women with a HDL cholesterol level above 60 mg/dL (1.6 mmol/L) have 

a risk for MI which is one-third that of women

with a level of less than 40 mg/dL (1.0 mmol/L).

Contrary to popular opinion, women with high

HDL cholesterol levels are not immune to MI.

• Triglycerides: Women with triglyceride levels

below 150 mg/dL (1.7 mmol/L) have a risk of

MI one-third lower than women with levels

above 240 mg/dL (2.7 mmol/L).

CVD is a more

common cause

of morbidity and

mortality for

women in most

of the world than

osteoporosis and

cancer combined.
280

• Diabetes: Women with diabetes by history or

glycemia (fasting plasma glucose > 126 mg/dL

(7.0 mmol/L) and/or 2 hour postchallenge 

glucose above 199 mg/dL (11.1 mmol/L) have a

two- to fourfold increased risk of MI compared

to women without diabetes. About half of

women with Type 2 diabetes do not know they

have it. Diabetes is often first diagnosed when

the patient has a MI.

4.1.2 Other Assessments

History

• Presence of any of the risk factors above.

• Symptoms compatible with transient ischemic

attack, CHD, or lower extremity atherosclerosis.

• Use of HRT, antihypertensive drugs, lipid-lowering therapy, aspirin, and medication for diabetes.

Physical examination

• Pulses, auscultation for cardiac murmurs, and

arterial bruits.

• Blood pressure at first visit. Women who have

optimal blood pressure levels (< 130/85 mmHg)

are rechecked every 2 years (Europe: women 

> 40 years: every year),

those with normal levels 

(< 140/90 mmHg) are

rechecked every year. Women

with levels > 140/90 mmHg

need confirmation.

• Height, weight, waist 

circumference, calculate

body mass index.

Laboratory tests

• Fasting glucose, total cholesterol, HDL cholesterol, triglycerides, calculated LDL cholesterol

at first visit. For women without known CHD,

the desirable lipid levels are LDL cholesterol 

< 130 mg/dL (3.4 mmol/L), triglycerides 

< 150 mg/dL (1.7 mmol/L), and HDL

cholesterol levels > 45 mg/dL (1.3 mmol/L).

• Repeat measurements that are normal every 

5 years.

• Evidence does not support further screening for

diabetes. Case finding may be appropriate in

persons who have central obesity, high triglycerides, or a positive family history. Repeat 

glucose tests for women whose fasting blood

glucose is elevated because the diagnosis of 

diabetes needs a confirmatory test. Women

whose fasting plasma glucose is between 110

(6.1 mmol/L) and 126 mg/dL (7.0 mmol/L) 

or whose 2 hour glucose is between 140 (7.8

mmol/L) and 200 mg/dL (11.1 mmol/L) are 

at high risk of future diabetes.

• In some countries, homocysteine measurement

is recommended.

Other tests for CHD, cerebral arterial disease, and

peripheral vascular disease as indicated by symptoms.

The combined effect of two or more risk factors is

more powerful than any single risk factor, and some

risk factors commonly occur together. (For example,

screening for diabetes may be most appropriate in

persons with high blood pressure or high triglyceride levels.) When one risk factor is found, the

presence of other factors should be sought and an

assessment of overall risk should be made by

counting the number of risk factors plus a 10-year

risk assessment as in the National Cholesterol

Education Program’s Adult Treatment Panel III

Report (NCEP ATP III) or as an assessment of the

10-year risk as recommended in European guidelines. Risk assessment can be used to motivate the

patient to make lifestyle changes and comply with

medication.

4.2 Prevention and Treatment

Even in the absence of clinical trial data, lifestyle

and diet recommendations can be made to all

women, not just those with heart disease risk factors or disease, because the diet, physical activity,

and not smoking recommendations represent a

return toward the evolutionary norm.

The main risk factors

for CHD are: high

blood cholesterol,

high blood pressure,

diabetes, and 

cigarette smoking.
281

4.2.1 Lifestyle

• At each visit, reinforce nonsmoking status, or

strongly encourage patient (and family) to stop

smoking and avoid secondhand smoke. Prescribe

counseling, nicotine replacement, or other 

pharmacotherapy as indicated in conjunction

with behavioral therapy or a formal smoking

cessation program.

• Encourage a minimum of 30 minutes of moderate-intensity dynamic exercise, e.g., brisk walking, at least 3 days a week,

supplemented by an increase

in daily lifestyle activities.

Women who want to do more

than the minimum should be

encouraged to do so.

Recommend medically supervised programs for women

who have had a recent MI or

revascularization procedure.

• Encourage gradual weight loss for overweight

women through a combination of physical

activity and portion control, healthy food choices, and recognition of triggers to overeating.

Refer to weight loss support group or formal

nutritional counseling when appropriate.

• Encourage positive coping mechanisms for

stress (e.g., substitute physical activity for

overeating or smoking in response to stressful

life situations).

4.2.2 Diet

• Encourage a well-balanced and diversified eating pattern that is low in saturated fat and high

in fresh fruits and vegetables and fiber. Prefer

fats with higher monounsaturated content (e.g.,

olive oil, canola oil). Prefer seafood and skinless chicken to red meat. Prefer soft unsaturated

margarine to hard margarine or butter. Use skim

milk and skim milk products or at most 1 percent milk instead of products with a higher fat 

content. Limit the intake of high-cholesterol

foods, avoid fast-food meals. Consume more

than five servings of fruits and vegetables daily.

Total dietary fiber intake from food should be

25–30 g per day.

• A clinical trial showed that eating fish two to

three times per week reduced the risk of CVD.

• Encourage increased dietary consumption of

omega-3 fatty acids.

• A clinical trial showed that a “Mediterranean

diet,” supplemented with alpha-linoleic acid,

significantly reduced the risk of recurrent coronary events in patients with heart disease.

• Diets rich in antioxidant vitamins (i.e., nuts,

fruits, and vegetables) are preferred over vitamin supplements.

• Limit salt intake to 6 g per day. A reduced

salt/reduced saturated fat diet has been shown to

reduce blood pressure in clinical trials.

• Prefer spices to salt in food preparation. Reduce

intake of canned and commercial bakery goods,

which are usually high in salt.

• Limit alcohol to less than one to two glasses per

day: one glass equals 4 ounces of wine (approx.

120 mL), 12 ounces of beer (approx. 360 mL), or

11

/2 ounces of 80-proof spirits (approx. 45 mL).

4.2.3 Pharmacotherapy

Blood pressure

• Achieve and maintain blood pressure < 140/90

mmHg or lower if tolerated. If blood pressure

remains above 140/90 mmHg after 3 months of

reduced dietary salt, saturated fats and attempted

weight loss, or if initial level is above 160/100

mmHg, initiate individualized pharmacotherapy.

Goal blood pressure < 130/80 mmHg if diabetic.

Beta-blockers, low-dose diuretics, and

angiotensin converting enzyme inhibitors have

been shown in clinical trials to reduce the risk

of MI in patients with high blood pressure.

Women with

diabetes ...

have a twoto fourfold

increased risk 

of MI ...
282

Lipids and lipoproteins

• LDL cholesterol

a) In women without CHD or CHD risk equivalents (other forms of atherosclerotic disease,

diabetes, or 10-year risk more than 20 percent), the desirable LDL cholesterol level is

< 130 mg/dL (3.4 mmol/L).

• If the LDL cholesterol level is > 130

mg/dL (3.4 mmol/L) and two or more

other risk factors are present, or the 10-

year risk of MI is more than 10 percent,

implement intensive lifestyle intervention

and consider pharmacotherapy. If the 10-

year risk is less than 10 percent, consider

pharmacotherapy if the LDL cholesterol is

> 160 mg/dL (4.1 mmol/L).

• If the LDL cholesterol level is > 190

mg/dL (4.9 mmol/L), pharmacotherapy 

is usually required.

b) In women with CHD or CHD equivalents,

the desirable LDL cholesterol level is 100

mg/dL (2.6 mmol/L) or lower, and pharmacotherapy is generally required.

• Triglycerides and HDL cholesterol

• If the triglycerides are >150 mg/dL (1.7

mmol/L) and the HDL cholesterol is below

40 mg/dL (1.0 mmol/L), treatment should still be aimed primarily at the LDL level.

Lowering triglycerides and

raising HDL levels become

secondary targets of therapy

and may influence the choice

of drugs. Women with elevated

triglycerides as their only lipid

abnormality usually respond to

intensive lifestyle measures.

Some patients with very high triglyceride

levels respond best to fibrates or niacin.

• Choice of drugs

• Statins are the drugs of choice for high LDL

cholesterol levels, irrespective of the levels

of triglycerides or HDL cholesterol. Statins

have been shown in clinical trials to reduce

the risk of MI and stroke.

For women with moderate elevations of LDL

cholesterol, raised triglycerides, and low HDL

cholesterol levels, statins are the first choice.

Fibrates and niacin have not been shown in

randomized clinical trials to reduce CHD risk

in women, although recommended in

AHA/ACC (American Heart Association/

American College of Cardiology) guidelines

for low HDL or high triglycerides. Start statin

therapy promptly in patients with acute coronary syndrome.

HRT given orally reduces LDL cholesterol

by 10 percent, raises HDL cholesterol by 

10 percent, and raises triglycerides by 20

percent. HRT is not recommended for management of lipid disorders because of the

lack of clinical trial evidence showing cardiovascular benefit.

Diabetes

• Target preprandial blood glucose in the range 

of 80–120 mg/dL (4.4–6.7 mmol/L), bedtime

100–140 mg/dL (5.5–7.8 mmol/L), Hgb A1c 

< 7 percent

• Maintain LDL cholesterol < 100 mg/dL

(2.6 mmol/L) and triglycerides < 150 mg/dL

(1.7 mmol/L)

• Maintain blood pressure < 130/80 mmHg (optimal < 120/75 mmHg)

• In clinical trials, the initiation of oral HRT is

accompanied by a two- to fourfold increased

risk of venous thromboembolism and a small

early increased risk of CHD and stroke. Based

on observational studies, a reduction in risk for

CHD after 2 or more years is possible, but the

clinical trial evidence is lacking. Some experts

Even in the absence

of clinical trial data,

lifestyle and diet 

recommendations

can be made 

to all women ...
283

see no reason to discontinue HRT in women

who have been treated for many years, in view

of the expected benefit for osteoporosis. Based

on clinical trial data, an increased risk of venous

thromboembolic disease persists for at least 4

years. The absolute increase in risk for venous

thromboembolism is small—approximately two

excess events in 8,000 treated women. This risk

may be reduced in women taking aspirin or statins.

• A history of venous thromboembolic disease is

a contraindication to HRT.

• Low-dose aspirin can be recommended for

women with established CVD (based on clinical

trial data and probably for high-risk women [by

inference only]). There is some concern that the

risk benefit ratio may be different in women,

who seem to have a higher risk of stroke than

men. Consider clopidogrel or warfarin if aspirin

is contraindicated.

• Beta-blockers: If there are no contraindications

(e.g., severe bradycardia, high degree heart

block, acute heart failure, asthma, active peripheral vascular disease) start beta-blockers within

hours of hospitalization for MI and acute 

coronary syndromes, or as soon as possible

thereafter to lower the risk of reinfarction and

of cardiac failure.

• ACE inhibitors. If there are no contraindications

(e.g., renal artery stenosis, aortic stenosis, or

severe hypotension), start ACE inhibitors within

hours of hospitalization for MI, or as soon as

possible thereafter, to lower the risk of reinfarction and of cardiac failure. Use ACE inhibitors

to lower the risk of MI and death in patients

with cardiac failure, left ventricular dysfunction,

or high risk for CHD.

4.2.4 Complementary and Alternative Therapies

• Trials of vitamin E and beta-carotene supplements have failed to show benefit for CVD 

prevention.

5. CANCERS (BREAST, CERVIX, 

COLORECTAL, ENDOMETRIAL, 

OVARY, AND LUNG)

The major cancers that occur in postmenopausal

women are breast, cervix, colorectal, endometrial,

ovary, and lung.

In observational studies, the increased risk of

breast cancer after 5 or more years of estrogen

replacement therapy is similar to the risk associated with a delayed menopause or with obesity. In

some of these studies, breast cancer risk was higher in women who used estrogen plus a progestin

and higher in women who used estrogen plus progestin cyclically.

Endometrial cancer is associated with endogenous

or unopposed exogenous estrogen levels. An

increased risk of endometrial cancer occurs in

menopausal women who have low levels of progestin to counterbalance the stimulating effect of

estrogen on the endometrium. A 3-year clinical

trial has shown that endometrial hyperplasia, a

uterine cancer precursor, occurs in 10 percent of

women for each year of unopposed estrogen use.

A number of observational epidemiological studies

(including both prospective and case-control studies)

have consistently shown that women on HRT have

reduced risks of developing colorectal cancer or

adenoma and of dying from colorectal cancer. There

is weak evidence from observational studies that

HRT increases the risk of ovarian and lung cancer.

Much of the increased risk for cancers in postmenopausal women can be linked to the effects of age

and accumulated lifetime exposure to carcinogens.

5.1 Assessment

5.1.1 Risk Factors

Nonmodifiable risk factors

• Family history of breast, ovarian, or colorectal

cancer, especially in a first-degree relative.

• Age. Most cancer rates increase with age. The

year-by-year increase in breast cancer rates 
284

persists but is less steep in women who do not

take estrogen after the menopause.

• Previous history of cancer (invasive and in situ).

• Precursor lesions (benign proliferative breast

disease, colorectal polyps, endometrial hyperplasia, and high grade squamous intra-epithelial

lesions of the cervix infected with selected variants of human papillomavirus [HPV]).

• Reproductive and menstrual factors: Early

menarche and late menopause increase risk for

breast cancer, and possibly also endometrial and

ovarian cancer. Early first pregnancy and multiparity decrease the risk for breast and ovarian

cancers. Multiparity also reduces the risk of

endometrial cancer.

Modifiable risk factors

• Estrogen treatment: Excess

exogenous estrogen in the

postmenopausal years increases risk for breast and endometrial cancers. It is unknown

whether lower doses of estrogen will have different risks

and benefits. Use of a progestin with the estrogen may

increase breast cancer risk, but

it decreases endometrial cancer risk if taken in an adequate

regimen, either 10–14 days

per month or daily. Past oral

contraceptive use greater than

1 year decreases endometrial

and ovarian cancer risk.

• Overweight: Heavier postmenopausal women

are at increased risk for cancer of the breast,

endometrium, and colon. The risk for breast

cancer in obese women is comparable to that

for long-term HRT.

• Nutrition: Women whose usual diet is low in fat

and high in vegetables, fruits, and fiber have a

reduced risk for colorectal and breast cancer.

Recent clinical trials found no reduced risk of

colon polyps, a cancer precursor, after either a

high-fiber diet or a diet enriched with fruits and

vegetables.

• Physical activity: Physically active women may

have a reduced risk for colon cancer and possibly

also breast and endometrial cancer.

• Cigarette smoking: Women smokers are at

increased risk for lung, cervix, colorectal, oral,

esophageal, and pancreatic cancers, as well as

other less common epithelial cell cancers.

• Alcohol: Alcohol use increases the risk for

breast (probably by increasing endogenous

estrogen levels) and colon cancer, as well as

more rare head and neck cancers.

• Radiation: High doses of radiation, used in the

past for certain medical treatments, have been

associated with increased risk for several cancers.

• Other exposures: Women infected with specific

strains of HPV are at increased risk for cervical

cancer.

• High radiographic density on mammogram carries about a twofold increased risk for breast

cancer and may delay diagnosis by making

mammograms harder to read. A clinical trial

showed that this reversible condition occurs

within 1 year in about 15 percent of most postmenopausal women treated with estrogen alone

and in more than one-third of those treated with

estrogen plus a progestin.

5.1.2 Case Finding

History

• Presence of any of the risk factors above

Physical examination

• Height, weight

• Clinical breast exam

In observational

studies, the

increased risk of

breast cancer after 

5 or more years 

of estrogen 

replacement therapy 

is similar to the 

risk associated 

with a delayed

menopause or 

with obesity.
285

• Pelvic exam

• Colorectal screening (can include fecal occult

blood assay, flexible sigmoidoscopy, and

colonoscopy).

Specific tests

The selection of screening modality and frequency

will depend on individual and population prevalence of disease and available resources.a

• Mammograms: There is disagreement about the

benefit of mammograms before age 50, but

women taking HRT and those with other risk

factors may want to be tested. Mammograms

are usually performed annually or biannually.

Because women’s risk of breast cancer continues to increase with age, regular mammography

screening remains appropriate even in old age

although the benefit in women over age 75 has

not been tested.

• Cervical smears: In countries where cervical

cancer rates increase with age, cervical smears

should be continued into old age.

• Pap smears have poor positive predictive value

for postmenopausal women and do not have to

be performed more often than every 2–3 years

after a normal cytological result. The main advantage of an annual Pap smear is that it increases

overall adherence to regular examination.

Clinical observation shows no effect of HRT on

cytologic abnormalities.

• Special methods that include testing for carcinogenic HPV strains reduce the number of falsepositive results and the attendant anxiety and

cost. In the future, these tests may replace the

Pap smear as the gold standard for early detection of cervical cancer.

5.2 Prevention and Treatment

Despite a great deal of information on factors that increase

cancer risk, there are limited

data on what can be done to

reduce risk. There have been

few clinical trials of prevention

modalities. It is not clear that

reversing a risk factor will

reduce cancer risk.

Nevertheless, some practical

recommendations can be made.

5.2.1 Lifestyle

• Stop smoking.

• Limit alcohol use to less than one to two 

glasses per day: 1 glass equals 4 ounces of 

wine (approx. 120 mL), 12 ounces of beer

(approx. 360 mL), or 11

/2 ounces of 80-proof 

spirits (approx. 45 mL).

• Avoid unnecessary radiation.

• Avoid unopposed ERT if uterus is present.

• Avoid HRT for more than 5 years except in

presence of specific indications.

• Avoid postmenopausal weight gain.

• If overweight or obese, lose weight.

• Increase physical activity.

5.2.2 Diet

• Increase intake of vegetables, fruits, and fiber.

• Decrease fat and red meat intake.

a Horton R. Screening mammography—an overview revisited. Lancet 2001;358:1284–1285. Olsen O, Gotzsche PC. Cochrane review on screening for

breast cancer with mammography. Lancet 2001;358:1340–1342.

Much of the

increased risk 

for cancers in 

postmenopausal

women can be linked

to the effects of age

and accumulated

lifetime exposure 

to carcinogens.
286

5.2.3 Pharmacotherapy

Breast Cancer

• Consider tamoxifen use if high risk for breast

cancer; a North American clinical trial found a

reduced risk for breast cancer with 5-year use.

Tamoxifen increases the risk of endometrial

cancer, venous thromboembolism, and vasomotor symptoms.

• Although raloxifene is

not approved for prevention

or treatment of breast cancer, a 4-year trial of raloxifene in women with osteoporosis (not at high risk for

breast cancer) showed a

90-percent risk reduction

for estrogen-receptor positive breast cancer, and no

increased risk of uterine cancer. Breast density is

not increased with raloxifene use. A trial comparing raloxifene with tamoxifen is underway.

• When prescribing estrogen to women with an

intact uterus, prescribe at least 10–14 days 

per month of progestin, to reduce endometrial

cancer risk.

• Do not give progestin to women without a

uterus; it is not necessary, and some observational studies suggest that estrogen plus progestin increases the risk of breast cancer more

than estrogen alone.

5.2.4 Complementary and Alternative Therapies

• Despite much interest in complementary and

alternative therapies, there are no trial data on

their efficacy in reducing cancer risk. The most

attractive candidate is soy protein, based on

observational studies of low breast cancer risk

in countries with high soy intake.

• A trial of the effect of a low-fat, high-fiber diet

on the recurrence of colorectal adenomas, a cancer precursor, failed to show the benefit of such

a diet in reducing risk.

Other: very-high-risk patients

• Consider removal of at-risk organs.

• Very high risk for breast cancer: additional

screening by sonography.

• There is no trial evidence that additional screening such as pelvic ultrasound or Ca125 for

women at high risk for ovarian cancer or beginning mammography before age 40 for women 

at high risk for breast cancer will improve the

prognosis.

• Colonoscopy for women at high risk for 

colorectal cancer can be recommended based 

on clinical trial data.

6. DEMENTIA AND MENTAL HEALTH

For most disorders affecting the central nervous

system, there are inadequate data upon which to

base practice decisions. Alzheimer’s disease merits

particular mention, because it is common and a

major concern of older women.

6.1 Assessment

6.1.1 Risk Factors for Alzheimer’s Disease

• The only consistently identified risk factors are

age, family history, and apolipoprotein E ε4 allele.

• The risk of developing Alzheimer’s disease 

doubles approximately every 5 years through

the ninth decade of life.

• Uncommon forms of the illness that appear

before the seventh decade of life are often 

transmitted as autosomal dominant disorders.

• Dominant inheritance is not characteristic of

later-onset dementia, although family history

remains a risk factor in this age group.

• Some observational studies suggest other risk

factors for Alzheimer’s disease, including prior

history of head trauma, low educational achievement, presence of CHD, hypertension or hyperlipidemia, prior history of depression, and the

Despite much interest 

in complementary and 

alternative therapies,

there are no trial data

on their efficacy in

reducing cancer risk.
287

absence of HRT. The evidence for these associations is inconsistent.

• Polypharmacy and thyroid disease are two

examples of reversible causes of memory loss

in older adults.

• Depressed mood is fairly common in persons

with dementia; it may impair cognitive function

or be a consequence of it.

6.1.2 Case Finding for Suspected Dementia

• The medical, neurological, and psychiatric 

history should focus on

potential causes of cognitive and behavioral

change, including

stroke, endocrine disease (e.g., thyroid disorders), toxic exposures

(particularly the excessive use of psychotropic medications or medications with psychotropic side-effects),

and depression.

• Family history should be assessed.

• Functional decline should be documented.

• The mental status examination should evaluate

both cognition and mood. Commonly used tests

for cognitive function are the Mini-Mental State

Examination (MMSE) and the short Blessed

Test for Orientation-Memory-Concentration.

Standard validated questionnaires are available

for testing for depressed mood in the elderly

(e.g., the Beck Depression Inventory and the

Geriatric Depression Scale).

• Laboratory assessment in the patient with

dementia usually includes complete blood

count; serum electrolytes and glucose; tests 

of renal, liver, and thyroid function; and B-12

level. Screening for syphilis and HIV should 

be considered in at-risk populations.

• Brain imaging study (CT scan or MRI scan) is

often used to exclude space-occupying lesions,

evaluate suspected cerebrovascular disease, or

evaluate suspected hydrocephalus. The diagnostic yield for this procedure is low if the neurological examination is normal and the history

and examination are otherwise typical for

Alzheimer’s disease.

• A common cause of cognitive impairment in the

elderly is overmedication. A careful review of

all medications taken by the patient may lead to

the identification of a reversible cause of confusion or memory loss.

6.2 Prevention and Treatment

• There are no proven preventive measures for

Alzheimer’s disease. For prevention of vascular

dementia, it is reasonable to follow preventive

recommendations listed for CVD.

6.2.1 Lifestyle

• Ensure a safe, stable, and structured environment.

• Encourage social interventions such as power of

attorney and caregiver respite as appropriate.

6.2.2 Diet

• Diet should be well-balanced.

• Discourage excess alcohol use.

• Discourage smoking, which can pose a fire hazard.

6.2.3 Pharmacotherapy

• Reduce unnecessary or optional medications.

• Identify and treat depression and other behavioral disturbances when they are distressing to

patients or hinder their care.

• There is clinical trial evidence that drugs that

inhibit the breakdown of acetylcholine in the

brain are often of mild symptomatic benefit.

For most disorders

affecting the central

nervous system,

there are inadequate

data upon which 

to base practice

decisions.
288

• There is no clinical trial evidence that estrogen

improves symptoms or delays symptomatic 

progression in women with Alzheimer’s disease.

• There are no published long-term clinical 

trial data on potential effects of HRT on ageassociated cognitive decline.

• One clinical trial found that vitamin E slows

progression without improving cognition 

in patients with moderate dementia due to

Alzheimer’s Disease.

• One clinical trial of antihypertensive medication

in cognitively intact older adults with hypertension showed a small but significant difference 

in the rate of memory loss and the incidence of

dementia in those on active treatment.

• One clinical trial found raloxifene was associated with less cognitive decline in two cognitive

function tests in older women.

6.2.4 Complementary and Alternative Therapies

• There is limited trial evidence that gingko biloba may offer mild cognitive benefit when given

to patients with dementia.

7. CONCLUSIONS

In the last 20 years, menopause has become a

household word, with much better understanding

of its consequences. The growing numbers of 

postmenopausal women and clinical trials have

coincided to draw increasing attention to the perimenopausal and postmenopausal years. Better

studies of older therapies and the expanded number

of new choices today, with more in development

and evaluation, have complicated provider and

patient choices, but greatly improved the potential

for effective intervention.
289

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295

14. LIST OF ABBREVIATIONS

ACC American College of Cardiology

ACE angiotensin-converting enzyme

ACS acute coronary syndromes

ACTH adrenocorticotropic hormone

AF–1 activation function 1

AF–2 activation function 2

AHA American Heart Association

AHCPR Agency for Health Care Policy and Research 

AHRQ Agency for Healthcare Research and Quality 

AIRE Acute Infarction Ramipril Efficacy 

AP1 Activated Protein 1 

AR androgen receptor 

ArKO aromatase knockout 

ATP Adult Treatment Panel 

AVP anteroventral periventricular nucleus 

BARI Bypass Angioplasty Revascularization Investigation 

BCDDP Breast Cancer Detection and Demonstration Project 

BERKO ERβ knockout 

BMC bone mineral content 

BMD bone mineral density 

BMI body mass index 

CABG coronary artery bypass graph 

CAD coronary artery disease 

CAMS Council of Affiliated Menopause Societies 

CAST Chinese Acute Stroke Trial 

CBP CREB binding protein 

CEE conjugated equine estrogen 

ChAT choline acetyl transferase 

CHD coronary heart disease 

CI confidence interval 

CNS central nervous system 

CONSENSUS-I Cooperative North Scandinavian Enalapril Survival Study 

CPS-II Cancer Prevention Study II 
296

CRP C-reactive protein 

CT computed tomography 

CVD cardiovascular disease 

D&C dilatation and curettage 

DDT dichlorodiphenyltrichloroethane 

DERKO double ER knockout 

DES diethylstilbestrol 

DEXA dual energy x-ray absorptiometry 

DRI dietary reference intake 

DSM IV Diagnostic and Statistical Manual of Mental Disorders, 4th edition 

ECG electrocardiogram 

EGF epidermal growth factor 

eNOS endothelial nitric oxide synthase 

EPISTENT Evaluation of IIb/IIIa Platelet Inhibitor for Stenting 

EpRE/ARE electrophilic/antioxidant response element 

ER estrogen receptor 

ERA Estrogen Replacement and Atherosclerosis 

ERE estrogen-responsive element 

ERKO ERα knockout 

ERT estrogen replacement therapy 

FARs floating absolute risks 

FDA Food and Drug Administration 

FMP final menstrual period 

FSH follicle-stimulating hormone

GABA gamma-aminobutyric acid 

GBDS Global Burden of Disease Study 

GH growth hormone 

GnRH gonadotropin-releasing hormone 

GUSTO IIb Global Use of Strategies To Open Occluded Coronary Arteries in Acute Coronary Syndromes 

HATs histone acetyl transferases

HDL high density lipoprotein 

HERS Heart and Estrogen/Progestin Replacement Study 

hGH human growth hormone 

HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A

HOPE Heart Outcomes Prevention Evaluation 

HPA hypothalamo-pituitary axis 

HPV human papillomavirus 

HRT hormone replacement therapy 

HSDD hypoactive sexual desire disorder 

5-HT 5-hydroxytryptamine 

ICAM-1 intracellular adhesion unit 

ICD-10 International Statistical Classification of Diseases and Related Health Problems 
297

ICI Imperial Chemical Industries PLC 

IGF-I insulin-like growth factor 

IL-1b interleukin-1b 

IMS International Menopause Society 

ISIS International Studies of Infarct Survival 

IU international unit 

IUD intrauterine contraceptive device 

LBD ligand-binding domain 

LDL low density lipoprotein 

LH luteinizing hormone 

Lp(a) lipoprotein(a) 

LV left ventricular 

MAPK mitogen-activated protein kinase 

MEK mitogen-activated protein kinase kinase 

MI myocardial infarction 

MMP matrix metalloproteinases 

MMSE Mini-Mental State Examination 

MORE Multiple Outcomes of Raloxifene Evaluation 

MPA medroxyprogesterone acetate 

MRI magnetic resonance imaging 

NCEP National Cholesterol Education Program 

NGF nerve growth factor 

NHANES III Third National Health and Nutrition Examination Survey 

NHLBI National Heart, Lung, and Blood Institute 

NIH National Institutes of Health 

NO nitric oxide 

NRMI National Registry of Myocardial Infarction 

NSABP National Surgical Adjuvant Breast and Bowel Project 

NSAIDs nonsteroidal anti-inflammatory drugs 

OAB overactive bladder 

OC oral contraceptive 

OR odds ratio 

ORWH Office of Research on Women’s Health

PAI plasminogen activator inhibitor 

PAMI Primary Angioplasty in Myocardial Infarction 

PEPI Postmenopause Estrogen/Progestin Intervention 

PIN prostatic intraepithelial neoplasia 

PKA protein kinase A

PKC protein kinase C 

PPARs peroxisome proliferator-activated receptors 

PR progesterone receptor 

PRL prolactin 
298

PTCA percutaneous transluminal coronary angioplasty 

PTH parathyroid hormone 

RCT randomized controlled trial 

RR relative risk 

RU486 mifepristone 

RUTH Raloxifene Use for The Heart 

SAD sexual aversion disorder 

SERM selective estrogen receptor modulator 

SERT serotonin reuptake transporter 

SHBG sex hormone binding globulin 

SHEP Systolic Hypertension in the Elderly Program 

SSRI selective serotonin reuptake inhibitors 

STAR Study of Tamoxifen and Raloxifene 

STOP Swedish Trial in Old Patients 

STS Society of Thoracic Surgeons 

SWAN Study of Women’s Health Across the Nation 

TGF transforming growth factor 

THC tetrahydrochrysene 

TNFa tumor necrosis factor a 

TPH tryptophan hydroxylase 

TTS transdermal therapeutic systems 

UI urinary incontinence 

VCAM-1 vascular cell adhesion molecule-1 

W/H waist/hip ratio

WHI Women’s Health Initiative 

WHO World Health Organization 

WISDOM Women’s International Study of Long Duration Oestrogen After Menopause

FOR MORE INFORMATION

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professionals, patients, and the public about the treatment, diagnosis, and prevention of heart, lung, and blood

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National Heart, Lung, and Blood Institute

NIH Publication No. 02-3284

July 2002