The Menopause, Hormone Therapy, and

Women's Health

May 1992

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Recommended Citation:

U.S. Congress, Office of Technology Assessment, The Menopause, Hormone Therapy, and

Women’s Health, OTA-BP-BA-88 (Washington, DC: U.S. Government Printing Office, May

1992).

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Foreword

Few topics in women’s medicine today are as fraught with confusion and controversy as the

question of appropriate treatments for menopausal symptoms and the prevention of negative

long-term health outcomes common to postmenopausal women—such as osteoporosis and

cardiovascular disease. A better understanding of the natural history of the menopause is critical to

providing better care. Despite its universality as an event in human female aging, the menopause

and its biology are incompletely understood. Researchers are becoming increasingly convinced,

however, that the loss of ovarian hormones plays a significant role in the development of age-related

problems in women.

If women and their physicians had a better understanding of predictors of risk, they could make

more informed decisions about interventions related to menopausal symptoms, cardiovascular

disease, osteoporosis, and gynecologic and breast cancer. Few other recently introduced medical

interventions have as great a potential for affecting morbidity and mortality as does hormone

therapy, which maintains estrogen levels in postmenopausal women to near those of premenopausal

women. Hormone therapy has pronounced effects on health risks: Some are reduced, some are

increased, and some remain uncertain, and these data are interpreted differently by various

scientific, medical, and consumer groups. The debate over hormone therapy focuses on whether it

should be used to treat menopausal symptoms for a short period of time, thereby reducing any risks

associated with long-term treatment, or whether it should also be used to prevent future disease,

thereby requiring longer treatment that could increase the risk of cancer. Convincing research into

alternatives to hormone therapy is limited. In addition, the true contributions to cardiovascular

disease and osteoporosis of such factors as lifestyle-e. g., diet, exercise, smoking-socioeconomic

status, race, and genetic predisposition deserve further investigation.

An October 1990 letter to the Office of Technology Assessment (OTA) from Representatives

Patricia Schroeder and Olympia Snowe, cochairs of the Congressional Caucus for Women’s Issues,

and Senator Brock Adams questioned whether current research programs at the National Institutes

of Health (NIH) and other public health service agencies adequately address the menopause.

Senator Adams and the Caucus requested that OTA study the current state of knowledge regarding

the menopause and its management, assess the scope and depth of existing research, and identify

those areas in need of further attention. Specifically, Congress was interested in hormone therapy,

the most common medical treatment for menopausal symptoms. In June 1991, Senator Barbara

Mikulski and Representative Henry Waxman endorsed the project and requested that OTA investigate as well the comparative effectiveness of alternatives to hormone therapy for the treatment

of menopausal symptoms and postmenopausal disease.

This Background Paper describes what is known about the natural progression of the menopause and its effect on women’s health, hormone treatment and prescribing practices, alternative

approaches, and research needs. Managing diseases and disorders among middle-aged women

requires more information to help practitioners differentiate those disorders whose causes stem from

a cessation of ovarian hormone production (and that are thus potentially treatable by hormone

therapy) from those that do not. Only then can misdiagnosis-or dismissal-of the medical

complaints of midlife women be prevented.

u JOHN H. GIBBONS

Director

iii
OTA Project Staff-The Menopause, Hormone Therapy, and Women’s Health

Roger C. Herdman, Assistant Director, OTA

Health and Life Sciences Division

Michael Gough, Biological Applications Program Manager

Kathi E. Hanna, Project Director

Suzie Rubin, Research Analyst

M. Catherine Sargent, Research Assistant

Alyson Giardini, Intern1

Editor

Leah Mazade, Garrett Park, MD

Support Staff

Cecile Parker, Office Administrator

Linda Rayford-Journiette, Administrative Secretary

Jene Lewis, Secretary

Contractors

Sheryl Sherman, Bethesda, MD

Lynn Rosenberg, Boston University School of Medicine, Boston, MA

1

September to December 1991.

iv
Chapter 1

Introduction
Contents

Page

ORIGINS AND ORGANIZATION OF THE REPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

CHAPTER 1 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Figure

Figure Page

1-1. The Transition from Reproductive to Nonreproductive Life . . . . . . . . . . . . . . . . . . . . . . . 4

Table

Table Page

1-1. Women’s Health Legislation Introduced in the 102d Congress . . . . . . . . . . . . . . . . . . . . 6
Chapter 1

Introduction

At the turn of the century, fewer than 5 million

American women were older than 50, the average

age at which the menopause occurs in this country.

In the first decade of the 21st century, more than 21

million women from the baby boom generation will

reach the age of 50 and become menopausal. In 1991

alone, 1.3 million women turned 50, marking the end

of reproductive fertility for those who have not

already been rendered sterile as a result of hysterectomy; they join the 35 million other women who

have reached the menopause-either surgically or

naturally-and who constitute more than one-third

of the total female population of the United States

(18). With a current life expectancy approaching 80

years, these women can expect to spend more than

a third of their life with reduced ovarian hormone

levels.

This increasing longevity and the changing demographics noted above will require dramatic changes

in the delivery of preventive and clinical health care

for women. Women already constitute a significant

portion of the practices of many physicians. Indeed,

more than 58 percent of the approximately 1.32

billion physician-patient contacts in 1989 were with

female patients, and women over the age of 44

accounted for more than 41 percent of these contacts

(19).

Furthermore, growing awareness of the role of

gender in differential patterns of disease and disability in later life underscores a critical need for

gender-specific perspectives in developing research

agendas and methodologies. Women constitute approximately 59 percent of the U.S. population aged

65 and older, and about 72 percent of the population

aged 85 and older (20). Substantive progress in

understanding the etiology and clinical picture of

age-related disease among women will require

increased sensitivity to their inherent biological and

psychosociocultural differences. Such progress is

fundamental to accurate diagnosis and effective

treatment to reduce morbidity and mortality and

maintain the independence of the rapidly growing

population of postmenopausal women.

A better understanding of the natural history of

the menopause is critical to providing better care.

Despite its universality as an event in human

female aging, the menopause and its biology are

incompletely understood. Researchers are becoming increasingly convinced, however, that the

loss of ovarian hormones plays a significant role

in the etiology of age-related pathology in women.

Managing diseases and disorders among middleaged women requires more information to help

practitioners differentiate those disorders whose

etiologies stem from a cessation of ovarian hormone

production (and that are thus potentially treatable by

hormone therapy) from those that do not. Only then

can misdiagnosis-or dismissal--of the medical

complaints of midlife women be prevented.

As the average woman approaches age 50, her

ovaries-the primary source of the female hormone

estrogen-gradually cease to function as they have

since menarche. As follicle depletion occurs in the

ovaries, ovarian hormone production slows, and the

menstrual cycle typically becomes irregular and

finally ceases. For the purposes of this report, the

term menopause is defined as the final menstrual

period that a woman experiences, although menopause colloquially describes the transition from the

reproductive to the nonreproductive state. The date

of the menopause can be accurately pinpointed: It is

retrospectively diagnosed after a year with no

menstrual periods (9,21). The less frequently used

term climacteric refers to the phase during which a

woman passes from the reproductive to the nonreproductive state. The last few years of the climacteric and the first year after the menopause are the

perimenopause. The menopause, a single event, is

easy to define; the climacteric and perimenopausal

periods are much more difficult to quantify and

evaluate, particularly from the patient’s perspective.

The terms premenopausal and postmenopausal describe, respectively, the state of active ovarian

estrogen production and the state of absent ovarian

estrogen production (see figure l-l).

Women whose menses are stopped surgically by

removing the ovaries have a sudden and atypical

postmenopausal experience. Nevertheless, in studies of the menopause, this group of women is often

mistakenly included with those who experience a

natural menopause (2,9,12). This report makes an

effort to clarify the distinction between natural and

surgical menopausal issues whenever they arise.

–3–
4 . The Menopause, Hormone Therapy, and Women’s Health

Figure l-l—The Transition from Reproductive to Nonreproductive Life

35 - 45 46 - 55 56 - 65

years years years

-

!-

.

,., , , !-,

,., > ! ,.,

,., , ,.,

,., , ,.,

,,, , ,.,

,., , ! ,.,

,.! > , ,.,

ti: Cl post

Early climacteric Perimenopause L----- Late climacteric —

NOTE: In this report the perimenopause is defined to be the Iast few years of the earlyclimacteric and the first year after

the menopause.

SOURCE: Adapted from M. Notelovitz, ‘The Non-Hormonal Management of the Menopause,” J.W.W Studd and Ml.

Whitehead (eds.), The Menopause (Oxford, UK: Blackwell Scientific Publications, 1988).

Few topics in women’s medicine today are as

fraught with confusion and controversy as the

question of appropriate treatments for menopausal

symptoms and the prevention of the long-term

health outcomes associated with postmenopausal

women-osteoporosis and cardiovascular disease.

Because decreased estrogen appears to underlie the

disturbing symptoms of the menopausal period as

well as the susceptibility to bone loss that often leads

to osteoporosis, it is not surprising that the administration of estrogen relieves some of these problems.

Since 1937, practitioners have known that estrogen therapyl prevents the occurrence of such menopausal symptoms as hot flashes and vaginal dryness

(6). The 1960s and early 1970s saw a dramatic

increase in retail prescriptions for noncontraceptive

estrogens for the treatment of these symptoms. Some

attribute the rise in use to the best-selling book

Feminine Forever by Robert Wilson (22), who

claimed that the menopause could be averted and

aging allayed with estrogen therapy.

In 1975, however, two case-control studies produced risk estimates that women who used estrogen

therapy were four to seven times more likely to

develop endometrial cancer than women who did not

(8). After further reports of a possible association

between estrogen use and endometrial cancer, sales

of estrogen dropped by almost 30 percent (8). The

subsequent decline in estrogen prescriptions was

followed by a decline in the rate of endometrial

cancer.

Women and the medical establishment consequently became more conservative in their use of

estrogen. An additional factor in this trend was the

fear of increased risk of breast cancer resulting from

estrogen use, a fear that has never been satisfactorily

resolved. Breast cancer strikes one of every nine

women in the United States; it is the second most

frequent malignancy among women, constituting 26

percent of all cancers (lung cancer is the most

frequent) (l). About 50 percent of breast tumors

require estrogen for growth. For some women,

increasing the odds of developing breast cancer in

any way is unacceptable, and they either refuse

estrogen therapy altogether or refuse to comply with

prescribed treatment regimens.

In trying to determine the extent of the risk of

endometrial cancer associated with estrogen use,

researchers found that adding a progestin to estrogen

could protect women against endometrial cancer by

opposing the effects of the estrogen (hence the terms

1 The use of estrogen for the relief of hot flashes is commonly referred to as estrogen replacement therapy, or ERT. Because some consumer groups

oppose the notion that the menopause causes an estrogen deficiency tbat requires replacement, OTA uses the term esrrogen therapy, or ET, to dwribe

this practice.
Chapter 1--Introduction • 5

Photo credit: National Cancer Institute

Women are living as much as a third of their life

postmenopausally. Decisions about hormone treatment

and its effect on subsequent health are based on

uncertainty for many women.

opposed and unopposed estrogen).2 Estrogen stimulates the growth of endometrial tissue (the lining

of the uterus) while progestins cause shedding of the

estrogen-thickened endometrium, lessening the chances

that cancer will develop. Progestins have side

effects, however, that lead many women to cease

therapy. Nevertheless, it has become increasingly

more common to prescribe both estrogen and a

progestin, or combined hormone therapy, for menopausal women who still have an intact uterus.

Recent studies have shown that estrogen may play

a role in preventing cardiovascular disease (3,4,7,

11), which adds a new incentive for prescribing

hormones. The effect of progestin on cardiovascular

disease prevention, however, is unknown. Since

progestins at least partially reverse the favorable

effects of estrogen on circulating cholesterol levels,

the addition of a progestin might diminish or

completely eradicate the protective effect against

cardiovascular disease provided by unopposed estrogen (10).

The debate over hormone therapy—in particular unopposed estrogen—focuses on whether it

should be used to treat menopausal symptoms for

a short period of time, thereby reducing any risks

associated with long-term treatment, or whether

it should also be used to prevent future disease,

thereby requiring longer treatment that could

increase the risk of cancer. For most women, the

short-term use of hormones has known benefits (e.g.,

relief of hot flashes) and some known risks (e.g.,

endometrial cancer); long-term use has known risks

(e.g., endometrial cancer) and benefits (e.g., prevention of osteoporosis and cardiovascular disease), as

well as unknown outcomes (e.g., risk of breast

cancer). The Nurses’ Health Study, the largest

longitudinal study of women in the world, found an

increased risk of breast cancer associated with

“current use” of estrogen (5). As with any form of

medication, the benefit of relief of symptoms must

be weighed against adverse side effects or complications.

ORIGINS AND ORGANIZATION

OF THE REPORT

Congressional interest in matters related to the

health of women has mounted in the past 5 years.

Numerous bills have been introduced (see table l-l)

to address the apparent lack of attention to women’s

health issues by agencies of the Public Health

Service (PHS), in particular, the National Institutes

of Health (NIH) and the Food and Drug Administration (FDA). An October 1990 letter to the Office of

Technology Assessment (OTA) from Representatives Patricia Schroeder and Olympia Snowe, cochairs of the Congressional Caucus for Women’s

Issues, and Senator Brock Ada.ms questioned whether

current research programs at NIH and other PHS

agencies adequately addressed the menopause. Senator Adams and the caucus requested that OTA study

the current state of knowledge regarding the menopause and its management, assess the scope and

depth of existing research, and identify those areas

2 me ~dditi~~ of a pmges~ t. the es~ogen rexen is a p~ctice commo~y referr~ to ss hormone replacement therapy, or ~~ For the Kt.iiSOIIS

cited in footnote 1, OTA refers to this form of treatment as combined hormone therapy, or C’HT. Collectively and generally, the term hormone therapy

describes either eslrogen therapy or combined hormone therapy, when a distinction is not necessary.
6. The Menopause, Hormone Therapy, and Women’s Health

Table l-l—Women’s Health Legislation Introduced

in the 102d Congress

Title l-Research

Women’s Health Research Act

Clinical Trials Fairness Act

Women’s Mental Health Research Act

Women and Alcohol Research Equity Act

Breast Cancer Basic Research Act

Contraception and Infertility Research Centers Act

Sense of Congress Resolution Regarding Contraceptive

Research

Women and AIDS Research Initiative Amendments

Ovarian Cancer Research Act

Osteoporosis and Related Bone Disorders Research, Education,

and Health Services Act

Title I/-Services

Breast Cancer Treatment Informed Consent Act

Women’s Health Care Coverage Expansion Act

The Mickey Leland Adolescent Pregnancy Prevention and

Parenthood Act

Adolescent Health Demonstration Projects

COBRA (Consolidated Omnibus Budget Reconciliation Act of

1985) Displaced Family Amendments

Federal Employee Family Building Act

Title I//-Prevention

Medicaid Infant Mortality Amendments

Medicaid Women’s Basic Health Coverage Act

Breast Cancer Screening Safety Act of 1991

Medicare Bone Mass Measurement Coverage Act

Women and AIDS Outreach and Prevention Act

Infertility y Prevention Act

SOURCE: Congressional Caucus for Women’s Issues, 1992.

in need of further attention. Specifically, Congress

was interested in hormone therapy-both opposed

and unopposed estrogen use-the most common

medical treatments for menopausal symptoms. In

June 1991, Senator Barbara Mikulski and Representative Henry Waxman endorsed the project and

requested that OTA investigate as well the comparative effectiveness of alternatives to hormone therapy

for the treatment of menopausal symptoms and

postmenopausal disease.

Clearly, widespread interest in understanding sex

differences in disease morbidity and mortality exists

and could lead to improvements in prevention,

treatment, and care for women. Pressure from

Congress for action has led to a new NIH initiative

to study the effects on women’s disease risk of

changes in diet and exercise patterns, the use of

hormones, and smoking cessation; the study focuses

specifically on the risks of cancer, cardiovascular

disease, and osteoporosis. Many experts believe that

the menopause and the physiological changes that

accompany reduced ovarian function play a significant role in the etiology of these diseases.

This report focuses on the menopause as a

delineating point in the life of women. Chapter 2

addresses what is known about the factors leading up

to and causing the diminishment of ovarian production of estrogen, and how these changes immediately

affect the health and well-being of women; it also

discusses the long-term health consequences of

reduced ovarian estrogen production. Chapter 3

describes the risks and benefits of estrogen therapy

(ET) and combined hormone therapy (CHT), the

most common treatments for menopausal symptoms. The chapter also presents information about

nonhormonal approaches to management of menopausal symptoms and why women choose the

treatments they do. The marketing and regulation of

the hormones prescribed for menopausal symptoms

and prevention of osteoporosis and cardiovascular

disease are described in chapter 4, together with

what is known about prescribing practices. Chapter

5 sets forth the areas in which research is needed and

discusses the role of the Federal Government in

addressing those needs. Also included are data on

the current Federal investment in research in those

areas. Chapter 6 provides a summary and conclusions.

Previous OTA reports on women’s health are

Costs and Effectiveness of Screening for Cervical

Cancer in the Elderly (15), Infertility: Medical and

Social Choices (16), Breast Cancer Screening for

Medicare Beneficiaries (14), and Adolescent Health

(13). An additional forthcoming OTA report is an

assessment of Policy Issues in the Prevention and

Treatment of Osteoporosis (17). That report addresses the costs and effectiveness of the use of

estrogen for the treatment of osteoporosis.

1.

2.

3.

4.

CHAPTER 1 REFERENCES

American Cancer Society, Cancer Facts and Figures1991 (Atlanta, GA: American Cancer Society, 1991).

Avis, N.E., and McKinlay, S.M., “Health-Care

Utilization Among Mid-Aged Women,” Annals of

the New York Academy of Sciences, vol. 592,

Multidisciplinary Perspectives on Menopause, M.

Flint, F. Kronenberg, and W. Utian (eds.) (New York

NY: New York Academy of Sciences, 1990), pp.

228-256.

Barrett-Connor, E., and Bush, T.L., “Estrogen Replacement and Coronary Heart Disease,’ Cardiovascular Clinics 19(3):159-172, 1988.

Bush, T. L., Fried, L.P., and Barrett-Connor, E.,

“Cholesterol, Lipoproteins, and Coronary Heart
Chapter 1--Introduction Ž 7

Disease, ’ Clinical Chemistry 34(8B):B60-

B7O, 1988.

5. Colditz, G.A., Stampfer, M.J., Willette, W. C., et al.,

“Postmenopausal Hormone Use and Risk of Breast

Cancer, Twelve-Year Followup of the Nurses’

Health Study,” in press.

6. Cyran, W., “Estrogen Replacement Therapy and

Publicity,” Frontiers of Hormone Research, vol. 2,

P.A. van Keep and C. Lauritzen (eds.) (Basel,

Switzerland: S. Karger, 1973).

7. Egeland, G.M., Kuller, L.H., Matthews, K.A., et al.,

“Hormone Replacement Therapy and Lipoprotein

Changes During Early Menopause,” Obstetrics and

Gynecology 76(5, Pt. 1):776-782, 1990.

8. Ernster, V.L., Bush, T.L., Huggins, G.R., et al,,

“Benefits and Risks of Menopausal Estrogen and/or

Progestin Hormone Use, “ Preventive Medicine 17:301-

323, 1988.

9. Kaufert, P., Lock, M., McKinlay, S., et al., “Menopause Research: The Korpilampi Workshop,” Social

Science and Medicine 22(11 ):1285-1289, 1986.

10. LaRosa, J. C., George Washington University Medical Center, Washington, DC, personal communication, September 1991.

11. Lobo, R.A., “Cardiovascular Implications of Estrogen Replacement Therapy,” Obstetrics and Gynecology 75(4, Suppl.):18S-25S, 1990.

12. Roos, N.P., ‘‘Hysterectomies in One Canadian Province: A New Look at Risks,” American Journal of

Public Health 74(1):39-46, 1984.

13. U.S. Congress, Office of Technology Assessment,

Adolescent Health, vol. 1, OTA-H-468 (Washington,

DC: U.S. Government Printing Office, April 1991).

14. U.S. Congress, Office of Technology Assessment,

Breast Cancer Screening for Medicare Beneficiaries: Effectiveness, Costs to Medicare, and Medical

Resources Required, OTA Staff Paper (Washington,

DC: U.S. Government Printing Office, November

1987).

15. U.S. Congress, Office of Technology Assessment,

Costs and Effectiveness of Screening for Cervical

Cancer in the Elderly, OTA-H-65 (Washington, DC:

US. Government Printing Office, February 1990).

16. U.S. Congress, Office of Technology Assessment,

Infertility: Medical and Social Choices, OTA-BP358 (Washington, DC: U.S. Government Printing

Office, May 1988).

17. U.S. Congress, Office of Technology Assessment,

Policy Issues in the Prevention and Treatment of

Osteoporosis (Washington, DC: U.S. Government

Printing Office, in press, 1992).

18. U.S. Department of Commerce, Bureau of the

Census, Projections of the Population of the United

States, by Age, Sex, and Race: 1988 to 2080, Current

Population Reports, Series P-25, No. 1018 (Washington, DC: U.S. Government Printing Office, 1989).

19. U.S. Department of Health and Human Services,

Public Health Service, Centers for Disease Control,

National Center for Health Statistics, “Vital and

Health Statistics, Current Estimates From the National Health Interview Survey,” DHHS Pub. No.

90-1504, 1989.

20. U.S. Department of Health and Human Services,

Public Health Service, National Institutes of Health,

National Institute on Aging, “Research and Research

Findings on Women’s Health Issues,” report to the

Senate Committee on Appropriations, March 1991.

21. Utian, W. H., “Menopause, Hormone Therapy, and

Quality of Life,” Menopause: Evaluation, Treatment, and Health Concerns, C.B. Hammond, F.P.

Haseltine, and I. Schiff (eds.) (New York, NY: Alan

R. Liss, Inc., 1989).

22. Wilson, R. A., Feminine Forever (New York NY: M.

Evans, 1966).
Chapter 2

Understanding the Menopause
Contents

Page

THE MENOPAUSE: HISTORICAL, SOCIAL, AND CULTURAL

PERSPECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

BIOLOGY AND SYMPTOMATOLOGY OF THE MENOPAUSE . . . . . . . . . . . . . . . . . . . 15

Hysterectomy or Surgical Menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Changes in Mood, Behavior, and Sexuality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

LONG-TERM CONSEQUENCES OF CHANGES IN OVARIAN

HORMONE LEVELS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 23

Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 27

CHAPTER 2 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 28

Boxes

Box Page

2-A. Evolution of Medical Thought Concerning the Menopause . . . . . . . . . . . . . . . . . . . . . . . 12

2-B. Cultural Variations in Positive Perceptions of the Menopause and Aging . . . . . . . . . 14

2-C. Cultural Variations in Negative Perceptions of the Menopause and Aging . . . . . . . . . 16

2-D. Changing Attitudes About ’’MENOPOZ” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

2-E. The Production of Estrogen and Progesterone in the Reproductive Cycle . . . . . . . . . 18

2-F. The Hot Flash . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

2-G. Hysterectomy: An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21

Figures

Figure Page

2-l. Relation of Age, Oocyte Number, and the Menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

2-2. Percentage of Hysterectomies With Bilateral Oophorectomy,

United States, 1985-87 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

2-3. Percentage of Women Reporting Feelings About Menopauseby

Menopause Status, 1981-82 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

2-4. Percentage of Deaths From Specific Conditions Among U.S. Women

Over 50 Years of Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

2-5. Conceptual Model of the Pathogenesis of Fractures Related to Osteoporosis.. . . . . . 25

2-6. Deaths From Coronary Heart Disease by Age and Sex, United States, 1986 . . . . . . . 27

Tables

Table Page

2-1. Rates of Hysterectomies by Age and Geographic Region, United States, 1972-87 . . 20

2-2. Number of Hysterectomies by Age and Diagnosis, United States, 1985-87 . . . . . . . . 22
Chapter 2

Understanding the Menopause

Medical science has yet to provide systematic,

objective information about the biological and

medical implications of the transition women make

from a reproductive to a nonreproductive status. For

centuries, women have viewed the cessation of the

menses at the least with misinformation and at the

worst with alarm and dread. But in recent years, ‘the

change of life’ has begun to elicit greater attention

from biomedical science. That interest, coupled with

women’s greater awareness about their own health

and their willingness to ask questions, has led to

more and better research on the etiology, symptomatology, and sequelae of the menopausal period. Still,

as chapter 5 of this report indicates, such research is

nowhere near complete.

Most descriptions of the menopausal process

rely on clinical impressions (with little or no data)

or on small samples of women selected from

patient populations rather than from the general

public. This pattern of investigation was true 20

years ago and has not changed appreciably (56). As

a result, the extent to which women suffer from the

symptoms of menopause is unclear. Some women

are uncomfortably symptomatic; others report little

or no discomfort. This clinical variability has

contributed to the debate about the appropriate

management of a natural process of aging in women.

Women who suffer, and the doctors who treat them,

are more likely to advocate a treatment approach,

while those who report few symptoms are more

sympathetic to the avoidance of medical interventions. A discussion of the most common treatments

for menopausal symptoms, estrogen therapy (ET)

and combined hormone therapy (CHT), appears in

chapter 3. Also discussed in chapter 3 are the uses of

ET and CHT for prevention of disease in later life.

The next section presents a brief historical and

cultural perspective on the menopause. The sections

that follow it discuss the biology and symptomatology of the perimenopause and the long-term

health consequences faced by some postmenopausal

women.

THE MENOPAUSE:

HISTORICAL, SOCIAL, AND

CULTURAL PERSPECTIVES

Throughout Western medical history, physicians

have sought to understand and explain the menopause. Prior to the 20th century, the medical

profession saw it as a physiological crisis that could

result, under certain circumstances, in the development of disease (11). It has also been called a disease

in and of itself. As early as A.D. 600, medical

writings described the cessation of menstruation

between the ages of 35 and 50 and linked it to a

woman’s lifestyle, attributing menopause to the

“excesses of society” (91). Throughout history,

social norms and attitudes, as well as the degree of

understanding of menstruation and female physiology attained by the medical profession (see box

2-A), have influenced the evolution of medical

thought regarding the menopause.

The menopause elicits a variety of societal

responses, the specifics of which depend on a

woman’s particular cultural milieu. Thus, in addition to variations in the type and incidence of

symptoms reported by menopausal women, there

exists a wide range of cultural reactions to and

repercussions accompanying the end of the childbearing years. In some Eastern cultures, for exarnple,

the community may recognize the occurrence of the

menopause through a ritual. Alternatively, as in the

Papago culture, it may be completely ignored, to the

extent that the language affords it no name (30,44).

Besides variation in cultural cognizance and recognition of the menopause, anthropologists have observed different effects on the role of the woman

ranging from an increase in freedom and status (see

box 2-B) to the complete loss of role (see box 2-C).

In fact, however, cross-cultural studies of the menopause are sparse, and some researchers ascribe the

meagerness of anthropological offerings in this area

to a historical lack of attention to the experience of

women by the formerly male-dominated field of

ethnography (30).

–11–
12 . The Menopause, Hormone Therapy, and Women’s Health

Box 2-A—Evolution of Medical Thought Concerning the Menopause

1777—John Leake, in his book Chronic or Stow Diseases Peculiar to Women, proposed a link between

menopause “at this critical time of life, around age 50,” and the development of “various diseases of the chronic

kind.” He proceeded to delineate the effects of the cessation of the menses: “pain and giddiness of the head, hysteric

disorders, colic pains, and a mid-life female weakness . . . intolerable itching at the neck of the bladder and

contiguous parts are often very troubling. ” In addition, he described possible psychological effects inasmuch as

“women are sometimes affected with low spirits and melancholy.” Such repercussions, as well as the peculiarity

of the menopause to human beings, were attributed by Leake to the “many excesses introduced by luxury, and the

irregularities of the passions.” Leake accounted for the lack of a corollary occurrence in other species by stating

that “quadrupeds and other animals are entirely exempt [from such disease] by living comfortable to their natural

feelings.”

1845-Columbat de l'Isere, in his Treatise of the Diseases of Females, included a chapter on the menopause

that contained the fallowing: “Compelled to yield to the power of time, women now cease to exist for the species

and hence forward live only for themselves. Their features are stamped with the impress of age and their genital

organs are sealed with the signet of sterility.. . It is the dictate of prudence to avoid all such circumstances as might

tend to awaken any erotic thoughts in the mind and reanimate a sentiment that ought rather to become extinct, . .

in fact, everything calculated to cause regret for charms lost and enjoyments that are ended now forever.”

Previously, he had offered an analogy to describe a woman at the menopause: She “now resembles a de-throned

queen, or rather a goddess whose adorers no longer frequent her shrine. Should she stall retain a few courtiers, she

can only attract them by the charm of her wit and the force of her talents. ”

1876-Merson asserted that the menopause is “always a time of trial, often of suffering and danger.”

1882-Tilt determined that the menopause was an event bearing “evil effects.”

1887—Borner proclaimed the insufficiency of medical knowledge regarding the menopause and encouraged

further study, asserting that “the climacteric, or so-called change of life in women, presents, without question, one

of the most interesting subjects offered to the physician, and especially to the gynecologist in the practice of his

profession. The phenomena of this period are various and changeable, that he must certainly have had a wide

experience who has observed and learned to estimate them all. SO ill-defined are the boundaries between the

physiological and the pathological in this field of study, that it is highly desirable in the interest of our patients of

the other sex, that the greatest possible light should be thrown on this question.”

1887—Farnham Summarized the relationship between the menopause and psychiatric disorders as "the ovaries,

after long years of service, have not the ability of retiring in graceful old age, but become irritate& transmit their

imitation to the abdominal ganglia, which in turn transmit the irritation to the brain, Producing disturbances in the

cerebral tissue exhibiting themselves in extreme nervousness or in an outburst of actual insanity.”

1897-Currier produced a historical evaluation of the importance of menstruation indifferent cultures in The

Menopause. In addition to observations concerning the dearth of scientific attention to the subject and the lack of

a known corollary event in animals, Currier examined the variation in the appearance of symptoms, noting that the

menopause was uneventful for the majority of women. Comparisons were made in regard to variation in women’s

experience of the menopause both between societies, contrasting Eskimos and American Indians with the French

and Irish and within a society, postulating that “highly bred," “civilized” women and “those with many troubles

and ills” appeared to be the main sufferers, Furthermore, the assertion was made that predisposing factors were

evident in women with severe menopausal symptoms.

1963--Physician Robert A. Wilson offered a disparaging depiction of the psychological state of the

menopausal woman when they state&in Feminine Forever, that “a large percentage of women.. . acquire a vapid

cow-like feeling called a ‘negative state.’ . . . It is a strange endogenous misery. . . the world appears as though

through a gray veil and they live as docile, harmless creatures, missing most of life’s values.” In addition, in an

article in Look magazine, Wilson listed 26 “symptoms of menopause”: nervousness, irritability, anxiety,

apprehension, hot flashes, night sweats, joint pains, melancholia, palpitations, crying spells, weakness, dizziness,

severe headache, poor concentration, loss of memory, chronic indigestion insomnia, frequent urination, itching of

the skin, dryness of the eye, nose, and mouth, backache, neuroses, and a tendency to take alcohol and sleeping pills

or even to contemplate suicide.
Chapter 2-Understanding the Menopause ● 13

1966R&ert A. Wilson concluded that, “in the course of my work, spanning four decades and involving

hundreds of carefully documented clinical cases, it became evident that menopause . . . is in fact a deficiency

disease.. . . To cure diabetes, we supply the lacking substance in the form of insulin. A similar logic can be applied

to menopause-the missing hormones can be replaced.”

1967—Phillip Rhoades painted the situation as a calamity, asserting that “many women are leading an active

and productive life when this tragedy strikes. They remain attractive and mentally alert. They deeply resent, what

to them, is a catastrophic attack on their ability to earn a living and to enjoy life.”

1967—Brewer and de Costa, in their textbook on gynecology, wrote as follows: “Emotional instability is

another outstanding symptom of this phase of life. Nervousness and anxiety are extremely frequent. The patient may

feel that the end of her useful life has come, that now she is old, that she has lost her appeal as a woman, and that

nothing is left to her. She cries easily; she flares up at her family and friends; she is irritable and may have difficulty

in composing her thoughts or her reactions. Often the patient maybe extremely depressed. A person who has been

extremely emotional most of her life will without much doubt have severe emotional disturbances during the

climacteric.’

1968--Dunlop proclaimed that the menopause “is the trigger for the powder keg of emotions slowly

smoldering somewhere in the hypothalamus. ”

1970--K. Achte, in “Menopause From the Psychiatrist’s Point of View,” reported that “the assumption has

been put forward that women’s ability to work reduces to a quarter of the normal by menopause.”

1970-Howard Osofsky and Robert Seidenberg, in the American Journal of Obstetrics and Gynecology,

perpetuated misconceptions about the psychological repercussions of the menopause and reinforced the image that

reproductive organs and capacity constitute the sum total of the female. They asserted that “it is no wonder that

. . . women become depressed around the time of menopause; professionals and society have helped to ensure this

reaction. At an age in life when a man is in the upswing of active social and professional growth, woman’s service

to the species is over. Professionals, including female experts, define the woman’s role as one of mortification and

uselessness.’

1986-Lila Nachtigall and Joan Rattner Heilman published Estrogen, The Facts Can Change Your Life, which

purports to offer “the latest word on ERT [estrogen replacement therapy]: what the new safe estrogen replacementh

can do for great sex, strong bones, good looks, longer life, preventing hot flashes” (cover).

1991—The Massachusetts Women’s Health Study reported that “menopause, as a natural event, appears to

have no major impact on health or health behavior. Any increase in symptomatology appears to be relatively small

and transitory, occurring primarily in the perimenopause. The majority of women barely notice the menopause and

health care utilization does not increase during menopause.”

SOURCES: Adapted from S.E. Bell, “Sociological Perspectives on the Medicalization of the Menopause,” Annals of the New York Academy

of Sciences, vol. 592, Multidisciplinary Perspectives on Menopause, M. Flint F. Kronenberg, and W. Utian (eds.) (New York NY:

New York Academy of Sciences, 1990), pp. 173-178; M.J. Goodman “A Critique of Menopause Research,” Changing

Perspectives on Menopause, A.M. Voda, M. Dinnerstein and S.R. O’Donnell (eds.) (Austin TX: University of Texas Press 1982);

J.B. McKinIay, S.M. McKinlay, and D.J. Brambi1la “Health Status and Utilization Behavior Associated With Menopause,”

American Journal of Epidemiology 125(1):110-121, 1987; E. Perlmutter and P.B. Bart “Changing Views of ‘The Change’: A

Critical Review and Suggestions for an Attributional Approach,” Changing Perspectives on Menopause, A.M. Voda, M.

Dinnerstein and S.R. O’Donnell (eds.) (Austin, TX: University of Texas Press, 1982); B. Seaman and G. Seaman, Women and the

Crisis in Sex Hormones (NeW York NY: Rawson Associates Publishers, Inc., 1977); P.J. Schmidt and D.R. Rubinow,

“Menopause-Related Affective Disorders: A Justification for Further Study,” American Journal of Psychiatry 148(7):844-852,

1991; W.H. Utian, Menopause in Modern Perspective: A Guide to Clinical Practice (New York NY: Appleton-Century-Crofts,

1980).

The menopausal experience encompasses a Newfoundland woman, when defining herself as

complex interaction of sociocultural, psychologi- menopausal, includes symptom experience, the mencal, and environmental factors as well as biologi- opausal status of women in her peer group, the

cal changes relating strictly to altered ovarian occurrence of specific life, events, changes in status

hormone status (42). Endocrine changes and the and role, and her chronological age (43). Japanese

cessation of menses are certainly one way of women who have not menstruated for more than 12

describing the menopause, but cultural factors also months might still report themselves as without

shape it and can strongly influence how particular signs of menopause (see app. A) (43). Thus, the

women define their status (43). For example, a cessation of menstruation is not necessarily the

297-910 0 – 92 - 2
14 ● The Menopause, Hormone Therapy, and Women’s Health

Box 2-B-Cultural Variations in Positive Perceptions of the Menopause and Aging

Although the relevant data are somewhat limited, there is evidence that in some non-Western cultures, the

menopause is considered a positive event in a woman’s life, entitling her to certain privileges such as greater

mobility, the right to exercise authority over members of the younger generation, and increased status and

recogniton beyond the household unit. Many of the benefits of reaching the menopause in these societies come from

the removal of constraints and prohibitions imposed on menstruating women; paradoxically, this positive view of

the menopause thus reflects a negative cultural disposition toward the menstrual cycle itself. Some instances of

positive change, particularly those pertaining to increased authority within the immediate family, may be a

repercussion more of the maturation of offspring than of the cessation of menstruation. All of the changes, however,

entail the improvement of a woman’s life situation in conjunction with aging. Cultural studies of the roles of women

in society provide a multitude of positive examples of the role of the postmenopausal female. For example:

. The Yoruba of West Africa allow older women, who are free from childbearing responsibilities, to

participate in the long-distance travel required for profitable trade.

● Among Bengali women, who are traditionally confined to the village, older, upper-class women are entitled

to make one or two religious pilgrimages every year to distant religious sites.

• In Moroccan society, women are perceived as excessively sexual and damaging to men. As a result, the sexes

are separated, for the most part, during a woman’s childbearing years. But once a woman reaches the

menopause, she is considered to be asexual and is permitted to move freely within the world of the male.

• The Yonomamo of South America, known for their particularly poor treatment of younger women, extend

to older women a great deal of kindness and respect, owing to the fact that old women are believed to be

somewhat sacred. Warring amongst tribes includes the practice of stealing women; however, older women

are considered neutral, and this neutrality extends to protection from enemy sorcery. In addition, older

women are the only members of a tribe who are able to travel freely throughout the land.

• A similar freedom to travel unsupervised, usually for the purpose of communication, is permitted

postmenopausal women of both the Kanuri, of the Lake Chad region of Africa, and the Tiwi, an aboriginal

people from the islands off northern Australia.

● Among the Mandurucu of South America, the oldest woman maintains authority over the household, which

may exceed 50 people. In addition, she controls the complex, labor-intensive preparation of food and holds

the key to the food storage area. The menopause releases Mandurucu women from societal constraints on

demeanor and behavior, and is perceived as graduation of the female to the status and role of a male.

marker by which women define themselves as become more outspoken about this last reproductive

menopausal. Treating this time in a woman’s life as

a‘ ‘medical’ condition warranting medical attention

has raised concerns about the medicalization of a

natural life event (18,63).

Popular opinion (and many medical experts) continue to portray the menopause as a major negative

life event of the same magnitude as the loss of a

spouse or a job (6). It signifies the end of reproduction and the acceleration of aging (both of which are

viewed with dread by many members of Western societies that extol the family and youthful sexuality).

A common stereotype is that of menopausal women

as depressed hypochondriacs, facing the end of

usefulness and life and, in Western cultures, finding

solace in the doctor’s office. Slowly, these images

and myths are giving way to different pictures.

Women are becoming more assertive and more

informed consumers of health care. Open discussion

of sexuality and reproduction has led women to

phase of their lives. Much-needed studies of menopausal women have also helped to debunk some of

the myths. For example, research has shown that

menopausal women do not use health care services

at a rate higher than would be expected with

increases in age (6,52). Thus, the so-called menopausal syndrome may be more related to personal

characteristics than to the menopause per se (6,28,

29,56).

More and more, women are seeing the menopause

as a highly individualized experience that deserves

openness and discussion, not embarrassing stigmatization. Part of this change in perception maybe due

to increasing press and media coverage of the

menopause in recent years and its appearance as the

subject of public service announcements and television situation comedies. In fact, far from viewing the

menopause as something shameful, some women

have learned to recognize and announce this impor-
Chapter 2-Understanding the Menopause ● 15

. The position and power of the shaman are available to women only after the menopause in both the

Plains Cree and Winnebago Indian cultures. The postmenopausal women of the Winnebago may sit,

for the first time, alongside men during ceremonial feasting.

• The Bemba of East Africa reserve many leadership roles, both political and social, for older women. The

Nacimbusa, are a respected position reserved for an older woman, conducts the intricate initiation rites for young

girls and acts as midwife for their deliveries. She also gives permission for a woman to resume intercourse

after a waiting period following the birth of a child.

. A belief in supernatural interaction following the menopause is found in Indian villages in Mexico where

the curandera, a ceremonial priestess, is often a woman who is past the menstrual cycle.

. Among the Navajo, menstruating women are constrained by a number of taboos. The high-status role of

hataalii, or ceremonialist, is only available to postmenopausal women. Postmenopausal Navajo women are

also able to assume the role of singer, or curer, as well as the diagnostic roles of star-gazer and hand-trembler.

In some cultures, aging is a time for equality between the sexes. Postmenopausal women are viewed as elders

and are accorded senior status equal to that of senior men. Examples include the following:

● Among the Nayar of Kerala in southwest India advancing age is marked by a rite-of-passage ceremony that

involves both men and women. A jubilee is held on the individual’s 60th birthday, after which “respectable

people are supposed to retire from worldly life.”

● Among the Qemant of Ethiopia, a simple rite of passage called kasa ushers both men and women into ‘‘the

status of a venerated elder . . . who do[es] most of the debating and ha[s] the greatest voice in making

decisions.” Requirements for ascension to this reserved status, which “signifies marked closeness to

Mezgana (God),” are the appearance of gray hairs for the man and the occurrence of the menopause for the

woman. The Qemant believe that individuals at this stage of life have reached an age at which they are “too

old to sin any longer. ” Interestingly, such elevated elders of either sex are prohibited from entering a place

where women are menstruating.

• Both the Hare Indians of Canada and the Chinese signal a person’s change in status to that of elder with a

symbolic change in form of address.

SOURCES: Adapted fromJ.K. Brown “A Cross-Cultural Exploration of the End of the Childbearing Years”; J. Griffen “Cultural Models for

Coping With Menopause”; and A.L. Wright, “Variation in Navajo Menopause: Toward an Explanation” Changing Perspectives

on Menopause, A.M. Voda, M. Dinnerstein and S.R. O’Donnell (eds.) (Austin, TX: University of Texas Press, 1982).

tant change and to see it as the natural event it is (see during the menopausal period is described in the

box 2-D) (79) .

Yet although women are beginning to change

their attitudes about the menopause, the biological

sequelae and consequences of this event are nevertheless a dramatic change in the physiological

profile of a woman. The short- and long-term

consequences of reduced ovarian estrogen production vary widely and have only recently been

documented. Physicians may understand the

hormonal changes of this period in physiological

terms, but they still lack good estimates of the

percentages of women who will have symptoms

and who will not. One reason for this gap in

knowledge is that acquiring it involves extensive

study of cycling women, which is generally avoided

because of the complexity of hormonal changes and

the wide variability among women (54). What is

known about the biological changes that occur

next section.

BIOLOGY AND

SYMPTOMATOLOGY OF

THE MENOPAUSE

The menopause is colloquially known as “the

change of life” because it signifies the end of reproductive fertility. This event is a completely

natural, normal biological phenomenon; it is a

significant component of the reproductive cycle and

is accompanied by profound hormonal changes.

Natural menopause (as opposed to surgical menopause, which results from removal of the ovaries) is

generally believed to be due to exhaustion of the

remaining ovarian follicles, the multicellular structures that contain the germ cell, or “egg,” and that

produce the steroid hormones estrogen and progesterone (see figure 2-l). The actual causes of follicu-
16 ● The Menopause, Hormone Therapy, and Women’s Health

Box 2-C--Cultural Variations in Negative Perceptions of the Menopause and Aging

Anthropological investigation has found that in some cultures the menopause elicits a variety of negative

societal responses. In much of the Western world, as well as in some non-Western cultures, the menopause is an

event that women are taught to dread through societal myths regarding the psychological effects of the climacteric

and of aging in general. Cross-cultural surveys of negative reactions to the menopause reveal that the end of the

reproductive years may be accompanied by a loss of role or by the transition to an anomalous role. The former

reaction does not preclude the latter in fact, the loss of one’s role in the community may result in the adoption of

a role that seems abnormal or inconsistent with expectations.

Alternatively, a culture may offer no overt reaction to the menopause whatsoever. Nonresponse may not seem

intuitively negative; however, inasmuch as cultural silence limits a woman’s knowledge, it may impair her

understanding of and ability to discuss her own physiological changes, and result in a sense of anomalous being.

For example:

• In the Twi of Ghana, the postmenopausal woman may lose the role of wife because her husband may take

younger wives, although the menopause does not precipitate actual divorce. The distress caused by such

displacement has sometimes resulted in the menopausal woman’s believing that she has become a witch,

eliciting confessions of wrongdoing.

* Until recently in Ireland, the belief that no role was possible for women following the end of their

reproductive life prompted some rural women to confine themselves to bed until their death years later.

● The cutural perception that death may occur in conjunction with or as a result of the menopause has been

found among the Sinkaietk, a southeast group of the Salish Indians from the Pacific Northwest of North

America.

• Yoruban women, lacking adquate information about the menopause, believe that menopausal women are

actually pregnant but that witchcraft is preventing the pregnancy from continuing to its normal conclusion.

The same belief has been found among Twi women.

SOURCES: Adapted from J. Griffen “Cultural Models for Coping With Menopause,” and BAR. Kearns, “Perceptions of Menopause by

Papago Women,” Changing Perspectives on Menopause, A.M. Voda M. Dinnerstein, and S.R. O’Donnell (eds.) (Austin, TX:

University of Texas Press, 1982).

Box 2-D-Changing Attitudes About “MENOPOZ"

In May 1991, Dorothy Mitchell of Seattle, WA, received a letter from the State’s Department of Licensing

asking that she return her customized license plates, which read “MENOPOZ.” “It has come to our attention that

the phrase used on your personalized plate, MENOPOZ, is offensive to good taste and decency,” wrote Bob

Anderson, the department’s assistant directorof vehicle services. After returning the replacement plates and refusing

to give up her customized plates, Mitchell was told by a department official that she could be stopped for canceled

plates.

Mitchell said she got the idea for the MENOPOZ plate after she went with her husband to get an oil change

for his truck and ended up buying a sporty white Dodge Daytona with an orange stripe. She later told her father that

the impulse buy must have been part of a menopausal phase and decided to put that on her license plate. She said

the plates had resulted in “a lot of fun I wouldn’t have had otherwise.” A few days after the story was broadcast

by the wire services, Mitchell was notified by licensing director MaryFaulk, aged 50, that she could keep the plates.

Faulk said, “I don’t think a normal process of aging to be in bad taste.”

SOURCE: Adapted from Associated PressWise stories, May 24 and May 26, 1991.

lar depletion, and hence the menopause itself, are be preceded by an accelerated rate of depletion of

unknown and puzzling, considering the finding that follicles, which results from changes in the brain

the number of follicles that remain in the ovaries in leading to altered neuroendocrine stimulation of the

the first half of the fifth decade of a woman’s life ovaries (71).

may range from 350 to 28,000 (91). On the basis of

studies in aged rodents and in humans, researchers The natural menopause is due as much to nonrehave postulated that the menopause in humans may sponse by the depleted remaining follicles to follicle1
Chapter 2-Understanding the Menopause ● 17

Figure 2-l—Relation of Age, Oocyte Number,

and the Menopause

250,000

O

g 150,000

& 100,000 e

2

50,000

/

/

I

/’

/’ /

/

/

/

I I I 1 I o

0 20 30 40 50 60 70

Age in years

SOURCE: Adapted from D.R. Mattison, M.S. Nightingale, and K. Shiromizu, “Effects of Toxic Substances on Female Reproduction,”

Environmental Health Perspectives 48:43-52, 1983.

stimulating hormone (FSH) as to the total exhaustion of the remaining ovarian follicles (see box 2-E).

Some investigators postulate that if these follicles

could be reactivated, the menopause would be

delayed (62).

Although age-related changes in the menstrual

cycle and its associated hormonal patterns are not

well characterized, it is believed (but has not yet

been demonstrated) that a gradual decline in overall

ovarian function and in the production of estrogen

and progesterone begins when a woman is in her 30s

(61,86,87). During the middle to late portion of a

woman’s fifth decade, anovulatory cycles or cycle

irregularities and, not uncommonly, episodic bouts

of heavy uterine bleeding of unpredictable frequency and duration begin to increase. These

changes mark the start of the perimenopausal, or

transitional, phase. The perimenopause is frequently

accompanied by symptoms of varying intensity that

are believed to reflect marked fluctuations in levels

of estrogen and progesterone or outright deficiency

(see box 2-E for a discussion of estrogen and

progesterone) (87). The tissues that are most affected

by reduced estrogen are the ovaries, uterus, vagina,

breast, and urinary tract. Tissues such as the

hypothalamus (part of the neuroendocrine system),

skin, cardiovascular tissue, and bone may also be

affected (90).

The age of onset of the menopause varies greatly

among women. Although the average age of women

at the menopause is between 50 and 51 (12,23,57,95),

Photo credit: National Cancer Institute

More and more, women are seeing the menopause as a

highly individualized experience that deserves openness

and discussion, not embarrassing stigmatization.

some women may stop menstruating much earlier.

There is no evidence that this median age has tended

to increase (92). Although the average age of onset

of puberty has decreased over time, there is no

indication of a relationship between a woman’s age

at menarche and the timing of the menopause (91).

Moreover, age at menopause does not appear to

depend on race, marital status, or geography. Early

menopause has been consistently associated with

smoking, but the exact nature of this effect remains

speculative (12). Smokers, on average, experience

the menopause nearly 2 years earlier than nonsmokers (12). Women who have never had children also

tend to experience an earlier menopause (58). If the

menopause occurs before age 40, as it does in

roughly 8 percent of women, it is considered

“premature” ovarian failure, not menopause (17,20).

There is some evidence that the age at which

women experience the menopause is in part
18 • The Menopause, Hormone Therapy, and Women’s Health

Box 243—The Production of Estrogen and Progesterone in the Reproductive Cycle

Hormones are chemical messengers that are produced by specialized glands and released into the bloodstream.

Three groups of hormones are relevant to female reproductive status: releasing factors, pituitary gonadotropin, and

sex steroids. Their actions are explained below.

● Gonadotropin-releasing hormone (GnRH), produced in the hypothalamus, induces the pituitary gland to

release the pituitary gonadotropin: follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

● FSH stimulates the maturation of the ovarian follicle, or egg, and induces the synthesis of the sex steroid

estradiol, the most potent naturally occurring estrogen in humans. The ovary accounts for more than 90

percent of total body production of estradiol. other forms of estrogen, such as estrone, are produced by other

glands, such as the adrenal, and by peripheral conversion of circulating hormones, such as testosterone.

These other sources account for 10 percent of premenopausal estrogen production. The first detectable

endocrine manifestation of reproductive aging is a gradual increase in plasma FSH levels. This rise becomes

apparent almost a decade before the menopause, despite apparently normal ovulatory cycles. Significantly

elevated levels of FSH are in themselves a diagnostic criterion of the approach of the menopause.

● LH stimulates egg release and formation of the corpus luteum. The corpus luteum also synthesizes another

sex steroid, progesterone, as well as estradiol. Sometime after the FSH level increases, there is a concomitant

increase in serum LH levels, usually around ages 45 to 50.

Immediately after estradiol and progesterone are produced, they are released into the bloodstream and

transported throughout the body. As noted in the text, many kinds of tissue located throughout the body can have

receptors for estradiol, for progesterone, for both, or for neither of these hormones.

The synthesis and release of hormones vary from moment to moment and from day to day; their cycling nature

produces the menstrual cycle. The ovarian reproductive cycle each month is a repetitive, self-cycling mechanism

that continues for as long as the ovary is capable of response, that is, for as long as there are functional ovarian

follicles present. Once the ovary becomes depleted, as it does gradually during the climacteric, the ability to

reproduce will end. Following the menopause, levels of estradiol and estrone drop, but, as might be expected, the

level of estrone falls to a relatively lesser extent than that of estradiol because it continues to be produced by other

glands (e.g., adrenal). Estrone, therefore, becomes the major free estrogen in the circulation, and progesterone

production ceases. The plasma levels of the sex steroid androgen increase, relative to the reduction in estrogen. The

postmenopausal ovary is a potential source of androstenedione and testosterone, which are then available for

conversion to estrone.

SOURCE: Adapted from W.H. Utian, Menopause in Modern Perspective:A Guide to Clinical Practice (New York, NY: Appleton-CenturyCrofts, 1980).

genetically determined, but smoking seems to be indicate that women often have little idea of the

the best predictor of when the menopause occurs.

The transition from a reproductive to a nonreproductive state is gradual for women who undergo

natural menopause; consequently, as a woman

approaches the menopause, her menstrual function

may change gradually rather than ceasing abruptly.

Clinical studies of women have shown that approximately 10 percent will have sudden amenorrhea—

i.e., sudden stoppage of menstrual periods (58); 70

percent report oligomenorrhea, or abnormal menstrual periods (intervals of 36 to 90 days between

periods) or hypomenorrhea (regular menses but

decreased in amount); and 18 percent report menorrhagia (bleeding of excess duration), metrorraghia

(bleeding irregularly between cycles), and hypermenorrhea (excessive bleeding) (78). Given these

variations, it is not surprising that some studies

alterations to expect in their menstrual cycles as they

become perimenopausal (78). Data show that the

severity of most menopausal symptomatology is

related to the length of time since the last period.

That is, symptoms decline in severity as time

passes. This is not true of all symptoms, however.

Genital symptoms, such as vaginal atrophy,

which can affect between 20 to 40 percent of

women (62), appear to worsen with time (91).

In the United States and in Western countries, the

most common menopausal symptom is the vasomotor “hot flash,” which is estimated to occur in at

least 50 percent of U.S. women at some point during

the menopausal years (58). Estimates of the incidence of hot flashes from population studies in the

United States and worldwide have ranged from 25 to

85 percent, depending on the geographic region (47).
Chapter 2-Understanding the Menopause . 19

The vasomotor symptoms of the hot flash (which

may persist from 5 to 10 years or longer tier the

permanent cessation of menstruation) have been

described as “recurrent, transient periods of flushing, sweating, and a sensation of heat, often accompanied by palpitations, feelings of anxiety, and

sometimes followed by chills” (see box 2-F) (47).

The majority of women may experience only a

sensation of warmth and minor discomfort; 15 to 25

percent of women, however, experience severe or

frequent hot flashes (as many as 10, or even more,

per day) and often find them to be associated with

repeated episodes of interrupted sleep, fatigue,

nervousness, anxiety, irritability, depression, and

memory loss (90). Night sweats, the nocturnal

version of the hot flash, are usually conceded to be

worse than hot flashes (17). Of those women who

have hot flashes, 80 percent complain of them for

more than 1 year, and 25 to 50 percent experience

them for longer than 5 years (3).

For most women, symptoms subside within the

first 3 to 5 years (or sooner) after the menopause;

for other women, particularly those who undergo

surgical menopause as a result of bilateral oophorectomy (bilateral removal of the ovaries), symptoms may be more severe and long-lasting (47).

Within 4 to 5 years after the cessation of menstruation, some women who are not using hormonal

therapy begin to experience signs of atrophy in the

vagina, urethra, and bladder base. Consequences of

atrophic changes include dyspareunia (difficult or

painful intercourse), repeated vaginal infections,

urinary tract infections, and dysuria (painful or

difficult urination) (60). These women may also

experience urinary stress incontinence (the inability

to refrain from discharging urine under such stresses

as jogging, exercising, sneezing, or even laughing).

Studies indicate that incontinence is more common

in women who have undergone vaginal hysterectomies than in women who experience a natural

menopause (17). Additional physical complaints

among menopausal women are pain in muscles and

joints, headaches, and increased weight (5).

Women who have had both ovaries removed

before the onset of the menopause experience more

severe menopausal symptoms than women who

experience a natural menopause (18). Past studies of

menopausal symptoms have mistakenly combined

women who experience a natural menopause with

those who have had a surgical menopause. This error

has resulted in problematic and, in some cases,

Box 2-F—The Hot Flash

The hot flashes experienced by many women

during their menopausal years, although quite

variable across women, are generally characterized

by a sudden feeling of intense warmth throughout

the upper part of the body, often accompanied by

flushing of the neck and face and sweating. A cold,

clammy sensation or chills may follow. Flashes

vary in intensity, frequency, and duration within

one person and among different individuals. They

may cause discomfort, embarrassment, and loss of

sleep. Sometimes an aura precedes the hot flash by

several seconds. During this period, heart rate and

finger blood flow begin to increase (finger blood

flow and temperature are easily measured indicators). Then there is a sensation that the flash is about

to occur, which is followed immediately by an

increase in finger temperature of up to 6 ‘C and

sweating, a drop in skin temperature in areas of

sweating such as the forehead and chest, and a

subsequent drop in internal temperature of 0.1 to

0.6 ‘C. Hot flashes are associated with a sharp rise

in blood levels of the hormone epinephrine (a potent

stimulator of heart function that increases heart rate,

cardiac output, and systolic blood pressure) and a

simultaneous decline in the hormone norepinephrine (which increases blood pressure dramatically).

An increase in circulating luteinizing hormone is

also associated with most hot flashes, as is an

elevation of blood neurotensin-like reactivity.

SOURCES: Adapted from National Institute on Aging, Research Advances in Aging, 1984-1986, NIH Publication No. 87-2862, March 1987, and V. Ravnikar,

“Physiology and Treatment of Hot Flushes,”

Obstetrics and Gynecology 75(4, Suppl.), 1990, PP.

3S-8S.

erroneous characterizations of the progression of the

perimenopause; it may also be responsible for

overstatements about common symptomatology.

Hysterectomy or Surgical Menopause

Currently, hysterectomy is one of the most

commonly performed inpatient surgical procedures

in the United States, with more than 650,000

performed each year. Of all surgical procedures

performed annually on men or women, only the

number of caesarean sections exceeds this figure

(66).

More than 18 million women living in the United

States have had a hysterectomy. This figure translates to 19 percent of all women over the age of 18.
20 • The Menopause, Hormone Therapy, and Women’s Health

Table 2-l—Rates of Hysterectomies (per thousand) by Age and Geographic Region, United States, 1972-87

Age and region 1972 1975 1980 1981 1982 1983 1984 1985 1986 1987

15 and older

United States. . . . . . . . . . . . . . 8.3 8.8 7.1 7.3 6.9 7.1 6.9 6.9 6.6 6.6

Northeast . . . . . . . . . . . . . . . . . 6.7 6.6 5.3 4.7 4.7 5.4 4.8 4.3 4.4 4.1

Midwest . . . . . . . . . . . . . . . . . . 7.9 9.0 7.5 7.2 7.1 6.8 6.6 6.6 6.8 6.5

South . . . . . . . . . . . . . . . . . . . . 9.6 9.9 8.7 8.7 8.5 8.5 8.3 8.3 7.6 7.4

West. . . . . . . . . . . . . . . . . . . . . 8.9 9.6 6.4 7.9 6.6 6.9 7.2 7.8 7.0 8.1

15 to 44 years

United States . . . . . . . . . . . . . . 8.9 9.3 7.6 7.9 7.5 8.0 7.4 7.4 6.9 7.0

Northeast . . . . . . . . . . . . . . . . . 6.4 5.8 4.9 4.3 4.2 5.0 3.8 3.7 3.6 3.5

Midwest . . . . . . . . . . . . . . . . . . 7.8 9.1 7.7 7.2 7.1 7.5 6.7 6.5 7.0 6.7

South . . . . . . . . . . . . . . . . . . . . 11.7 12.0 10.3 10.7 10.5 10.8 10.0 9.9 8.9 8.4

West . . . . . . . . . . . . . . . . . . . . . 9.0 9.0 5.9 7.9 6.7 6.9 7.9 8.2 6.8 8.7

45 to 64 years

United States . . . . . . . . . . . . . . 10.0 11.0 8.8 8.3 7.8 7.7 8.1 8.1 8.1 8.0

Northeast . . . . . . . . . . . . . . . . . 9.3 10.2 7.6 6.9 6.6 7.9 8.4 6.5 7.3 6.2

Midwest . . . . . . . . . . . . . . . . . . 10.8 12.4 9.2 9.5 9.1 8.3 8.7 8.8 8.9 8.5

South . . . . . . . . . . . . . . . . . . . . 9.0 9.1 8.8 7.5 7.8 7.0 8.0 8.4 7.5 7.9

West . . . . . . . . . . . . . . . . . . . . . 11.5 13.7 9.6 9.7 7.6 8.0 7.0 8.6 9.3 9.7

65 and older

United States . . . . . . . . . . . . . . 2.7 3.2 3.1 3.7 3.7 3.2 3.6 3.5 3.3 3.4

Northeast . . . . . . . . . . . . . . . . . 2.7 3.0 2.9 2.9 3.4 3.0 2.9 3.2 2.7 3.3

Midwest . . . . . . . . . . . . . . . . . . 2.8 2.5 4.5 3.6 4.2 2.6 3.8 4.1 3.3 3.5

South . . . . . . . . . . . . . . . . . . . . 2.5 3.4 2.2 3.5 3.1 3.0 3.2 2.3 3.2 3.4

West . . . . . . . . . . . . . . . . . . . . . 2.9 4.3 2.9 5.2 4.4 5.1 4.9 5.2 4.1 3.7

SOURCE: National Center for Health Statistics, ’’National Hospital Discharge Surveys," 1987.

At present rates, 37 percent of all women will be

hysterectomized before they reach 60 years of age

(9). The widespread prevalence of this procedure

and the sizable regional variations seen in the rates

of its performance (see table 2-1) have generated

much controversy regarding the risks and benefits of

hysterectomy to the continuing health of American

women (see box 2-G).

Hysterectomy performed in conjunction with the

removal of both ovaries and the fallopian tubes has

become increasingly more comrnon (see figure 2-2).

According to the National Center for Health Statistics, between 1965 and 1984, the rate of performance

of this procedure (known as total hysterectomy and

bilateral salpingo-oophorectomy) increased from

25 percent of all women undergoing hysterectomy to

41 percent. The bulk of this increase was in women

45 to 64 years of age.

I Prior to the 1970s, one commonly reported—and

I controversial-reason for performing a bilateral I

1 oophorectomy in conjunction with a hysterectomy \

in the absence of any obvious pathology was to

prevent ovarian cancer, which occurs at a rate of 1 in

every 70 women (2,94). It was widely believed that

the only function of the ovaries after childbearing

was to produce estrogen and progesterone, and

because these hormones could be adequately replaced, the ovaries were considered expendable

(94).

It has long been documented that hysterectomy

alone in the premenopausal patient is associated

with increased risk—perhaps three times greater

than among nonhysterectomized women--of coronary artery disease (16,75). Recent evidence also

supports the concept that bilateral oophorectomy

increases the risk of coronary heart disease (19),

possibly as a result of altered lipoprotein profiles. In

addition, the incidence of osteoporosis is higher in

young women who undergo bilateral oophorectomy

than in women who experience a natural menopause

(38). Hysterectomized women have a greater loss of

bone density and a higher incidence of osteoporotic

fractures than women of an equivalent age with

intact uteri.

Some studies have suggested that even women

whose ovaries have been retained after hysterectomy

have undergone some changes that are sufficient to

cause menopausal symptoms and adverse alterations

in lipid levels and bone metabolism (38,94). These

changes occur at a reduced rate compared with
Chapter 2-Understanding the Menopause ● 21

Box 2-G—Hysterectomy: An Overview

The term hysterectomy refers to the surgical removal of the uterus. The first hysterectomy was allegedly

performed more than 16 centuries ago by Soranus in the Greek city of Ephesus, and the practice was continued with

little success throughout the 16th and 17th centuries. Hysterectomy was not developed further until the 18th century,

when university-trained physicians entered the field of midwifery. At that time, medical technology had not

advanced sufficiently to allow hysterectomy to become a practical procedure. The mortality rate of the operation

continued to approach 90 percent and was thus limited to obvious, life-threatening gynecological conditions.

Indications for the surgery remain controversial. Some estimates show that 10 percent of all hysterectomies are

performed for life-threatening conditions. The remaining 90 percent are classified as elective hysterectomy and are

performed for quality-of-life considerations or for the prevention of pregnancy or disease.

The notion that a woman who has completed her family no longer has a specific need for her uterus is often

referred to as the useless uterus syndrome. Prevention of pregnancy or disease as an indication for hysterectomy

is becoming less common and is no longer viewed as sufficient cause for the procedure without evidence of further

pathology. One study has shown that only 1.3 percent of all women would be helped by hystereetomy as a preventive

procedure to guard against cervical or endometrial cancer. A woman undergoing an elective hystectomy at the

age of 35 could increase total life expectancy by only 2.4 months.

The most common diagnostic indication for hysterectomy in women of all ages is uterine fibroids, benign

fibromuscular growths that can be found in more than 25 percent of women over the age of 35. From 1985 to 1987,

this diagnosis accounted for 30 percent of all hysterectomies. During the same period, endometriosis accounted for

19 percent of all hysterectomies, followed by uterine prolapse at 16 percent, cancer at 10 percent, and endometrial

hyperplasia as an additional 6 percent. Diagnoses also differ between age groups. Nineteen percent of

hysterectomies are concentrated in the youngest age group and are performed for such indications as menstrual

disorders, pelvic peritoneum, and diseases of the parametrium.

Although quality-of-life considerations are of the utmost importance to women experiencing the pain of uterine

prolapse, endometriosis, or other non-life-threatening conditions, many argue that hysterectomy is not necessarily

the treatment of choice. As with any major surgery, there is a substantial risk of complications that must be balanced

against the benefits. The morbidity rate for hysterectomy is between 25 and 50 percent for all operations performed.

Despite the risks of possible complications, hysterectomy remains the second most commonly performed

surgical procedure in the United States. There are vast regional differences in the rates of the procedure, suggesting

professional disagreement about the appropriateness of hysterectomy for some indications. Within the United

States, hysterectomy rates are highest in the south and lowest in the Northeast. The high rates in the South are mainly

the result of an increased number of younger women-between the ages of 15 and 44-undergoing the operation.

Other factors that affect the rate of hysterectomies are race and income. The only racially relevant data available

focus on black versus white women: The rate of hysterectomies performed on black women is higher than for white

women, although the absolute number performed on white women is greater. With regard to income levels,

indications are that women with very low incomes and women with very high incomes are most likely to have a

hysterectomy. This finding could be explained by the availability of Medicaid and health insurance at the extremes.

Physicians who are reimbursed on a fee-for-service basis perform up to 25 percent more hysterectomies than do

physicians who are salaried or reimbursed on a cavitation basis. The implications of such statistics are that a

combination of patient and physician characteristics, including monetary compensation, age, race, and income,

rather than a narrowly defined medical need, explain much of the variation in regional hysterectomy rates.

SOURCES: American College of Obstetricians and Gynecologists, Understanding Hysterectomy (Washington, DC: 1987); G.A. Bachman

“Hysterectomy: A Critical Review,” Journal of Reproductive Medicine 35(9):839-862, 1990; C.L. Easterday, DA. Grimes, and

J.A. Riggs, “Hysterectomy in the United States,” Obstetrics and Gynecology 62(2):203-212, 1983; A.S. Kasper, "Hysterectomy

as a Social process,” Heath and Public Policy 10(1):109-127, 1985; C.J. Mackety, “Alternative to Hysterectomy,” Today’s OR

Nurse 8(4):10-14, 1986; R. Pokras, “Hysterectomy: Past, Present and Future,” Statistical Bulletin 70(4):12-21, 1989 N.P. Roos,

“Hysterectomy: Variations in Rates Across Small Areas and Physicians’ Practices,” American Journal of Public Health

74(4):327-335, 1984.

women who have had both ovaries removed. Current are usually removed if there is no increased surgical

recommended practice is to perform an oophorec- risk to the patient (94).

tomy on a premenopausal woman only if it is The vast majority of women who undergo hysterdetrimental to the woman’s health to conserve her ectomy do so between the ages of 35 and 44 (see

ovaries. In the postmenopausal patient, the ovaries table 2-2). The average age for this procedure is 42.7
22 ● The Menopause, Hormone Therapy, and Women’s Health

,

Figure 2-2—Percentage of Hysterectomies With

Bilateral Oophorectomy, United States, 1985-87

Percent

70 I

 -

6 0

50

40

30

20

10

0

Age

m 20-39 EZZ

Cl 40-4 9 m

30-39

50 +

SOURCE: National Center for Health Statistics, “National Hospital Discharge Surveys,” 1987.

and has remained fairly constant over the years. The

concentration of hysterectomies in this middle age

range means that even if the overall rate remains

constant, the absolute number of hysterectomies

performed will increase substantially as the baby

boomers move into this age bracket. The effects of

the surgery can be extensive; loss of ovarian

hormones is but one, albeit a significant, consequence.

Changes in Mood, Behavior, and Sexuality

For centuries, disturbances of mood and behavior

have been associated with reproductive endocrine

system change (77). Psychiatric syndromes linked to

reproductive function in women have included

postpartum (puerperal) psychosis and depression,

premenstrual syndrome (PMS), posthysterectomy

depression, and menopausal psychiatric syndromes

(24). Much of the current understanding of these

disorders is based on myths, unwarranted assumptions, and conclusions derived from outdated, poorly

constructed studies (24). As a result, substantial

controversy remains.

Mood and behavioral changes associated with

cessation of a woman’s reproductive function ‘have

been poorly characterized, if not dismissed” (77).

Researchers know that estrogen-sensitive cells lie

throughout the peripheral and central nervous systems (76). In addition, the cardiovascular system is

replete with cells that are sensitive to estradiol (the

most potent naturally occurring estrogen in humans)

and progesterone; their receptor activity is localized

in smooth muscle in the walls of arteries and in

endothelial cells throughout the vascular tree. Estrogens increase arterial blood flow (70); investigators

thus suspect that decreases in blood flow combined

with cell atrophy resulting from estrogen depletion

may play a role in the somatic changes (e.g., vaginal

dryness) that are often attributed to changes in

sexual function during the years immediately before

and after the menopause.

For many years, doctors believed that menopausal

depression (referred to previously as involutional

melancholia) was a syndrome characterized by

agitated psychotic depression and somatic (bodily)

preoccupation. Despite the fact that 25 percent of all

cases of involutional melancholia were diagnosed in

men, the syndrome was attributed to physiological

and psychological effects of the perimenopause. In

the past 25 years, little evidence has been found to

Table 2-2—Number of Hysterectomies (in thousands) by Age and Diagnosis, United States, 1985-87

Diagnosis

Endometrial

Age Total Cancer hyperplasia Fibroids Endometriosis Prolapse Other

Total . . . . . . . . . . . . . . . . . . . . . . . 1,967 198 114 593 372 318 372

15 to 24 years . . . . . . . . . . . . . . . 37 5 z z 8 4 18

25 to 34 years . . . . . . . . . . . . . . . 424 37 10 63 111 58 145

35 to 44 years . . . . . . . . . . . . . . . 760 29 26 302 179 90 134

45 to 54 years . . . . . . . . . . . . . . . 421 27 42 188 64 58 42

55 to 64 years . . . . . . . . . . . . . . . 148 39 21 23 8 43 14

65 vears and older . . . . . . . . . . . 176 60 14 15 z 65 20

NOTE: Estimates under 10,000 are not considered reliable and should be used with caution.

Z—Too few records sampled to produce an estimate.

SOURCE: National Center for Health Statistics, “National Hospital Discharge Surveys,” 1987.
Chapter 2-Understanding the Menopause ● 23

support the idea of separate depressive disorders

occurring in the menopausal years (24,36,77). Studies associate the psychiatric symptoms with age but

not with reproductive status (10). In addition,

physical symptoms of the menopausal period do not

correlate with the psychiatric symptoms that have

been seen; psychosocial and psychological variables

such as life events, relationships with children, and

marital status show a stronger correlation (10). A

further point is that physical symptoms occur in

some women without psychiatric symptoms and

vice versa. Women who experience an artificial

menopause as a result of surgery are an atypical

subgroup that physicians tend to see more frequently and from whom they may derive a

distorted image of the typical menopausal woman

(53,55). Even for hysterectomized women, however,

the evidence is contradictory regarding a higher rate

of psychopathology or depression following hysterectomy (18, 24,58).

Studies of the attitudes of North American women

about the menopause are consistent with the lack of

evidence of an absolute relationship between it and

depression. Of a cohort of 7,500 women participating in the Massachusetts Women’s Health Study, 70

percent reported relief or neutral feelings about the

cessation of their menses (see figure 2-3) (6). In

addition, although rates of depression were slightly

higher for perimenopausal women, this trend was

largely explained by discomfort with menopausal

symptoms (e.g., sleep loss, hot flashes) and appeared

to be transitory. In fact, women who were already

depressed were more likely to report menopausal

symptoms; a change in menopausal status was not a

significant predictor of becoming depressed. Factors

correlating with depression included stress from

interpersonal relationships, decline in physical

health, and change in marital status (53,58). Studies

based in southeast England report similar findings

(58). Some studies have concluded that the women

who experience the most distress at the menopause

are those who have relied on their childbearing and

child-rearing roles for status and esteem (59). (In

fact, studies have demonstrated that women of

childbearing age, particularly those with young

children at home, tend to report more emotional

problems than women of other ages (36).) For the

majority of women, the natural menopause is not a

major crisis and does not influence their opinion of

their general health (36).

Figure 2-3—Percentage of Women Reporting

Feelings About Menopause by Menopause Status,

1981-82

Percent

‘“~

50

40

30

20

10

nw

Regret Mixed Neutral Relief

Feelings

Menopause status

_ Surgical n ■ 2,130 ~ Natural n ■ 2,409

m Peri- n = 2,037 ‘kX$X! Pre- n ■ 9 3 5

SOURCE: N.E. Avis and S.M. McKinlay, “A Longitudinal Analysis of

Women’s Attitudes Toward the Menopause: Results From the

Massachusetts Women’s Health Study,” Maturitas 13:71, 1991.

Some women report decreased sexual desire

during the perimenopausal and postmenopausal

periods. Most evidence, however, shows that sexual

pleasure among older women is not compromised

over time, although not much is known about their

sexuality (8). Researchers thus attribute the decline

in sexual satisfaction reported by some women to

hot flashes and a decrease in vaginal lubrication and

flexibility (17).

In summary, understanding of the relationships among aging, the menopause, and behavioral change is incomplete. Many studies have

relied on small samples of self-selected women

seeking treatment for symptoms. As a result, the

actual prevalence of minor psychological and

somatic symptoms directly related to lowered

levels of ovarian estrogen remains speculative at

best.

LONG-TERM CONSEQUENCES

OF CHANGES IN OVARIAN

HORMONE LEVELS

In addition to the acute symptoms associated with

the menopause, the lack of ovarian estrogens appears to contribute to the onset of other postmenopausal diseases such as osteoporosis and cardiovascular disease, two leading causes of morbidity and

mortality in older women (see figure 2-4). Diseases

associated with aging in women, such as osteoporosis and cardiovascular disease, are difficult to

correlate explicitly with estrogen deficiency be-
24 ● The Menopause, Hormone Therapy, and Women’s Health

I

Figure 2-4-Percentage of Deaths From Specific

Conditions Among U.S. Women Over 50 Years of Age

Percent of deaths

‘“~

50

40

30

20

10

0

= Cardiovascular disease = Other cancers

m Breast cancer m Accidents, suicide

SOURCE: T.L. Bush, “The Epidemiology of Cardiovascular Disease in

Postmenopausal Women,” Annals of the New York Academy of

Sciences, vol. 592, Multidisciplinary Perspectives on Menopause, M. Flint, F. Kronenberg, and W. Utian (eds.) (New York,

NY: New York Academy of Sciences, 1990), p. 264.

cause aging and genetics are also important

influences on the development of these diseases.

A number of studies, however, indicate the profound

effects of estrogen deficiency in these syndromes

(35,46,68,82).

Research has identified estrogen receptors in the

uterus, hypothalamus, pituitary, vagina, urethra,

breast, and liver. Preliminary studies have also

found estrogen receptors in bone. Before the menopause, the ovary secretes 50 to 300 micrograms of

estradiol per day directly into the systemic circulation. After the menopause, ovarian estradiol production nearly ceases, but 5 to 20 micrograms per day

are produced from estrone in the liver and fatty

tissue. Studies have shown that this drop in estrogen

correlates with rapid bone loss, which predisposes a

woman to osteoporosis, and a loss of protection

against coronary heart disease (22,34,37,82,83).

Each of these long-term consequences of ovarian

estrogen reduction is discussed below.

Osteoporosis

The first report of a link between ovarian hormone

insufficiency and increased bone loss came in 1940,

when studies by Albright and colleagues revealed

that almost all of a cohort of patients with osteoporotic fractures were also postmenopausal and that

women who had had their ovaries removed were

disproportionately represented (l). Today, an. impressive body of literature has accumulated on this

linkage, and the Office of Technology Assessment

is conducting a major assessment of Policy Issues in

the Prevention and Treatment of Osteoporosis (88).

Osteoporosis is a syndrome composed of a complex, heterogeneous group of disorders with multifactorial determinants attributable to variables of

age, sex, race, heredity, and environment (see figure

2-5). Although there is considerable confusion about

the exact definition of osteoporosis, a clinically

appropriate meaning is that the loss of bone (or

osteopenia) has progressed to the point that specific

parts of the skeleton are so fragile that they have an

enhanced susceptibility to, or the actual presence of,

fractures (41). One of the most common sites of bone

loss is the vertebrae, where spontaneous crush

fractures can lead to curvature of the spine, frequently manifested as a “dowager’s hump,” loss of

height, and pain. Fractures of the hip (especially at

the neck of the femur) and the radius are also

frequently occurring manifestations of this disorder

(74).

Although age-related bone loss is a universal

phenomenon and the problems of bone loss and

osteoporosis are shared by aging men, osteoporosis

is considered primarily a disorder of women in

Western societies because the impact of the disease

on Caucasian women is much more profound and

pervasive. As for men, age is a major factor in the

etiology of this condition; but in middle-aged

women, bone mass and osteoporosis are related

more to menopausal status than to chronological age

(80). A telling finding illustrates the preeminence of

the ovarian hormones in the maintenance of bone

mass: the level of bone density in a group of

50-year-old women who had had their ovaries

removed 20 years earlier was comparable to that

reported in a group of 70-year-old women who had

experienced a natural menopause 20 years earlier or

contemporaneously with the oophorectomized group

(72). Premenopausal women over the age of 30 may

lose less than 1 percent of their bone tissue yearly;

such losses may reach 3 to 5 percent per year for the

5 to 10 years that follow the cessation of the menses

(64). Women who have been hysterectomized are

more likely to develop osteoporosis than women

who experience a natural menopause (18).

The traumatic and debilitating consequences of

osteoporosis, especially in the form of hip fractures,

are a major health concern. To the aging woman,
Chapter 2-Understanding the Menopause ● 25

Figure 2-5—Conceptual Model of the Pathogenesis of Fractures

Related to Osteoporosis

Aging Q

Menopause

\t -

Local

factors Fractures

Sporadic

factors

Trauma

I I

SOURCE: L.J. Melton, “Epidemiology of Osteoporosis: Predicting Who Is at Risk,” Annals of the New York Academy

of Sciences, vol. 592, Multidisciplinary Perspectives on Menopause, M. Flint, F. Kronenberg, and W. Utian

(eds.) (New York, NY: New York Academy of Sciences, 1990), p. 295.

such consequences may entail frailty, personal

suffering, and loss of independence. The relationship between osteoporosis and fractures is currently a point of debate (54,88). Fractures are often

a result of falls; low bone density is neither

necessary nor sufficient for hip fracture, although it

may be necessary for vertebral fracture (54). Nevertheless, complications arising from hip fractures

give rise to a substantial risk of mortality: Between

12 and 20 percent of hip fracture patients die within

3 months of the fracture (73,74). To the Nation,

osteoporosis represents burgeoning health care costs

within a population that is growing rapidly in size.

Direct and indirect costs of osteoporotic fractures in

the United States have been estimated at more than

$7 billion, with the cost of hip fractures in women

alone accounting for more than $5 billion (65).

It has been estimated that 25 percent of Caucasian

women over the age of 70 and 50 percent over the

age of 80 will have evidence of vertebral fractures.

Given present levels of exercise and past dietary

habits, by the age of 90, one-third of all Caucasian

women will have sustained a hip fracture (69). The

marked effect of gender is obvious from the lower

incidence of osteoporosis in men: They experience

only one-half as many hip fractures per capita as

women (73). These projections of incidence have

limitations, however, because they are based on

women who are presently diagnosed as osteoporotic. It may be accurately inferred that these

women have lived different lives from the 40-yearold women of today. Thus, projections of the

incidence of osteoporosis would be more valid if

they controlled for such factors as smoking,

exercise, and diet (17).

Bone mass, bone fragility, and the riskof fractures

are all integrally related. The amount of bone in the

elderly skeleton, a key determinant in its susceptibility to fractures, is believed to be a function of two

major factors: the peak amount of bone mass

previously attained and the rate of loss of bone mass

thereafter (32). The importance of hereditary factors

in peak bone mass is illustrated by the observation

that African American women attain greater spinal

bone mass than Caucasian women and have a lower

incidence of osteoporotic fractures (45,50). Peak

bone mass is determined to a large extent by the

genetic inheritance of the individual (67); other

important factors include dietary calcium (40,51),

vitamin D consumption, exposure to sunlight (21),

physical activity or exercise (40), small frame, low

weight, cigarette smoking, and excess alcohol and

caffeine consumption (4).

Many of the factors that affect the attainment of

peak bone mass also affect rates of bone loss; other

influences include physiologic stresses such as

pregnancy, lactation, and immobilization (85). But

hormonal status, reflected primarily by estrogen and

progesterone levels, exerts the greatest effect on

rates of decline in skeletal mass. Because accelerated bone loss is a frequent occurrence during the

perimenopause, the change in ovarian function is
26 . The Menopause, Hormone Therapy, and Women’s Health

Photo credit: National Cancer Institute

Men and women differ dramatically in rates of

cardiovascular disease until after the menopause when

women begin to catch up.

believed to be pivotal in the pathogenesis of

postmenopausal osteoporosis (39,60,80).

Studies have shown that the loss of bone mass in

the perimenopausal period is a generalized phenomenon that affects all parts of the skeleton (27). In the

first 5 years after cessation of the menses, vertebral

bone may be lost at rates ranging from 2 to 8 percent

(27,60). During this same period, 20 percent of the

lifetime loss in femoral neck bone mass may occur

(33).

Osteoporosis is a significant clinical problem

related to decreased bone mass. Women at highest

risk for osteoporosis are Caucasian or Oriental,

postmenopausal or hysterectomized, and thin; they

generally have small frames and a family history of

osteoporosis. Risk factors associated with lifestyle

include low calcium and vitamin D intakes, caffeine

and alcohol use, smoking, and lack of exercise. The

most effective management for osteoporosis is

prevention. Changes in lifestyle can lower a person’s

risk, as can estrogen therapy. Chapter 3 describes the

use of estrogens to prevent accelerated bone loss.

Cardiovascular Disease

Cardiovascular diseases (CVD), which include

both heart disease and stroke, are the leading cause

of mortality in women, accounting for approximately 50 percent of all deaths in women over the

age of 50 (figure 2-4) (13). Mortality rates are low

among younger women: e.g., among women aged 30

to 34 years, the rate was 2 per 100,000 in 1986, about

28 percent the rate among men the same age. In

contrast, among women 55 to 59 years old, the rate

was 106 per 100,000 in 1986 (89). As women

approach old age, their risk of dying from heart

disease approaches that of men of the same age (see

figure 2-6). CVD is also one of the foremost causes

of serious morbidity and disability. It has been

estimated that 37 percent of all hospital days of

postmenopausal women are attributable to CVD and

that total annual health care costs for CVD in women

are in excess of $9 billion (14). Yet despite these

dramatic figures, until recently, relatively few

studies-either population studies of potential

risk factors or clinical studies evaluating the

efficacy of treatment regimens for CVD—have

included women. This could be due in part to the

mistaken belief that the 8- to 10-year lag in the

development of CVD morbidity and mortality among

women as compared with men means that women

are not significantly affected by CVD. Another

reason for the relative neglect of women’s studies of

CVD could be efficiency. Because rates of CVD are

higher in men than in women—at every age--a

given study will have more endpoints, and hence

more precision, by studying men. This preference

for using men as the subjects of clinical studies has

led to neglect of the uniquely female aspects of some

CVD risk factors (81). Sex differences in the

management of CVD have also been documented

(84): Women tend to receive less aggressive treatment than men for the same symptoms (7).

Available evidence attests to the role of the

natural menopause in the loss of apparent protection

against CVD, although it does not delineate the

precise mechanisms involved (49,81,82,83,93). The

incidence of CVD in women increases markedly

after the menopause (see figure 2-6) with each year

of estrogen reduction and increasing age constituting an enhanced risk (48). The importance of a lack

of endogenous ovarian hormones in the development of CVD is further supported by the finding that

women who have had a bilateral oophorectomy have

a substantially greater risk of CVD than do women

with intact ovaries (15,19,26,48).

Evidence clearly shows that high levels of highdensity lipoprotein (HDL) cholesterol and low

levels of low-density lipoprotein (LDL) cholesterol

are protective against the development of atherosclerosis (31,49). Research has also shown that the

menopause (both natural and surgical) is associated

with changes in serum lipid profiles, such as a
Chapter 2-Understanding the Menopause .27

Figure 2-6—Deaths (per 100,000) From Coronary Heart Disease by Age and Sex,

5.0

4.0

3.0

2.0

1.0

0

Women

Men

United States, 1986

—

40- 45- 50- 55- 60- 65- 70- 75- 80- 85+

0.013 0.027 0.055 0.106 0.207 0.363 0.644 1.125 2.047 4.501

0.057 0.108 0.206 0.342 0.555 0.831 1.321 2.004 3.141 5.377

Deaths per 100,000

= Women m Men

SOURCE: T.L. Bush, “The Epidemiology of Cardiovascular Disease in Postmenopausal Women.” Anna/s of the New

York Academyof Sciences, vol. 592, Multidisciplinary Perspectives on Menopause, M. Flint, F. Kronenberg,

and W. Utian (eds.) (New York, NY: New York Academy of Sciences, 1990), p. 264.

decline in the levels of HDL cholesterol and a rise in

the levels of LDL. These changes maybe factors in

the development of an increased risk of CVD (14).

Estrogen may lower LDL levels by increasing

clearance of LDL particles from plasma, a hypothesis that derives from studies showing that estrogen

increases the number of hepatic LDL receptors in

animals (93). Estrogens may also induce hypertriglyceridemia by increasing the rate of very low

density lipoprotein (VLDL) production (93).

Much of the evidence to support the finding of

a cardioprotective effect for estrogen has come

from prospective studies of women on estrogen

therapy (81), which have shown that estrogen

users experience half as many cardiovascular

events as nonusers (13,14,15,34,49,82,83). In addition, a large number of studies are reasonably

consistent in demonstrating that women with early

bilateral oophorectomy are at increased risk of CVD

(82). Epidemiologic association does not necessarily

establish cause and effect, since there is always the

lingering possibility that women who choose to take

estrogens have other characteristics that explain

their lower risk of heart disease (25). Only randomized, controlled clinical trials can demonstrate

conclusively that oral estrogen use reduces the

incidence of cardiovascular disease (see ch. 5 for

a discussion of research needs). In 1991, however,

prospective epidemiologic research controlled for

confounding risk factors to an extent sufficient to

suggest strongly that postmenopausal estrogen therapy has an independent, significant protective effect

against CVD. Chapter 3 discusses the use of

hormone therapy for prevention of CVD.

SUMMARY

The menopause is a time of normal physiological

change in a woman’s life that often coincides with

changing family or work environments. The transition through the perimenopause varies greatly among

women both within and across cultures. Symptomatology varies enormously, with some women reporting few or no symptoms and others reporting

extreme discomfort. Hot flashes, the most common

complaint of the perimenopause, occur in at least 50

percent of U.S. women at some point during the

menopausal years. Women whose ovaries have been
28 ● The Menopause, Hormone Therapy, and Women’s Health

I

removed experience more severe and more abrupt

symptoms.

Debate continues about the effects of reduced

ovarian hormones on mood, behavior, and sexuality.

In general, however, there is an evolving consensus

that no absolute relationship exists between the

menopause and depression. Factors that correlate

better with depression include stress, decline in

physical health, and change in marital status. Methodological difficulties have plagued the untangling

of relationships among the menopause, aging, and

behavioral change.

The short-term effects of changes in levels of

endogenous estrogen, in the form of hot flashes

and bodily changes, are but one concern. Possibly

of equal or greater consequence are the potential

long-term effects of depleted circulating estrogen

on bone and the cardiovascular system.

The next chapter describes what is known about

the treatment of both short-term and long-term

consequences of the menopause, as well as the

reasons women or their physicians select particular

treatments.

1.

2.

3.

4.

5.

6.

I

7.

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Whelan, E.A., Sandier, D.P., McConnaughey, D.R.,

et al., “Menstrual and Reproductive Characteristics

and Age at Natural Menopause,’ American Journal

of Epidemiology 131(4):625-628, 1990.
Chapter 3

Treatment of Menopausal

Symptoms and Prevention

of Future Disease
Contents

Page

ESTROGEN THERAPY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

COMBINED HORMONE THERAPY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

USE OF HORMONES TO PREVENT BONE LOSS AND PROTECT

AGAINST OSTEOPOROSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

USE OF ESTROGENS TO PREVENT CARDIOVASCULAR DISEASE .............39

CANCER RISKS OF HORMONE THERAPY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Endometrial Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .40

Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41

Hepatobiliary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43

PROFESSIONAL GUIDELINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46

ALTERNATIVE TREATMENTS FOR MENOPAUSAL SYMPTOMS ..............46

Progestins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46

Nonhormonal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47

Nondrug Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

USE OF HORMONE THERAPY AMONG MENOPAUSAL WOMEN ..............48

prevalence of Use of Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

Users of Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49

Women’s Decisionmaking About Hormone Therapy ● . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Compliance With Replacement Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

MENOPAUSE CLINICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Clinical Care and Referral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 52

PATIENT AND PROFESSIONAL EDUCATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54

CHAPTER 3 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55

Boxes

Box Page

3-A. Tamoxifen and Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

3-B. Cultural Variations in the Presentation and Treatment of the Menopause . . . . . . . . . . 51

3-C. Menopause and Hormone Therapy Educational Materials . . . . . . . . . . . . . . . . . . . . . . . . 55

Figures

Figure Page

3-1. Women’s Use of Information Regarding Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . 50

3-2. Percentage of Women Who Identified Consequences of Osteoporosis . . . . . . . . . . . . . 53

3-3. Percentage of Women Who Identified Risk Factors for Osteoporosis . . . . . . . . . . . . . . 53

Tables

Table Page

3-1. Contraindications to Estrogen Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

3-2. Estrogen and Progestin Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

3-3. Recent U.S. Studies of Hormone Therapy and Breast Cancer . . . . . . . . . . . . . . . . . . . . . 44

3-4. European Studies of Hormone Therapy and Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . 45
Chapter 3

Treatment of Menopausal Symptoms

and Prevention of Future Disease

As the previous chapter notes, the state of

knowledge concerning the role of estrogen in the

development of menopausal symptoms and the

development of age-related disorders is deficient.

This knowledge gap leads to uncertainty about the

most appropriate treatments for symptoms during

the perimenopause and about preventive measures

for disease occurring in the postmenopausal years.

Estrogen has been proven effective in the amelioration of hot flashes and in slowing the rate of bone

loss, and it plays a role in protection against

cardiovascular disease, although the causal explanation remains speculative. Yet it can simultaneously

increase the risks of endometial and breast cancer.

These competing risks and benefits create a clinical

conundrum. As the population ages, with more

women facing the decision of whether to make use

of this drug, calls for more complete and better

formulated information are likely to increase in

volume. This chapter explores the basis for and use

of hormones to treat perimenopausal symptoms and

postmenopausal disease, and describes what is

known about nonhormonal interventions such as

other therapeutics, nutrition, and exercise. It also

describes the menopause clinic, a new setting for

addressing the health needs of midlife and older

women. Last, it presents what is known about the

reasons women seek the treatments they do.

ESTROGEN THERAPY

Hormone therapy that uses estrogen alone (ET) is

by far the single most efficacious treatment strategy

in the management of acute perimenopausal symptoms. Orally administered ET is 95 percent effective

in reducing the severity and frequency of hot flashes

and is frequently prescribed for the relief of insomnia resulting from vasomotor changes (59). In

vaginal cream form it is prescribed to reverse

atrophic urogenital changes (87). Symptom relief

may not occur until at least 2 weeks of treatment

have been administered. Side effects of estrogen use

may include headache, breast tenderness, bloating,

and water retention.

Estrogen therapy uses both conjugated (derived

from the urine of pregnant mares) and synthetic

estrogens; synthetic agents, however, are used at

much higher doses and more frequently for contraception than for treatment of menopausal symptoms.

Both conjugated and synthetic hormones control

symptoms at equivalent doses (11).

The restoration of a sense of well-being, termed a

‘‘mental tonic’ effect (109,1 10), has also been

attributed to estrogen use, although there is no

evidence documenting such an effect (see ch. 2).

Recent data on the biobehavioral aspects of the

menopause (see ch. 2) suggest that physicians need

to look more deeply into the root causes of emotional

distress in menopausal women before prescribing

estrogen. Although evidence shows that estrogen

may affect the central nervous system, anxiety and

depression in menopausal women often have other

causes that deserve investigation. Estrogen’s documented relief of hot flashes alone may improve the

general mood of women who have been uncomfortable. Estrogen therapy may also alleviate depression

in some women, although routine use of estrogens to

treat postmenopausal women for depressive symptoms may be inappropriate (95). On balance, when

standardized tests are used, estrogens do not appear

to improve emotional well-being (50).

In terms of metabolic effects, oral estrogen

therapy maintains higher serum high-density lipoprotein (HDL) cholesterol levels (“good cholesterol”) and lower serum low-density lipoprotein

(LDL) cholesterol levels (’’bad cholesterol’ (27,93).

Daily administration of the routine dose of estrogen

(0.625 milligram [mg]) slightly lowers LDL cholesterol levels and raises HDL levels by about 15

percent (114). Estrogen therapy thus brings these

levels to a point that is comparable to premenopausal

values and that also is associated with a lower

incidence of cardiovascular disease (15,66,70,114).

Estrogen has other metabolic effects as well. For

example, it increases serum triglycerides-the storage form of lipids-by as much as 20 percent; the

significance of this action, however, is unknown

(78,93). For the most part, this level of triglyceride

elevation does not produce any increased risk of

atherosclerosis or pancreatitis (60). The transdermal

use of estrogen, on the other hand, does not affect

–35–
36 ● The Menopause, Hormone Therapy, and Women’s Health

triglycerides at all and also is not associated with the

same increase in HDL that is seen with oral therapy.

This difference in effect from the two types of

administration has important clinical consequences.

Physicians should prescribe oral estrogens for patients with low HDL; they should prescribe transdermal estrogen therapy for those patients whose initial

clinical profile includes hypertriglyceridemia (78,1 14).

Estrogens may also affect the prostaglandinthromboxane system, causing vascular dilatation

and reduced platelet aggregation (71,85). In addition, estrogen therapy reduces serum calcium and

phosphorus levels, and decreases urinary excretion

of calcium; these changes (with others) restore a

metabolic profile characteristic of a reduced rate of

accelerated bone loss—and thus a reduced risk of

development of osteoporosis (63).

Estrogens can be taken in a variety of different

preparations, by various routes of administration,

and in different dosages. Oral preparations are most

often prescribed; other, less common routes of

administration are subcutaneous implants (not approved for use in the United States), transdermal

skin patches, or percutaneous (cream) applications

(also not available in the United States). Nonoral

applications deliver estrogen directly into the systemic circulation; as a result, they can be given in

lower doses to achieve the appropriate physiological

levels because they avoid the ‘first-pass’ effect that

occurs in the liver, where a substantial proportion of

ingested estrogens of greater potency are converted

into estrogens of reduced potency (e.g., estrone

sulfate) (75).

However, nonoral estrogen preparations may

have negative aspects that should be balanced

against their favorable qualities. For example, the I1

potential cardiovascular benefits of nonoral prepara- b

tions are uncertain because they do not produce 1

lipoprotein profiles as rapidly as oral formulations

(35,52,103). Where oral estrogen will increase HDL

cholesterol in 4 to 8 weeks, nonoral estrogen may

take 12 to 24 weeks (34). Additional drawbacks in

the use of the transdermal patch are its greater cost t

I compared with oral administration and the tendency

of the adhesive to produce skin irritations (erythema)

in approximately 17 to 30 percent of users (24,98).

! Historically, contraindications to the use of estrogen include reproductive and especially estrogensensitive tumors, thromboembolitic disease, and

acute liver disease. Previously, a recent myocardial

infarction or cerebrovascular accident (see table 3-1)

were also considered contraindications, but with the

knowledge now available, more patients who have

experienced previous thromboembolic disease, myocardial infarction, and cerebrovascular disease are

being placed on hormonal therapy (78).

One of the well-known effects of estrogen alone

(i.e., unopposed estrogen) is its stimulation of

endometrial proliferation, which can lead to hyperplasia (uncontrolled growth) and sometimes to

endometrial cancer (for further discussion, see the

later section on the cancer risks of hormone therapy). Since the end of the 1970s, scientists have

consistently reported an excess incidence of endometrial cancer in nonhysterectomized users of

unopposed estrogen (46). These data have resulted

in important changes in estrogen administration.

First, lower doses of estrogen, commonly 0.625 mg

per day of conjugated estrogens, are being prescribed; second, as discussed later, cyclic therapy

using a combination of estrogen and a progestin is

generally recommended.

COMBINED HORMONE THERAPY

Some clinicians and medical groups recommend

adding a progestin (also known as a progestogen) to

estrogen therapy because progestins oppose some of

the actions of estrogen and prevent endometrial

overgrowth, irregular bleeding, and excess risk of

endometrial cancer. When a progestin is added to

estrogen therapy, the treatment is considered to be

‘‘combined’ and is often referred to as hormone

replacement therapy, or HRT. As previously noted,

for the purposes of this report, an estrogen/progestin

regimen is referred to as combined hormone therapy,

or CHT. Cyclic (also known as sequential) use of a

progestin for at least 10 to 12 days during a 25-day

schedule of estrogen (or during a schedule of

continuous estrogen use) reduces the risk of endometrial cancer by inhibiting continued proliferation of the endometrium and inducing its maturation

and complete shedding (116).

The progestins that were initially used in CHT

were derivatives of testosterone and 19-nortestosterone. Thus, in addition to their progestogenic properties, they also had androgenic (masculinizing) effects. The most widely used progestin in the United

States is medroxyprogesterone. More recently, natural progesterone in the form of micronized progesterone has become available, although it is not yet
Chapter --Treatment of Menopausal Symptoms and Prevention of Future Disease ● 37

Table 3-l-Contraindications to Estrogen Use

Absolute contraindications Relative contraindications Subjective complaints

Stroke Cigarette smoking/significant Nausea/gastrointestinal irritation

Recent myocardial infarction nicotine abuse Headaches

Breast cancer Fibrocystic breast disease Breakthrough bleeding

Endometrial adenocarcinoma Familial hyperlipidemias Depression

Other estrogen-dependent tumors Hypertension aggravated by fluid retention

Acute liver disease estrogen therapy

Pancreatic disease Pancreatitis

Gallbladder disease Hepatic porphyria

Chronic impaired liver function Endometrial hyperplasia

Recent venous thromboembolic event Leiomyomata uteri

Chronic thrombophlebitis Endometriosis

Undiagnosed vaginal bleeding Migraine headache

SOURCE: R.L. Young, N.S. Kumar, and J.W. Goldzieher, “Management of Menopause When Estrogen Cannot Be Used,” Drugs 40(2):220-230, 1990.

approved for use in this country. The Food and Drug

Administration (FDA) has approved the use of

progestins for the treatment of amenorrhea, abnormal uterine bleeding, and endometriosis. No progestin has been approved for use in CHT, but

physicians continue to prescribe them for this

purpose (see ch. 4). Progestins alone are effective in

treating hot flashes and can be used when estrogen

is contraindicated. However, most progestin use

related to CHT occurs in conjunction with estrogen.

Physicians most often prescribe combination

therapy for women with intact uteri to counteract

the increased risk of endometrial cancer associated with estrogen therapy. There is no official

standard or protocol for administering or prescribing combination therapy and no conclusive

studies to indicate which regimen is most beneficial. In addition, studies that meet adequate design,

duration, and sample-size requirements have yet to

be performed to deterrnine conclusively the risks and

benefits of long-term use (more than 10 years) of

combined therapy (9).

Frequently, the use of a progestin in combination

with estrogen therapy is associated with unpleasant

side effects, both physical (breast tenderness, bloating, edema, abdominal cramping, weight gain) and

psychological (anxiety, irritability, depression). Cyclical progestin use (see below) also results in

withdrawal bleeding; this is frequently perceived as

a major source of inconvenience and is one of the

principal reasons for lack of compliance with

prescribed regimens among older women. Clinicians are experimenting with various regimens that

will either make bleeding more predictable or

eliminate it entirely (69). The most commonly

prescribed regimens are cyclic administration of

estrogen and progestin, continuous administration of

estrogen plus intermittent progestin, and, increasingly, continuous/combined administration of estrogen and progestin (see table 3-2). Cyclic administration typically uses estrogen for the first 25 days of

the calendar month and adds progestin on days 14 to

25. Both hormones are stopped for the last days of

the month at which point withdrawal bleeding

occurs. Another cyclic method involves daily use of

both estrogen and progestin for 21 days, followed by

7 days of no use of either hormone. A regimen of

continuous use of estrogen with intermittent progestin involves administration of estrogen every day

and administration of progestin for the first 12 days

of the calendar month. Withdrawal bleeding typically occurs for several days after progestin use is

stopped. Under the continuous/combined regimen,

estrogen and progestin are both administered daily,

and withdrawal bleeding is diminished or eliminated.

The side effects of progestins vary according to

the type used and the dosage. For example, depression is reported more often in patients for whom

Provera is prescribed than in those receiving the

19-nortestosterone derivatives such as Norlutate

(78). By reducing the dose or by prescribing natural

progesterone, some of these side effects can be

avoided (78).

Short-term studies have shown that the addition of

a progestin may attenuate the cardioprotective lipid

profile of higher levels of HDL cholesterol produced

by unopposed estrogen (116). Longer studies (6 to

12 months or more) have shown no adverse effects

(33,35,52,53,99,103). Regardless of these uncertainties, most physicians recommend the use of

combination therapy, perhaps because the long-
38 . The Menopause, Hormone Therapy, and Women’s Health

Table 3-2—Estrogen and Progestin Regimens

Common Doses Used

Estrogens Progestins

0.3 mg conjugated estrogen 5 mg medroxyprogesterone acetate

0.625 mg conjugated estrogen 10 mg medroxyprogesterone acetate

0.9 mg conjugated estrogen 2.5 mg medroxyprogesterone acetate

1.25 mg conjugated estrogen 5 mg norethindrone acetate

0.05 mg transdermal estrogen 5 mg norethindrone

0.10 mg transdermal estrogen

Typical Regimens

Cyclic estrogen plus progestin

Estrogen: days 1 to 25 (0.625 mg or transdermal patch changed two times/week)

Progestin: days 14 to 25 (5 or 10 mg)

Stop both: days 26 to end of the month

OR

Estrogen and progestin: days 1 to 21 (estrogen-0.625 mg or transdermal patch changed two times/week; progestin-5 or 10 mg)

Stop both: last 7 days of the month

Continuous estrogen with intermittent progestin

Estrogen: 365 days/year (0.625 mg or transdermal patch changed two times/week)

Progestin: days 1 to 12 of the month (5 or 10 mg)

Continuous/combined

Estrogen and progestin daily (estrogen+O.625 mg or transdermal patch changed two times/week; progestin—2.5 mg)

SOURCE: W. Utian, Managing Your Menopause (New York, NY: Prentice Hall Press, 1990).

term risks associated with the addition of a progestin are not well defined, while those of endometrial cancer from unopposed estrogens are

well established. Unfortunately, studies designed to

define risks and benefits more clearly have met with

a number of problems. High dropout rates (up to 30

percent) have plagued most of these efforts, in large

part because at least within the first 3 months, not

only may it be difficult to establish amenorrhea but

regular withdrawal bleeding may be supplanted by

more bothersome chronic and irregular bleeding

patterns (116). Consequently, no data are available

on the long-term effects on the endometrium of

combination therapy. In addition, it has yet to be

proved that this treatment maintains or increases the

benefits of unopposed estrogen on the skeletal or

cardiovascular systems, or improves compliance

among users. In general, clinical researchers in

the field consider unopposed estrogen acceptable

as long as there is adequate monitoring for

endometrial cancer with yearly biopsies (13).

USE OF HORMONES TO PREVENT

BONE LOSS AND PROTECT

AGAINST OSTEOPOROSIS

Researchers have long recognized the extreme

sensitivity of the skeleton to the loss of ovarian

hormones as a result of natural and especially

surgical (oophorectomy) menopause; they have also

documented the profound effect of exogenous estrogen (externally administered) on the maintenance of

bone mass and skeletal integrity (38). In addition,

studies have shown that long-term use of estrogen

protects against postmenopausal bone loss (74) and

osteoporosis (30,38,65) for as long as 10 years-and

possibly longer. Although the specific mechanisms

of the protective effects of estrogen are unknown, it

is generally accepted that estrogen suppresses the

enhanced rate of bone breakdown characteristic of

acute ovarian hormone deficiency in oophorectomized and perimenopausal women (38,43). At the

same time, it conserves stores of skeletal calcium by

promoting more efficient absorption and utilization

of dietary calcium (44), restores serum calcium and

phosphorus (critical to healthy bone), and increases

alkaline phosphatase (a useful biological marker of

the bone remodeling cycle) to levels comparable to

those in premenopausal women (64). Once estrogen

replacement stops, however, bone loss resumes, and

at a rate faster than normal. For this reason, some

physicians advocate extended estrogen therapy (10

to 15 years), and some even advocate lifelong use.

The treatment of established postmenopausal

osteoporosis remains unsatisfactory, because available therapies can do little more than slow the

progression of bone loss. Prevention of the disorder

is still the best strategy (notwithstanding a recent
Chapter 3--Treatment of Menopausal Symptoms and Prevention of Future Disease ● 39

report that showed that therapy with estrogen and

calcium could retard bone loss in the hip and even

promote increased vertebral density in postmenopausal osteoporotics) (64). Currently, there is no

acceptable therapy that can restore lost interconnections of architectural elements of bone (which serve

structurally to provide biomechanical stability) or

prevent further fractures in patients who have

osteoporosis. However, some researchers have speculated that estrogen used for 5 years after the

menopause--when bone loss is the most accelerated—

can decrease by 50 percent a woman’s chances of

suffering a hip fracture later in life (81). This claim

has been the subject of some controversy (17).

Other factors that are believed to be important in

maintaining g skeletal integrity include dietary calcium and physical exercise. Inadequate dietary

calcium is known to exacerbate bone loss (45), and

women who are beyond the acute menopausal phase

(or at least 5 yearn postmenopause) may realize

benefits in bone mineral conservation from increased dietary intake of calcium (25). Yet even

megadoses of calcium cannot compare with the

effectiveness of estrogen therapy in successfully

preventing the accelerated bone loss that may occur

during the perimenopause (89). Interestingly, several reports have shown that combining highcalcium supplements with a hormone regimen

increases the efficacy of estrogen in skeletal

conservation (31,86). This finding suggests the

possibility of using lower doses of estrogen, which

could reduce the side effects of CHT and increase

compliance with the regimen.

Physical exercise has a positive effect on muscle

and skeletal mass and strength, whereas immobilization is known to promote bone loss. But no studies

are available to show that the estrogen reduction

component of the perimenopause can be successfully overcome by exercise. Preliminary data from

one study show that within the first 5 years of the

perimenopause, women can slow down the rate of

bone loss with aerobic exercise three times a week

(78). However, no controlled trials have been able to

demonstrate a decrease in the incidence of fracture

after either dietary or exercise interventions, although weight-bearing exercise is frequently recommended for women.

USE OF ESTROGENS

TO PREVENT

CARDIOVASCULAR DISEASE

Cardiovascular disease (CVD) is by far the

leading cause of death in the United States. Thus,

even minor changes in risk as a result of estrogen

therapy could improve the Nation’s collective

health. Initially, concerns were raised about the

safety of exogenous estrogens and their effect on the

heart; these concerns stemmed from the serious

adverse effects attributable to the use of oral

contraceptives. For example, the high-dose, highpotency estrogen preparations used in oral contraceptives in the 1960s brought an increased occurrence of thrombosis, severe hypertensive episodes,

and massive hypertriglyceridemia with pancreatitis

or overt diabetes (55). In addition, some more recent

studies of noncontraceptive estrogen preparations

have shown an increased risk of cardiovascular

morbidity and mortality in users of postmenopausal

estrogens compared with nonusers (117). Nevertheless, the preponderance of the evidence suggests that estrogen therapy is associated with very

substantial reductions-greater than 50 percent—

in the risk of cardiovascular disease and associated mortality (12,21,42,47,66,102).

In one meta-analysis of 19 studies, 15 show a

reduction in risk among estrogen users, 2 show no

effect, and 2 report an increased risk (29). A more

recent meta-analysis looked at the results of 16

prospective studies and found decreased risks in 15

of them ( 101). A recent report has shown that the risk

of death from stroke, myocardial infarction, and

cardiovascular death in current estrogen users has

been reduced by almost 50 percent, with a reduction

in overall mortality of 40 percent after 15 years of

use (47). Furthermore, estrogen use has been associated with enhanced survival in women with angiographic evidence of coronary artery disease (105);

it has also been associated with a reduced risk of

stroke in the presence of other, concurrent risk

factors such as hypertension, obesity, and previous

myocardial infarction (79).

The mechanisms of the cardioprotective effect

of exogenous estrogen are unclear. Recent work

has shown that in newly menopausal women, oral

estrogens may confer a protective effect by maintaining levels of HDL and LDL cholesterol at

premenopausal values (27). Data from the Lipid
40 • The Menopause, Hormone Therapy, and Women’s Health

Research Clinics show a 65 percent reduction in

CVD mortality, which suggests that a large proportion of the beneficial effects of estrogen on CVD

endpoints may be mediated by the elevation of HDL

cholesterol levels (14). It also appears that the

reduction in LDL cholesterol that occurs with

estrogen therapy (although less consistently observed) may play a cardioprotective role (9). In one

study, estrogen users had LDL levels approximately

7 percent lower than those of nonusers. Such a

difference would correspond theoretically to about a

14 percent reduction in CVD risk (60,100). In fact,

it now appears that oophorectomy alone in the

premenopausal patient may be associated with

increased risk of coronary heart disease as well as

with osteoporosis (115).

As is the case in assessing the risk of endometrial cancer, one finds little information on the

long-term effects of hormone therapy on endpoints of CVD when regimens other than unopposed oral estrogens are involved. Some data on

the short-term effects of combination therapy suggest that progestins may oppose the favorable HDL

and LDL profiles, achieved by estrogen alone (66);

others show few, if any, adverse effects on lipid

profiles, especially with the use of medroxyprogesterone acetate, an oral progestin that is modestly

androgenic (9,27).

Nonhormonal, behavioral interventions, such as

smoking cessation, dietary modification, exercise,

and weight reduction (or control), may also have

beneficial effects on risk factors for osteoporosis and

CVD, but, again, there are few available data. The

use of such interventions, in addition to or in lieu

of hormone therapy (particularly in asymptomatic

women without an enhanced risk of osteoporosis),

deserves study, especially since these approaches

pose potentially fewer risks than replacement therapy (76).

Until recently, many researchers have seen the use

of postmenopausal estrogen as a marker for socioeconomic, clinical, constitutional, or lifestyle variables that a priori place postmenopausal estrogen

users at lower risk for cardiovascular disease (21).

This belief has prevailed because women for whom

estrogen is prescribed are generally healthier, leaner,

and of higher socioeconomic status than women

who are not so treated. In addition, most of the

women evaluated in previous studies were treated

with conjugated equine estrogen, usually administered without a progestin and probably prescribed in

higher doses than would be recommended today.

Therefore, any conclusions about the cardioprotective effects of estrogen cannot necessarily be extrapolated to other estrogens, to lower doses, or to

estrogen used in combination with progestin (8). In

1991, however, results from the Nurses’ Health

Study virtually eliminated the biases in selection

(and recall) that have plagued other studies and

eliminated the confounding variables usually attributed to studies of estrogen therapy and CVD, such as

the contribution of age, access to medical care, and

risk factors (e.g., cigarette smoking, diabetes, hypertension, hypercholesterolemia) (102). The results of

this study suggest a causal association between the

use of estrogen and a reduced risk of coronary

disease, although the causal effect was not established. The study also did not consider the effects of

added progestins on CVD. Until carefully controlled

clinical trials are completed, the contribution of

estrogen to reduction of CVD cannot be fully

understood.

CANCER RISKS OF

HORMONE THERAPY

Estrogens and progesterones, although naturally

occurring substances, are drugs whose administration carries some risks. The risk of endometrial

cancer associated with the use of unopposed

estrogen is well documented (29). The association

of estrogen use and breast cancer remains speculative, but there is evidence that long-term use

(for 10 years or more) can increase risk. Of more

than 44 studies on estrogen therapy and breast

cancer, some found significant increases in some

subgroups of women while others found significant

decreases in other subgroups (26,34). The cancer

risks posed by progestins remain speculative as well;

their effect on the breast in particular is a matter of

controversy and has not been the subject of adequate

investigation.

Endometrial Cancer

Early studies of estrogen therapy without the

addition of progestin found increases in the risk of

endometrial cancer of two- to twentyfold in postmenopausal women (54). More recent studies evaluating the use of unopposed estrogen at the current

lower doses show that such administration carries at

least a fivefold increased risk of endometrial cancer

(7). This kind of cancer is relatively rare and is not
Chapter .3-Treatment of Menopausal Symptoms and Prevention of Future Disease ● 41

Photo credit: National Cancer Institute

Regular exercise, a healthy diet, moderate alcohol

consumption, and a smoke-free environment contribute

to reductions in heart disease and cancer.

fatal in the vast majority of cases associated with

estrogen use (29). In addition, the endometrial

cancer that appears to be caused by estrogen use is

of a lower grade and becomes apparent at an earlier

stage than endometrial cancer that arises in nonusers

(100). Advocates of the use of estrogen to prevent

osteoporosis and CVD argue that any increased risk

of endometrial cancer pales in comparison to the

benefits gained from preventing these diseases

(18,102). In addition, they claim, endometrial cancer

is easily detected by routine, periodic endometrial

biopsy; if cancer is found, a hysterectomy can be

performed. However, the assumption that physicians

‘will prescribe, or that women will

endometrial biopsies is problematic.

Breast Cancer

After lung cancer, breast cancer

leading cause of death from cancer

1991, an estimated 175,000 women

make use of,

is the second

in women. In

will be diagnosed as having breast cancer, and the lifetime risk

of this disease for U.S. women has risen to one in

nine. Furtherrnore, 44,500 American women will die

of this disease in 1991 (2). Any adverse effect of

exogenous estrogens on the risk of breast cancer,

even if small, would be highly significant, given

the high baseline risk, as well as the high cost to

society, of this illness.

A woman’s cumulative lifetime exposure to

estrogen is strongly related to her risk of developing

breast cancer. The earlier a woman begins to

menstruate, and the greater the number of ovulatory

cycles (an index of cumulative estrogen and progesterone exposure), the greater her risk of breast

cancer. Artificial menopause, brought about by

oophorectomy, has been shown to markedly reduce

the risk of breast cancer, possibly because it lowers

a woman’s lifetime exposure to estrogen (90,107).

Thus, risk is inversely related to age at either

artificial or natural menopause. Recently, some

doctors have begun prescribing an experimental

synthetic hormone, tamoxifen, for the treatment of

breast cancer, along with surgery (see box 3-A).

The relationship between the use of estrogen and

breast cancer is far more controversial than the link

between estrogen and endometrial cancer. Evidence

from experimental and clinical studies supports the

concept that overstimulation of a target tissue by

hormones involved in the regulation of that tissue

may play an important role in causing cancers,

particularly those of the breast and reproductive tract

(46). It is generally accepted that endogenous

(naturally occurring) estrogens play an important

role in the causation of breast cancer (56). Despite a

wealth of epidemiologic studies (26,104), it has been

difficult to prove that exogenous estrogens, given at

the time of the menopause, have a similar effect. The

often conflicting results of these studies stem from

the complexity of the biological issues addressed,

the heterogeneity of the populations studied, inherent biases arising from the study methodologies, and

the variety of approaches chosen, including the

assessment of subgroup populations.

In particular, the nature of the treatment and

control populations that are being studied, and

variations in the dose, duration, and type of estrogen

used may be responsible for the substantial differences in the estimated increase in risk to be found

among many of the studies (26,104). A recent

meta-analysis summarizing the literature suggests

that conjugated estrogens at dosages less than or

equal to 0.625 mg per day probably do not pose a

substantially increased risk of breast cancer, particu-
42 ● The Menopause, Hormone Therapy, and Women’s Health

Box 3-A—Tamoxifen and Breast Cancer

Tamoxifen is a synthetic hormone that is widely used as an adjuvant to surgery for the treatment of breast

cancer. Its use leads to a demonstrably lower risk of the occurrence of new breast tumors and in the recurrence of

breast cancer. In studies thus far, tamoxifen has demonstrated both estrogenic and antiestrogenic effects, but it is

not well characterized It has an antiestrogenic effect on the breast and an apparently estrogenic effect on the

endometrium, vaginal mucosa, lower urinary tract, and (possibly) cholesterol and bone. The side effects also are

not well understood but are known to include menopausal-like symptoms (especially hot flashes), depression,

increased risk of blood clots, and increased risk of endometrial cancer.

Based on the successful use of tamoxifen in the prevention of new tumors and of recurrence of cancer in breast

cancer patients, both the United States and the United Kingdom plan to undertake long-term prevention studies of

tarmoxifen in healthy women. Both studies are 5-year, randomized, double-blind placebo-controlled trials in which

half the women will receive tamoxifen and half will receive a placebo. The U.S. study will be conducted by the

National Surgical Adjuvant Breast and Bowel Project and is jointly sponsored by the National Cancer institute and

the National Heart, Lung, and Blood Institute. It is slated to beginin January 1992 and will ultimately involve 16,000

healthy women who are at increased risk for breast cancer, as determined by age or family history. The study will

be conducted at 70 centers. The U.K. study will include 10,000 women.

No one disputes the need for research into the prevention of breast cancer, but these studies nonetheless have

provoked controversy both within and outside the scientific community. Many argue that healthy women should

not be treated with a drug whose side effects are not well understood for the prevention of a disease that they may

or may not get. These arguments are countered by contentions similar to those made for the use of unopposed

estrogens for the treatment of menopausal symptoms and the prevention of osteoporosis and cardiovascular disease:

the risks-e.g., the development of endometrial cancer, which is readily treatabl-are outweighed by tamoxifen’s

potential beneficial effect on the prevention of breast cancer. Some researchers suggest that the increased risk of

endometrial cancer seen with tamoxifen can be countered by concurrent use of progestin. The controversy

surrounding the planned trials is particularly intense because they constitute the first time that a large number of

healthy women will be given a drug for cancer prevention.

SOURCES: The Wal Street Journal, “Tamoxifen Helps Prevent New Tumors in Breast Cancer Patients, Study Finds,” Sept. 18, 1991; G.

Kolata, “A Powerful Hormone To Be Tested in War To Prevent Breast Cancer,” The New York Times, Sept. 19, 1991, section B,

p. 6; ‘T. Fornander, B. Cedermark A. Mattson, et al., “Adjuvant Tamoxifen in Early Breast Cancer: Occurrence of New Primary

Cancers,” The Lancet, Jan. 21, 1989, pp. 117-119; A. Miodrag, P. Eklund, R. Burton, et al., “Tamoxifen and Partial Oestrogen

Agonism in postmenopausal Women” Age and Ageing 20:52-54, 1991; A. Oakley, “Tamoxifen: In Whose Best Interest?” New

Scientist, June 22, 1991, p. 12; "Tamoxifen Breast Cancer Prevention Study Should ‘Proceed,’” F-D-C Reports 53(27):T&G4

T&G-5, July 8, 1991.

larly if the duration of use does not exceed 10 years (19,20). The study did not consider the effect of a

(26). Some studies, however, have shown an increased risk with increasing duration of use or with

daily dosages greater than 1.25 mg per day (90). In

I June 1991, an advisory committee to the FDA

b

, agreed that long-term, unopposed estrogen therapy

, is associated with a slightly increased incidence of

breast cancer, citing an increased risk of 30 percent

after 15 years of use. But also in 1991, investigators

working on the Nurses’ Health Study reported no

effect of duration of use of estrogens on the risk of

breast cancer. This study found that the risk of breast

I cancer was significantly elevated among current

users (33 percent) but was not increased for past

users. The authors speculate that the lack of a

duration effect suggests that estrogens may act

acutely to increase risk and that this effect is

reversible, perhaps within 2 years of cessation of use

woman’s age at the menopause. On the one hand,

younger age at menopause is associated with a lower

risk of breast cancer; on the other hand, women who

experience early menopause generally show greater

use of hormone therapy (84). Additional contributing risk factors, such as benign breast disease and

family history of breast cancer (29), have received

inadequate exploration in relation to hormone use.

Table 3-3 summarizes the conflicting results of five

studies conducted since 1985.

A cautious interpretation of the best available

data is that estrogen therapy is associated with an

increase in the risk of breast cancer. This increased risk is on the order of 30 to 80 percent and

appears to be no larger than a doubling of risk.

Moreover, the increased risk appears to be

limited to users of more than 15 to 20 years’
Chapter 3--Treatment of Menopausal Symptoms and Prevention of Future Disease ● 43

,

Photo credit: National Cancer Institute

A laboratory technician performing an estrogen receptor

assay on breast tissue to assist in the determination of

treatment for a breast cancer patient.

duration and may be concentrated among those

with other risk factors for the disease. The

increased risk may also be restricted to those

women who used doses larger than the current

dose of 0.625 mg per day of conjugated estrogen—

many studies fail to separate the effects of

duration of use from those of higher dose (106).

No study of the risk of breast cancer among

women using estrogen has found an increase in

mortality-but few have addressed this issue directly (26,104). Studies that have examined cancer

mortality have found reduced risk of death from

breast cancer among estrogen users; other studies

have found an increase in the number of smaller,

earlier stage tumors (18). These findings suggest that

ET (or the patient characteristics associated with its

use) may increase the rate of diagnosis of breast

cancer, rather than its true incidence or mortality

from it, reflecting, in part, a detection bias. In

addition, researchers speculate that exogenous

estrogen stimulates growth of slow-growing, lowgrade tumors that are less aggressive; once

estrogen is withdrawn, survival is better than

among women who have never used estrogens

(18,34,102). In any case, it appears unlikely that

progestins will have a protective effect, as they do on

the endometrium (13,18,36,49).

Finally, evidence is lacking to determine the

effect on breast cancer of adding progestins to

estrogen (49). It has been hypothesized that estrogen

plus a progestin would be more carcinogenic than

estrogen alone (58). Indeed, some preliminary evidence from European studies suggests that adding a

progestin to estrogen may pose higher risks for

breast cancer than are found with the use of estrogen

alone (10,32) (see table 3-4). One Swedish study

reported a tendency toward a fourfold increase in

breast cancer in women who used combined therapy

for 6 to 9 years (10). The kind of estrogen commonly

used in Sweden is estradiol, which is similar in effect

to the conjugated estrogen preparations usually

prescribed in the United States (11).

Critics of the study claim that because of wide

confidence intervals the increased risk is not statistically significant (23,5 1). The possibility of detection

bias should also be considered: Swedish physicians

may require more frequent physical examinations

for women to renew hormone prescriptions (23,28).

On the other hand, because the reasons for the

prescription or nonprescription of CHT usually are

not specified, the role of selection bias is difficult to

identify in nonrandomized studies. For example, in

the one study citing a protective effect, a reluctance

to use estrogens (with or without progestin) among

women with potential risk factors—such as family

history of breast cancer or a history of late age at first

pregnancy or no pregnancy—may have contributed

to the finding of a reduced risk of breast cancer (36).

In the U.S. studies evaluated for this report, the

hormonal regimen consisted of unopposed, conjugated estrogens. Long-term data on the effect of

added progestins on risk for breast cancer are

extremely limited, and accumulated knowledge

from these studies is inconsistent and controversial (29). A carefully designed, large-scale study of

the potential causal role in breast cancer of exogenous menopausal progestins is needed (see ch. 5).

Hepatobiliary Disease

Another possible risk associated with ET is a

greater likelihood of gallbladder disease; it is

estimated that 131 out of 100,000 cases of gallblad-
44 . The Menopause, Hormone Therapy, and Women’s Health

o +

1 0

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.-

.

.

.

.

.

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.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

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.

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Table 3-4—European Studies of Hormone Therapy and Breast Cancer

Duration of Use

Relative 95 percent

Authors, year Study design Subjects Years riska

confidence interval Comments

Bergkvist et al., 1989

(Sweden) . . . . . . . . . . . . . . . . . Population-based; 23,244 exposed, 253 cases; 6 to 8 1.3 0.9 to 1.9 Six or more years of use; risk=

prospective; ages 35 and older; 9+ 1.7 1.1 to 2.7 1.8, conjugated

cohort 6 percent premenopausal conjugated estrogen:

relative risk = 1.3, estrogen

+ progestin: relative risk =

4.4

Ewertz, 1988 (Denmark) . . . . . . . Population-based; 1,486 cases; 6 to 8 1.8a 1.0 to 3.4b Risk increased for sequential

case control 1,336 controls 9 to 11 1 .3b 0.7 to 2.5 estrogen + progestin and

estrogen; interaction

between age at

menopause and estrogen

use

aThe referent is never users of hormone therapy.

bEsti mates are for women who experience a natural menopause.

SOURCE: B. Hulka, “Hormone Replacement Therapy and the Risk of Breast Cancer,” CA-A Cancer Journa/l for Clinicians 405:291, 1990,
46 • The Menopause, Hormone Therapy, and Women’s Health

der disease can be attributed to estrogen therapy.

Orally administered estrogens are absorbed through

the small bowel and pass to the liver where they are

metabolized before fully entering the circulation.

Some investigators have speculated that these

hormones might stimulate gallstone formation, but

until 1988 the evidence was inconclusive, given that

the only available studies were conducted when

estrogens were prescribed at higher doses (48). In

1988, researchers found that the risk of gallbladder

disease in estrogen users persists after therapy ends,

concluding that the effect of estrogen use on the

gallbladder should be considered in weighing the net

risks and benefits of the use of estrogen (82).

PROFESSIONAL GUIDELINES

It is standard in medical practice for professional

associations or societies to issue standards or

guidelines for practice regarding drugs and procedures. In the case of hormone therapy, the American

College of Obstetrics and Gynecology (ACOG) has

been the most active group in issuing such guidance.

In June 1986, ACOG published a technical bulletin

on estrogen therapy (3). The publication listed

indications for use, which include vasomotor effects

(hot flashes) and osteogenic, cardiovascular, genitourinary, and gonadal symptoms (this last for use in

adolescent girls for treatment of hypogonadism).

Other considerations for use include dermatologic

and psychological indications. The ACOG publication also listed complications associated with ET

including hyperplasia and endometrial cancer,

breast cancer, and hepatic effects. Contraindications

for use are unexplained vaginal bleeding, acute liver

disease, chronic impaired liver function, acute vascular thrombosis, and breast and endometrial cancer.

Last, the publication discussed management and

prescribing practices for the drug.

More recently, in July 1988, ACOG issued a

technical bulletin (4) on osteoporosis, describing the

physiology and diagnosis of the disease, dietary and

exercise regimens as prevention, and the use of

estrogen to slow the rate of bone loss. In February

1990, the college issued a committee opinion (5),

which concluded that in women with a history of

endometrial carcinoma, estrogens could be used for

the same indications as for other women, except that

the selection of appropriate candidates for therapy

should be based on prognostic indicators and the

level of risk that the patient is willing to assume. If

the patient is free of tumor, concluded the committee, ET cannot result in recurrence. If she is

harboring an estrogen-dependent neoplasm in her

body, it will eventually recur; however, ET may

result in an earlier recurrence. The report concluded

that the need for progestational agents in addition to

estrogen is unknown at present.

In 1988, the first International Consensus Conference on progestin use in postmenopausal women

concluded that progestins are indicated for opposing

the effects of estrogen on the endometrium. The

group further concluded that the effect of progestins

on breast tissue was unknown, as was its effect on

the cardioprotective benefits provided by estrogen

(108).

The American College of Physicians is in the

process of drafting a position paper on ET, but it is

not available at the time of this writing (96).

ALTERNATIVE TREATMENTS

FOR MENOPAUSAL SYMPTOMS

Estrogen is the most widely used treatment for

menopausal symptoms, specifically, for vasomotor

symptoms or hot flashes. But estrogen is contraindicated for a number of women, and consequently they

and others seek nonhormonal and nondrug treatments for these symptoms. There is limited research

on alternatives to hormone therapy, which consist of

the use of other hormones, nonhormonal drugs, and

nondrug products, and widespread clinical investigation into most of these treatments is nonexistent.

Many small-scale studies have been done, however,

and evidence shows that these treatments are somewhat successful in remedying hot flashes (although

none are as effective as estrogen). Anecdotally,

many women reportedly try ‘‘home remedies’ to

alleviate menopausal complaints. It is not clear,

however, whether these remedies are effective and if

they are, for what level of severity of complaints

(80).

Progestins

Some physicians prescribe progestins for hot

flashes, although no progestin formulation has

received FDA approval for this indication. Evidence

that progestins are effective in relieving hot flashes

includes studies of depomedroxyprogesterone acetate (depo-MPA), medroxyprogesterone acetate

(MPA), and megestrol acetate. Depending on the

dose, depo-MPA, which was studied among women

with endometrial cancer, relieved hot flashes by as
Chapter 3—Treatment of Menopausal Symptoms and Prevention of Future Disease ● 47

much as 85 percent. Other studies showed that oral

administration of MPA, which is the active ingredient in Provera and Amen, reduced hot flashes 15 to

87 percent of the time, again depending on the dose

(1,113). These studies also found a strong placebo

effect. Women treated with a placebo experienced a

25.9 percent decrease in hot flashes; they had an

additional 34.5 percent reduction when they were

then given MPA. Women who began treatment with

MPA experienced a 73.9 percent decline in symptoms, but their hot flashes worsened when MPA

administration stopped and a placebo was given

(94). Megestrol acetate decreased hot flashes by as

much as 90 percent, but its administration was

accompanied by side effects that included bloating,

irregular vaginal bleeding, breast tenderness, and

mood changes (113). Because of the side effects,

the evidence of placebo effect, and the fact that

progestin does not improve vaginal atrophy or

protect against osteoporosis, the use of progestin

to treat hot flashes is only recommended for

women for whom estrogen is contraindicated or

undesirable.

Nonhormonal Drugs

Physicians may also prescribe nonhormonal drugs

for hot flashes, and one such drug, Bellergal, has

FDA approval for the treatment of menopausal

disorders, specitlcally, hot flashes, sweating, restlessness, and insomnia. Bellergal contains phenobarbital, belladonna, and ergotamine tartrate and is

potentially addictive (83). It has a 50 percent

effectiveness rate for the relief of hot flashes, but its

potentially addictive effects warrant careful use

(113). No other drugs that have been tested and that

are used to treat hot flashes have been approved by

the FDA for this use; nonetheless, doctors use many

types of drugs to relieve these symptoms, despite the

lack of FDA approval and of appropriate labeling for

such an indication. These drugs include

sedatives and tranquilizers,

nonsteroidal anti-inflammatory agents,

alpha-adrenergics,

antidopaminergics,

beta-blockers,

opiate receptor antagonists,

aromatic aminoacid decarboxylase inhibitors,

and

nonsteroidal antiestrogens.

One popular nonhormonal drug treatment is

Catapres transdermal patches, which use a form of

clonidine, an antihypertensive (75). This treatment

is best tolerated by hypertensive patients and can

reduce hot flashes by as much as 40 percent. Side

effects include dizziness, dry mouth, fatigue, irritability, and nausea (113,1 18). Inderal, another antihypertensive drug (a beta-blocker), has also been used

successfully (75). Other alpha-adrenergic drugs that

are prescribed for hot flashes include aldomet and

lofexidine. Veralipride is an example of an antidopaminergic compound that in many clinical studies has demonstrated a 60 to 80 percent reduction in

hot flashes; it is also effective for treating severe

flushing (118). Beta-blockers-sotalol, for example

reduce hot flashes as well. The mechanisms of action

for the different kinds of substances are not well

understood, and many of the drugs have been studied

only in very small patient populations. In addition,

although many of these compounds can be used to

treat hot flashes, they are not effective for other

menopausal symptoms, including vaginal dryness,

atrophy, anxiety, and sleeplessness, and they do not

protect against osteoporosis (118). Studies are needed

to increase knowledge about alternatives to hormone

therapy for women who choose not to undergo

long-term treatment or for whom estrogen is contraindicated (67,68).

Nondrug Treatments

Alternative, nondrug therapies for hot flashes

exist, but their efficacy and extent of use are

largely unknown, and much of what evidence

exists is anecdotal. Natural remedies for menopausal symptoms include vitamins, garlic and herbs,

ginseng, biofeedback, diet and nutrition, and exercise.

For example, some women claim that vitamin E

gives them more energy and an improved sense of

well-being, and that it relieves hot flashes and

vaginal dryness. In fact, clinical study has demonstrated its effectiveness, both in its elemental form

and as derived from the diet. Reports also indicate

that other vitamins, including vitamins B and C, help

relieve menopausal symptoms (73,97). Garlic and

herbs, used in moderation, have been recommended

by some to treat symptoms; examples of effective

herbs include chamomile, catnip, hops, and passion

flower (73).
48 • The Menopause, Hormone Therapy, and Women’s Health

Ginseng, which is a root and a source of plant

estrogen, is the natural remedy most often mentioned for the relief of menopausal symptoms. It can

be taken in capsule form; as a tea, powder, or syrup;

or in the root form. Clinical research on ginseng is

limited, and much of the evidence for its effectiveness is anecdotal and historical in nature. No clinical

studies have been done to measure the effectiveness

of ginseng compared with a placebo, and its use for

the treatment of menopausal symptoms is neither

officially endorsed nor regulated by the FDA (97).

Biofeedback has been noted as a treatment for hot

flashes, because of its use in treating hypertension,

stress, and tension headaches, and its demonstrated

effectiveness in regulating body temperature. Little

research has been done, however, and little information is available to assess the extent of its use or its

effectiveness in relieving hot flashes. There are

minimal research data on the effect of exercise on the

alleviation of hot flashes, although one study

showed positive effects and a decrease in severity

with exercise (112). Whatever its effectiveness may

be in treating hot flashes, exercise is encouraged for

the prevention of bone loss and osteoporosis.

USE OF HORMONE THERAPY

AMONG MENOPAUSAL WOMEN

Although natural menopause does not necessarily

result in increased use of health care services (6),

segments of the medical community continue to

view it as a disease or as a disease-causing condition

requiring treatment. The belief of some physicians

that ET or CHT should always be prescribed at

menopause, combined with conflicting information

concerning the risks and benefits of hormone

therapy, has resulted in fluctuations over the past 30

years in the prescription of noncontraceptive hormonal products. These factors generate a number of

research issues pertaining to women’s use of

hormone therapy. Although examination of the use

of hormone therapy among menopausal women is

far from complete, investigators have shed some

light on several questions:

●

●

●

●

How prevalent is the use of hormone therapy at

menopause?

Who uses hormone therapy?

What factors affect a woman’s decision to use

hormone therapy?

Do women comply with prescribed regimens?

Why or why not?

The following sections describe what is known.

Prevalence of Use of Hormone Therapy

The lack of good data on the use of hormone

therapy is a major problem because it confuses

any interpretation of risks and benefits. If it is not

clear how many women are actually using such

therapy, projections of risks and benefits are

bound to be erroneous. There are no definitive

figures on the number of women who currently use

either ET or CHT; as a result, several studies have

employed trends in sales to estimate use. In 1985, for

example, it was observed that retail prescriptions of

noncontraceptive estrogens had increased steadily

between 1966 and 1975 (57). By 1976, however,

sales had dropped by about 30 percent after reports

of a link between estrogen and increased risk of

endometrial carcinoma; sales continued to decline

until 1980 (92). After 1980, noncontraceptive estrogen sales began increasing once again with the

discovery that adding progestin to estrogen therapy

offset the increased risk (92). As of 1980, lower

doses apparently were being used, and a trend

toward concurrent prescription of progestins was

being seen (57).

An analysis of the type of diagnoses associated

with the prescriptions dispensed revealed a number

of findings. These estimates offer some perspective

on the percentage of the population exposed to

noncontraceptive estrogen and progestin in 1983; it

must be recognized, however, that these figures

underestimate actual exposure levels when shortterm treatment is taken into consideration (57).

Findings include the following:

The estrogens were used primarily for menopauserelated conditions in women.

Virtually all of the estrogen prescriptions for

men were for treating prostate cancer in the

elderly (57).

A national picture of hormonal exposure is

difficult to piece together inasmuch as the number of

noncontraceptive estrogen and progestin prescriptions dispensed per capita varies according to

geographic location. For example, by the end of its

5-year project, the Massachusetts Women’s Health

Study found that 9.2 percent of the study population

was being treated with hormonal products (6). By

contrast, a study of a California community conducted in 1986-87 generated very different numbers.

In a telephone survey of 954 postmenopausal
Chapter 3—Treatment of Menopausal Symptoms and Prevention of Future Disease ● 49

women between the ages of 50 and 65 years, 32

percent reported estrogen use, and 6 percent of those

reporting estrogen use also reported use of progestin

(41). This higher usage on the West Coast ties in

with data showing that although 21 percent of the

U.S. population resides on the East Coast, past

studies have shown that only 12 percent of prescriptions for noncontraceptive estrogen are written there

(57).

All of these results conflict with findings in recent

surveys of physicians, however. These investigations showed that 75 to 95 percent of gynecologists

would prescribe estrogen therapy for most of their

patients. Estimates from pharmaceutical marketing

surveys, on the other hand, found a 43 percent use

rate among women living in the western portion of

the United States (41).

Users of Hormone Therapy

In addition to geographic variation in the number

of women using replacement therapy, researchers

have identified other usage trends. The California

community study noted earlier found no differences

between users and nonusers in their histories of high

cholesterol, diabetes, or heart problems. However,

women who used estrogen therapy were younger,

thinner, lived in smaller household units, and were

less likely to be widowed (41). The younger age of

hormone users may reflect a greater proportion of

recently menopausal women, as well as efforts to

control menopausal symptoms and decrease bone

density loss (41).

Another study examined the prevalence and

determinants of use of estrogen in 9,704 nonblack

women 65 years of age or older (mean age, 71.7).

These investigators found that 14 percent of the

women reported current use of oral estrogen, with 11

percent taking estrogen alone and 2.8 percent taking

estrogen with progestin. Hysterectomy was strongly

associated with the choice to use estrogen (hysterectomized women were five times more likely to have

taken estrogen and two times more likely to continue

using it for a long time) (16).

The finding of lower body weights among estrogen users may be partly attributable to increased

menopausal symptoms resulting from lower endogenous estrogen levels or to the awareness of

physicians of the increased risk for osteoporosis

among thinner women. The findings that estrogen

users are less likely to be widowed and that they

have fewer people living in their households maybe

associated with a greater level of health-careseeking behavior (41).

Women’s Decisionmaking

About Hormone Therapy

The discrepancy between the stated prescribing

philosophies of physicians and the actual use of

hormone therapy suggests that menopausal women

may be assuming the role of informed consumer

rather than accepting without question the treatments prescribed by their doctors. Preliminary

5-year data from the Massachusetts Women’s

Health Survey found that among patients receiving

hormone therapy for the first time, 20 to 30 percent

never filled their prescriptions because they were not

fully convinced of the benefits and safety of such

therapy (87). The participation of patients in decisionmaking has received considerable attention

within the medical arena. Not involving women in

the decision to take hormones can lead to women

carrying unfilled prescriptions (91).

Research to evaluate the decisionmaking of women

regarding hormone therapy has sought to identify

and systematically assess the factors that affect these

judgments (92). One study evaluated 252 women

from the general population between 45 and 55 years

of age; all had an intact uterus and were not currently

receiving hormone therapy (92). Because the study

predated the evidence linking the use of estrogen

with the possibility of decreased risk of cardiovascular disease, the only decisional factors considered

were the occurrence of hot flashes, risk of fractures

as a result of osteoporosis, risk of endometrial

cancer, and treatment regimen. Investigators discovered that the women fell into three main groups, each

of which represented a different approach to the

decision to use hormone therapy. The largest group

placed the most emphasis on relief of hot flashes and

agreed to receive the combined regimen. The

decision of women in a second, smaller group

incorporated considerations of both hot flashes and

the risk of osteoporotic fracture, as well as the risk

of endometrial cancer associated with use of the

unopposed estrogen regimen but not with use of the

opposed regimen. This group was more likely to take

the combined therapy. The third and smallest group

considered the relief of hot flashes and the risk of

osteoporotic fracture in making their decisions;

however, in sharp contrast to the other groups, they

were less likely to take the combined therapy,
50 • The Menopause, Hormone Therapy, and Women’s Health

possibly because of negative reactions to the resumption of cyclic bleeding (see figure 3-l).

This study concluded that the women studied

gave high priority to the short-term impact of

hormone therapy on their lives and did not make

their decisions based on the risks of morbidity

and mortality (92). In effect, they afforded greater

weight to considerations of quality of life over

quantity of life. The women in the study also

reported that they felt disenfranchised from the

health care system; they contended that providers

did not listen to them and that they felt they had had

inadequate information on which to base a decision

concerning hormone therapy (91).

Compliance With Replacement Regimens

Compliance obviously becomes a consideration

for those women who have made the decision to use

either ET or CHT. Rates of long-term compliance

are difficult to calculate, but at least some studies

have shown that most women who are receiving

oral therapy take their medication only sporadically. Those who discontinue treatment generally do

so because of the fear of endometrial cancer,

although unwanted side effects may also play a role

in their decision (87). Data on 301 postmenopausal

women receiving various forms of estrogen revealed

a compliance rate of only 30 percent, although those

who received combined therapy adhered more

closely to their regimens over the years than did

women who were receiving other forms. Further

research to develop regimens that will decrease side

effects, especially bleeding, may aid compliance

(87).

MENOPAUSE CLINICS

The terms women’s health center and menopause

clinic are used to market a wide range of medical

facilities and services. Women’s health centers,

including hospital-based women’s health centers,

office-based physician practices, government health

departments, and independent clinics, serve the

medical needs of women, and some target midlife

and older women by offering menopause programs.

Many centers and clinics specialize in obstetrics and

gynecology and provide few services beyond routine

care; others are more comprehensive, offering some

combination of education, referral services, diagnostic services, support groups, and clinical care,

including primary care, and mental health services

(61,68); still others additionally conduct research.

Figure 3-l—Women’s Use of Information Regarding

Hormone Therapy

Standardized regression weights

0.8 I

n

0.6 II I I

-0.61 I

Group) I Group II Group Ill Group IV

n ■ i20

n Hot flashes

= Cancer--

estrogen

only

n = 83 n ■ “ 4 0 n ■ “ 9

Factor key

E%ZZ Osteoporosis ~ C%;~;~;\

= Treatment progestin

SOURCE: M. Rothert, D. Rovner, M. Holmes, et al., “Women’s Use of

Information Regarding Hormone Replacement Therapy,” Research in Nursing and Health 13:355-366, 1990.

The services vary widely and may be no different

from those provided by the same establishment

before it was renamed or identified by the words

“women’s health center’ or ‘‘menopause clinic.”

In part, the lack of definition of menopause clinics

and related services has resulted in many permutations of such facilities in the United States and no

reliable source of information to determine the

overall number of centers and clinics or to characterize them on the continuum between comprehensive

centers offering truly specialized services and centers that are simply using the term as a marketing

tool (11 1). Such clinics may be a uniquely Western

phenomenon; as box 3-B describes, women in

Eastern cultures are less likely to seek treatment for

menopausal symptoms. This discussion focuses on

the established, better organized menopause clinics

that comprise both hospital-based and independent

facilities and that provide a multidisciplinary approach to women’s health.

One of the main benefits that patients and doctors

attribute to such clinics is that complete, coordinated

medical care is available in one facility. In one

appointment, in one place, a woman can expect a

complete medical workup, basic diagnostic tests,

advice and education about midlife issues (particularly hormone therapy), and, if she desires, nutritional, exercise, and psychological counseling. Many

women find the menopause clinic an attractive
Chapter 3--Treatment of Menopausal Symptoms and Prevention of Future Disease • 51

Box 3-B-Cultural Variations in the Presentation and Treatment of the Menopause

To date, very little cross-cultural research has been conducted on women’s experience of the menopause.

Although many gynecologists recognize that the interplay between organic changes and cultural perspective

influences a woman’s experience, nonmedically oriented research concerning the menopause is severely limited.

In 1976, the International Menopause Society was established to provide a forum for dialogue across disciplines,

as well as cultures, concerning the menopause. Results from cross-cultural, cross-disciplinary studies provide an

interesting comparison for evaluating the experiences of American women. Some of these findings appear below.

Little variation in age at menopause--around 50 years of age-was found in a study of seven Asian

countries: South Korea Taiwan (Republic of China), Hong Kong, the Philippines, Malaysia, Singapore, and

Indonesia. Although age at menopause in this study was similar to findings regarding age at menopause in

Western cultures, the study reported less severe symptoms than have been found in similar research

conducted in the West.

Of the menopausal Taiwanese women studied, 69 percent reported mild symptoms, only 32 percent

consulted doctors regarding menopausal symptoms, and of these doctors, only 12 percent prescribed

medication, primarily tranquilizers.

In Malaysia of 400 menopausal women interviewed, 89 percent rated their health as good, and only 20

percent sought medical care for symptoms. Of those seeking treatment, 84 percent were prescribed

medication; however, only 47 percent complied with the prescribed regimen.

A study in the Philippines interviewed 500 women, aged 40 to 55, and found that 67 percent rated their health

as good and 31 percent stated that they were seeking medical treatment for climacteric symptoms,

Investigators saw no apparent correlation between health rating or treatment seeking and the individual’s

ethnic background, income, or education level. Of those seeking medical treatment, 86 percent received

prescriptions for medication, primarily tranquilizers; of those, 52 percent complied with the treatment that

was prescribed.

Among Pakistani women, researchers found classical climacteric symptoms at least twice as frequently

among affluent women as among poor women. In addition, affluent women were more likely to seek medical

care for climacteric symptoms.

Preliminary data have been reported from research in Thailand concerning the perception of the menopause

among psychiatric personnel and middle-aged women. The data indicate that Thais regard any anomalous

or inappropriate behavior by women as a sign of the menopause despite the fact that women between the

ages of 40 and 55 present for treatment of psychiatric problems less frequently than any other age group.

Research in Indonesia revealed variations in age and severity of symptoms among educated, uneducated,

rural, and urban women. The study was conducted in Central- Java and in the less developed, less

Westernized Minangkabau culture of West Sumatra. Investigators found that the average age at menopause

for urban, educated Central Javanese women was 50.2 years--roughly equivalent to that of American and

European women. But rural and less educated Central Javanese women experienced menopause on average

between the ages of 46 and 47; Minangkabau women experienced it on average between the ages of 47 and

48. The study also found that urban, educated Central Javanese women underwent “the same types of

stresses and had the same health care and diet as European women. ” In contrast to the number of women

in the United States and Europe who report moderate (75 to 85 percent) or severe (10 percent) vasomotor

symptoms (i.e., hot flashes), approximately 32 percent of Minangkabau and 22 percent of Central Javanese

women report such symptoms.

SOURCES: Adapted from the proceedings of the Sixth International Congress on the Menopause, Bangkok, Thailand, Oct. 29 to Nov. 2, 1990

(New Jersey: Parthenon 1990). Specifically, M. Boulet, “The Menopause and the Climacteric in Seven Asian Countries”; C.

Chirawatkul “Perception of the Menopause Among Psychiatric Personnel and Middle-Aged Women in KhonKaean"; JR.

Jalbuena “Menopause Among Filipino Women”; C.-H. Liu “Medical Care-Seeking Behaviour Among Climacteric Women in

Taiwan”; N.M, Nasri Ismail, “A Study on Menaopausea in Seven Far-Eastern Countries-Malaysia”; S. Watsi “Age and

Symptoms of Menopause in a Pakistan Community”; also M. Flint and R.S. Samil, “Cultural and Subcultural Meanings of the

Menopause,” Annals of the New York Academy of Sciences, vol. 592, Multidisciplinary Perspectives on Menopause, M. Flint, F.

Kronenberg, and W. Utian (eds.) (New York, NY: New York Academy of Sciences, 1990), pp. 134-148.
52 ● The Menopause, Hormone Therapy, and Women’s Health

option for obtaining comprehensive health care and

assessment of health risks. In addition, such clinics

can foster continuity of care and might improve

patient compliance, especially with recommended

diagnostic care (e.g., mammography) (72).

Clinical Care and Referral

Wellness achieved through health promotion and

disease prevention is one of the goals of menopause

clinics. Doctors who approach the health of women

at midlife from a comprehensive perspective speak

of treating women in terms of physical, mental, and

environmental” health. This kind of treatment is best

rendered through a multidisciplinary approach to the

problems associated both with menopause and aging

(78). Because women’s health risks for many

conditions-cancer, cardiovascular disease, stroke—

increase with age, comprehensive health care, including early screening for disease, is advocated by

many doctors.

Menopause clinics usually employ gynecologists

or internists (at least on apart-time basis) to provide

basic clinical care. Sometimes a woman’s primary

care physician is on the staff of the clinic; alternatively, a woman maybe sent by her own doctor to a

menopause clinic for comprehensive attention and

evaluation regarding menopause. The extent of care

offered on site varies but usually includes a medical

history; a routine physical examination, including

pelvic exam, pap smear, and breast exam; diagnostic

tests, including blood work, x-rays, mammography,

and osteoporosis screening; and a decision on the

use of hormone therapy. The comprehensive approach to basic clinical care also involves an

assessment of health needs beyond the basic physical exam: nutrition and exercise, cardiovascular

fitness, bone densitometry, and mental health, especially psychological care and career counseling.

Depending on the findings of the basic exam,

clinical care beyond the basic, primary level may be

indicated (37,110).

Referral to outside specialists is one of the

services offered by menopause clinics. Because

many clinics are based in hospitals, patients may

have access to a range of specialists, including

cardiologists, endocrinologists, surgeons, radiologists, urologists, psychologists, physical therapists,

and specialists in cancer and osteoporosis who can

be consulted for specific health problems (39,40). In

addition, patients may be referred to nutritionists and

exercise physiologists who can help establish diet

and exercise routines to promote health and wellness. Other common medical offerings available at

the clinic or by referral include urodynamics training

(to deal with urinary incontinence) and sex therapy

(78).

Preventive medicine and wellness approaches, for

the most part, are not reimbursed by insurance (88).

Many of the services offered at menopause clinics,

including most of the advanced-technology bone

densitometry tests for osteoporosis, cardiovascular

fitness testing, nutrition counseling, and individual

counseling and education, often are not covered by

insurance plans. These services are optional but are

often encouraged. Other services such as mammography, basic blood work, the physical examination,

and pap smears may or may not be covered. Despite

their apparent benefits, menopause clinics remain inaccessible to a majority of the population

because a large proportion of the services they

offer are elective in nature and are not reimbursed.

Questions have been raised about the routine use

of high-technology equipment and diagnostic tests,

especially bone densitometry to determine bone

loss, to inform the decision to prescribe long-term

hormone therapy. The use of bone densitometry is

certainly indicated for women with high risk factors

for osteoporosis, and it can be used as part of the

decisionmaking process of whether to prescribe

estrogen. However, what constitutes normal bone

mass and whether bone densitometry can predict

future hip fractures are debatable (22).

PATIENT AND PROFESSIONAL

EDUCATION

Patients and health care professionals alike tend to

know relatively little about the menopause and the

risks of conditions that may be associated with it

(39,40). Indeed, there is no consensus within the

medical community about the definition of the

menopause and the risks and benefits associated

with hormone therapy, and little information about

the natural progression through the menopause and

the years that follow. Moreover, there is no agreement on what constitutes a ‘‘normal’ menopause

and few conclusive research findings on the normal

hormonal changes associated with aging.
Chapter 3--Treatment of Menopausal Symptoms and Prevention of Future Disease ● 53

Figure 3-2-Percentage of Women Who Identified Consequences of Osteoporosis

Permanent disability

I Hip fracture I

I Curvature of the spine

I

18%

20%

Bones fracture easily 14%

Restricts mobility/crippling 13%

Loss of height 7%

I Death due to injury I 6%

I Don’t know 2 4%

SOURCE: A Gallup survey of 760 women, aged 45 to 75, sponsored by the National Osteoporosis Foundation. The

survey has a margin of error of +/- 4 percentage points.

Figure 3-3-Percentage of Women Who Identified Risk Factors for Osteoporosis

Caucasian

I Slender build

I Family history

I

27%

240/.

39 ”/0

Early menopause I 4990

Poor diet (lack of calcium) I

. 810/0

Lack of exercise 720/o

I Smoking

I Alcohol consumption

I

5 2%

4 0 %

SOURCE: A Gallup survey of 760 women, aged 45 to 75, sponsored by the National Osteoporosis Foundation. The

survey has a margin of error of +/– 4 percentage points.

One of the most pressing concerns of many

midlife women is that they do not know where to

turn for understandable, high-quality menopause

counseling. A recent survey revealed that very few

women could identify the risk factors for osteoporosis and even fewer could name its consequences (see

figures 3-2 and 3-3). Many women do not understand the complex biological changes that are

associated with the menopause and find themselves

without the basic facts needed to ask questions. The

FDA has recently corroborated this perception by

acknowledging that patients are reluctant to ask their

doctors or pharmacists questions about medication

and generally do not receive information unless they

explicitly ask for it. The FDA announced that it will

begin to address this issue by producing informational materials to be given to patients with their

prescriptions and will encourage doctors and phar-
54 ● The Menopause, Hormone Therapy, and Women’s Health

macists to inform patients about all aspects of drug

use (62).

Education of both patients and doctors is important. Individual practitioners, menopause clinics,

community health centers, and hospitals provide a

variety of educational materials and programs and

often sponsor group sessions and community outreach seminars. Physicians can participate in continuing medical education to learn more about the

menopause and hormone therapy. A wide range of

topics are included in education campaigns geared

toward both midlife women and physicians, including an explanation of the menopause and potential

symptoms; changes in the risks of cancer, heart

disease, and osteoporosis that occur after the menopause and with increasing age; the pros and cons of

hormone therapy; and the role of diet, nutrition, and

exercise programs in health promotion and disease

prevention (39,40,88).

The menopause clinic at the University of California, San Diego, is an example of a comprehensive

education program. Patients attend a one-time,

4-hour clinic that includes group discussions and

individual counseling; they also complete a medical

history, symptom checklist, and self-assessment

instrument, and are given a bibliography of menopause literature, a diary to record symptoms and

behavior, a monthly record sheet, and access to the

‘‘Hot Flash’ telephone number for further questions

and contact with clinic staff. Unfortunately, most

women nearing the age of menopause do not have

access to such a facility or to this kind of educational

program.

The information most readily available to patients

is provided by drug manufacturers. Some companies

insert educational material in the advertising copy

for their products or make it available separately.

Such advertising campaigns provide information to

consumers about the menopause and estrogen therapy—at the same time that they promote the use of

specific products. Two examples include CIBA’s

advertisements for Estraderm and Wyeth-Ayerst’s

ads for Premarin. CIBA provides a menopause

information packet free of charge to customers,

which can be obtained by calling a toll-free number

or by mailing in a coupon from the advertisement.

The kit includes a letter explaining the menopause

and estrogen therapy; a question-and-answer booklet about the Estraderm transdermal system, a patient

package insert and a flier detailing the use of

Estraderm, a booklet about the changes a woman can

expect at midlife, and a placebo Estraderm patch.

Wyeth-Ayerst has mounted an educational advertising campaign for Premarin and osteoporosis.

Again, a toll-free number is given in the advertisement for consumers to call for information, which

includes a pamphlet entitled “What You Should

Know About Estrogen Deficiency and Osteoporosis,’ a fact sheet from the National Osteoporosis

Foundation, and a personalized letter explaining

Premarin’s role in preventing osteoporosis. Also

included is a form that entitles consumers to a free

exercise videotape, courtesy of Wyeth-Ayerst, following a consultation with their doctor. Although

this information is accurate, many women choose to

seek other sources of information, free from drug

company influence (see box 3-C). Consistent and

unbiased information about the menopause and the

risks and benefits of hormone therapy designed for

the layperson needs to be more widely dispersed.

SUMMARY

Estrogen therapy and, increasingly, combined

hormone therapy remain the treatments of choice for

physicians who treat women seeking relief from the

acute symptoms of the menopause, although some

women have found relief through nonhormonal and

nondrug therapies and, in fact, the majority of

women do not seek treatment at all. Estrogen has

been found to slow bone loss that could lead to

increased risk for osteoporosis and subsequent

fractures and appears to have a protective effect

against cardiovascular disease. However, even the

short-term use of estrogen increases a woman’s risk

for endometrial cancer and possibly breast cancer;

the risk becomes still greater with long-term use,

especially when estrogen is used for more than 15

years. The addition of a progestin greatly reduces the

risk of endometrial cancer. The effects of progestin

on the cardioprotective aspect of estrogen have yet

to be determined. In addition, the long-term effects

of progestin on the endometrium and breast are

unknown. Women who discontinue use of hormone

therapy after a few years may experience a “rebound

effect,’ or return of symptoms, and bone loss again

accelerates. These competing risks and benefits pose

a dilemma for women and a challenge for their

physicians.

Convincing research into alternatives to hormone

therapy is limited. The true contributions to cardio-
Chapter 3-Treatment of Menopausal Symptoms and Prevention of Future Disease ● 55

Box 3-C—Menopause and Hormone Therapy Educational Materials

The most readily available information regarding menopause and hormone therapyis produced and distributed

by drug companies, but there are also many other sources of information of which many women and their physicians

may be unaware. Educational and informational materials designed for both those in the medical community and

laypersons are available from a variety of sources including books, periodicals, private newsletters, and publications

from national associations and government agencies.

A search of the Library of Congress’s book collection resulted in 148 titles related to the menopause, and the

1991-92 edition of the reference book Books in Print lists 22 titles under “menopause” and others under estrogen

and hormones. Many books can be found at the public library or in bookstores, often in the health section.

Them are a variety of newsletters written about health and aging issues, some of which include information

related to the health of midlife and older women and others that are devoted exclusively to this population. Examples

of the latter include A Friend Indeed (for women in the prime of life), Box 515, Place du Parc Station, Montreal,

Canada, H2W 2P1; Menopause News, 2074 Union Street, Suite 10, San Francisco, CA 94123; Hot Flash

(Newsletter for Midlife and Older Women), National Action Forum for Midlife Older Women, c/o Dr. Jane Porcino,

Box 816, Stony Brook, NY 11790-0609; and Health Facts, Center for Medical Consumers, 237 Thompson Street,

New York NY 10012.

Government agencies and private associations are other sources of information and educational material

related to the menopause, the aging process, and concerns of midlife and older women. The following are some of

the groups that provide information either free of charge or for a small fee: National Women’s Health Network,

American Association of Retired Persons, American College of Obstetrics and Gynecology, National Institute on

Aging, National Institutes of Health, National Council on Patient Information and Education, U.S. Pharmacopeial

Convention, and the American Medical Association.

Despite the availability of these resources, more unbiased information explaining the menopause and outlining

the risks and benefits of hormone therapy needs to be developed and made more widely available.

SOURCE: Office of Technology Assessment 1992.

vascular disease and osteoporosis of such factors as ican College of Obstetricians and Gynecologists,

lifestyle, socioeconomic status, race, and genetic

predisposition deserve further investigation (see ch.

5). Women are given hormone therapy for a variety

of reasons but often do not comply with treatment.

Such noncompliance must be considered when risks

and benefits are calculated and prescribing policy is

determined. Increasingly, menopause clinics and

women’s health centers provide services to help

women make decisions about treatment. The course

of treatment, its utility, and its cost ultimately

influence not only outcomes but who receives care.

1.

2.

3.

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Chapter 4

Hormone Products

and Prescription
Contents

Page

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

MARKET INFORMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Labeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63

Generics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

PRESCRIBING PRACTICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

Estrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Progestins and Combined Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

PROMOTION OF HORMONE THERAPY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71

CHAPTER 4 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 71

Boxes

Box Page

4-A. Bioequivalence for Generic Conjugated Estrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

4-B. Prescribing Practices in California . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .69

Tables

Table Page

4-1. Estrogens and Progestins Used for Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

4-2. New Prescriptions (Rx) of Premarin by Specialty, 1990 . . . . . . . . . . . . . . . . . . .......68

4-3. Premarin Prescriptions (Rx), 1990 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .68

4-4. Estrogen Therapy by Geographic Region, January-December 1991...............70
Chapter 4

Hormone Products and Prescription

INTRODUCTION

Doctors can choose from a variety of different

brand-name products, drug formulations and dosages, and possible treatment regimens when they

prescribe estrogen therapy (ET) or combined

hormone (i.e., estrogen combined with a progestin)

therapy (CHT) for postmenopausal women. In the

United States, nearly 20 estrogen products are on the

market and approved for use in treating menopausal

symptoms; two products have the additional indication of prevention of osteoporosis. There are also

progestin products that, although not officially

approved for use in CHT, are commonly prescribed

for it. A number of pharmaceutical manufacturers

compete in the estrogen and progestin marketplace

and conduct research and development on new

formulations, routes of administration, and combination products. Until 1991, when the Food and

Drug Administration (FDA) withdrew its approval,

several generic formulations of conjugated estrogens were also on the market.

The effects of long-term use of hormone therapy

for the prevention of osteoporosis and cardiovascular disease have received much attention in recent

years. Drug labeling for estrogen has been changed

to include the osteoporosis indication, and the FDA

is currently considering adding cardiovascular disease information to estrogen labeling. Doctors

employ estrogen and progestin in many different

ways; e.g., they may prescribe the use of unopposed

estrogen or combination forms (cyclic, sequential, or

continuous/combined) of both products. There is

little agreement on the optimal prescription for CHT,

although for women with intact uteri, some regimen

of continuous estrogen combined with progestin is

the approach favored by most physicians.

This chapter considers information relevant to the

commercial market for hormone therapy, the products that are used, and promotion practices. It

addresses the labeling of approved estrogen and

progestin products and discusses efforts that have

been made to change the labeling to include

indications for long-term preventive use. The chapter also describes the attempts to gain approval for

generic estrogens and discusses prescribing information.

MARKET INFORMATION

Three classes of estrogens are used for hormone

therapy: natural estrogens, conjugated equine estrogens, and synthetic estrogens. Wyeth-Ayerst’s Premarin, the most commonly prescribed estrogen

product, is a conjugated estrogen derived from the

urine of pregnant horses; in 1990 it was the fourth

most prescribed drug in the United States (13).

Premarin was approved by the FDA in 1942 for the

treatment of menopausal symptoms. Because it was

approved before the 1962 amendments to the Food,

Drug, and Cosmetic Act, Wyeth-Ayerst was required to prove only safety and not efficacy. The

product was later evaluated under the Drug Efficacy

Study Implementation (DESI) program and judged

effective in 1972 (3).

Since the introduction of Premarin the FDA has

approved other estrogens, both natural and synthetic, for the treatment of menopausal symptoms,

and, in the United States, there are currently 11

manufacturers of estrogen products and 5 manufacturers of progestin products used in hormone therapy

(see table 4-l). CIBA’s Estraderm transdermal

estrogen patch, an alternative to daily oral administration, approved by the FDA in 1986, is the newest

estrogen product available. According to senior

managers at Wyeth-Ayerst, total sales of estrogen

products were close to $460 million in 1990, and

Premarin held a 68 percent market share.

Three different progestins are used in CHT:

medroxyprogesterone acetate, norethindrone, and

norethindrone acetate. Upjohn’s Provera, amedroxyprogesterone acetate, is the most commonly prescribed progestin for CHT. Provera has been on the

market since 1959, although its use in CHT began

much later.

Labeling

Title 21 of the U.S. Code governs drug labeling

and defines a label as any display of written, printed,

or graphic material on or accompanying a drug,

including the actual label, the package insert, and

any other material that provides information about

the drug (21 U.S.C. Sec. 321 [k][m]). The FDA

requires that the following information appear on the

package label or package insert: the name and place

-63–
64 ● The Menopause, Hormone Therapy, and Women’s Health

I

‘* . w

Photo credit: National Institutes of Health

Conjugated estrogen, the most widely prescribed drug for estrogen therapy, is derived from the urine of pregnant mares.

of business of the manufacturer, packer, or distributor; a description of the drug, including, at a

minimum, the proprietary name and other established names of the drug, the type of dosage form

and route of administration, qualitative and quantitative ingredient information, pharmacological or

therapeutic class of the drug, and chemical name and

structural formula. The label or insert must also

contain a concise factual summary of the clinical

pharmacology and actions of the drug in humans,

information on the indications and usage of the drug,

contraindications to use, warnings that explain

adverse reactions and potential hazards of use,

precautions for use and information for patients, an

expiration date, an identifying lot or control number,

and information about the quantity of the container

(21 CFR 201.1, 201.10, 201.17, 201.18, 201.50,

201.56,201.57,21 1.137).

Once a drug is approved by the FDA, doctors can

prescribe it for uses other than those named in the

labeling, providing the decision is based on sound

scientific evidence or medical opinion. The FDA is

responsible for ensuring that a drug manufacturer

has demonstrated safety and efficacy for its product;

it is not within the FDA’s jurisdiction to dictate to

physicians the proper practice of medicine.

Estrogens

Labeling for all estrogens approved for use in

hormone therapy includes a boxed warning stating

that estrogens “have been reported to increase the

risk of endometrial cancer’ and ‘should not be used

during pregnancy.’ The FDA-approved indications

for use of estrogen products, which are listed in the

1991 Physician’s Desk Reference (PDR), are “moderate to severe vasomotor symptoms associated with

menopause, female hypogonadism, palliative therapy for advanced prostate cancer, palliative therapy

for breast cancer in select circumstances, atrophic

vaginitis, kraurosis vulvae, primary ovarian failure,

female castration, and atrophic urethritis.” Both

Premarin and Estraderm are approved for the prevention of osteoporosis, and Premarin is also approved for the treatment of this condition (8).

The PDR explicitly states that “there is no

adequate evidence that estrogens are effective for

nervous symptoms or depression which might occur

during menopause and they should not be used to

treat these conditions.” Several estrogen products,

including the Premarin derivatives PMB-200 and

PMB-400, and Menrium, contain tranquilizing or

antianxiety agents. PMB-200 and PMB-400 are

indicated for treatment of vasomotor symptoms and

associated tension and anxiety but only when

estrogens alone have not alleviated symptoms.

Epidemiologic data have suggested that the use of

unopposed conjugated estrogens by women who

have undergone hysterectomies results in cardioprotective effects and a reduction in cardiovascular

mortality by as much as 50 percent (21). In 1990, the

FDA’s Fertility and Maternal Health Drugs Advi1
Chapter 4--Hormone Products and Prescription • 65

Table 4-l—Estrogens and Progestins Used for Hormone Therapy

Brand name Generic name Manufacturer

Estrogens

Estinyl . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Estrace . . . . . . . . . . . . . . . . . . . . . . . . . . .

Estraderm . . . . . . . . . . . . . . . . . . . . . . . .

Estratab . . . . . . . . . . . . . . . . . . . . . . . . . .

Estratest . . . . . . . . . . . . . . . . . . . . . . . . . .

Estratest H.S. . . . . . . . . . . . . . . . . . . . . .

Estrovis . . . . . . . . . . . . . . . . . . . . . . . . . . .

Menrium . . . . . . . . . . . . . . . . . . . . . . . . . .

Ogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Premarin . . . . . . . . . . . . . . . . . . . . . . . . .

Premarin with methyltestosterone..

PMB-200, PMB-400 . . . . . . . . . . . . . . .

TACE . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Diethylstilbestrol . . . . . . . . . . . . . . . . . .

Menest . . . . . . . . . . . . . . . . . . . . . . . . . . .

Feminone . . . . . . . . . . . . . . . . . . . . . . . . .

Progestins

Provera . . . . . . . . . . . . . . . . . . . . . . . . . . .

Amen . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Curretab . . . . . . . . . . . . . . . . . . . . . . . . . .

Aygestin . . . . . . . . . . . . . . . . . . . . . . . . . .

Norlulate . . . . . . . . . . . . . . . . . . . . . . . . . .

Norlutin . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ethinyl estradiol

Micronized estradiol

Transdermal 17-estradiol

Esterified estrogen

Esterif ied estrogen with

methyltestosterone

Half-strength Estratest

Quinestrol

Esterified estrogen plus

chlordiazepoxide (antianxiety drug)

Estropipate

Conjugated equine estrogens

Conjugated equine estrogens

plus methyltestosterone

Premarin plus meprobomate

(tranquilizing agent)

Chlororianisene

DES, synthetic estrogen

Esterified estrogen

Esterified estrogen

Medroxyprogesterone acetate

Medroxyprogesterone acetate

Norethindrone acetate

Norethindrone acetate

Norethindrone acetate

Norethindrone

Schering

Mead Johnson Laboratories

CIBA

Reid-Rowell

Reid-Rowell

Reid- Rowell

Parke-Davis

Hoffman-La Roche

Abbott Laboratories

Wyeth-Ayerst

Wyeth-Ayerst

Wyeth-Ayerst

Marion Merrell Dow

Eli Lilly

Smith Kline Beecham

Upjohn

Upjohn

Carnick Laboratories, Inc.

Reid-Rowell

Wyeth-Ayerst

Parke-Davis

Parke-Davis

SOURCE: Office of Technology Assessment, 1992.

sory Committee recommended that the labeling for

conjugated estrogens be changed to reflect its

potential cardiovascular benefits; it also strongly

suggested that more studies be conducted, including

a secondary intervention trial for women who have

experienced cardiovascular disease and a large

cohort study to evaluate subgroups of women at

particular risk for developing cardiovascular disease. The decision by the advisory committee to

recommend the change in the labeling of conjugated

estrogens was nearly unanimous, with one committee member abstaining from the vote. Despite

several substantial gaps in knowledge (e.g., the lack

of long-term data from randomized clinical trials, a

lack of consensus on and knowledge about optimal

dosages and regimens and which subgroups of

women are most likely to benefit from its use), the

medical community generally agrees that evidence

of unopposed estrogen’s cardioprotective effects

support general recommendations for its use (20).

Wyeth-Ayerst, the manufacturer of Premarin, is

actively seeking this labeling change, but the FDA

is still evaluating the submitted data to determine

Premarin’s cardioprotective effects and has yet to

make changes in the labeling (7,17).

The PDR lists several absolute contraindications

to estrogen use: ‘‘known or suspected breast cancer,

estrogen-dependent neoplasia, pregnancy, and undiagosed abnormal genital bleeding” (16). Thromboembolitic disorders or a history of such disorders

associated with estrogen use has historically been

identified as contraindications, but advances in

medical knowledge now allow women with these

conditions to use estrogen (14). In addition, many

relative contraindications and side effects are taken

into consideration in the decision to prescribe

estrogens.

Progestins

The labeled indications for progestins are “secondary amenorrhea, abnormal uterine bleeding related to hormonal imbalance when there is no

organic pathology present (e.g., fibroids or uterine

cancer), and endometriosis. ” Contraindications are

“thrombophlebitis, thromboembolic disorders, cerebral apoplexy (or a past history), markedly impaired liver function, liver disease, breast cancer,

undiagnosed vaginal bleeding, missed abortion, and

use as a diagnostic pregnancy test. ’ No progestin

has been approved for use in treating meno-
66 . The Menopause, Hormone Therapy, and Women’s Health

I

pausal symptoms or in conjunction with estrogen

for such treatment, although it is standard

practice to prescribe progestin together with

estrogen for women with an intact uterus to

protect the endometrium. In addition, progestin is

sometimes prescribed alone for the treatment of hot

flashes when estrogen cannot be used (see the later

section on prescribing practices).

Combined Hormone Therapy

The PDR discusses the use of progestins to

counter the increased risk of endometrial hyperplasia associated with the use of unopposed estrogen.

Under a section entitled “Precautions” in the

labeling for both estrogen and progestin, the PDR

addresses concomitant estrogen and progestin use:

Studies of the addition of a progestin for 7 or more

days of a cycle of estrogen administration have

reported a lower incidence of endometrial hyperplasia. Morphological and biochemical studies of the

endometrium suggest that 12 to 13 days of progestin

are needed to provide maximal maturation of the

endometrium and to eliminate any hyperplastic

changes. Whether this will provide protection from

endometrial carcinoma has not been clearly established. There are possible additional risks that may

be associated with the inclusion of progestin in

estrogen replacement regimens. The potential risks

include adverse effects on carbohydrate and lipid

metabolism. The choice of progestin and dosage

may be important in minimizing these adverse

effects.

A great deal of controversy has arisen over

whether to change the labeling to reflect a recommendation for the use of CHT for women with intact

uteri. The use of CHT reduces the risk of endometrial hyperplasia that occurs with unopposed estrogen use, but other risk-benefit comparisons-for

osteoporosis, breast cancer, and cardiovascular disease--

are less conclusive and more controversial. The use

of CHT was the subject of an FDA advisory

committee (the Fertility and Maternal Health Drugs

Advisory Committee) meeting in June 1991. The

FDA sought information from the committee on

several topics: the associations between the use of

estrogens and progestins and the risk of endometrial

cancer, breast cancer, osteoporosis, and cardiovascular disease; the effects on those risks of the use of

specific estrogens and progestins when given at

various dosages and in various regimens; and the

risks and benefits of ET compared with CHT. The

committee agreed that estrogen labeling should

be changed to more positively endorse the recommended use of CHT for the treatment of menopausal symptoms and the prevention of osteoporosis (when indicated) for women with intact

uteri. The committee concluded, however, that

the data were inadequate to identify the effect of

added progestin on the risk of breast cancer or on

cardiovascular protection, or to determine how

specific estrogen and progestin compounds, in

various dosages and regimens, affect the riskbenefit balance. Despite the lack of data on

long-term progestin use, the committee also recommended that the FDA consider new drug applications for CHT compounds, should they be submitted.

Generics

The FDA, in the spring of 1991, withdrew

approval for generic conjugated estrogens on the

basis of demonstrated bioinequivalence (5,6). The

definition of bioequivalence, which is the basis for

approval of generics, requires that the generic

product include the same therapeutic ingredient and

that its rate and extent of absorption be the same as

the innovative product—in this case, Premarin.

Information available only after approval of the

generic conjugated estrogens showed different rates

of absorption for several of them, and concern about

the therapeutic significance of these differences led

the FDA to reconsider its original approval decision

(l). The FDA issued a revised guidance (i.e.,

guidelines for conducting studies to show bioequivalence) for the approval of generic conjugated

estrogens in August 1991 (see box 4-A). Currently,

several manufacturers are seeking approval for

generic equivalents of Premarin, but the FDA has

estimated that it will be several years before any

products will be on the market (4).

PRESCRIBING PRACTICES

Obstetricians and gynecologists write the largest

percentage of prescriptions for estrogens and progestins used in hormone therapy, but many other

specialists care for midlife women and also prescribe

these hormones. According to data collected by

Wyeth-Ayerst, in terms of percentage of Premarin

prescriptions written, obstetricians and gynecologists are followed by family practitioners, internists,

general practitioners, and other specialists (see table

4-2).
Chapter 4--Hormone Products and Prescription • 67

Box 4-A—Bioequivalence for Generic Conjugated Estrogens

The Food and Drug Administration’s (FDA) Generic Drugs Advisory Committee made recommendations in

early 1991 concerning bioequivalence testing and approval of generic conjugated estrogen products. The

comparison product is Premarin, and part of what makes demonstrating bioequivalence to Premarin so difficult is

that Premarin itself is quite complex. Premarin is derived from the urine of pregnant mares and has 10 components:

estrone sulfate, equilin sulfate, 17-a dihydroequilin, 17-ß dihydroequilin, 17-a estradiol, 17-ß estradiol, delta (8,9)

dehydroestrone, equilenin, 17-a dihydroequilenin, and 17-ß dihydroequilenin. Nine of these components are

currently commercially available, but delta (8,9) dehydroestrone is not. Premarin contains about 50 to 60 percent

estrone sulfates, 22.5 to 32.5 percent sodium equilin sulfate, and 7.5 to 20 percent unspecified conjugated estrogens.

The United States Pharmacopoeia (USP), the legal standard for drugs in the United States, specifies properties,

action, use, dosages, strength, and purity. Conjugated estrogens are derived, either in whole or in part, from equine

urine, or they may be produced synthetically using estrone and equilin. Currently, the USP requires only two

compounds to be present in a conjugated estrogen product: sodium estrone sulfate and sodium equilin sulfate.

Additionally, such products “may contain other conjugated estrogenic substances of the type excreted by pregnant

mares.” In February 1991, the FDA Generic Drugs Committee recommended that changes be made to the USP

monograph for conjugated estrogens to make the required contents more specific, which would result in generic

products (when approved) that are closer in composition to Premarin.

The committee recommended that the 10 components of Premarin be divided into several categories:

● therapeutic moieties, which independently demonstrate therapeutic activity and are required components;

. concomitant components, which are present in a substantial amount in the innovator product but for which

independent therapeutic activity has not been established-these components are required to be present in

quantities that fall within set upper and lower limits;

● components requiring a limit test, Which allows no more than a specific percentage, which can be zero, to

be present; and

● signal impurities, which must not exceed a set upper limit but which may be zero, provided the product is

adequately stable.

The committee proposed that the generic product contain two therapeutic moieties present in Premarin--estrone

sulfate and equilin sulfate; three concomitant components—17-a dihydroequilin, 17-ß dihydroequilin, and 17-a

estradiol; two limit tests for 17-ß estradiol and delta (8,9) dihydroestrone; and signal impurities for equilenin, 17-a

dihydroequilenin, and 17-ß dihydroequilenin. The other five components of Premarin are not required in generic

products. The USP is currently revising its monograph for conjugated estrogen tablets and considering a redefinition

of content requirements. The FDA issued a revised guidance for bioequivalence studies in August 1991, and several

companies are pursuing approval of generic products.

SOURCES: D.B. Burlington Deputy Director, Office of Drug Evaluation II, Center for Drug Evaluation and Research Food and Drug

Administratiom , testimony before the Subcommittee on Aging, Committee on Labor and Human Resources, U.S. Senate, Apr. 19,

1991; Food and Drug Administratiou Guidance, Conjugated Estrogen Tablets, August 1991;transcript of the FDA Generic Drugs

Advisory Committee meeting held in February 1991.

Most of the relatively scarce research on physi- number of prescriptions dispensed (both new and

cian prescribing practices concentrates on gynecolo- refill prescriptions) and the number of times a drug

gists and family practitioners. Several studies of the is mentioned during visits to a physician. Some

prescribing patterns and strategies of doctors and the product-specific information is available from pharindications they follow for use of hormone therapy maceutical manufacturers, but the more comprehenreveal significant prescription by gynecologists ‘of

estrogens, and to a lesser extent progestins, for

postmenopausal women (9,11,18). Two surveys

conducted in California reveal frequent prescription

of both estrogens and progestins in this geographic

region (see box 4-B).

Most of the available information on the prescription of estrogens and progestins provides data on the

sive information is derived from two pharmaceutical

marketing research data bases: the National Prescription Audit (NPA) and the National Disease and

Therapeutic Index (NDTI), which are maintained

and distributed on a limited basis by a private

consulting firm, IMS America, Ltd.

The NPA tracks prescriptions dispensed by a

panel of 2,500 retail pharmacies and gives national
68 • The Menopause, Hormone Therapy, and Women’s Health

Table 4-2—New Prescriptions (Rx) of Premarin

(tablets only) by Specialty, 1990

New Rxs Percent Percenta

Specialty (000s) share change

Obstetricians/gynecologists..... 2,897 43.0 +14

Family practitioners . . . . . . . . . . . . 1,353 20.1 +17

Internal medicine . . . . . . . . . . . . . . 983 14.6 +19

General practitioners . . . . . . . . . . . 492 7.3 + 3

All others . . . . . . . . . . . . . . . . . . . . . . 1,010 15.0 +18

Total . . . . . . . . . . . . . . . . . . . . . . . . . 6,735 100.0 +15

aCompared with 1989.

SOURCE: National Prescription Audit, IMS America, Plymouth Meeting,

PA, 1991.

estimates of prescription volume. The data these

pharmacies provide for estrogens include all dosage

forms and estrogen/androgen combinations. The

second data base, the NDTI, collects information

from a panel of approximately 2,130 office-based

physicians who report on each patient they see or

have contact with in any way during a 48-hour

period each quarter. All mentions of a drug are

reported-whether as a prescription written or

dispensed, as the administration of a drug, or as a

recommendation (9). Private researchers and the

FDA’s Division of Epidemiology and Surveillance

have also performed several analyses of prescriptions of noncontraceptive estrogen and progestin.

The latest available published data from these

sources are from 1986.

Estrogens

Until 1990, according to NPA data, 1975 was the

peak year for prescriptions containing noncontraceptive estrogen, with 28 million dispensed from

retail pharmacies. At about that time, new information became available about the increased risk of

endometrial cancer associated with the use of

estrogen, and estrogen prescriptions tapered off until

1980, when they began to increase, a trend that has

continued. Between 1979 and 1986, the prescription

of oral estrogen, the form most often used to treat

menopausal symptoms, increased 117 percent (9). In

1990, retail pharmacies in the United States dispensed more than 30 million prescriptions for

noncontraceptive estrogens, surpassing the previous

peak in 1975 (10).

The vast majority of estrogen prescriptions are for

oral preparations, which accounted for 88 percent of

I all prescriptions in 1986 (9). Conjugated estrogens I

are most often prescribed, and Premarin is the

preparation most commonly used. In 1990, Premarin

accounted for 61.9 percent of all prescriptions (both

new and refills) for oral and transdermal estrogen

(see table 4-3). According to NPA data, in 1981,11

million prescriptions for conjugated estrogens were

dispensed, about 95 percent of which were for

Premarin. In 1987, 16 million prescriptions were

dispensed, of which 75 percent were for Premarin.

(Most of this increase in prescriptions can be

attributed to the prescription of generic conjugated

estrogens; as of the spring of 1991, however, these

preparations were no longer on the market(5). There

is great geographical diversity in estrogen use and

prescribing patterns by region within the United

States (see table 4-4) (11).

The most common diagnosis mentioned in relation to the prescription of estrogen is menopausal

symptoms. In 1990, according to the NDTI, diagnosis of menopausal or climacteric states accounted for

47 percent of the prescriptions of noncontraceptive

estrogens. The next most common diagnosis was

unspecified endocrine disorder, followed by primary

ovarian failure/premature menopause, postoperative

followup exam, vaginitis/vulvovaginitis, artificial

menopause, unknown/unspecified cause of morbidity and mortality (or other), osteoporosis, and

malignant neoplasm of the prostate. These diagnoses

together accounted for 90 percent of those associated

with the use of noncontraceptive estrogen. Although

prevention of osteoporosis is an approved indication

for Premarin and Estraderm, osteoporosis accounted

for only 2 percent of the diagnoses mentioned (10).

Other studies show that osteoporosis has rarely been

given as a distinctive diagnosis for ET, although

mention of this condition is increasing over time. In

1974, prevention or treatment of osteoporosis was

mentioned during 1.4 million physician visits; in

1986, this figure had risen to 1.8 million (9).

Progestins and Combined Hormone Therapy

Approved indications for the use of progestins are

treatment of amenorrhea, abnormal uterine bleeding,

and endometriosis. As noted earlier, no progestin

Table 4-3-Premarin Prescriptions (Rx), 1990

Number Percent of total oral and

(000s) transdermal estrogen Rx

New Rx . . . . . . . . . . . . . . 6,735 64.5

Refill Rx . . . . . . . . . . . . . 12,105 60.6

Total Rx . . . . . . . . . . . . . 18,840 61.9

SOURCE: National Prescription Audit, IMS America, Plymouth Meeting,

PA, 1991.

)

I

I
Chapter 4--Hormone Products and Prescription ● 69

Box 4-B—Prescribing Practices in California

Two studies have been published concerning the prescribing practices of hormone therapy among San Diego

and Los Angeles gynecologists. Both studies used mailed surveys to garner responses from the doctors, one group

of which was listed under gynecology in the 1985 San Diego telephone directory, while the other was composed

of members of the Los Angeles County Obstetrics and Gynecology Society. It is important to remember that

regional differences in prescribing practices for hormone therapy have been shown to exist, with the West Coast

having a demonstrated higher incidence of use. The results of these studies follow.

A 1985 survey of 166 (108 respondents) San Diego gynecologists showed that between 79 and 83 percent

(depending on the length of time as practicing physicians) prescribed estrogens for at least 75 percent of recently

postmenopausal women, and that 58 percent prescribed estrogens for virtually all such patients. Seventy-three

percent usually prescribed estrogen therapy for 10 years or more, and none reported prescribing estrogen for less

than 1 year. The San Diego gynecologists most commonly prescribed 0.625-mg Premarin daily. None of the doctors

that had been in practice for less than 10 years at the time of the survey prescribed oral estrogens without a progestin.

Menopausal symptoms, followed by the prevention of osteoporosis, were the major indications and reasons cited

for hormone therapy.

A 1984/1985 survey of 516 (330 respondents) Los Angeles gynecologists revealed prescribing patterns similar

to those found in San Diego. Routine use of hormone therapy was indicated by 94 percent of the respondents for

women with intact uteri and by 97 percent for women without uteri. Ninety-seven percent preferred using Premarin

for women with and without uteri, and O.625 mg of Premarin daily was the overwhelmingly favored dose (80 percent

and 76 percent, respectively). Eighty-six percent routinely prescribed a progestin for women with intact uteri.

Ninety-five percent used medroxyprogesterone acetate, with 73 percent prescribing 10 mg daily and 20 percent

prescribing 5 mg daily. Surprisingly, 47 percent reported prescribing progestin for women without uteri.

The Los Angeles study compared the 1985 results with data from a 1975 survey of Los Angeles gynecologists.

The preferred dosage decreased from 1.25 mg of Premarin daily in 1975 to 0.625 mg in 1985. The use of progestin

therapy increased from 17 percent in 1975 to 86 percent in 1985, and the dose and brand remained the same (10

mg daily of medroxyprogesterone acetate). For women without intact uteri, the percentage of doctors prescribing

a progestin increased from 11 percent in 1975 to 47 percent in 1985. The use of progestins for women without a

uterus was not explained in the study.

SOURCES: E. Barrett-Connor, “Postmenopausal Estrogens--Current Prescribing Patterns of San Diego Gynecologists,” Western Journal of

Medicine 144:620-621, 1986; R.K. Ross, A. Paganini-Hill, S. Roy, et al., “Past and Present Preferred Prescribing Practices of

Hormone Replacement Therapy Among Los Angeles Gynecologists: Possible Implications for Public Health," American Journal

of Public Health 78(5) :516-5 19, 1988.

has been approved for use in CHT, although doctors only 18 percent of diagnoses related to progestin

prescribe it for this purpose, and most progestin use

related to hormone therapy is in conjunction with

estrogen. Studies have shown that progestin is

effective in treating hot flashes, and it is sometimes

used for this indication when estrogen is contraindicated. Doctors prescribe CHT most often for women

with intact uteri to counteract the increased risk for

endometrial cancer associated with ET.

In parallel with estrogen use, progestin use

gradually increased through 1976, at which point it

began to decrease. Like estrogen, however, it began

to rise in 1981 and has continued to increase since

then. Thus, 1983 saw the dispensing of 3.2 million

prescriptions for progestins, and that number continued to increase rapidly between 1984 and 1986. In

1979,79 percent of progestins were prescribed to be

used alone, and menopausal problems represented

prescriptions. In 1986, only 37 percent of prescribed

progestins were used alone, and menopausal symptoms represented 59 percent of mentioned diagnoses. Concomitant use of estrogens and progestins has

increased over time and was common in 1986. The

increase in progestin prescriptions evident after

1982 coincides with the trend toward the use of oral

progestin with oral estrogen (9,11).

There is no official standard or protocol for

administering or prescribing CHT. Furthermore, no conclusive studies have been performed

that indicate which regimen is most beneficial,

and there have been no studies that meet design,

duration, and sample size requirements for determining conclusively the risks and benefits of

long-term use of CHT (2). The current Postmenopausal Estrogen/Progestin Intervention (PEPI) trial
70 ● The Menopause, Hormone Therapy, and Women’s Health

Table 4-4-Estrogen Therapy by Geographic Region,

January-December 1991ab

Percent Base

Region States share (000s)

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 10,626

South Central . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 3,656

South Atlantic . . . . . . . . . . DE, DC, MD, VA WV, NC, SC, GA, FL

West South Central . . . . . LA, AR,TX, OK

East South Central . . . . . . TN, AL, MS, KY

West . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 2,950

Pacific . . . . . . . . . . . . . . . . WA, CA, OR, HI, AK

Mountain . . . . . . . . . . . . . . MT, CO, WY, lD, UT, AZ, NM, NV

North Central . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2,503

East North Central . . . . . . OH, IN, MI, lL, Wl

WestNorth Central . . . . . . IA, NE, MN, SD, ND, MO, KS

East . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 1,517

Middle Atlantic . . . . . . . . . NJ, PA, NY

New England . . . . . . . . . . MA, RI, NH,VT, ME, CT

aClasses52112 (estrogens oral) and 52114 (estrogens topical) drug occurrences (physician mentions in thousands).

bPhysician Drug and Diagnosis Audit (PDDA) geographic regions conform to standard U.S. Census regions. PDDA is

a nationally projected sample and is not designed to be a subnational database.

SOURCE: Scott-Levin Associates, Physician Drug and Diagnosis Audit, January-Deoember 1991.

being conducted by the National Institutes of Health

is investigating the effects on intermediate endpoints

of different regimens of CHT used for 3 years each

(12). No combination estrogen and progestin products are currently approved in the United States,

although some have entered clinical testing; combination products are available in Europe. Many

different regimens of CHT are prescribed by physicians; indeed, anecdotal information indicates that

as many as 19 different regimens are prescribed in

the United States and more than a hundred are

prescribed in Europe (21).

One of the main drawbacks to CHT is the

incidence of unwanted withdrawal bleeding related

to the administration of progestin. Clinicians thus

are experimenting with various regimens that will

either make bleeding more predictable or eliminate

it entirely. The most commonly prescribed regimens

are cyclic administration of estrogen and progestin,

continuous administration of estrogen plus intermittent progestin, and, increasingly, continuous/combined administration of estrogen and progestin.

Cyclic administration typically prescribes estrogen

for the first 25 days of the calendar month and adds

progestin on days 14 through 25. Both hormones are

stopped for the last several days of the month at

which point withdrawal bleeding occurs. Another

cyclic method involves daily use of both estrogen

and progestin for 21 days, followed by 7 days of no

hormone use. This regimen also results in withdrawal bleeding. Continuous use of estrogen with

intermittent progestin prescribes estrogen everyday,

365 days of the year, and adds progestin for the first

12 days of each calendar month. Withdrawal bleeding typically occurs for several days after progestin

use is stopped, with the length and intensity of the

bleeding dependent on the dose and type of progestin used (15). Amenorrhea is often achieved after

several months of use of continuous/combined

therapy. Increasingly, clinicians are prescribing

continuous/combined therapy in an attempt to avoid

withdrawal bleeding.

PROMOTION OF

HORMONE THERAPY

Pharmaceutical manufacturers market their drugs

in several ways: they send sales representatives to

meet with individual physicians, place advertisements in medical journals, sponsor symposia and

meetings, and fund clinical research on their products. In addition, pharmaceutical companies provide

public education about medical conditions and drug

use. FDA regulations prohibit companies from

promoting drugs for unapproved uses; thus, manufacturers of progestin products may not promote

their products for use in treating menopausal symptoms. They do fired research, however, both within

their companies and within the medical community,

to investigate this use.
Chapter 4--Hormone Products and Prescription • 71

Many advertisements for estrogen products feature pictures of attractive women who appear barely

old enough to be menopausal. Often the women in

the pictures are exercising or vacationing. Even

advertisements focusing on osteoporosis (e.g., a

recent Wyeth-Ayerst advertisement) feature relatively young-looking women. Many ads focus on

femininity, sex appeal, and emotional and marital

issues. The captions below have been used in recent

advertisements:

●

●

●

“Menopause Myth No. 1: No man in his right

mind would be interested in a menopausal

woman,’ and “Menopause Myth No. 2: You’d

better leave sports to the youngsters.” These

were both used by CIBA in its promotion of

Estraderm, along with the statement, ‘Now the

change of life doesn’t have to change yours. ”

“Calcium every day. Aerobics every week.

Bone loss every year. She needs Premarin to

help prevent further bone loss,” used by

Wyeth-Ayerst.

“I feel more like a woman again,” used by

Reid-Rowell in its promotion of Estratest,

Estratab, and Curretab. This ad also includes

the following: ‘‘Hormones can make an important difference in a woman’s life. These

hormones can affect the way a woman feels

about herself and those she loves. ’

The first ad was directed toward consumers in

women’s magazines, while the second two ads

appeared in professional journals for physicians (6).

The implication in these ads is that without

hormones, women will experience serious loss (15).

Medical information required by the FDA is also

part of these ads, and some contain further explanation of the menopause and menopausal symptoms.

Many of the ads focus attention on a woman’s looks

and emotions, however, rather than on the scientific

and medical effects of the drugs, and some have been

criticized as demeaning, insulting, and degrading to

menopausal women (19).

In addition, pharmaceutical companies fund individual and group research teams that conduct studies

of their products or perform research in relevant

medical areas; they also sponsor clinical trials of

their drugs, as well as symposia and conferences that

promote the exchange of both scientific and product

information. Companies often contribute to commercial exhibitions held at professional meetings

and promote their products to the attendees. Many

researchers who study the menopause and related

fields receive funding from pharmaceutical companies, a not uncommon practice in clinical research.

SUMMARY

There are 11 U.S. manufacturers of estrogen and

5 U.S. manufacturers of progestins. Three classes of

estrogens are used for hormone therapy: natural

estrogens, conjugated equine estrogens, and synthetic estrogens. Three progestins are used as well:

medroxyprogesterone acetate, norethindrone, and

norethindrone acetate. In 1990, total sales of estrogen products were close to $460 million. Premarin,

the top-selling estrogen and the fourth most prescribed drug in the United States, held a 68-percent

market share.

Approved estrogen products have labeled indications for the treatment of the vasomotor symptoms

associated with the menopause; Estraderm is approved for the prevention of osteoporosis and

Premarin for both the treatment and prevention of

this condition. The FDA is considering changes in

labeling that would reflect the cardioprotective

effect of unopposed estrogen use. None of the

progestins used in CHT has been approved by the

FDA for the treatment of menopausal symptoms, but

this use is common medical practice. FDA is

considering labeling changes that reflect a recommendation for the use of CHT for women with intact

uteri. The approval of generic conjugated estrogens

remains a topic of debate within industry and at the

FDA.

Obstetricians and gynecologists write more than

40 percent of estrogen prescriptions and general

medicine physicians another 20 percent; all of these

physicians most commonly prescribe conjugated

oral estrogens. In 1990, more than 30 million

prescriptions for noncontraceptive estrogens were

dispensed, and the most common diagnosis associated with these prescriptions was relief of menopausal symptoms. Doctors commonly prescribe

progestins for use with estrogen in women with

intact uteri, but there is no officially approved

regimen of CHT. Research continues to explore the

long-term effects of CHT and different regimens to

reduce side effects, especially withdrawal bleeding.

Many in the field of menopause research and

women’s health believe that serious gaps exist in the

menopause and hormone therapy knowledge base,

particularly in the area of long-term effects (see ch.
72 ● The Menopause, Hormone Therapy, and Women’s Health

5). In the absence of sufficient research, especially

on long durations of use, doctors are beginning to

use CHT for long-term preventive therapy and

pharmaceutical companies are pursuing labeling

changes for existing estrogen and progestin products. Identifying and then closing these gaps are

important tasks that will affect the market for

hormone products.

1.

2.

3.

4.

5.

6.

7.

8.

9.

CHAPTER 4 REFERENCES

“Abbreviated New Drug Applications for Conjugated Estrogens; Proposal to Withdraw Approval;

Opportunity for a Hearing,’’ Federal Register 55(30):

5074-5078, 1990.

Barrett-Connor, E., “Postmenopausal Estrogens—

Current Prescribing Patterns of San Diego Gynecologists,” Western Journal of Medicine 144:620-621,

1986.

“Certain Estrogen-Containing Drugs for Oral or

Parenteral Use,” Federal Register 37(143):14826,

1972.

“Conjugated Estrogens’ Rate of Absorption Should

Be Measured-FDA Advisory Committee; New

Generic Formulations Could Take at hast Two

Years To Develop,” F-D-C Reports 53(9):9-10,

1991,

“Conjugated Estrogen Tablets; Withdrawal of Approval of 28 Abbreviated New Drug Applications,”

Federal Register 56(57):12376-12377, 1991.

Dodd, D., Wyeth-Ayerst, Philadelphia, PA, personal

communication, September 1991.

“Estrogen Replacement Therapy Should Include a

Progestin To Reduce Risk of Endometrial Cancer

Advisory Committee Says; FDA To Consider Combo

NDAs,” F-D-C Reports 53(25):11, 1991.

“FDA Approves Using Estrogen To Treat PostMenopausal Osteoporosis,” Associated Press wire

service, Oct. 30, 1991.

Hemminlu“, E., “The Use of Combined EstrogenProgestin Replacement Therapy,’ International Jourrud of Technology Assessment in Health Care

4:511-519, 1988.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

Kaufman, S., Medical Officer, FDA, Epidemiology

Branch, Division of Epidemiology and Surveillance,

Office of Epidemiology and Biostatistics, Rockville,

MD, personal communication, July 1991.

Kennedy, D.L., Baum, C., and Forbes, M.B., “Noncontraceptive Estrogens and Progestins: Use Patterns

Over Time,” Obstetrics and Gynecology 65(3):441-

447, 1985.

Mebane, I., Epidemiologist, National Institutes of

Health, Bethesda, MD, personal communication at a

workshop sponsored by the Office of Technology

Assessment, “Menopause and Hormone Replacement Therapy: Policy and Practice,” Washington,

DC, Mar. 22, 1991.

Merz, B., ‘‘Pharmaceutical List Tracks Hit Parade of

Prescriptions,” American Medical News 34(9):4,

1991.

Notelovitz, M., Women’s Medical and Diagnostic

Center and the Climacteric Clinic, Gainesville, FL,

personal communication, 1991.

O’kmy Cobb, J., A Friend Indeed, Montreal,

Canada, personal communication, September 1991.

Physicians Desk Reference, 45th ed. (Oradell, NJ:

Medical Economics Data, 1991).

‘‘Prema.rin Cardioprotective Effect To Be Reconsidered,’ F-D-C Reports 53(17) :T&G-3-T&G4, 1991.

Ross, R.K., Paganini-Hill, A., Roy, S., et al., “Past

and Present Preferred Prescribing Practices of

Hormone Replacement Therapy Among Los Angeles

Gynecologists: Possible Implications for Public

Health,” American Journal of Public Health 78(5):

516-519, 1988.

Seaman, B., and Seaman, G., Women and the Crisis

in Sex Hormones (New York, NY: Rawson Associates Publishers, Inc., 1977).

Starnpfer, M., Harvard University School of Public

Health, Boston, MA, personal communication, November 1991.

Transcript of the meeting of the FDA Fertility and

Maternal Health Drugs Advisory Committee, June

20-21, 1991.
. - - —. — —— — —. . . . . — . . ——- — .- —-——

Chapter 5

Current Research and

Future Needs
Contents

Page

CURRENT STATE OF RESEARCH ON THE MENOPAUSE AND

POSTMENOPAUSAL WOMEN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .76

The Baltimore Longitudinal Study of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

The Framingham Study . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

The Healthy Women Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

The Leisure World Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

The Lipid Research Clinic Mortality FoIlowup Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

The Massachusetts Women’s Health Study, Part 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

The Nurses’ Health Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79

Postmenopausal Estrogen/Progestin Interventions Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

The Tremin Trust: An Intergenerational Research Program . . . . . . . . . . . . . . . . . . . . . . . . 81

METHODOLOGIC CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Understanding the Effects of the Menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

Evaluating the Effects of Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

Requirements for a Randomized Trial of Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . 83

The Women’s Health Initiative Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

FILLING THE RESEARCH GAPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Biological Systems That Deserve Special Attention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

Effects of Ovarian Hormone Levels: Modalities of Study . . . . . . . . . . . . . . . . . . . . . . . . . . 92

FEDERAL INVESTMENT IN MENOPAUSAL AND RELATED RESEARCH .......92

National Institutes of Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

Alcohol, Drug Abuse, and Mental Health Administration . . . . . . . . . . . . . . . . . . . . . . . . . . 93

SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

CHAPTER 5 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 95

Boxes

Box Page

5-A. Development of Animal Models for the Menopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

5-B. Menopause-Related Research at the National Institutes of Health . . . . . . . . . . . . . . . . . 94

Tables

Table Page

5-1. Estimated Volume of General Research Related to the Menopause and

the Postmenopausal Period of the National Institutes of Health,

Fiscal Year 1991 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

5-2. Estimated Volume of Research Related to the Menopause and Hormone

Therapy of the National Institutes of Health, Fiscal Year 1991 . . . . . . . . . . . . . . . . . . . 93

5-3. Extramural Research Related to the Menopause at the Alcohol, Drug Abuse,

and Mental Health Administration, 1989-91 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Chapter 5

Current Research and Future Needs

Since 1983, the U.S. Public Health Service (PHS)

has been working to outline an agenda for women’s

health. In that year, the Assistant Secretary for

Health commissioned the PHS to form the Task

Force on Women’s Health Issues to “identify those

women’s health issues that are important in our

society today and to lay out a blueprint for meshing

those issues with the priorities of the Public Health

Service” (60). In the ensuing years, controversy

over the adequacy of the Federal response to the

health service and health science needs of American

women has persisted; debates range from whether

enough research dollars are allocated to women’s

health issues, to whether women are sufficiently

represented in clinical trials, to whether treatment of

disease varies (inequitably) depending on the sex of

the patient.

In response to the controversy about attention to

research on women’s health, the research activities

supported by the National Institutes of Health (NIH)

were inventoried by the General Accounting Office

(GAO), based on finds expended in 1987, to

determine resource allocation according to gender.

The inventory used the following criteria to identify

health problems:

●

●

●

●

●

diseases or conditions that are unique to women

or to some subgroup of women,

diseases or conditions that are more prevalent

among women,

diseases or conditions that are more serious for

women or for some subgroup of women,

diseases or conditions for which the risk factors are different for women or for some

subgroup of women, and

diseases or conditions for which the interventions are different for women or for some

subgroup of women (30).

The inventory determined that 13.5 percent of the

NIH budget for fiscal year 1987—approximately

$778 million-was spent on women’s health issues

(30). Certain groups interpreted this figure to mean

that, conversely, 86.5 percent of NIH funds went for

research focusing on men’s health. NIH responded

that 80 percent of all its research funds were

allocated “either for studies of diseases which affect

both men and women or for fundamental research

which has significance for all segments of our

population” (30). The inventory did not address

whether such research included women in the study

populations or used female animal models.

The issue of including women in NIH-funded

research study populations has generated growing

concern among members of Congress, many of

whom regard NIH’s response to the matter as

inadequate. Congress, therefore, requested GAO to

review NIH policy and practices in this area. GAO

reported that NIH had “made little progress in

implementing its policy to encourage the inclusion

of women in research study populations” (58).

NIH’s response to this criticism was that, “[if] the

GAO had done a complete examination of all the

data, it would have found that, in the vast majority

of research studies, clinical trials and large-scale

studies, women are well represented in the study

population” (30). On August 24, 1990, in the NIH

Guide for Grants and Contracts, the agency published a revised, strengthened announcement regarding the inclusion of women in clinical studies. This

expanded Policy Notice was republished on February 8, 1991, and will be reprinted twice a year.

In reaction to the controversy and concern produced in Congress by the GAO report, the NIH

Office of Research on Women’s Health was estabPhoto credit: National Institutes of Health

Building 1, National Institutes of Health, site of the Office for

Women’s Health Research.

–75–
76 . The Menopause, Hormone Therapy, and Women’s Health

lished in September 1990 to strengthen and enhance

NIH efforts to improve the prevention, diagnosis,

and treatment of illness in women and to enhance

research related to diseases and conditions that

affect women. This office, and the Office of Science

of the Alcohol, Drug Abuse, and Mental Health

Aministration (ADAMHA), provided the Federal

funding figures for research on the menopause and

related topics that are presented in this chapter. In

addition to presenting these data, the chapter discusses methodologic considerations relevant to studies of the menopause and its treatment, describes

completed and ongoing menopause-related studies,

and suggests areas for future research.

CURRENT STATE OF RESEARCH

ON THE MENOPAUSE AND

POSTMENOPAUSAL WOMEN

Previous chapters have referred to the results of

studies relevant to the effects of the menopause on

the current and future health of women. In addition

to these studies, several large-scale investigations

with long-term followup involve postmenopausal

women. These studies do not necessarily address

transmenopausal changes, and hence the impact of

the menopause per se, but some of the data they have

collected are relevant to these issues. The following

section briefly summarizes the objectives and some

of the principal findings of these investigations.

The Baltimore Longitudinal Study of Aging

The Baltimore Longitudinal Study of Aging

(BLSA), begun in 1958, is an intramural study of the

National Institute on Aging to investigate normal

human aging. The participants are highly motivated;

they are self-recruited, mostly white, educated

professionals who return every 2 years for 21/2 days

of medical, physiological, nutritional, and psychological evaluation (48). The women’s cohort was

added in 1978. Currently, 441 women, ranging from

20 to 97 years of age, participate in this ongoing

observational study. One of its major objectives is to

identify and characterize cross-sectional and longitudinal age-related changes among a host of physiological, behavioral, and psychological variables

observed in a healthy, community-dwelling population. A second objective is to elucidate risk factors

for particular age-related diseases.

Preliminary findings of the BLSA have included the observation that women before the

menopause have a lower incidence of hypertension and heart disease. In addition, diagnoses of

cardiovascular disease differ between the sexes:

women present for treatment with more angina

than men but with fewer myocardial infarctions.

More men than women are likely to undergo

surgery to remedy their cardiovascular problem.

Physical fitness, measured as maximal oxygen

consumption during treadmill testing, is less in

women than in men (in large part because women

have a lower level of muscle mass) and declines with

age in both sexes. Although women have a greater

percentage of body fat than men, they also have a

lower waist-to-hip ratio (WHR) in their distribution

of fat (which suggests a reduced risk of hypertension, diabetes, cardiovascular disease, and mortality

compared with men, who have a higher WHR).

Although a surge in WHR occurs in postmenopausal

women, at any given age, women still have a lower

fat distribution ratio than men. The full significance

of the WHR is not understood, however, and the

meaning of the difference between men and women

on this measure is even less clear (57).

Given its broad-based multidisciplinary approach and capacity for longitudinal followup,

the BLSA could conduct highly cost-effective

research into the effects of the transition through

the menopause on many important biological and

environmental factors. Ultimately, these data

could be used to generate information about

perimenopausal risk factors relevant to morbidity in women. However, the inclusion in the study

of only approximately 100 women between the ages

of 40 and 60 limits its ability to distinguish the

effects of the menopause from longitudinal changes

or to describe perimenopausal attributes.

The Framingham Study

The Framingham Study began in 1948 as a

prospective long-term surveillance study to identify

factors related to sex, heredity, and environmental

variables (e.g., educational and occupational status,

physical activity, smoking) that might be involved in

the development of atherosclerotic and hypertensive

heart disease. The effort is funded by the National

Heart, Lung, and Blood Institute of NIH.

The study recruited two-thirds of the population

of Framingham, MA (with the later addition of 740

volunteers), as participants; of these individuals,

who were all between the ages of 30 and 59, 2,873
Chapter-- Current Research and Future Needs • 77

were women. This cohort was offered a physical

exam, a standardized cardiovascular exam, and a

chest x-ray every 2 years. Medical and family

histories were taken, and samples were obtained to

determine blood glucose, cholesterol, and hematocrit; urinalysis was performed for other chemistries.

Endpoints, or indicators, of coronary artery and

cerebrovascular morbidity and associated mortality

were evaluated.

The study produced several interesting menopause-related findings. Menopause in this population occurred about a year earlier in smokers

(at 49.3 years) than in nonsmokers (50.1 years).

Transition through the menopause (naturally or

as a result of bilateral oophorectomy) was associated with a rise in levels of hemoglobin and serum

cholesterol; it was not associated with changes in

body weight, blood pressure, glucose, or vital

capacity (22). The study also found an increase in

the incidence of coronary heart disease among

postmenopausal women compared with premenopausal women, as well as an increase in the

severity of the disease when women came to

treatment. Surgical menopause was associated with

a 2.7-fold increase in the risk of coronary heart

disease (19). A particularly important finding was

that estrogen users who were also smokers had an

increased risk of myocardial infarction (65). Moreover, contrary to most studies of users of estrogen,

the Framingham researchers found a 50 percent

increase in the risk of cardiovascular disease and a

doubling of the risk of cerebrovascular disease in

estrogen users compared with nonusers. This result

occurred despite the more favorable lipoprotein

profiles (higher HDL [high-density lipoprotein]

cholesterol and lower LDL [low-density lipoprotein]

cholesterol) of estrogen users.

Further consideration of the Framingham findings

has produced some reevaluations of these conclusions, however. A reanalysis of the data from the

study has revealed that the apparent elevation in risk

was not significantly different when only myocardial infarction was considered; in addition, the

findings concerning overall elevation in risk were

sensitive to the investigator’s choice of baseline risk

data (52). Moreover, there were only 302 estrogen

users in the cohort (51).

In a recent study of offspring of participants in the

original Framingham research, postmenopausal estrogen users were shown to have higher levels of the

297–910 0 - 92 - 6

principal protein constituent of HDL, lower LDL

cholesterol and glucose levels, and lower diastolic

blood pressure than nonusers. Estrogen use was

associated with higher levels of HDL cholesterol,

but only in women who had undergone oophorectomies (10).

In the original study population, the form of

hormone therapy was oral conjugated estrogens

(usually Premarin). In the offspring study, Premarin

again was the principal therapy used, but 10 percent

of hormone users were also taking progestins (which

were not identified). Neither study, therefore, provides data regarding the effect of progestins on

cardiovascular disease.

The Healthy Women Study

The Healthy Women Study was begun in 1983

and originally consisted of a cohort of 541 Pittsburgh, PA, women who were premenopausal and

between the ages of 42 and 50 (36). It was funded,

in part, by the National Heart, Lung, and Blood

Institute of NIH. The objective of this 5-year

prospective longitudinal study was to document

normal transmenopausal changes in biological and

behavioral characteristics, especially those relating

to cardiovascular disease. The study excluded women

who had hypertension, thyroid disease, or diabetes

mellitus, as well as those who had undergone

hysterectomy or bilateral oophorectomy. Medications that might alter the risk factors under investigation were not permitted. Researchers evaluated

blood pressure and collected specimens to assess

menopausal status, related hormones, and glucose

and lipid metabolism. They also assessed medical

histories, body size and shape variables, and lifestyle

variables such as dietary intake, physical activity,

and smoking history.

Although a natural transition through the

menopause appeared to have no effect on blood

pressure, glucose metabolism, or caloric consumption or expenditure, it was associated with

an increase in LDL cholesterol and a decline in

HDL cholesterol (36). In addition, declining

estrogen levels during the perimenopause were

significantly related to the worsening lipid profile

(32). Weight gain, a common menopausal occurrence, was significantly associated with a worsening

of cardiovascular risk factors such as increases in

blood pressure, total and LDL cholesterol, triglycerides, and fasting insulin (66). Compared with
78 ● The Menopause, Hormone Therapy, and Women’s Health

nonusers, postmenopausal women who used estrogen (with or without the progestin medroxyprogesterone acetate) had lipoprotein and cholesterol

profiles compatible with a reduced risk of atherogenesis. However, estrogen users also had elevated

systolic blood pressure and elevated triglyceride

levels (16).

Analyses of the data from this 5-year study are

continuing to appear and will provide much needed

insight into the natural history of the menopause

with respect to the effects of changes in ovarian

hormone levels on risk factors for diabetes and

cardiovascular disease. Because regimens of

hormone therapy are self-selected and not randomized, however, caution is advisable in interpreting

the effects of such therapy on measured outcomes.

Furthermore, continued followup is critical to ident@ possible links between changes attributable to

the menopause and long-term endpoints of morbidity and mortality.

The Leisure World Study

This prospective study of 8,881 postmenopausal

female residents of a retirement community in

southern California evaluated the use of estrogen in

terms of overall mortality (21). The women were

almost entirely Caucasian, moderately affluent, and

well educated. Their median age at the time of study

was 73 years. After 71/2 years of following the

women, there had been 1,447 deaths. Women with

a history of estrogen use had an age-adjusted,

all-cause mortality rate that was 20 percent lower

than that of lifetime nonusers. Mortality decreased with increasing duration of use and was

lower among current users than among women

who had used estrogen only in the distant past.

Current users with more than 15 years of estrogen

use had a 40 percent reduction in overall mortality.

Among oral estrogen users, relative risks of death

could not be distinguished by specific dosages of the

oral estrogen taken for the longest time.

Women who had used estrogen showed reduced

mortality from all categories of acute and chronic

arteriosclerotic disease and cerebrovascular disease,

compared with nonusers. This group of women also

had a reduced rate of mortality from cancer, although

this reduction was not statistically significant. Mortality from all remaining causes combined was the

same for estrogen users and lifetime nonusers.

The Lipid Research Clinic Mortality

Followup Study

The Lipid Research Clinics (LRC) Prevalence

Study was a cross-sectional study conducted at 10

North American clinics between 1971 and 1976; it

was funded, in part, by the National Heart, Lung, and

Blood Institute of NIH. Its objective was to describe

the distribution of plasma lipids and lipoproteins

within populations of American men and women to

determine the relationship between hyperlipoproteinemia and cardiovascular disease. A subset of the

population was selected for followup in the Lipid

Research Clinic Mortality Followup Study, which

provided information on the associations between

the reported use of estrogen and subsequent cardiovascular and all-cause mortality. The study’s female

cohort consisted of 2,270 women (40 percent of

whom were selected on the basis of elevated lipid

levels) aged 40 to 69. The women underwent assessments of blood pressure, blood chemistries

including lipid profiles, evaluations of body weight

and size variables, electrocardiograms, and 24-hour

dietary recalls. To relate environmental and physiological variables to cardiovascular disease, researchers administered questionnaires on lifestyles, menstrual history, reproductive status, and medication

use.

After following the cohort for nearly 51/2years,

investigators found that overall mortality was

lower (60 percent less) among estrogen users

compared with nonusers (7). In addition, when

they assessed the relationship between mortality

from all causes and estrogen use with respect to the

status of pelvic surgery, they found that compared

with nonusers, estrogen users who were bilaterally

oophorectomized had the greatest reduction of risk

(nearly 90 percent less) followed by hysterectomized women (66 percent less) and gynecologically

intact menopausal women (46 percent less).

In a later LRC report after 81/2 years of followup

(8), a large portion of the 66 percent reduction in risk

of mortality from cardiovascular disease could be

explained (statistically) by the elevation levels of

HDL cholesterol. In addition to higher HDL cholesterol levels, users of estrogen also had decreased

levels of LDL cholesterol.

Additional findings in women (that are not strictly

related to the menopause or to hormone therapy)

included the absence of a cross-sectional relation-
Chapter 5-Current Research and Future Needs . 79

ship between serum cholesterol and either dietary

cholesterol or the ratio of dietary polyunsaturated to

saturated fats. The LRC data support the conclusion that high levels of HDL cholesterol constitute

a strong, independent protective factor—HDL

cholesterol 1evels being an important known

lipid-related risk factor for cardiovascular disease in women. Although LDL cholesterol levels in

women who experience a natural menopause or

bilateral oophorectomy may be elevated compared

with levels in premenopausal women, the relationship of this variable to cardiovascular disease in

women appears to be less consistent. Among women

in the study, LRC findings also showed the wellknown positive relationships among smoking, obesity, and cardiovascular disease, and the apparent

cardioprotective effect of limited (moderate) alcohol

consumption.

Several features of the LRC study warrant careful

consideration when interpreting its results. The use

of estrogen in the study was self-selected rather than

randomly assigned, and reports of the study do not

indicate the reasons for its use or nonuse. Although

the results of the study addressed the issue of

potential selection bias, confounding as a result of

self-selection cannot be ruled out. Because most of

the women were taking oral estrogens, the findings

do not apply to nonoral estrogens or to estrogens

combined with progestins. Moreover, dose-response

relationships were not evaluated, nor was the effect

of duration of estrogen use assessed. Although the

use of estrogen is associated with an overall

favorable lipoprotein pattern, estrogen users in

the study had substantially elevated triglyceride

levels, implications of which for cardiovascular

disease are unclear. Finally, the study did not

address the effect of longitudinal changes on biochemical or physiological variables as women

traversed the menopause.

The Massachusetts Women’s

Health Study, Part 2

Part 2 of the Massachusetts Women’s Health

Study is a 5-year prospective followup study of a

cohort of 427 pre- and perimenopausal women; the

study, Part 1 of which was begun in 1982, is being

supported by a grant from the National Institute on

Aging (NIA) of NIH. The cohort was assembled

from a previously studied, community-based random sample of 2,500 premenopausal Massachusetts

women who were believed to be representative of

U.S. women in general.

The objectives of this study are to obtain biological, anthropometric, psychosocial, and lifestyle data

from women as they traverse the menopause. The

study will assess changes in reproductive hormones

and related parameters and determine their relationship, if any, to changes in bone mass and cardiovascular risk factors (e.g., lipid and lipoprotein profries). An important goal of the project is to

provide valuable basic information on normal

changes associated with the transition through

the menopause, which are needed to distinguish

normal from pathophysiologic changes in reproductive physiology, bone mass, and cardiovascular risk factors. Study designers hope to continue

followup beyond the original 5-year term to assess

relationships between intermediate outcomes of

morbidity and mortality and hypothesized risk

factors (37).

The Nurses’ Health Study

The Nurses’ Health Study is a prospective project

based on mailed questionnaires that have been

updated at 2-year intervals since 1976 (15). It is

supported, in part, by various institutes of NIH. The

main objective of the study is to determine the

relationships among lifestyle and environmental or

exposure variables (e.g., dietary factors, cigarette

smoking, use of oral contraceptives and hormone

therapy, estrogen in particular) and diabetes, cardiovascular disease, and cancer in women. The initial

cohort consisted of approximately 122,000 married

female registered nurses who were 30 to 55 years of

age and living in 11 States when the study began.

Findings from a recent report on the project

show that although postmenopausal women who

had used noncontraceptive estrogens in the past

had no increased risk of breast cancer, even after

more than 10 years of use, the risk of this cancer

among current users increased 40 percent (15).

Researchers found no relationship between the

risk of breast cancer and dietary fat intake,

cigarette smoking, or past use of oral contraceptives; nevertheless, the risk of breast cancer was

increased by 50 percent for current users of the
80 ● The Menopause, Hormone Therapy, and Women’s Health

pill compared with nonusers.1 A 30 percent

greater risk of breast cancer was seen among

women who consumed between three and nine

drinks of alcohol per week. Family history of

breast cancer, early menarche, late age at the

birth of a woman’s first child, or nulliparity also

increased the risk of breast cancer.

With regard to risk deriving from the use of

hormones, oral contraceptives were associated with

a reduced risk of ovarian and endometial cancer.

Not unexpectedly, unopposed postmenopausal estrogens were strongly associated with an increased

risk of endometrial cancer.

At the end of the first 4 years of followup, results

indicated that the use of estrogen was associated

with a reduced risk of cardiovascular morbidity and

mortality. Compared with women who had never

used estrogen, women who had used estrogen at

least once had an age-adjusted risk of coronary

disease that was only 50 percent of the expected

risk; current users had a risk that was only 30

percent of that expected (15). In a later report based

on 6 years of followup, researchers noted that in this

cohort of women (which now ranged in age from 36

to 61), a natural menopause did not increase the

age-adjusted risk of cardiovascular disease. However, the relative risk more than doubled for bilaterally oophorectomized women if they had never used

estrogen. The enhanced risk in oophorectomized

women was eliminated by estrogen use (14).

Other variables that increased the risk of cardio1 vascular morbidity and mortality in women were

cigarette smoking, obesity, diabetes, and current but

not past oral contraceptive use. Moderate alcohol

consumption led to reduced risk of heart disease but

more than tripled the risk of subarachnoid hemorrhage.

I

I

I Assessments of the relationships among hormone

therapy and morbidity and mortality are limited to

those that consider the use of unopposed conjugated

oral estrogens; in fact, 74 percent of estrogen users

in the study report the use of Premarin. In addition,

the use of estrogen therapy is self-selected rather

than randomly assigned. Because data in this study

I are obtained by questionnaire and because the

30,000 blood samples obtained since 1989 have not

yet been evaluated (due to a lack of sufficient funds),

the study is unable as yet to assess longitudinal

transmenopausal changes in physiology (13).

In 1991, the Nurses’ Health Study reported on 10

years of followup of 48,470 postmenopausal women

who did not have a history of cancer or cardiovascular disease when they entered the study. After

adjusting for age and other risk factors, the

overall risk of major coronary disease in women

currently taking estrogen was found to be 44

percent lower than expected (54).

Postmenopausal Estrogen/Progestin

Interventions Trial

The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial is a newly begun double-blind,

placebo-controlled clinical trial of oral conjugated

estrogens (Premarin), either unopposed or combined

with one of two types of progestin (either Provera or

micronized progesterone), in postmenopausal women.

The study will also examine two schedules of

combined therapy with Provera: cyclical Provera (10

mg given for days 1 through 12 of a woman’s

menstrual cycle) or continuous Provera (2.5 mg

given daily every day). The National Heart, Lung,

and Blood Institute of NIH administers the study and

is the primary funder; co-funders include the National Institute of Child Health and Human Development, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute

of Diabetes and Digestive and Kidney Diseases, and

NIA. The trial is being conducted at seven centers

throughout the United States and involves 120

women at each center. Total funding is expected to

exceed $10 million.

The primary objective of the trial is to describe the

relationships between the various regimens and

differences in cardiovascular risk factors related to

plasma HDL cholesterol, systolic blood pressure,

plasma fibrinogen, and plasma insulin. The project’s

secondary objective is to assess the effect of these

regimens on lipoprotein profiles and metabolism,

endometrial changes, bone mass in the lumbar spine

and hip, several measures of quality of life, body

mass index, renin substrate, plasma renin activity,

aldosterone, and a number of factors relating to

blood clotting.

1 The increased risk in current users is speculated to be due to an acceleration in the growth and detection of estrogen-dependent tumors in women

, at risk.
Chapter 5--Current Research and Future Needs • 81

This study will provide important interdisciplinary data and fill key gaps in knowledge of the

short-term effects of various hormone therapy

regimens on risk factors for diabetes, cardiovascular disease, and osteoporosis. But the limited

picture provided by a 3-year study needs to be

enhanced by continued long-term followup to

determine the effect of these regimens on endpoints related to morbidity and mortality from

disease within the cardiovascular and skeletal

systems. Another limitation of the study arises from

the decision to evaluate only hormone regimens that

use conjugated oral estrogens. Transdermal and

other nonoral routes of administration of estrogen

warrant investigation, given their potential value for

hormone therapy pharmacodynamics. There is also

a need to understand the effects of nonoral estrogen

on risk factors for cardiovascular disease and osteoporosis. A further limitation of the study, according

to some critics, is that it is too small to measure an

adequate number of endpoints in a reasonable

amount of time (51).

The Tremin Trust: An Intergenerational

Research Program

The Tremin Trust Research program on Women’s

Health was initiated in 1934 at the University of

Minnesota and continues today at the University of

Utah as a nonprofit program supported primarily

through grant awards and contributions. The project,

originally titled the Menstruation and Reproductive

History program, initially sought to determine the

magnitude of the variability in the menstrual cycle

among women. In 1935, the project began with a

pilot study in which participating University of

Minnesota women students recorded the onset and

cessation of menstrual bleeds in an effort to dispel

the common myth that all women menstruate

according to the same cycle, i.e., every 28 days.

Between 1934 and 1965, three primary groups of

women were enrolled in the program: a 1930s panel

of 2,350 women, a 1960s panel of 1,367 women, and

an Alaskan panel of 1,000 women, including both

Alaskan Native and Caucasian residents. Over the

years, a fourth group of women, comprising the

daughters and granddaughters of women in the

original panels, has been developed. At present,

1,316 women—representing all four groups and

ranging in age from the early teens to the mid-nineties

remain active as recordkeepers. Of these currently

active participants, 852 are menstruating and 464 are

nonmenstruating. The study employs as main datagathering instruments a menstrual calendar card, a

medical report form, and a health report form.

The Tremin Trust is currently conducting the

Menstrual and Reproductive History (MRH) Followup Study in collaboration with the National

Institutes of Environmental Health Sciences to

gather health data from approximately 1,000 women

who participated in the original MRH research

program prior to 1940. The aim of the study is to

examine the link between menstrual and reproductive history and a variety of health outcomes,

including longevity. The Midlife Women’s Health

Study, another effort of the Tremin Trust in collaboration with Pennsylvania State University, is evaluating women between the ages of 35 and 50 who are

still menstruating to document the physical and

emotional changes they experience as they approach

the menopause (50).

METHODOLOGIC

CONSIDERATIONS

Epidemiology is the study of the relationships of

various factors that determine the frequency and

distribution of disease; its aim is to estimate or

closely approximate cause and effect. Studies of the

menopause and the onset of age-related disease are

necessarily epidemiologic in nature because populations must be studied (or observed) to better

understand the associations among symptoms, the

menopause, declining hormone levels, and disease.

Studies of the effects of hormone therapy can be

conducted as trials (which are usually randomized)

to determine the safety and efficacy of the treatment

(46). Randomized intervention trials and observational studies are both epidemiologic research; both

are expensive and time-consuming because of the

need to conduct studies that are large enough to have

adequate statistical power to distinguish among a

variety of potential effects.

In randomized trials, participants are randomly

assigned either to a group that will be treated with

the factor of interest (in this case, either estrogen

therapy (ET) or combined hormone therapy (CHT))

or to a group that will receive placebo treatment.

(Sometimes this group receives the “standard”

treatment rather than a placebo.) The purpose of

randomization is to equalize other causes or correlates of the disease across the treatment groups; it is
82 . The Menopause, Hormone Therapy, and Women’ s Health

particularly valuable for equalizing the distribution

of causes that are unknown or not readily measured.

Sometimes randomization is infeasible, unethical,

or unnecessary. In the absence of randomized trials,

cause and effect can often be established by the

results of observational studies, which, taken together, rule out explanations other than causality.

Some of these ‘other explanations’ include chance,

selection bias, and information bias (46). A number

of ongoing investigations have attempted to evaluate

the effects of the menopause and treatment. Most of

these studies have been observational and have

contributed to a greater understanding of the menopause and the health of women.

Understanding the Effects of the Menopause

It is not possible to use randomized trials to assess

the effects of the menopause on the occurrence of

disease: a researcher cannot assign the age at which

natural menopause will occur in a woman, and it

would be unethical to randomly assign women to a

group that would undergo surgical menopause

merely for the sake of a research protocol. Observational studies are adequate research designs in most

instances. A key concern in such studies, though, is

the possibility of a biased assessment of the effects

of surgical menopause, which could result from the

‘‘selection’ of women to this procedure; i.e.,

women who undergo surgical menopause may be at

higher or lower risk for certain diseases.

Observational studies, particularly case-control

and followup studies, have provided considerable

evidence about the effects of the menopause on a

woman’s risk for a variety of diseases. The data

indicate that natural or surgical menopause at an

early age reduces the risk of breast cancer (27) and

increases the risk of osteoporosis (38), and that

surgical menopause at an early age increases the risk

of cardiovascular disease (53). Problems posed by

differences between natural and surgical menopause and subsequent risks for disease can be

overcome by conducting large studies that have

adequate statistical power to distinguish among

the different effects.

I Evaluating the Effects of Hormone Therapy

Unlike research on the menopause per se, assessing the health effects of hormone therapy may

, require more rigorous research than is possible

, through observational studies (2,62). Bias may be a

difficult, even intractable, problem with observational studies because women often ‘select’ themselves to receive therapy (or their doctors select

them). For example, hormone users may differ from

nonusers in terms of factors that influence the risk of

acquiring cardiovascular disease but that are unknown or difficult to measure. If the selection factors

(i.e., factors that would “cause” a woman to use

hormones) are strongly related to the risk of the

disease in question, it maybe necessary to conduct

trials in which women are assigned randomly to

receive hormone therapy or placebo to ensure that

the selection factors—and their effects-are equalized between hormone users and nonusers.

The confounding action of such factors is known

as selection bias. Because factors responsible for a

woman’s assignment to a group in a nonrandomized

trial influence the results of the trial in ways that

cannot be quantified or even identified, researchers

cannot be certain that the effects being observed are

attributable to treatment or to extraneous or accompanying factors (6). For example, many studies do

not provide the reasons for prescribing or not

prescribing estrogen for a woman. Because physicians prescribe estrogen most frequently for symptomatic relief, users initially may be physiologically

different from nonusers in their susceptibility to

symptoms, and this may be related, in turn, to

susceptibility to subsequent disease. Alternatively,

women who are found in the nonuser category in

studies may be intolerant to hormone therapy, and

are thus different from users by virtue of physiological factors that influence tolerance.

It has long been suspected that selection bias

might be contributing to a “healthy user” effect in

hormone therapy studies. Doctors may not prescribe

hormones, or may discontinue their use, for women

with preexisting illness, women with a family

history of contraindications (e.g., cancer or liver

disease), or women who develop such contraindications during therapy. This kind of confounding

effect could result in an apparent excess of morbidity

or mortality in nonusers of hormones, compared

with users. A healthy user effect can also occur as a

result of better medical care: physicians require

hormone users to undergo more frequent physical

examinations than nonusers to renew their prescriptions.

In observational studies, selection factors can be

taken into account by statistical “control” for
Chapter 5-Current Research and Future Needs ● 83

confounding variables such as cigarette smoking,

hypertension, and a wide range of other factors that

may be related both to hormone use and the risk of

disease (54). If statistically controlling for such

variables does not alter the results of the study, an

absence of bias is assumed. There are circumstances,

however, in which statistical control maybe inadequate. Factors generally considered under the headings of “lifestyle” or ‘socioeconomic status” may

be related to the risk of particular diseases, and they

may also be strongly related to the decision to

commence or adhere to hormone therapy. But it may

be difficult or impossible to control for the effects of

these factors because they cannot be measured with

adequate precision. In that case, it may be possible

to achieve adequate control only by means of

randomization.

For many years, these methodological uncertainties have led to doubts about the existence of a

relationship between cardiovascular disease and

estrogen therapy. In 1991, however, the Nurses’

Health Study (54) addressed many of these concerns

about the effects of selection bias. The study design

controlled for the various confounding variables,

and the results of the study demonstrated an

association between the use of estrogen and reduced

risk of coronary artery disease.

Controlled, randomized prospective trials can

overcome the confounding effects of selection

bias by randomly assigning participants to experimental groups. This kind of study design can

produce an unbiased assessment of the effects of

hormone therapy vis-à-vis its risks and benefits,

but it cannot provide an understanding of the

whole scope of risks and benefits. Some effects are

simply too uncommon to be assessed, even in a

large, randomized trial. In addition, some effects,

such as reduced mortality from hip fracture, take a

long time to become manifest (51).

With the exception of the Healthy Women’s

Study, the Massachusetts Women’s Health Study,

and future findings from PEPI, the preceding largescale studies provide, at best, quite limited information on normal hormonal and physiological changes

in women as they progress through the menopausal

years. Other, smaller-scale studies offer little additional help. Moreover, few ongoing studies include the objective of evaluating longitudinal

changes (beginning with premenopausal women)

to determine the effect of ovarian hormone

deficiency on the endpoints of other diseases (in

addition to cardiovascular conditions) whose

clinical presentation may be temporally removed

from the menopause.

Requirements for a Randomized Trial of

Hormone Therapy

Randomized trials to assess the health effects of

hormone therapy must be large enough to detect

protective effects against cardiovascular disease and

osteoporosis (or fractures); they must also be of

sufficient duration to detect effects that may occur

only after relatively long use. Both the use of

unopposed estrogen and combination therapy

should be assessed. In addition to cardiovascular

disease and osteoporosis and fractures, other outcomes of interest are breast cancer, endometrial and

other gynecologic cancers, and cerebrovascular

disease. Also worth studying (from the risk side of

the benefit-risk ratio) is hysterectomy and the

morbidity associated with this procedure: concerns

have been raised that women receiving hormone

therapy are more likely to undergo hysterectomy,

possibly because bleeding is a side effect of use

(2,62).

Trials should be designed to assess both incidence

and mortality. Comparisons of total morbidity and

mortality among the treatment groups are important

for determiningg overall risks and benefits, but an

‘‘overall’ comparison is insufficient to better understand individual risks. For example, researchers

should compare effects among various age groups

because the benefit-risk ratio may be different at

different ages. For hormone therapy, the major

benefits may be seen among older women, whereas

the major risks may be borne by younger ones; such

an outcome would influence the interpretation of the

benefit-risk ratio for hormone therapy. The costs of

the drug and medical care for each treatment group

should also be considered in the comparison of

benefits and risks (45).

It will be desirable to continue following participants after a trial ends because the adverse effects of

hormone therapy on the risk of breast cancer may not

become apparent for a number of years. Randomized trials of hormone therapy will be neither

easy to conduct nor inexpensive. For both cardiovascular disease and osteoporosis, the protective

effect of estrogen therapy appears to be related to the

duration of use: women may have to take the drugs
84 . The Menopause, Hormone Therapy, and Women’s Health

I

for relatively long periods (10 to 15 years) before a

protective effect becomes apparent. Hormone therapy, particularly combination therapy, can have

unpleasant side effects. To be successful, a trial to

detect the effects of long durations of hormone

therapy use must include major efforts to encourage

adherence to therapeutic regimens (45).

The Women’s Health Initiative Trial

The Women’s Health Initiative intervention trial,

proposed by NIH, includes a randomized trial of

hormone therapy, currently in the planning stages.

The trial will assess not only hormone therapy but

the effects of a low-fat diet and calcium/vitamin D

supplements as well. It is fashioned as a ‘3 x 2 x 2’

factorial design in which women who agree to

participate will be randomized first to one of three

groups: estrogen alone, a progestin and an estrogen,

or a placebo. Each of these groups will then be

divided into a low-fat diet or a no-diet group

(creating six study groups). These six study groups

will each be randomized once again-into calcium/

vitamin D-supplementation or no-supplementation

groups. (The scientific justification for trials of the

low-fat diet and of calcium/vitamin D supplements

has been questioned by some epidemiologists (45,51).

For purposes of the present discussion, however, the

assumption is made that these interventions are

justified.)

The designers of the trial believe that a factorial

design is more “efficient” than separate trials,

because fewer women are needed than if each

treatment were being tested in a separate trial. This

argument would be persuasive if the treatments had

few and minor side effects and if they were simple

to administer (e.g., a single pill taken daily). For

example, in the Physician’s Health Study, which

used a ‘‘2 x 2" factorial design in which men were

assigned to aspirin only, beta carotene only, both, or

placebo, there was a‘ ‘run-in’ phase before the trial

to screen out men who had serious side effects; in

addition, each of the men took only a single pill per

day (55). In the Women’s Health Initiative trial,

however, one treatment does not meet the requirement of having few and minor side effects, and

another is not simple to administer: hormone therapy—particularly combination therapy-has common and serious side effects (e.g., bleeding) that

discourage adherence, and the low-fat diet requires

major changes in the choice and preparation of

foods. Good adherence to these treatments will

require a serious commitment on the part of the

participants over along period of time (9 years is the

planned length of the trial).

No feasibility studies have been conducted to

test whether women will adhere to hormone

therapy coupled with any of the other treatment

conditions (i.e., low-fat diet, calcium/vitamin D

supplementation), nor are there plans to carry

out such investigations. Yet several sources suggest that adherence over the long run may be a

problem. These include data from observational

studies on the proportion of women who have ever

used hormone therapy and who use it for long

periods (2); experience with adherence problems in

the PEPI trial, a randomized trial of hormone therapy

(2); and results from a feasibility study of adherence

to a low-fat diet (21). It is reasonable to predict that

adherence to multiple treatments will be poor,

particularly over a period of 9 years. Consequently,

the likelihood is high that the trial, as designed, will

fail to detect treatment effects, even if they exist

(45).

FILLING THE RESEARCH GAPS

Only in the past few decades have researchers

begun to understand the potential effects of ovarian

hormone levels on morbidity and mortality, effects

that appear to be of even greater import in the light

of increasing life expectancies for U.S. women. A

hormonal component is now believed to be involved

in the etiology of osteoporosis and probably in the

cardiovascular diseases as well. Metabolic alterations are possible during the perimenopause and

may occur in very different biological systems.

The implications of short-term menopausal

symptoms for subsequent pathophysiology, as

well as the effects of the symptoms themselves,

have never been studied. Undoubtedly, the absence

of an understanding of ovarian hormone action and

of the effects of ovarian hormone levels on nonreproductive target tissues has severely constrained

the generation of hypotheses. A further complicating

factor is the marked differences among women with

respect to the manifestation of menopausal symptoms and susceptibility to chronic diseases. A major

challenge in research to develop strategies to prevent

disease and maintain the health of older women lies

in exploring the consequences of acute, short-term

symptoms, as well as the effect of long-term

reductions in ovarian hormones on the development
Chapter 5--Current Research and Future Needs ● 85

of disease—particularly conditions that have a long

latency period or that are temporally removed from

the menopause.

As the proportion of older women in the population continues to grow, the need to focus on the

prevention of morbidity and disability in this group

increases as well. Prevention will require an understanding of the potential effect of modifying lifestyle

variables (e.g., nutrition, exercise, smoking) and the

identification and use of appropriate intervention

strategies (both hormonal and nonhormonal). Determining appropriate strategies requires substantially

improved knowledge of the natural history and

sequelae of the menopause, and of the role of

exogenous and endogenous estrogens and progestins in the etiology and prevention of disease.

An understanding of the physiological consequences of reduced ovarian hormone levels requires

protocols and subject selection procedures that can

assess the effects of age and type of menopause

(natural or surgically induced by hysterectomy or

bilateral oophorectomy) on intermediate biological

variables and, ultimately, on the risk of disease.

Sensitivity to the potential roles of age and type of

menopause is also important in assessing the

effects of hormone therapy because there may be

marked differences between younger and older

women in tissue-specific responses to therapy

and in the benefits to be realized in oophorectomized women compared with those who experience a natural menopause. Other important covariates include the time elapsed since the menopause

before commencement of hormone therapy, as well

as a woman’s history of prior use of hormones.

Biological Systems That Deserve

Special Attention

The Ovary

Normal variations in the cyclical hormone patterns of premenopausal women and age-related

changes in the patterns of secretion of the gonadotrophins and of estrogen and progesterone are still

incompletely understood. Assessments of postmenopausal ovarian function are needed to compare the

risks and benefits of ovarian conservation when

hysterectomies are performed. Greater understanding of the reasons for the continued production of

estrone (a weaker estrogen), androgens, and testosterone by the ovaries of some postmenopausal

women is also required (47). Improved knowledge

of the function of the postmenopausal ovary is

essential to determine whether the current surgical practice of removing healthy as well as

diseased ovaries during a hysterectomy is warranted. Basic research questions include the following:

●

●

●

●

●

●

●

What factors differentiate those women with

continued ovarian secretory capability from

those without such capability?

What does a fictional postmenopausal ovary

secrete, and how long does it remain functional?

What are the advantages and disadvantages of

continued ovarian production of these steroid

hormones or precursors?

Are there fewer or less severe menopausal

symptoms among women with continued ovarian secretion?

Are rates of bone loss lower in these women?

Do they have an increased risk of reproductive

tissue cancer (increased breast, endometrial, or

ovarian cancer)?

Does a more androgenic ovarian output pose

increased risk of cardiovascular disease?

The symptoms of reduced ovarian hormone levels

(especially the intensity and frequency of hot

flashes) are more severe in oophorectomized women

than in women who experience a natural menopause

(31); oophorectomized women are also more likely

to report depression, loss of libido, and dyspareunia

(12). Epidemiological studies show that, compared

with women who experience the menopause naturally, oophorectomized women have an increased

risk of cardiovascular disease (19,14) and significantly greater rates of bone loss (23). Research that

controls for or evaluates the role of age at the time

of oophorectomy is critical to an objective assessment of the consequences of oophorectomy compared with those of the menopause. For example, the

risk of breast cancer is substantially reduced by

premenopausal oophorectomy—the degree of protection being related (inversely) to the age of the

woman at the time of surgery (57). To better

understand the relationship between current medical

practice and long-term health outcomes, the following questions need to be answered:

. How widespread is the practice of prophylactic

oophorectomy in pre- and postmenopausal

women, and why are there regional differences?
86 . The Menopause, Hormone Therapy, and Women’s Health

i

I

●

●

●

●

What are the factors that influence judgments

by physicians regarding the necessity of removing healthy ovaries?

What are the risks and benefits of oophorectomy?

Can women who undergo oophorectomy be

assured that they will be able to tolerate

hormone therapy and that it will have beneficial

effects comparable to those offered by potentially 5 to 10 years of endogenous gonadal

hormones?

Will long-term use of hormone therapy be

required for oophorectomized women, and if

so, will this increase the risk of (breast) cancer?

In addition to oophorectomies, hysterectomies

and tubal ligations are common surgical procedures

among U.S. women. Hysterectomies are performed

in many pre- as well as postmenopausal women.

Tubal ligations may be performed in relatively

young, fertile women to prevent conception. Although data are scarce, this procedure may be

associated with gonadal hormone deficiency and

such symptoms as dysfunctional uterine bleeding

and menorrhagia (1 1).

The effects of hysterectomy and tubal ligation on

ovarian function are currently unknown, although

studies have shown that hysterectomized women

experience more severe menopausal symptoms (44,

49). Do these procedures compromise ovarian function and hasten menopause in premenopausal women?

Clearly, more research is necessary to understand

the consequences of elective pelvic procedures for

ovarian function.

The Breast

Some observational studies suggest that the use of

unopposed estrogen or of combined hormone therapy, particularly for many years, may result in small

increases in the risk of breast cancer (17,56). As is

the case for osteoporosis, bias owing to selection

factors is less likely to be a problem in these studies

than in studies of cardiovascular disease. Women

who are more highly educated are at increased risk

of breast cancer, whereas thin women are at lower

risk. Thus, potential bias from selection factors is not

consistently in one direction, as it is in studies of

cardiovascular disease.

Randomized trials that are designed to assess

whether hormone therapy increases the risk of

breast cancer cannot be carried out because it is

unethical to test a drug that is believed to have

either a harmful effect or no effect on the

occurrence of the disease in question. Therefore,

information about breast cancer from randomized trials must come from trials designed to

assess possible protection against other diseases.

These data may be sparse because trials designed on

the basis of the sample sizes needed to detect

protection against cardiovascular disease and osteoporosis may be too small to detect increases in the

risk of breast cancer. In addition, such increases may

be related to longer durations of use than are required

to reduce the risk of cardiovascular disease or

osteoporosis. (For this reason, continued followup

after the trial is desirable.) Thus, some information

will be available from trials, but the most informative data on the influence of hormone therapy on the

risk of breast cancer may come from observational

studies (45).

Observational studies (case-control and followup studies) of hormone therapy in relation to

breast cancer risk must be large enough to detect

relatively small increases in risk that may occur

after very long durations of use or well after use

is completed. It is particularly important to assess

combination therapy because the few data currently

available on this regimen raise the concern that it

may increase the risk of breast cancer more than

unopposed estrogen (17,56). It will also be important to control carefully for the age at menopause:

because the risk of breast cancer is less for women

who experience an early menopause, and because

such women are also likely to use hormone therapy

for longer periods than women who experience a

later menopause, failure to adequately control for

age at menopause could mask a harmful effect of

hormone therapy on the risk of breast cancer.

Glucose and Lipid Metabolism

The role of declines in ovarian hormones in

age-related increases in insulin resistance and the

development of adult-onset or type II diabetes is

another important issue that deserves study. Insulin

resistance has profound adverse effects on glucose

and lipoprotein metabolism and may play a prominent role in atherogenesis and cardiovascular and

renal diseases. Yet information is limited both on the

effects of transmenopausal hormonal changes and

on the influence of exogenous estrogen or progestins

(4). There is a critical need for an objective

evaluation of short- and long-term effects of pro-
Chapter S-Current Research and Future Needs ● 87

gestins on insulin secretion and action because

previously progestins have been associated with the

development of insulin resistance and compensatory

hyperinsulinemia in experimental studies with rhesus

monkeys and in studies of oral contraceptive use in

women (3). Most important, although short-term use

of progestins may not adversely affect glucose

metabolism, after 6 months of use, a progressive

hyperglycemia and hyperinsulinemia may occur

(39). A recent report showed that glucose tolerance

and fasting and 2-hour insulin levels were not

adversely affectedly the use of a progestin (Provera)

in combination with Premarin, compared with unopposed Premarin; however, the study did not consider

duration of use of the combination form (3). The

PEPI trials will address some of these concerns.

There is considerable evidence that the responsiveness of glucose and lipid metabolism in women,

particularly premenopausal women, to diet, weight

loss, and exercise is considerably less than the

responsiveness in men of the same age (l). In the

case of exercise, responsiveness in postmenopausal

women may become more like that in men, implying

that endogenous estrogen may act as a physiological

buffer, dampening the response of lipids to such

factors as diet, weight loss, and exercise. This and

many other issues related to lipid metabolism and

the effects of postmenopausal hormone therapy have

yet to be examined (33). Body fat distribution, which

is believed to be important in differentiating lipoprotein risk factors in men and women, may be an

important risk factor for men that is not present in

women (33,42).

A highly atherogenic form of low-density lipoprotein that appears in increasing quantities after

menopause (9) also deserves further investigation,

as does lipoprotein (a), which increases throughout

the menopausal years (33). The effects of estrogen

or progestin on the levels of these lipoproteins are

unknown (33).

Cardiovascular System

The bulk of research regarding the role of estrogen

in cardiovascular disease has focused on changes in

lipid and lipoprotein metabolism. Considerable evidence indicates that an important component of the

reported cardioprotective effect of exogenous (unopposed) estrogen is mediated by elevated HDL

cholesterol and, to some extent, by reduced LDL

cholesterol (34). Because of the ongoing development of different estrogen preparations and routes of

administration, as well as changes in the formulation

and scheduling of progestins (which area necessary

component of hormone therapy for women with a

uterus), the effects of such therapy on lipid metabolism will continue to be an area of active research.

Important variables in natural history studies of

the menopause as well as in controlled randomized

trials of the use of estrogen and progestin include

effects on blood pressure and blood coagulation

factors. Another important area of study is the effect

of lipoprotein metabolism changes on the vessel

wall and on the atherogenic process itself, including

effects on cholesterol uptake, vascular reactivity,

plaque formation, oxidation of lipoproteins, and

local platelet function (33). The long- and short-term

effects of progestins on hemostasis and blood

pressure are obviously of great concern because

thromboembolic and hypertensive episodes were

associated with early use of oral contraceptives. The

PEPI trial will address some of these concerns.

Other critical areas of study in humans are the

assessment of transmenopausal changes and of

changes in coronary perfusion, cardiac output, and

physical performance that result from hormone

therapy. As discussed in box 5-A, the development

of animal models—in particular, studies using

ovariectomized monkeys-shows great promise for

studies of the direct effect of estrogens and progestins on the production and amelioration of

human-like atherosclerosis.

Much of the available evidence from observational studies suggests that estrogen users have a

reduced risk of cardiovascular morbidity and mortality (17,54); thus, an important issue to be addressed

is whether women with preexisting cardiovascular

disease will likewise benefit from hormone therapy

and in what ways. Also deserving of study is a

determination of the effects of hormone therapy

among women with known risk factors (e.g., hypertension, hyperlipoproteinemia) for cardiovascular

disease.

Randomized trials are needed to determine

what proportion, if any, of the observed reduction in risk is due to a real effect of estrogen and

what proportion, if any, is due to selective use of

estrogen by women already at reduced risk of

cardiovascular disease. Such a trial would, of

course, also assess the effect of combination therapy.

There is as yet no informative evidence on the effect

of this drug regimen; because progestins can affect
88 . The Menopause, Hormone Therapy, and Women’s Health

Box 5-A—Development of Animal Models for the Menopause

Animal models are useful in understanding basic biological mechanisms, formulating hypotheses, and

providing evidence of cause-and-effect relationships. It is generally difficult, expensive, or time-consuming to study

risk factors in humans because tissues affected by pathophysiological changes may not be readily (or ethically)

available and decades may be required for the manifestation of pathophysiological processes. Furthermore,

reproducible outcomes, which are fundamental to establishing direct evidence of cause and effect, may be

confounded by the severely limited ability to ensure compliance-that is, to control for lifestyle and environmental

variables in free-living populations. An additional problem in securing such outcomes is the difficulties that arise

in trying to use randomized designs, which prevent bias in the allocation of subjects to treatment regimens.

Although rats have a strain-dependent 4- or 5-day estrus cycle (rather than a 28-day menstrual cycle) and do

not experience a menopause, the ovariectomized rat has been proposed and used as an animal model for human

postmenopausal osteoporosis, because the loss of ovarian hormones in rats, as in women, results in decreased bone

density and more fragile long bones. As in oophorectomized women, ovariectomized rats also have deficits in

intestinal calcium absorption, which contribute to the loss of bone mass.

Although it is commonly believed that the ovariectomized rat is not the best animal model because its skeleton

continues to grow, this finding is probably not due to any species-specific anomaly but rather to the use of juvenile

animals that have not attained skeletal maturity. The selection of a mature rat (before ovariectomy is performed)

is essential as a paradigm, because bone loss in postmenopausal women obviously occurs only after the attainment

of skeletal maturity. Although the ovariectornized rat is a convenient, practical animal model of bone loss,

significant differences in bone morphology with respect to the organizational pattern of skeletal components,

compared with humans, limit its widespread use+

Attempts have been made to overcome this drawback as well as to develop an animal model that has a more

relevant reproductive physiology and that is susceptible to atherogenesis. Researchers at the Arteriosclerosis

Research Center (ARC) and Comparative Medicine Clinical Research Center at Wake Forest University’s Bowman

Gray School of Medicine (Winston-Salem, NC) have begun evaluating the utility of cynomolgus monkeys as

models for menopause-related pathophysiology.

For the past decade, researchers at the ARC have conducted randomized, controlled intervention trials using

cynomolgus monkeys to explore the physiological and cellular mechanisms by which estrogens and progestins

affect not only bone metabolism and bone density but also coronary artery atherogenesis and vascular tissue

responsivity. Because this species of monkey is susceptible to diet-induced atherogenesis, and because female

cynomolgus macaques have a reproductive physiology more comparable to that of humans than the reproductive

physiology of other primates, these investigators have been able to study directly and simultaneously the role of

ovarian hormones on endpoints of both atherogenic and osteoporotic processes. Their investigations have produced

valuable insights that would be impossible to achieve from studies of humans.

Scientists from the ARC have provided substantial evidence that the ovariectomized female cynomolgus

macaque is a highly appropriate model for the study of menopause-related pathophysiology. The center has studied

the effects of ovariectomy and ovarian hormone treatment on bone histomorphometry, bone density, and

biochemical parameters of bone metabolism. Researchers have also observed changes in histomorphometric

parameters (indicative of a loss of architectural elements) and biochemical markers of bone breakdown that are

similar to those seen in postmenopausal women with osteoporosis.

With regard to cardiovascular disease, ARC studies have shown that coronary artery atherosclerosis in female

cynomolgus monkeys appears to be morphologically similar to that in women. Furthermore, ovariectomy in this

species results in a doubling of the extent of atherosclerosis. Most important, these investigators observed that

ovariectomized monkeys given estrogen or estrogen plus progesterone showed a marked inhibition in the

progression of atherosclerosis compared with ovariectomized monkeys receiving placebo. It thus appears that the

ovariectomized cynomolgus monkey may be a highly appropriate model to study the pathogenesis of age-related

diseases in middle-aged and older women.

SOURCES: Office of Technology Assessment adapted from C. Gennari, D. Agnusdei, P. Nardi, et al., “Estrogen Preserves a Normal Intestinal

Responsiveness to l,25-Dihydroxyvitamin D3 in Oophorectomized Women” Journal of Clinical Endocrinology and Metabolism

71(5):1288-1293, 1990; R.P. Heaney, R.R. Reeker, and P.D. Saville, “Menopausal Changes in Bone Remodeling,” Journal of

Laboratory and Clinical Medicine 92(6):964-970, 1978; D.N. Kalu, C.-C. Liu, R.R. Hardin, et al., “The Aged Rat Model of Ovarian

Hormone Deficiency Bone Loss,” Endocrinology 124(1):7-16, 1989; P.D. Saville, “Changes in Skeletal Mass and Fragility With

Castration in the Rat: A Model of Osteoporosis,’ Journal of the American Geriatric Society 17(2):155-166, 1969.
Chapter 5-Current Research and Future Needs ● 89

serum lipids adversely, the effect of combination

therapy on the risk of cardiovascular disease may not

be favorable (17).

Finally, better understanding of the role that

estrogen plays in protecting premenopausal women

against cardiovascular disease may lead to better

diagnosis and treatment of cardiovascular disease in

postmenopausal women. For example, some researchers have suggested that the perception that

women tolerate cardiovascular disease better than

men and hence have a better prognosis may be due

in part to the inclusion of women without cardiovascular disease (who are misdiagnosed as having

angina) in female patient populations with cardiovascular disease (64). This misunderstanding of the

clinical presentation and prognosis of the disease in

women may in turn lead to less aggressive preventive interventions (e.g., prescribing therapies, risk

factor modification) and the postponement of referral for further noninvasive testing. Because women

may be referred for procedures such as coronary

bypass surgery later in the course of their disease

than are men, they may be older and their condition

more serious; not surprisingly, they experience

increased operative mortality (29). As this one

example demonstrates, deficiencies in the ability

to diagnose cardiovascular disease in women and

ultimately deliver better medical care can be

corrected only by increased understanding of the

etiology and course of cardiovascular disease in

this population group.

Skeletal System

Given the bone status of those women already

diagnosed as osteoporotic, it is estimated that half of

all Caucasian women will develop vertebral fractures and one-third will suffer hip fractures by the

age of 90 (43). Yet at least 50 percent will not have

osteoporotic fractures even in extreme old age.

Although estrogen deficiency undoubtedly plays a

major role in the development of this disease by

increasing the rate of bone loss throughout the

skeleton, not all perimenopausal women lose bone at

the same rate. Furthermore, although enhanced

perimenopausal bone loss occurs at all sites, the

effect of reduced endogenous estrogen levels on

rates of loss varies from site to site; that is, the spine

shows the greatest rate of estrogen-sensitive loss

compared with the hip and radius, which reflect a

greater component attributable to age.

Because estimates of bone loss in women may

be based on study populations that commingled

oophorectomized women with those who had

experienced a natural menopause (not to mention

smokers, women who never exercised, and women

with a variety of other contributing risk factors),

perceptions of what constitutes a “normal” rate

of menopausal bone loss may be distorted, leading to overestimates of the number of women who

are at risk for osteoporosis. The effects of a natural

menopause (and of reduced ovarian hormone levels)

need to be evaluated separately and compared with

the effects arising from oophorectomy (and from

ovarian hormone deficiency) on site-specific rates of

bone loss. These studies should also include an

assessment of the effect of age at menopause (and

years from menopause) on rates of bone loss.

Answers to these questions may help distinguish

women who lose bone quickly from those who lose

bone slowly.

Sensitive, specific metabolic markers are needed

to indicate when skeletal depletion is occurring and

to help monitor both early and later responses to

treatment. Such markers should be capable of

quantifying bone resorption and formation and the

degree of imbalance between the two (59).

Research is also needed at the cellular level to

determine the role of in vivo estrogen deficiency and

the effects of estrogen therapy on the factors that

regulate the coupling of processes of bone formation

with those of bone resorption. Many physicians

advocate estrogen therapy as the most effective

available treatment for prevention of osteoporosis,

but it is not clear how long estrogen (or combined

therapy) should be prescribed to prevent fractures in

later life. Also unknown is the length of time during

which hormone therapy is effective in preventing or

reducing rates of bone loss.

Research is needed to answer the following

questions:

●

●

●

●

Is estrogen therapy as effective in the femur as

in the vertebrae?

What is the effect of long-term progestin use on

skeletal mass?

What is the cumulative effect of periods of

starting and stopping estrogen, a practice believed to be common among users of hormone

therapy (26,37)?

Are the effects of estrogen cumulative, or is

there a threshold in terms of duration of use? Is
90 • The Menopause, Hormone Therapy, and Women’s Health

●

●

there an acceleration of bone loss when therapy

is discontinued?

Do the benefits to be realized (in bone density

maintained or fractures reduced) depend on the

age of the patient or the number of years

postmenopause?

Is the initiation of estrogen therapy in postmenopausal older women (over age 65) effective in

preventing further bone loss and fractures?

Many observational studies suggest that both the

use of unopposed estrogen and of combined therapy

reduce the incidence of osteoporosis (or fractures)

(17). Bias resulting from selection factors is likely to

be less of a problem in these studies than in studies

of cardiovascular disease. Thinness is related to an

increased risk of osteoporosis and physical activity

to a decreased risk. The presence of bias as a result

of thin women ‘selecting’ themselves for hormone

therapy will be in the direction of underestimation of

a protective effect of therapy, whereas bias owing to

the self-selection of physically active women will be

in the direction of overestimation. In contrast, bias

from selection factors in studies of cardiovascular

disease is more consistently in the direction of

producing an apparent protective effect of hormone

therapy. If the only issue, then, was the effect of

hormone therapy on the risk of osteoporosis, randomized trials might not be deemed necessary.

However, in the context of trials to assess the effects

of hormone therapy on cardiovascular disease, it is

worthwhile to assess osteoporosis as well.

Nutrition, Energy Balance, and

Body Composition

With the exception of considerable clinical data

on calcium consumption, few studies of middleaged women have examined the effects of the

menopause or of hormone therapy on the requirements for vitamins, minerals, and other nutrients.

Alterations in the efficiency of absorption, excretion, and metabolism of various nutrients are known

to occur during periods of altered ovarian hormone

levels such as those that occur during pregnancy or

oral contraceptive use. It was also demonstrated

recently that oophorectomy reduces calcium absorption (18). Because it is likely that the efficiency of

processes related to nutrient assimilation, utilization, and retention may be compromised or altered

by the ovarian hormone deficiency characteristic of

the menopausal period, actual nutrient requirements

may be different in peri- and postmenopausal

women compared with premenopausal women. Considering the potential impact of nutrition on the

prevention or modification of disease processes, an

assessment of nutrient requirements in menopausal

women should be an area of high priority.

Data on the relationships among weight gain and

changes in dietary patterns and caloric intake in

middle-aged women are also severely limited, particularly with regard to changes in ovarian hormone

status. Increases in weight are common in middleaged women and are strongly associated with

enhanced risks of diabetes and cardiovascular disease (66). In fact, an increased risk of cardiovascular

morbidity and mortality-which persisted even after

controlling for the influence of weight on blood

pressure and cholesterol—has recently been demonstrated in overweight, middle-aged women (35).

Although the effects of hormone therapy on body

weight in humans have not been systematically

explored, it has been reported that estrogen users

appear to be significantly slimmer and taller than

nonusers at all ages (4). Studies in rodents (63) and

nonhuman primates (28) have shown that the

gonadal hormones exert profound effects on food

intake, weight gain, and body composition. For

example, ovariectomy in rodents is associated with

overeating, rapid and profound increases in body

weight, and obesity. These changes can be prevented

or reversed with estrogen treatment. The addition of

a progestin, however, counteracts the effect of

estrogen and leads, again, to increases in weight and

obesity (63). Knowledge of the effects of estrogen,

especially in combination with progestins, on the

regulation of energy balance and adiposity in

middle-aged women is critical to appropriate prescribing of hormone therapy. (See box 5-A for a

discussion of animal models.)

Renal Function

Few studies of renal physiology have focused on

women in general, let alone on transmenopausal

changes or changes as a result of hormone therapy.

The kidney plays a major role in mineral homeostasis. Ovarian hormone deficiency and hormone

therapy are known to produce marked changes in

serum levels and urinary excretion of calcium and

phosphorus. An assessment of age- and menopauserelated alterations in renal function (particularly in

renal tubular function) will foster a better understanding of mineral homeostasis in women of all
Chapter 5-Current Research and Future Needs ● 91

ages and provide an additional perspective on

peri- and postmenopausal bone loss (47).

A study of water and electrolyte metabolism, with

which the kidney is integrally involved in both

pre- and postmenopausal women, could lead to

better understanding and hence more effective

treatment of problems related to water retention and

bloating. Such problems, which commonly occur

both premenstrually and as an unwanted side effect

of hormone therapy (often resulting in reduced

compliance with many hormone regimens), can

have marked adverse effects on the quality of life of

young and old women.

Pharmacology

It is presently assumed that any given pharmacologic agent administered to women will have similar

action, metabolism, and disposition, regardless of

where a woman maybe in her menstrual cycle or of

whether she is having regular cycles. Such an

assumption is also made regardless of whether a

woman is taking oral contraceptives or is postmenopausal and receiving hormone therapy. This assumption is surprising, given the possibility of profound

metabolic alterations (e.g., those reflected in severe

vasomotor instability or in changes in bone mineral

metabolism) that may result from the menopause,

oophorectomy, or hormone therapy. Scant attention

has been focused on the issue of whether ovarian

hormone status itself or alterations of metabolism

secondary to changes in ovarian hormone status may

affect pharmacodynamic responses.

Oophorectomized women who are not taking

estrogen show a marked reduction in vertebral bone

density and a substantial decline in intestinal calcium absorption compared with presurgery baseline

values. Oophorectomized women receiving estrogen therapy show no decline in bone mass or

calcium absorption (18). This suggests that comparable or presumably adequate blood levels of a given

drug or minerals do not ensure comparable pharmacodynarnics in physiological states that are dissimilar because of ovarian hormone status (whether as a

result of oral contraceptive use, menopause, or

hormone therapy). The question of impaired or

altered action of other pharmacologic agents on

other tissues as a result of changes in the levels of

ovarian hormones calls for critical examination. The

efficacy and side effects of drugs should be assessed

in populations of women whose ovarian hormone

status reflects that of future users of the drugs.

Exercise

Experts increasingly advocate physical activity

and exercise as being of benefit to the cardiovascular

and skeletal systems and contributing to a sense of

overall well-being by their positive effects on mood.

Sedentary behaviors and physical inactivity, on the

other hand, are associated with a higher incidence of

coronary heart disease and with underlying risk

factors for atherosclerosis-- e.g., obesity, hypertension, and diabetes (40).

Although physical fitness and cardiovascular

disease are not well studied among women, researchers have shown that in comparison with

sedentary women, women who regularly engage in

endurance activities have higher HDL cholesterol

levels (40). Furthermore, women who participate in

aerobic conditioning show improvements in glucose

tolerance and response to insulin (61). Studies have

also found that women who exercise have reduced

mortality from cardiovascular disease and cancer,

leading to a fourfold reduction in mortality from all

causes (5).

To achieve maximal benefits for the skeleton, it is

believed that exercise that has a significant weightbearing component is necessary (41). Although

moderate exercise may be effective in increasing or

preserving bone mass in the lumbar spine in

postmenopausal women, it is unclear whether the

beneficial effects of exercise extend to the period of

accelerated bone loss during the perimenopause. A

number of important questions arise regarding

specific recommendations for exercise prescription

in women. The effects of exercise on site-specific

changes in bone mass, on risk factors for cardiovascular disease, and on long-term endpoints such as

fractures and cardiovascular morbidity and mortality

all need to be evaluated. In particular, research is

needed to establish guidelines on the type, intensity,

frequency, and duration of exercise necessary to

derive maximal benefits to both the musculoskeletal

and cardiovascular systems and to avoid ineffective

training and possible injury. In older women, the

interaction of exercise with lifestyle or environmental factors such as nutrition or hormone therapy

deserves study, because it has been demonstrated

among younger women that calcium consumption

plays an important role in optimizing the potential

benefits of physical exercise on the skeleton (24).
92 ● The Menopause, Hormone Therapy, and Women’s Health

Effects of Ovarian Hormone Levels:

Modalities of Study

Given the present dearth of data, both short- and

long-term multidisciplinary observational studies

could make substantial contributions to an understanding of the natural history of the menopause.

Cohorts (of a sufficiently broad age range) of

premenopausal and postmenopausal women should

be included in initial subject populations to generate

immediate cross-sectional comparative data, as well

as to establish premenopausal values for the assessment of transmenopausal changes and long-term

outcomes. These studies should be multidisciplinary, cutting across the major biological and psychosociocultural systems. They should assess the role of

reproductive history vis-à-vis pregnancy and lactation, as well as the effects of cumulative exposure to

exogenous hormones such as diethylstilbestrol (DES)

and oral contraceptives.

There are almost no data on the menopausal

experience or on the use of hormone therapy

among women of color or women of various

ethnic backgrounds. The study of individuals from

different genetic backgrounds is valuable not only in

understanding unique pathophysiologies but also in

understanding differential susceptibilities to disease. For example, compared with Caucasians,

African Americans have a substantially lower risk of

osteoporosis but a much higher incidence of hypertension, diabetes, and cardiovascular and renal

disease. To date, however, research has largely

ignored the role played by the menopause and by

reduced ovarian hormone levels in these diseases

among African Americans and other ethnic subgroups.

With the exception of the PEPI study, there is a

decided lack of randomized placebo-controlled or

comparable-treatment clinical intervention trials, as

well as a lack of trials of clinical endpoints, that

address the effects of hormone therapy. Experimental randomized clinical trials of hormone therapy as

it affects morbidity and mortality are needed to

obtain an unbiased assessment of the effects of such

therapy, to develop algorithms regarding prescribing

practice, and to assess the effectiveness of nonhormonal interventions.

FEDERAL INVESTMENT IN

MENOPAUSAL AND RELATED

RESEARCH

In the summer of 1991, OTA requested that NIH

and ADAMHA provide budget data on research

related to the menopause. The responses of each

agency are reported below.

National Institutes of Health

The PHS has no standard definition of hormone

therapy that is used throughout the agency. Therefore, NIH chose the following definition, which was

provided by the National Institute of Child Health

and Human Development, to use in collecting

budget data:

Hormone therapy is the use of exogenous sex

hormones for the relief of menopausal symptomatology. The hormones may be synthetic or natural and

are derived from humans and animals. The concept

of hormone therapy pertains to the use of estrogen

and progesterone or synthetic progestin. Estrogen

therapy pertains to the use of only estrogen for the

same purposes. Hormone regimens pertain to any of

the above variations in terms of hormone dosage and

duration.

Data were derived from the NIH Computer

Retrieval of Information on Scientific Projects

(CRISP) database as well as directly from the

appropriate institute and center directors (ICDs).

CRISP is a major scientific information system

containing data on all research programs supported

by units within the PHS. Two searches of the CRISP

databases were conducted: one based on the single

term menopause, which included postmenopause,

and a second based on the terms menopause and

hormone replacement therapy. The first search

revealed $145.5 million in funding (see table 5-l);

nearly $72 million of that research is related to breast

cancer and is funded through the National Cancer

Institute.

The second search revealed no studies specifically associated with hormone therapy; consequently, the search was expanded to include the

following related terms: estrogen, estradiol, estriol,

estetrol, estrone, estrogen analog, diethylstilbestrol,

ethynylestradiol, mestranol, mestranol norethindrone,

and mestranol norethynodrel. Including these terms

revealed obligated total funding of $15.5 million for

fiscal year 1991 (see table 5-2). The figures in the
Chapter 5-Current Research and Future Needs ● 93

Table 5-l—Estimated Volume of General Research

Related tot he Menopause and the Postmenopausal

Period, National Institutes of Health,

Fiscal Year 1991

Total dollars Total number

Institute, center, or division (in millions) of projects

. —. National Institute on Aging . . . . . . . .

National Institute of Arthritis and

Musculoskeletal and Skin

Diseases . . . . . . . . . . . . . . . . . . . . .

National Cancer Institute . . . . . . . . .

National Institute of Diabetes and

Digestive and Kidney

Diseases . . . . . . . . . . . . . . . . . . . . .

National Institute of Child Health

and Human Development . . . . . .

National Heart, Lung, and Blood

Institute . . . . . . . . . . . . . . . . . . . . . . .

National Center for Nursing

Research . . . . . . . . . . . . . . . . . . . . . .

National Center for Research

Resources . . . . . . . . . . . . . . . . . . . . .

National Institute of Dental

Research . . . . . . . . . . . . . . . . . . . . . .

Total . . . . . . . . . . . . . . . . . . . . . . . . . . .

$ 5.6

7.8

119.7

3.9

1.3

5.2

0.4

1.2

0.4

$145.5

24

43

NA

22

7

21

2

52

2

173

NOTE: NA = Data not available.

SOURCE: National Institutes of Health, 1991.

table reflect the total funds awarded, including direct

and indirect costs.

The data have certain limitations that require

consideration. The CRISP database does not distinguish new projects from continuing ones; thus, the

dollar amounts do not reflect the total funds spent for

research related to the searched term. In addition, a

particular project may be counted more than once if

it is associated with more than one of the searched

index terms.

In total, NIH support for research related to the

menopause and its consequences includes studies of

basic reproductive, cellular, and molecular biology

and more clinically related investigations of, for

example, osteoporosis, coronary artery disease,

stroke, and cancers of the breast and uterus. In

addition, NIH supports research related to changes

in various organs and tissues that occur as a result of

the physiological changes associated with the cessation of ovarian functions. It also funds efforts that

address the resultant symptoms and signs of the

menopausal period that concern women and affect

their well-being. (See box 5-B for descriptions of the

types of research supported by various institutes of

NIH.)

297-910 0 - 92 - 7

Table 5-2—Estimated Volume of Research Related to

the Menopause and Hormone Therapy, National Institutes of Health, Fiscal Year 1991

Total dollars Total number

Institute, center, or division (in millions) of projects

National Institute on Aging . . . . . . . . $ 4.2

National Institute of Arthritis and

Musculoskeletal and Skin

Diseases . . . . . . . . . . . . . . . . . . . . . 1.8

National Cancer Institute . . . . . . . . . 1.6

National Institute of Diabetes

and Digestive and Kidney

Diseases . . . . . . . . . . . . . . . . . . . . . 2.3

National Institute of Child Health

and Human Development . . . . . . 0.5

National Heart, Lung, and Blood

Institute . . . . . . . . . . . . . . . . . . . . . . . 4.4

National Center for Nursing

Research . . . . . . . . . . . . . . . . . . . . . . 0.2

National Center for Research

Resources . . . . . . . . . . . . . . . . . . . . . 0.2

National Institute of Dental

Research . . . . . . . . . . . . . . . . . . . . . . 0.3

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . $15.5

15

10

NA

14

4

17

1

23

1

85

NOTE: NA = Data not available.

SOURCE: National Institutes of Health, 1991.

Alcohol, Drug Abuse, and Mental

Health Administration

ADAMHA, an agency of the PHS, also funds

research related to women’s health and the menopause. The three ADAMHA institutes-the National Institute on Alcohol Abuse and Alcoholism

(NIAAA), the National Institute on Drug Abuse

(NIDA), and the National Institute of Mental Health

(NIMH)-+onduct and fund research that is both

directly and indirectly related to the menopause.

Most of the work is done extramurally, but

ADAMHA also supports three full-time intramural

menopause researchers.

Grant abstracts for the three institutes were

analyzed for menopause-related topics. From 1989

to 1991, ADAMHA provided close to $5 million for

32 research grants that were directly related to the

menopause (see table 5-3). Many of these projects

are oriented toward basic research; only 7 of the 32

grants are for research on human subjects. Those 7

grants fired 3 projects that focus on alcohol effects

in postmenopausal women; biobehavioral studies of

narcotics abuse, including alcohol-induced changes

in endocrine function in postmenopausal women;

and research on the psychobiology and treatment of

perimenopausal mood disorders.
94 . The Menopause, Hormone Therapy, and Women’ sHealth

Box 5-B—Menopause-Related Research at the National Institutes Health

Many of the institutes, centers, and divisions (ICDs) of the National Institutesof Health contribute resources

and support to research on women’s health. Because of the various missions and objectives of the ICIDs, they may

place different emphases on the many areas of womens’ health. The following are the primary institutes that provide

resources to support research on the menopause and on hormone therapy.

The National Institute of Child Health and Human Development historically has been associated with issues

related to human development and the reproductive health of women. The Center for Population Research leads the

Federal Government’s effort in this regard. Through grants and contracts, the center sponsors work ranging from

basic biomedical research in the reproductive sciences to epidemiologic studies on the menopause and on the

postmenopausal period.

The National Heart, Lung, and Blood Institute (NHLBI) is supporting research that will contribute to an

understanding of how interventions to improve lipid and cholesterol profiles in postmenopausal women may be

useful in preventing the progression of coronary artery atherosclerosis. Other research supported by NHLBI

includes studies on postmenopausal use of estrogen and progestin in relation to the risk of coronary disease.

The National Cancer Institute supports studies of postmenopausal women that focus on the prevention,

treatment, screening, and detection of cancer and on the relationship of obesity, smoking prevention and cessation,

and hormone therapy to the development of malignancy.

The National Institute on Aging has begun a major new initiative related to hormonal therapies for

osteoporosis, which is reflected in the large increase in funds for the institute in fiscal year 1991. Studies range from

longitudinal studies of the menopause, bone loss, and aging to behavioral treatment of menopausal hot flashes.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) hasanendocrinology program

that includes a significant effort in support of research on the menopause and on hormone therapy. In addition,

NIDDK is involved in clinical and basic research on the action of estrogen on various tissues. The institute has a

strong research interest in this field, as well as in the closely related field of osteoporosis.

The National Center for Nursing Research supports basic and clinical interdisciplinary research related to

women’s health across the lifespan.

The National Institute for Dental Research supports research that examines the status of various oral tissues

during physiologic aging and, more specific to women’s health issues, the observable effects of the menopause and

hormone therapy on salivary gland functions.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases provides funds for research efforts

on osteoporosis, bone density, and pathological bone reabsorption along with research on the effects of estrogen

or combined hormone therapy.

Some studies supported by the National Center for Research Resources include, but are not limited to, exercise

intervention in relation to bone mineral content in postmenopausal women, ovarian steroids in menopausal women

with endometrial cancer, and thermoregulation during menopausal hot flashes.

SOURCE: National Institutes of Health, 1991.

I In response to the health promotion and disease SUMMARY

prevention goals of the PHS’s Healthy People 2000

program, NIMH is seeking to expand its research

base on issues related to women’s health through

basic, clinical, and epidemiologic research. Currently, the agency is designing a program that will

encourage extramural research on changes in women’s

mental health during the lifecycle; one of the

research goals of the program is related to changes

in mood and behavior that are associated with the

menopause.

As the proportion of older women in the U.S.

population continues to grow, the need for prevention or, alternatively, early diagnosis and treatment

of morbidity and disability in this group similarly

increases. The development of appropriate intervention strategies depends on substantially improved

knowledge in two areas: the natural history and

sequelae of the menopause and the role of estrogen

and progesterone deficiency and replacement in the

prevention or modification of disease.
Chapter 5-Current Research and Future Needs ● 95

Thus far, hormone therapy is the most efficacious

treatment modality for the amelioration of menopausal symptoms and prevention of osteoporosis.

Epidemiological and animal studies strongly suggest that estrogen therapy has the potential to reduce

morbidity and mortality from cardiovascular disease. But in the absence of randomized clinical

trials, a definitive, unbiased assessment of the

beneficial effects of estrogen with and without

progestin in preventing or ameliorating cardiovascular disease is not possible. Objective evaluation of the risks is likewise precluded. Moreover,

there are virtually no studies on the effects of

long-term use of estrogen with progestin (i.e.,

combined hormone therapy)—a recommended

treatment regimen for nonhysterectomized women.

Because estrogen and progesterone affect a host

of tissues throughout the body, future research

should foster an integrated, multidisciplinary approach, such as that used in the new PEPI trial in its

multiorgan system evaluation of risk factors and

intermediate points of disease. Furthermore, randomized clinical trials of this kind, with their

long-term followup studies and assessments of

multiple morbidity and mortality endpoints, are

crucial to an objective evaluation of risks and

benefits. Without such an evaluation, some of the

historical disasters that have accompanied the use of

exogenous ovarian hormones may be repeated: for

example, the increased risk of reproductive cancers

in mother and offspring from the use of (or in utero

exposure to) DES; the marked number of hypertensive and thromboembolic episodes attributed to use

of early formulations of the pill (which took 10 years

to uncover, even though the pill was being used by

millions of women) (25); and the excess of endometrial cancer in users of unopposed estrogens before

the recommendation that progestin should be added.

An increase in the quality of life of older women

depends on early improvements in diagnosis, which

in turn require the identification of risk factors (that

may be different from those for men) and the

development of practice plans with regard to preventive and therapeutic strategies. It also requires

objective findings from well-controlled studies to

determine who will benefit and how, for how long a

particular intervention (either hormonal or nonhormonal) will be effective, and in which body

systems. It requires increased understanding of

women’s physiology in general. And it requires the

Table 5-3-Extramural Research Related to the

Menopause, Alcohol, Drug Abuse, and

Mental Health Administration, 1989-91

Fiscal Institute Total ADAMHA

year Institute funding($) funding ($)

. --- . . . . . . . . . . .

1989 National Institute of

Alcohol Abuse and

Alcoholism

National Institute on

Drug Abuse

National Institute of

Mental Health

1990 National Institute of

Alcohol Abuse and

Alcoholism

National Institute on

Drug Abuse

National Institute of

Mental Health

1991 National Institute of

Alcohol Abuse and

Alcoholism

National Institute on

Drug Abuse

National Institute of

Mental Health

3-year total

$560,413

480,505

468,727

591,111

432,109

711,298

580,374

613,288

411,865

$1,509,645

1,734,518

1,605,527

$4,849,690

SOURCE: Alcohol, Drug Abuse, and Mental Health Administration, 1991.

dissemination of badly needed information regarding

1.

2.

3.

4.

5.

6.

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Chapter 6

Conclusions
Contents

Page

DETERMINING THE RELATIONSHIP BETWEEN THE MENOPAUSE

AND DISEASES OF AGING . ......*.*............**....,..****,.....*.**.* 101

RANDOMIZED CLINICAL TRIALS ARE NEEDED . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

REFINING ESTIMATES OF INDIVIDUAL RISKS AND BENEFITS

FROM HORMONE THERAPY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

CLARITY IN PRESCRIBING PRACTICES AND LABELING . . . . . . . . . . . . . . . . . . . . 105

INVESTIGATING ALTERNATIVES TO HORMONE THERAPY . . . . . . . . . . . . . . . . . 106

PROFESSIONAL AND PUBLIC EDUCATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

PROSPECTUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

Boxes

Box Page

6-A. Comparing Risks and Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Chapter 6

Conclusions

The menopause is defined as the final menstrual

period that a woman experiences. It is a single event,

retrospectively diagnosed after a year with no

menstrual periods. The period of time preceding a

woman’s last period and the frost year after the

menopause constitute the perimenopause. After a

woman experiences the menopause, she is considered postmenopausal. Throughout the perirmenopause, ovarian hormone production slows and finally ceases; at the end of this time, the female

hormone estrogen is no longer secreted by the

ovaries. This loss of ovarian estrogen can produce

symptoms such as hot flashes and night sweats and

is implicated in the development of osteoporosis and

cardiovascular disease. For these reasons, some

women and their physicians elect hormone therapy

for the treatment of symptoms or the prevention of

osteoporosis or cardiovascular disease. If a woman

is taking only estrogen (unopposed by a progestin),

the therapy is referred to as estrogen therapy, or ET.

If the woman’s ovaries have not been surgically

removed, common practice increasingly is to prescribe a progestin in addition to the estrogen.

(Estrogen alone increases the risk of endometrial

cancer; the addition of a progestin reduces that risk.)

Women who take both an estrogen and a progestin

are receiving combination therapy, which is commonly referred to as combined hormone therapy, or

CHT. In CHT, the estrogen is opposed by a

progestin. The term hormone therapy refers either to

ET or CHT.

Many American women now face the question of

whether to undergo hormone therapy during the

menopause and how long to continue it once it has

been elected. Few life events, other than aging,

affect as many people as the menopause. In the frost

decade of the 21st century, more than 21 million

women from the baby boom generation will reach

the age of 50 and become menopausal. Although

universal among women, the menopause is a

highly individualized experience: some women

may hardly notice it while others maybe disabled

by it. Often, physicians treat menopause monolithically, as a threat to health, without any recognition

that many women traverse the menopause and enter

old age with few medical problems. This clinical

variability has contributed to the debate about the

appropriate management of the menopause, as part

of the natural process of aging in women. Complicating any decision about using hormones for

treatment of the symptoms of menopause (e.g., hot

flashes, night sweats) is the issue of hormone

therapy and the risks it carries, both increased and

decreased, for osteoporosis, heart disease, and cancer.

As long as certain issues remain unaddressed and

unanswered, a woman’s decision regarding the

management of her menopause and the possible

reduction of future disease risk must be made under

conditions of confusion and uncertainty. Research

and time will answer some of the questions raised by

current menopause management practices; women

today, however, have no choice but to face this

conundrum with what is known. This background

paper reports on what is known about the menopause, hormone therapy, drug prescribing and review, and research needs. Much research has already

been conducted, and more is proposed. Interest in the

menopause and in the effects of reduced ovarian

hormone levels has accelerated in recent years,

producing new data that have yet to be fully

analyzed or comprehended. Despite increasing efforts to fully understand the mechanisms of the

menopause and its relationship to subsequent disease, many issues remain unresolved or in need of

attention. They are summarized here.

DETERMINING THE

RELATIONSHIP BETWEEN

THE MENOPAUSE AND

DISEASES OF AGING

One of the most pressing issues related to the

menopause is the lack of knowledge about characteristics of women that place them at higher or lower

risk for health problems during the menopause and

later in life. A better understanding of the natural

history of the menopause is critical. Despite its

universality in human female aging, the biology of

the menopause is incompletely understood. Substantive progress in understanding the etiology and

symptomatology of age-related disease among women

requires increased knowledge of their inherent

biological and psychosociocultural differences. Such

–l0l–
102 ● The Menopause, Hormone Therapy, and Women’s Health

progress is fundamental to accurate diagnosis and

effective treatment to reduce morbidity and mortality and to maintain the independence of the rapidly

growing postmenopausal population.

The significance of menopausal symptoms (i.e.,

hot flashes) to subsequent pathophysiology has

never been studied. Undoubtedly, incomplete understanding of ovarian hormone action and of the

effects of ovarian hormone levels in nonreproductive target tissues has severely constrained the

generation of hypotheses about this relationship. A

further complication is the marked interindividual

differences among women with respect to the

manifestation of menopausal symptoms, as well as

to susceptibility to chronic diseases. A major

challenge to the prevention of disease in older

women lies in exploring the effects of both

short- and long-term reductions in ovarian

hormones on the development of symptoms and

disease. Of particular interest are the effects of

reduced levels on the development of diseases that

may have along latency period or that are temporally

removed from the menopause.

As the proportion of older women in the population continues to grow, the need to focus on the

prevention of morbidity and disability increases as

well. Such prevention will require an understanding

of the potential consequences of modifying lifestyle

variables (e.g., nutrition, exercise, smoking cessation) and the identification and use of appropriate

intervention strategies (both hormonal and nonhormonal). Identifying appropriate strategies requires substantially improved knowledge of the

natural history and sequelae of the menopause, and

of the role of exogenous and endogenous estrogens

and progesterones in the etiology and prevention of

disease.

A more complete understanding of the physiological consequences of reduced ovarian hormone

levels requires research protocols and subject selection procedures that can assess the effects of age and

type of menopause (natural or surgically induced by

bilateral oophorectomy) on intermediate biological

variables and, ultimately, on the risk of disease.

Sensitivity to the potential role of age and cause of

menopause is also important in assessing the effects

of hormone therapy: there may be marked differences between younger and older women in tissuespecific responses to hormonal therapy and in the

benefits to be realized from such treatment in

oophorectomized women compared with those who

experience a natural menopause. Other significant

covariates include the time elapsed since the menopause before commencement of hormonal therapy

and a woman’s prior history of hormone use,

especially oral contraceptives.

RANDOMIZED CLINICAL TRIALS

ARE NEEDED

Thus far, estrogen therapy is the most efficacious

treatment modality for the amelioration of menopausal symptoms and the prevention of osteoporosis. Epidemiologic and animal studies strongly

suggest ET has the potential to reduce morbidity and

mortality from cardiovascular disease. But in the

absence of randomized clinical trials, a definitive,

unbiased assessment of the beneficial and adverse effects of estrogen with and without progestin in preventing or ameliorating cardiovascular disease is not possible. Objective evaluation of the risks is likewise precluded. Moreover,

there are virtually no studies on the effects of

long-term ET with progestin—a treatment regimen sometimes recommended for nonhysterectomized women.

Randomized trials to assess the health effects of

hormone therapy must be large enough to detect

protective effects against cardiovascular disease and

osteoporosis (or fractures); in addition, they must be

of long enough duration to detect effects that may

occur only after relatively long periods (10 years or

more) of use. Both the use of unopposed estrogen

and of combination therapy should be assessed to

identify any differential protective or risky effect. In

addition to cardiovascular disease and osteoporosis,

the risk of which may be reduced by hormone use,

other outcomes that reportedly increase with hormonal therapy-breast cancer, endometrial and other

gynecologic cancers, and cerebrovascular disease

are in need of evaluation. Also worth studying (on

the risk side of the benefit-risk ratio) is hysterectomy

and the morbidity associated with that procedure.

Disease incidence and mortality should be assessed. Comparisons of total morbidity and total

mortality among the treatment groups are important

to determine overall risks and benefits. Yet an

“overall’ comparison is insufficient. Rather, comparisons should be made among various age groups,

because the benefit-risk ratio may be quite different

at various ages. For example, the major benefits of
Chapter 6--Conclusions ● 103

hormone therapy may be more substantial for older

women, while the major risks may increase for those

who are younger; such an outcome would influence

one’s interpretation of the benefit-risk ratio for

hormone therapy. As these results are obtained, it

will become possible to calculate the costs of

treatment for each group and to compare them with

the benefits and risks.

For both cardiovascular disease and osteoporosis,

a protective effect of estrogen therapy appears to be

related to the duration of use: women may have to

take the drugs for relatively long periods (10 to 15

years) to prevent disease. In addition, because the

adverse effects of hormone therapy on the risk of

breast cancer also may not become apparent until

decades later, trials must be of sufficient duration to

detect any effects that may occur. A large study of

nurses showed that those nurses who had ‘‘ever

used” hormones were no more likely to develop

breast cancer than women who had never used them;

“current users, ” on the other hand, had a higher

incidence. These findings are interpreted to mean

that hormone therapy accelerates the development of

breast cancers in some women and that those cancers

are detectable soon after therapy begins. Furthermore, the findings indicated such cancers appear to

be less malignant than most breast cancers. The

nurses’ study, however, was a general investigation

into women’s health; other studies are needed to

examine each of these hypotheses in a more focused

way.

Besides the issue of sufficient duration of the

research, experimental design must be carefully

considered and treatment regimens carefully constructed. Hormone therapy, particularly combination therapy, can have unpleasant side effects. To

encourage adherence to combination therapy in

study groups will require substantial attention;

otherwise poor adherence could diminish the ability

of a trial to detect any effects from long durations of

use. For these reasons, randomized trials of hormone

therapy will be neither easy nor inexpensive to

conduct.

Because estrogen and progesterone affect a host

of tissues throughout the body, future research

should foster an integrated, multidisciplinary approach such as that used in the National Institutes of

Health (NIH) current Postmenopausal Estrogen/

Progestin Intervention (PEPI) Trial with its multiorgan system evaluation of risk factors and intermediate points of disease. Randomized clinical trials of

this kind, with their long-term followup studies and

assessments of multiple morbidity and mortality

endpoints, are crucial to an objective evaluation of

risks and benefits. Through the PEPI trial, NIH is

investigating the effects on intermediate endpoints

of different regimens of combined therapy used for

3 years each.

REFINING ESTIMATES OF

INDIVIDUAL RISKS AND

BENEFITS FROM

HORMONE THERAPY

If women and their physicians had a better

understanding of predictors of risk, they could make

more informed decisions about interventions related

to menopausal symptoms, cardiovascular disease,

osteoporosis, and gynecologic and breast cancer.

Few other recently introduced medical interventions have as great a potential for affecting

morbidity and mortality as does hormone therapy. Some risks are reduced, some are increased,

and some remain uncertain, and these dat a

continue to be interpreted differently by various

scientific, medical, and consumer groups.

Women who seek treatment for menopausal

symptoms and the doctors who treat them are more

likely to advocate a treatment approach, whereas

those who report few symptoms are more sympathetic to the avoidance of medical interventions. The

most common diagnosis mentioned in relation to

prescription of estrogen is menopausal symptoms.

Researchers are becoming increasingly convinced

that loss of ovarian hormones plays a significant role

in the etiology of age-related pathology in women,

yet the relationships are not clear. Although cessation of the menses is not a disease, many researchers

and clinicians believe that the resulting decrease in

ovarian hormone production can lead to disease in

some women, thereby justifying preventive intervention through hormone therapy, either as estrogen

alone or in combination with a progestin.

The debate over hormone therapy focuses on

whether it should be used to treat menopausal

symptoms for a short period of time, thereby

reducing any risks associated with long-term

treatment, or whether it should also be used to

prevent future disease, thereby requiring longer

treatment that could increase the risk of cancer.
104 ● The Menopause, Hormone Therapy, and Women’s Health

For most women, the short-term use of hormones

has known benefits (e.g., relief of hot flashes) and

some known risks (e.g., endometrial cancer); longterm use has known risks (again, endometrial

cancer) and benefits (e.g., prevention of osteoporosis

and cardiovascular disease), as well as unknown

outcomes (e.g., risk of breast cancer). To prevent

osteoporosis and cardiovascular disease, estrogen

must be taken for long periods of time, possibly until

death. The impact of such long-term use is not clear.

The effects of adding a progestin to the treatment are

even less clear, and in this case, the dilemma is

sharper.

Should women be treated with a drug to

prevent a disease they might never get? Across-theboard prescriptions for hormone therapy may, in

the aggregate, reduce morbidity and mortality. It

is a practice that must be questioned, however,

when some individuals will be placed at higher

risk, even though others benefit. Risks and

benefits must be considered individually.

Although the menopause can be expected to occur

naturally around age 50, many women, as many as

37 percent, will experience the symptoms of menopause at an earlier age owing to removal of their

ovaries through hysterectomy. Oophorectomized

women are also at higher risk for diseases of aging

such as osteoporosis and cardiovascular disease. In

this group of women, appropriate treatment for the

severe, sudden symptoms of the menopause following hysterectomy is a critical issue, and not as simple

as short-term relief. For many women, the use of

estrogen will be an essential postoperative therapy

that may have to be continued for 20 to 30 years.

Approximately 15 percent of women who are

eligible for hormone therapy are now receiving it.

This means 85 percent of eligible women either

do not want or need the therapy, or do not know

about it. There is little argument about the benefits

of estrogen for the alleviation of the most uncomfortable symptoms of the menopause, specifically, hot

flashes. Approximately 15 percent of women report

symptoms so disruptive that they consider them

disabling and consequently seek treatment. Although most women experience hot flashes, most do

not seek treatment. There have been no studies to

document the number of women who suffer severe

symptoms and either do not choose or do not know

how to seek treatment.

Photo credit: National Cancer Institute

Deciding which therapy to undergo, estrogen or combined,

is a sometimes oonfusing proposition.

There are a number of reasons women may not

elect to use hormone therapy. First, it is an optional

drug treatment; a woman’s life is not immediately

threatened if she ‘does without it.’ Second, women

who discontinue hormone therapy after a few years

may experience a ‘‘rebound effect,’ or return of

symptoms, and bone loss again accelerates. Some

women may want to put the experience of hot flashes

behind them more quickly by avoiding treatment.

Third, side effects such as cramping, water retention,

and withdrawal bleeding may be a disincentive to

continue or even to seek treatment. Fourth, and

perhaps the most critical, in considering long-term

use of hormones, women may fear cancer more than

heart disease. Discerning how the epidemiologic

data refine and define relative versus absolute

risk is complex, and interpretation of risks

depends on how women define quality of life (see

box 6-A).

Quality-of-life issues must be decided by each

woman. What is a disability to some women maybe

merely a nuisance to others. Research has demon-
Chapter 6-Conclusions ● 105

Box 6-A-Comparing Risks and Benefits

In late 1991, convincing data from the Nurses’ Health Study described the apparently protective effect of

postmenopausal estrogen replacement therapy in relation to cardiovascular disease. In discussing the findings of

the study as they relate to the competing risks and benefits posed by hormone therapy, Lee Goldman and Anna N.A.

Tosteson concisely articulated the quandaries of competing risks and benefits:

A fundamental and not widely appreciated principle of epidemiology is that relative risks should not be confused

with absolute risks. A twofold increase in the risk of a rare event may not be nearly as important as a 10 percent

decrease in the risk of a common event. Consider the following: from the age of 65 through the age of 74, a woman

has about a 6 percent risk of dying from ischemic heart disease, a 1 percent risk of dying from breast cancer, a 0.6

percent riskof dying from complications related to a hip fracture, and if her uterus has not been removed, a 0.4 percent

risk of dying from endometrial cancer. If the sum of epidemiologic evidence is approximately accurate, what will

estrogens do to those 10-year risks? A 60 percent reduction in the risk of hip fracture will lead to an absolute benefit

(a 0.36 percent absolute reduction) that is roughly equivalent to the absolute increase (0.30 percent) in the risk of breast

cancer attained with a relative increase in that risk by 30 percent. After these two competing factors have canceled

each other out what other issues are we left with? First, hip fracture is only one of the many complications of

osteoporosis, so there is substantial additional benefit from estrogen in this regard. Second estrogens relieve

perimenopausal symptoms, although it is uncertain how women will value this benefit as compared with the

inconvenience of estrogen-related bleeding.

Perhaps the most intense debates relate to heart disease and endometrial cancer. A 40 percent reduction in a 6

percent risk of death from ischemic heart disease would result in a substantial benefit (a 2.4 percent absolute reduction

in mortality), A sixfold increase in a 0.4 percent risk of death from endometrial carcinoma would result in a nearly

equivalent 2.4 percent increase in the absolute risk; however, epidemiologic data suggest that mortality is only about

10 percent as high for endometrial cancer associated with the use of exogenous estrogen as for “naturally occurring”

disease, presumably because of earlier detection brought on by symptoms and closer observation. If this much lower

risk is the true one, a major reduction in the incidence of ischemic heart disease with postmenopausal

estrogen-replacement therapy would greatly outweigh all other effects on life expectancy.

What individual women would do with this type of analysis is not clear. Numerical risks, although

quantitatively equal, may be perceived as qualitatively different. In addition, women will make decisions based on

their family history (or genetic risk) of disease and their own life experiences (e.g., a friend who dies of breast cancer,

an elderly neighbor hospitalized for repeated fractures). Risk assessment, even if sharpened over time, must be

considered in the light of risk perception when evaluating the current and future use of hormone therapy by

postmenopausal women.

SOURCE: L.Goldman and A.NA. Tosteson, "Uncertain ty About Postmenopausal Estrogen: Time for Action Not Debate,” New England

Journal of Medicine 325(11):800-802, 1991.

strated that women give high priority to the shortterm impact of hormone therapy on their lives and do

not make their decisions based on the risks of

morbidity and mortality. In effect, they afford

greater weight to considerations of quality of life

over quantity of life.

The lack of good data on the use of hormone

therapy is a major problem because it confuses any

interpretation of risks and benefits. If it is not clear

how many women are actually using ET or CHT,

projections of risks and benefits are bound to be

erroneous. The discrepancy between the stated

prescribing philosophies of physicians and the

actual use of hormone therapy suggests the menopausal woman may be assuming the role of informed

consumer rather than accepting without question the

treatments prescribed by her doctor.

CLARITY IN PRESCRIBING

PRACTICES AND LABELING

There is no official standard or protocol for

administering or prescribing combination therapy. Moreover, no conclusive studies have been

performed to indicate which regimen (opposed or

unopposed estrogen) is most beneficial. Finally,

no studies have been done that meet adequate

design, duration, and sample size requirements

to determine conclusively the risks and benefits

of long-term use of combined therapy.

At present, the Food and Drug Administration

(FDA) has approved no combination estrogen and

progestin product for sale in the United States,

although some are undergoing clinical testing. In

contrast, several combination products are available
106 ● The Menopause, Hormone Therapy, and Women’s Health

in Europe. Regimens that prescribe separate estrogen and progestin products are common both here

and in Europe. Anecdotal information indicates that

as many as 19 different regimens are prescribed in

the United States and more than 100 are prescribed

in Europe. This variety means that women face a

confusing range of options and often conflicting

recommendations.

In 1990, total sales of estrogen products were

close to $460 million. Premarin, the top-selling

estrogen, is the fourth most prescribed drug in the

United States. Estrogen products approved for

treatment of the menopause have labeled indications

for the treatment of vasomotor symptoms or hot

flashes, and Premarin and Estraderm have been

approved for the prevention of osteoporosis. None of

the progestins used in CHT have been approved by

the FDA for treatment of menopausal symptoms, but

their use for this purpose is common medical

practice. The FDA is considering changes in labeling of the hormones that would reflect the cardioprotective effect of unopposed estrogen use and whether

to recommend the use of combined estrogen and

progestin therapy for women with intact uteri.

The approval of generic forms of estrogens also

remains a topic of debate within the industry and at

the FDA. Until the spring of 1991, generic conjugated estrogens were on the market. In that year,

however, the FDA withdrew approval for these

compounds on the basis of demonstrated bioinequivalence.

Although Premarin is relatively inexpensive

(approximately $14 for a month’s supply), monitoring programs to screen for cancers of the

breast and uterus are not. If hormone therapy is

to be widely administered, consideration of costs

must include all relevant expenditures.

INVESTIGATING ALTERNATIVES

TO HORMONE THERAPY

Estrogen is the most widely used treatment for

menopausal symptoms, specifically, for vasomotor

symptoms, or hot flashes. But estrogen is contraindicated for a number of women; consequently, they

and others seek nonhormonal, nondrug treatments

for these symptoms. As with any drug, hormones are

not without side effects, a circumstance that may

dissuade some women from either starting or

maintainingg treatment. There is limited research on

alternatives to hormone therapy-i.e., other hormones, nonhormonal drugs, and nondrug products—

and large-scale clinical investigation of most of

these treatments is nonexistent. Many small-scale

studies have been done, however, and evidence

shows that these treatments are somewhat successful

in remedying hot flashes (although none is as

effective as estrogen). Anecdotal evidence indicates

that many women try “home remedies” for the

alleviation of menopausal complaints. It is not clear

how effective these remedies are and if so, for what

severity of complaint.

Convincing research into alternatives to

hormone therapy is limited. In addition, the true

contributions to cardiovascular disease and osteoporosis of such factors as lifestyle-e. g., diet,

exercise, smoking—socioeconomic status, race, and

genetic predisposition deserve further investigation.

Better understanding of these areas could identify

more effective alternatives to hormone therapy.

PROFESSIONAL AND

PUBLIC EDUCATION

Many studies have shown that women feel

disenfranchised from the health care system and

contend that providers do not listen to them. They

also report having inadequate information on which

to base a decision concerning hormone therapy.

Patients and health care professionals alike tend to

know relatively little about the menopause and about

the risks of conditions that may be associated with

it. There is no consensus within the medical community about even the definition of the menopause, let

alone the risks and benefits associated with hormone

therapy, and there is little information about a

woman’s natural progression through the menopause and the years that follow. Moreover, there is

no agreement on what constitutes a ‘‘normal’

menopause and few conclusive research findings on

the normal hormonal changes associated with aging.

Physicians and women need more and better

resources to learn about the menopause and hormone

therapy. Even the limited information now available

is not well distributed to women and their physicians. For example, better informed decisions would

flow from more information about the menopause

and potential symptoms; about changes in the risks

of cancer, heart disease, and osteoporosis that occur

after menopause and with increasing age; about the

pros and cons of hormone therapy; and about the role
Chapter 6-Conclusions ● 107

of diet, nutrition, and exercise programs in health

promotion and disease prevention.

PROSPECTUS

An enhanced quality of life for older women

depends on improvements in early diagnosis, which

in turn require the identification of risk factors (some

of which are entirely different from those for men)

and the development of strategies for prevention and

therapy. It also requires objective findings from

well-controlled studies to determine who will benefit and how, for how long a particular intervention

(either hormonal or nonhormonal) will be effective,

and how such interventions affect different body

systems and organs. Better quality of life for women

after the menopause also requires increased understanding of women’s physiology in general. And it

requires the dissemination of badly needed information relating to the menopause to physicians and

their patients.
Appendixes
Appendix A

The Menopause in Japan

Examination of the experiences of menopausal women

in a non-Western culture offers alternative perspectives to

North American attitudes toward the menopause. However, this is not necessarily inappropriate. Research on the

menopause in Japan reinforces the assumption that there

is universal menopausal experience.

Japanese women, with a current life expectancy of

more than 82 years, live longer than anyone else in the

world (2). But such longevity is a recent trend: in 1940,

the average age at death for Japanese women was 49.6

years (5). Thus, the population of postmenopausal women

in Japan historically has been small, and the limited

attention it has received within the Japanese medical

community is not surprising. Konenki”, the Japanese term

that describes the menopause, was created at the turn of

the century under the influence of German medicine (5).

Care and treatment for Japanese menopausal women has

begun to receive more attention recently; at the urging of

the Japanese gynecological association, the Japanese

Government approved the group of symptoms labeled

“climacteric syndrome” for inclusion in the list of

diseases covered under the Japanese socialized medicine

system (5).

The Japanese health care heritage reflects a longstanding interest in preventive medicine as well as the

more recent influences of, first, German and, subsequently, American medical thinking and practices (4).

The current Japanese medical system arose from a

historical arrangement in which physician payments were

contingent on the continuing good health, not the illness,

of the patient (4). Concern with a growing elderly

population, cultural commitment to prevention of disease,

and familiarity with Western medical research findings

might lead one to expect that hormone therapy would be

widely and increasingly used by menopausal Japanese

women. Yet, interestingly, hormone therapy is only

marginally prescribed by the Japanese medical profession

(2). One study conducted in 1974 concluded that only 2.6

percent of Japanese women aged 45 to 55 were currently

using replacement hormones, and followup studies have

revealed no significant increase in use (l).

This low level of utilization has been attributed to the

interaction of a complex set of factors: patterns of

morbidity and mortality among elderly Japanese, culturally constructed expectations and subjective experiences

associated with the end of menstruation, ideology about

who is susceptible to distress during menopause, and

patient and physician attitudes toward the use of physicians and medication (3,6).

The causes of death and disability among Japan’s

elderly are strikingly different from those of the West.

Currently, as it has been for more than 30 years, the

primary cause of death for both sexes in Japan is

cerebrovascular disease (3). Although breast cancer,

cardiovascular disease, and osteoporosis are predominant

concerns for aging North American women, incidence of

these conditions among Japanese women is relatively

low, although rates for breast cancer and heart disease

have been increasing slightly (3). The World Health

Organization estimates that the mortality rate for coronary

heart disease in Japanese women is about one-quarter the

rate for American women, and the mortality rate from

breast cancer is between one-quarter and one-third that in

North America (3). Reliable data on rates of osteoporosis

are lacking, but estimates are that, despite the lower

average bone mass and greater longevity of Japanese

women in comparison to Caucasian women, only about

half as many Japanese women are affected by osteoporosis (3).

Such variations in morbidity and mortality are poorly

understood at this time, but it is thought that they arise

from a complex combination of contributing factors

including dietary, genetic, and, possibly, cultural differences (3). Particular attention to lifestyle, rather than

genetic, protective factors against cardiovascular disease

may be justified in light of the fact that the death rates

from cardiovascular disease for Asian Americans over 45

years of age-while at least 60 percent lower than the rate

for Caucasian Americans of the same age group--are

higher than those observed in Japan (8). These differences

in the incidence of various chronic diseases in later life

may account in part for the lower rates of use of hormone

therapy for prevention in Japan, but questions remain

about its lack of use by the Japanese to combat

menopausal symptoms.

The hot flash, which is discussed in detail elsewhere in

this report, is a common experience of Western menopausal women, affecting at least 50 percent of American

women at some time during the menopause (7). But a

menopausal woman’s experience of a hot flash has been

found to be highly individualized; studies monitoring the

measurable skin temperature elevation and luteinizing

hormone secretion occurring during hot flashes report that

women do not always report corresponding subjective

experiences (9).

Relatively few menopausal Japanese women report

having hot flashes (6). In a survey of 1,141 nonhysterectomized Japanese women aged 45 to 55, researchers

recorded menopausal symptoms in the preceding 2 weeks

based on self-reporting (6). Only 9.5 percent of the

–111–
112 . The Menopause, Hormone Therapy, and Women’s Health

women surveyed reported a hot flash in the preceding 2

weeks, and only 3.6 percent reported night sweats during

the same period (6).

A study of 1,310 women, 45 to 55 years of age, in

Manitoba, Canada, reported that 30.9 percent had experienced a hot flush in the preceding 2 weeks and 19.8

percent had experienced night sweats (4). Nearly 20

percent of Japanese women acknowledge having a hot

flash at some point in the past; by contrast, 64.6 percent

of Canadian women who were surveyed have experienced

the symptom (4). Moreover, Japanese women encountered fewer difficulties with hot flashes than did Canadian

women (4). These differences may be related to, or

possibly account for, the fact that the Japanese language

has no direct translation for the term itself-despite the

Japanese sensitivity to bodily states (3).

Differences in symptomatology between Japanese and

North American women are not limited to the reported

incidence of hot flashes; Japanese women also report the

following with greater frequency than their American

counterparts: graying hair, changes in eyesight, shortterm memory loss, headaches, shoulder stiffness, dizziness, unspecified aches and pains, and lassitude (2). To

fully appreciate the implications of these variations, it is

helpful to examine cultural differences. Konenki”, the

Japanese equivalent of the menopause, is commonly

understood to be associated with aging; it is believed to

be a gradual transition beginning at age 40 or 45 and

entails an entrance into the latter stage of the life cycle(2).

Distressing symptoms of the menopause are not usually

linked in the Japanese mind to the cessation of the menses

(3). Indeed, the biological transition has been shown to be

inconsequential to Japanese women: 24 percent of

self-reported postmenopausal Japanese women said that

they had no sign of konenki, indicating that, for them, the

end of menstruation is not a significant marker in

comparison to the external signs of aging (3).

Such cultural differences extend to expectations about

who is susceptible to distress at the menopause. One view

of menopause symptoms in Japan is that such a‘ ‘disease’

is a result of modernity, “a luxury disease affecting

women with too much time on their hands who run to

doctors with their insignificant complaints” (2). Cultural

dispositions of this kind toward menopausal distress may

contribute to the low incidence of medical intervention

during this phase of a Japanese woman’s life. As revealed

by the symptomatological differences, however, the

reason for nontreatment is not clear-cut.

1.

2.

3.

4.

5.

6.

7.

8.

9.

Appendix A References

Kaufert, P., “Being a Menopausal Woman in Japan,

the USA, and Canada: The Social Context,” presented

at the 1991 North American Menopause Society

Annual Meeting, Montreal, September 1991.

Lock M., ‘‘Contested Meanings of the Menopause,”

Lancet 337:1270-1272, 1991.

Loclq M., “Culture of Menopause in Japan, United

States, Canada: Ideology and Experience,” presented

at the 1991 North American Menopause Society

Annual Meeting, Montreal, September 1991.

Lock M., “Hot Flushes in Cultural Context: The

Japanese Case as a Cautionary Tale for the West,” The

Climacteric Hot Flush, E. Schonbaum (cd.) (Basel:

Karger, 1991).

Lock M., “New Japanese Mythologies: Faltering

Discipline and the Ailing Housewife,” American

Ethnologist 15(1):43-61, February 1988.

bch M., Kaufert, P., and Gilbert, P., “Cultural

Construction of the Menopausal Syndrome: The

Japanese Case,” Maturitas 10:317-322, 1988.

McKinlay, S.M., Brambrilla,D.J., and McKinley, J.B.,

“Women’s Experience of the Menopause,” Current

Obstetrics and Gynecology 1:3-7, 1991.

U.S. Department of Health and Human Services,

Public Health Service, Centers for Disease Control,

National Center for Health Statistics, Health United

States 1990, DHHS Pub. No. (PHS) 91-1232

(Hyattsville, MD: National Center for Health Statistics, March 1991).

lhlandi, T., I-al, S., and Kinch, R.A., “Effect of

Intravenous Clonidine on Menopausal Flushing and

Luteinizing Hormone Secretion,” British Journal of

Obstetrics and Gynecology 90:854-857, 1983.
Appendix B

Workshop Participants and Reviewers

Workshop Participants—Hormone Replacement Therapy: Policy and Practice

Wulf H. Utian, Workshop Chair

MacDonald Hospital for Women

Cleveland, OH

Gloria Bachmann Amy M. Jones

Robert Wood Johnson Medical School Winston and Strawn

New Brunswick, NJ Washington, DC

Frances Dapas John LaRosa

Ciba-Geigy Corp. George Washington University Medical Center

Summit, NJ Washington, DC

Bruce Ettinger Robert Lindsay

Kaiser Permanence Medical Center Helen Hayes Hospital

San Francisco, CA West Haverstraw, NY

Marcha Flint Sonja McKinlay

Montclair State College New England Research Institute

Upper Montclair, NJ Watertown, MA

R. Don Gambrell, Jr. Irma L. Mebane

Medical College of Georgia National Heart, Lung, and Blood Institute

Augusta, GA Bethesda, MD

Linda Golden Morris Notelovitz

U.S. Food and Drug Administration Women’s Medical and Diagnostic Center and

Rockville, MD the Climacteric Clinic

Daira Hertel Gainesville, FL

Wyeth-Ayerst Laboratories

Philadelphia, PA

Barbara S. Hulka

University of North Carolina

Chapel Hill, NC

Reviewers

Judith Bowman

American Association of Retired Persons

Washington, DC

Trudy Bush

Johns Hopkins School of Hygiene

and Public Health

Baltimore, MD

Janine O’Leary Cobb

A Friend Indeed

Montreal, Quebec, Canada

Nora W. Coffey

HERS Foundation

Bala Cynwyd, PA

Graham A. Colditz

Harvard Medical School

Boston, MA

Frances Dapas

Ciba-Geigy Corp.

Summit, NJ

David Dodd

Wyeth-Ayerst Laboratories

St. Davids, PA

Agnes H. Donahue

Office on Women’s Health

Office of the Assistant Secretary for Health

Washington, DC

–113–

297–910 O – 92 - 9
114 ● The Menopause, Hormone Therapy, and Women’s Health

R. Don Gambrell, Jr.

Medical College of Georgia

Augusta, GA

Florence Haseltine

National Institute of Child Health and

Human Development

Bethesda, MD

Daira Hertel

Wyeth-Ayerst Laboratories

Philadelphia, PA

Amy M. Jones

Manatt, Phelps and Phillips

Washington, DC

P.G. Krasnow

HERS Foundation

Cynthia Pearson

National Women’s Health Network

Washington, DC

Norene F. Pease

National Women’s Health Resource Center

Washington, DC

Jane Porcino

National Action Forum for Midlife and Older Women

New York, NY

Marilyn Rothert

Michigan State University

East Lansing, MI

Meir Stampfer

Harvard Medical School

Boston, MA

Bala Cynwyd, PA Irene Stith-Coleman

Lewis H. Kuller

University of Pittsburgh

Pittsburgh, PA

John LaRosa

George Washington University Medical Center

Washington, DC

Patty Loooker

National Association of Women’s Health

Professionals

Evanston, IL

Sonja M. McKinlay

New England Research Institute

Watertown, MA

Congressional Research Service

Washington, DC

David B. Thomas

Fred Hutchinson Cancer Research Center

Seattle, WA

Wulf H. Utian

MacDonald Hospital for Women

Cleveland, OH

Morris Notelovitz

Women’s Medical and Diagnostic Center and

the Climacteric Clinic

Gainesville, FL
Appendix C

Acronyms and Glossary

Acronyms

ACOG —American College of Obstetricians and

Gynecologists

ADAMHA-Alcohol, Drug Abuse, and Mental Health

ARC

BLSA

CRISP

DES

DESI

ERT

ET

FDA

FSH

GAO

GnRH

HDL

HRT

ICD

LDL

LH

LRC

MPA

NCI

NCNR

NCRR

NDTI

NHLBI

NIAMS

NICHD

NIDA

NIDDK

NIDR

NPA

OTA

PDR

Administration

—Arteriosclerosis Research Center

-combined hormone therapy

—Baltimore Longitudinal Study of Aging

-Computer Retrieval of Information on

Scientific Projects

-cardiovascular disease

-diethylstilbestrol

—Drug Efficacy Study Implementation

(program)

-estrogen replacement therapy

-estrogen therapy

—Food and Drug Administration

—follicle-stimulating hormone

-General Accounting Office

—gonadotropin-releasing hormone

—high-density lipoprotein (cholesterol)

—hormone replacement therapy

—Institute and Center Director

—low-density lipoprotein (cholesterol)

—luteinizing hormone

—Lipid Research Clinic

—medroxyprogesterone acetate

—menstrual and reproductive health

—National Cancer Institute

—National Center for Nursing Research

—National Center for Research Resources

—National Disease and Therapeutic Index

—National Heart, Lung, and Blood Institute

—National Institute on Aging

—National Institute on Alcohol Abuse and

Alcoholism

—National Institute of Arthritis,

Musculoskeletal and Skin Diseases

—National Institute of Child Health and

Human Development

—National Institute on Drug Abuse

—National Institute of Diabetes and Digestive

and Kidney Diseases

—National Institute for Dental Research

—National Institutes of Health

—National Institute of Mental Health

—National Prescription Audit

—Office of Technology Assessment

—Physician’s Desk Reference

PEPI —Postmenopausal Estrogen/Progestin

Interventions Trial

PHS —Public Health Service

PMS —premenstrual syndrome

Rx —prescription

USP —United States Pharmacopoeia

VLDL —very low density lipoprotein (cholesterol)

—waist-to-hip ratio

Glossary

Amenorrhea: Absence or abnormal stoppage of the

menses.

Androgen/androgenic: Any substance, e.g., androsterone and testosterone, that stimulates male characteristics.

Angiogram: A picture of a blood vessel filled with

contrast medium.

Anovulular: Not associated with ovulation.

Atherosclerosis: A disease characterized by the thickening and loss of elasticity of the arterial walls in which

atheromas (a mass of plaque of degenerated thickened

arterial intima) containing cholesterol, lipoid material,

and lipophages are formed within the intima and inner

media of large and medium-sized arteries.

Atrophy: A wasting away; a diminution in the size of a

cell, tissue, organ, or part.

Beta-blockers: A class of drugs that block cardiac beta

receptors.

Bilateral oophorectomy: Surgical removal of both

ovaries.

Bioavailability: The degree to which a drug or other

substance becomes available to the target tissue after

administration.

Bioequivalence: The requirement that a generic product

include the same therapeutic ingredient, and that its

rate and extent of absorption be the same as the

innovative product.

Biofeedback: The provision to a person of visual or

auditory evidence of the status of an autonomic body

function, e.g., the sounding of a tone when blood

pressure is at a desirable level so that the person may

exert control over the function.

Cardiovascular disease: Diseases pertaining to the heart

and blood vessels.

Case-control studies: An epidemiologic study design

that involves two groups, those that have the disease or

condition being studied (the cases) and those that do

not (the controls), which are compared to a past or

existing characteristic relevant to the etiology of the

disease or condition.

–115–
116 • The Menopause, Hormone Therapy, and Women’s Health

Central nervous system: The part of the nervous system

that in vertebrates consists of the brain and spinal cord,

to which sensory impulses are transmitted and from

which motor impulses pass out, and that supervises

and coordinates the activity of the entire nervous

system.

Cholesterol: A sterol (fatty substance) produced by all

vertebrate cells, particularly the liver, skin, and intestine, and found most abundantly in nerve tissue. See

also high-density lipoprotein cholesterol and lowdensity lipoprotein cholesterol.

Climacteric: The syndrome of endocrine, somatic, and

psychic changes occurring at the end of the female

reproductive period (menopause).

Combined hormone therapy (CHT): The use of estrogen combined with progestin for the treatment of

menopausal symptoms, e.g., hot flashes, and/or the

prevention and treatment of osteoporosis; progestin

opposes the carcinogenic effects of estrogen on the

endometrium. Also known as hormone replacement

therapy (HRT).

Conjugated estrogens: The sodium salts of the estrogenic compounds, primarily estrone and equilin, that

are present as sulfate ester conjugates in pregnant mare

urine.

Contraindication: Any condition that renders a particular line of treatment improper or undesirable.

Coronary perfusion: The pumping of a fluid through the

heart by way of an artery.

Corpus luteum: A yellow glandular mass in the ovary

formed by an ovarian follicle that has matured and

discharged its ovum.

Cyclic regimen: Interrupted episodes with ongoing

medication.

Depomedroxyprogesterone acetate (depo-MPA): A

form of progestin.

Diethylstilbestrol (DES): A synthetic estrogenic compound used to treat menopausal symptoms, vaginitis,

and suppressed lactation.

Dyspareunia: Difficult or painful coitus/intercourse in

women.

Dysuria: Painful or difficult urination.

Endogenous: Produced within or caused by factors

within the organism.

Endometriosis: The presence of endometrial tissue (the

normal uterine lining) in abnormal locations such as

the fallopian tubes, ovaries, or the peritoneal cavity.

Endometrium: The mucous membrane lining the uterus.

Endothelium: The layer of epithelial cells that lines the

cavities of the heart and of the blood and lymph

vessels, and the serous cavities of the body.

Epidemiology: The study of the relationships of various

factors determining the frequency and distribution of

diseases in the human community.

Equine estrogen: Estrogen pertaining to, characteristic

of, or derived from the horse.

Erythema: Redness of skin due to congestion of the

capillaries.

Estradiol: The most potent naturally occurring estrogen

in humans.

Estrogen: A generic term for estrus-producing compounds; the female sex hormones including estradiol,

estriol, and estrone. In humans, the estrogens are

formed in the ovary, adrenal cortex, testis, and

fetoplacental unit and are responsible for female

secondary sex characteristic development; during the

menstrual cycle, they act on the female genitalia to

produce an environment suitable for fertilization,

implantation, and nutrition of the early embryo.

Estrogen is used as a palliative in postmenopausal

cancer of the breast and in prostatic cancer, as oral

contraceptives, and for relief of menopausal discomforts.

Estrogen deficiency: The notion that menopause causes

an estrogen deficiency that requires replacement.

Estrogen replacement therapy (ERT): See estrogen

therapy.

Estrogen therapy (ET): The use of estrogen for the relief

of menopausal symptoms, e.g., hot flashes, and/or the

prevention and treatment of osteoporosis. Also known

as estrogen replacement therapy (ERT).

Estrone: An estrogen isolated from pregnancy urine, the

human placenta, and palm kernel oil, and also prepared

synthetically.

Etiology: The science dealing with causes of disease.

Exogenous estrogen: Estrogen that is not produced

within the body but is provided by other means, e.g.,

tablets, injection, cream.

First-pass hepatic effect: See hepatic effect.

Follicle: The structure on the ovary surface that nurtures

a ripening oocyte. At ovulation the follicle ruptures

and the oocyte is released. The follicle produces

estrogen until the oocyte is released, after which it

becomes a yellowish protrusion on the ovary called the

corpus luteum.

Follicle-stimulating hormone (FSH): A pituitary

hormone, also known as a gonadotropin, that helps to

stimulate hormone and gamete production by the

ovaries and testes.

Follicular depletion: The gradual depletion of follicles in

the ovary.

Food and Drug Administration (FDA): The government agency responsible for drug approval.

Germ cell: Any cell of an organism whose function is

reproduction, e.g., gametes (ova and spermatozoa).

Gonadotropin: A substance that has a stimulating effect

upon the gonads, especially the hormone secreted from

the anterior pituitary.

Gonadotropin-releasing hormone (GnRH): The

hormone released from the hypothalamus that causes

secretion of gonadotropins from the pituitary gland.
Appendix C--Acronyms and Glossary ● 117

Healthy user effect: A phenomenon observed in epidemiologic studies in which subject participants exhibit lower incidence of morbidity or mortality than the

general population because they are generally in good

health while the less healthy either choose not to

participate in the study or are excluded.

Hemostasis: The arrest of bleeding, whether by the

physiological properties of vasoconstriction and coagulation or by surgical means.

Hepatic effect: Pertaining to the liver; the metabolism of

estrogen by the liver.

Hepatobiliary: Related to the gallbladder.

High-density lipoprotein cholesterol (HDL): A class of

cholesterol; low levels of HDL are associated with a

decreased risk of heart attack.

Hormone: A chemical substance produced in the body

that has a specific regulatory effect on the activity of

certain cells or a certain organ or organs.

Hormone replacement therapy (HRT): See combined

hormone therapy.

Hormone therapy: Collectively and generally, this term

describes either estrogen therapy or combined

hormone therapy when a distinction is not necessary.

See estrogen therapy, combined hormone therapy.

Hot flash: Sudden sensations of heat and flushing of the

face and torso.

Hyperinsulinemia: Excessive secretion of insulin.

Hypermenorrhea: Excessive menstrual bleeding, but

occurring at regular intervals and being of usual

duration.

Hyperplasia: Abnormal increase in the number of

normal cells in normal arrangement in an organ or

tissue, which increases its volume.

Hypertension: High arterial blood pressure; it may have

no known cause, or it may be associated with other

diseases.

Hypertriglyceridemia: An excess of triglycerides in the

blood.

Hypomenorrhea: Diminution of menstrual flow or

duration.

Hypothalamus: The part of the diencephalon forming the

floor and part of the lateral wall of the third ventricle;

anatomically, it includes the optic chiasm, mammillary

bodies, tuber cinereum, infundibulum, and pituitary

gland, but for physiological purposes the pituitary

gland is considered a distinct structure.

Hysterectomy: Excision of the uterus.

In vitro: Literally “in glass”; pertaining to a biological

process or reaction taking place in an artificial

environment, usually a laboratory.

In vivo: Literally “in the living”; pertaining to a

biological process or reaction taking place in a living

cell or organism.

Involutional melancholia: A prolonged psychotic reaction occurring in late middle life, characterized by

depression and paranoid ideas, also known as involutional psychosis.

Lactation: The secretion of milk

Life expectancy: An expected number of years of life

based on statistical probability.

Low-density lipoprotein (LDL) cholesterol: A class of

cholesterol; high levels of LDL are associated with a

greater risk of heart attack.

Luteinizing hormone (LH): A gonadotropin that, along

with FSH, stimulates and directs hormone and gamete

production of the ovaries and testes.

Medicalization: The practice of treating or defining

people’s experiences as medical problems.

Medroxyprogesterone acetate (MPA): A form of progestin.

Menopausal syndrome: Symptoms associated with

menopause, e.g., hot flashes, vaginal dryness, osteoporosis.

Menopause: Cessation of menstruation; the immediate

postreproductive phase of a woman’s life, when

menstrual function ceases due to failure to form

ovarian follicles and ova.

Menorrhagia: Excessive menstruation.

Menses: The monthly flow of blood from the female

genital tract.

Menstruation: The cyclic physiological discharge of

blood from the nonpregnant uterus, occurring usually

at approximately 4-week intervals during the reproductive period in female humans.

Metrorrhagia: Uterine bleeding, usually of normal

amount, occurring at completely irregular intervals,

the period of flow sometimes being prolonged.

Moieties: Any part or portion of a molecule.

Morbidity: The condition of being sick the sick rate; the

ratio of sick to well persons in a community.

Morphology: The science of organic forms and structure.

Mortality: The ratio of actual deaths to expected deaths;

the ratio of the total number of deaths to the population

of a specified area in a given time period, generally

figured in terms of number of deaths per 1,000,10,000,

or 100,000 of population.

Natural estrogen: An estrogen that is derived from

natural sources, e.g., conjugated equine estrogens.

Natural menopause: Menopause that occurs as a natural

part of the aging process, not surgically induced.

Neuroendocrine stimulation: Stimulation related to the

interactions between the nervous and endocrine systems.

19-nortestosterone: A form of progestin.

Norethidrone: A progestational agent similar in action to

progesterone.

Norethidrone acetate: A form of progestin.

Nulliparity: The state of being a woman who never has

borne a viable child.

Observational studies: An epidemiologic study in which

there is no artificial manipulation of the study factor.
118 . The Menopause, Hormone Therapy, and Women’s Health

Oligomenorrhea: Abnormally infrequent menstruation.

Oophorectomy: Excision of one or both ovaries.

Opposed estrogen: Estrogen that is used in conjunction

with progestin.

Osteoblast: A cell arising from a fibroblast, which, as it

matures, is associated with bone production.

Osteopenia: Any condition involving reduced bone

mass.

Osteoporosis: Abnormal rarefaction of bone; it maybe

idiopathic or occur secondary to other diseases.

Ovaries: Either of the paired female sex glands in which

ova are formed.

Pathophysiology: The physiology of discorded function.

Percutaneous: Performed through the skin.

Perimenopause: The time around the menopause.

Peripheral conversion: Conversion of estrogen outside

of the liver, in peripheral tissues.

Peripheral nervous system: The autonomic nervous

system, the cranial nerves, and the spinal nerves

including associated receptors.

Pharmacodynamics: The study of the actions of drugs

on living systems.

Pharmacokinetics: The rate of change in a physical or

chemical system, specifically in relation to drugs.

Pituitary gland: A gland at the base of the brain that

secretes a number of hormones related to reproduction.

Pituitary gonadotropins: Substances, released by the

pituitary, that act to stimulate the gonads.

Platelets: Any of the disk-shaped structures in the blood

of all mammals, chiefly known for their role in blood

coagulation.

PMS: See Premenstrual syndrome.

Postmenopause: The period of time after the menopause.

Premature ovarian failure: Condition characterized by

the failure to ovulate before the normal age of

menopause.

Premenopause: The stage of life before menstruation

stops.

Premenstrual syndrome: The pattern of symptoms

related to the menstrual cycle.

Progesterone: The steroid hormone produced by the

corpus luteum, adrenal cortex, and placenta which

serves to prepare the uterus for reception and development of the fertilized ovum by inducing secretion in

the proliferated glands. A synthetic preparation is used

in the treatment of functional uterine bleeding, menstrual cycle abnormalities, and threatened abortion.

Progestin: Originally, the crude hormone of the corpus

luteum; it has since been isolated in pure form and is

now known as progesterone. Certain synthetic and

natural progestational agents are called progestins.

Puerperal: Pertaining to a woman who has just given

birth to a child.

Randomized trials: An epidemiologic experiment in

which subjects are randomly allocated into groups, the

“study” and “control” groups, to receive or not to

receive an experimental preventive or therapeutic

procedure, e.g., a drug.

Relative risk: In epidemiology, the ratio of the incidence

of, or mortality from, a disease in a population exposed

to the factor under consideration to the corresponding

rate in a population not so exposed.

Releasing factors: Substances that act to release

hormones.

Selection bias: A distortion in the estimate of effect

resulting from the manner in which subjects are

selected for a study population.

Serum lipid profiles: A quantitative representation of the

level of serum lipids.

Serum triglycerides: Esters formed from glycerol and

one to three fatty acids; fats and oils are triglycerides.

Steroid hormones: Hormonal compounds containing

four carbon rings interlocked to forma hydrogenated

cyclopentophenanthrene-ring system.

Subarachnoid hemorrhage: A form of stroke characterized by bleeding between the pia mater and arachnoid

of the brain.

Surgical menopause: Menopause following the surgical

removal of the ovaries.

Symptomatology: The combined symptoms of a disease.

Synthetic estrogen: A synthetically produced/manufactured estrogen product.

Systemic circulation: Channels through which nutrient

fluids of the body flow; often restricted to the vessels

conveying blood.

Testosterone: A hormone secreted by the interstitial cells

of the testes, which functions in the induction and

maintenance of male secondary sex characteristics;

testosterone and its cypionate, enanthate, and propionate esters are used in palliative therapy in inoperable

carcinoma of the female breast and certain gynecologic

conditions.

Thromboembolitic disease: Disease related to the obstruction of blood vessels.

Thrombosis: The formulation or presence of a solid mass

formed in the living heart or vessels from constituents

of the blood.

Thyroid: An endocrine gland consisting of two lobes,

one on each side of the trachea, joined by a narrow

isthmus, producing hormones (thyroxine and triiodothyronine) that require iodine for their elaboration and

that are concerned in regulating metabolic rate; it also

secretes calcitonin.

Trabecular: Of or pertaining to a supporting or anchoring strand of connective tissue, e.g., a strand extending

from a capsule into the substance of the enclosed

organ.

Transdermal: Through the skin.
Appendix C-Acronyms and Glossary ● 119

Transmenopausal: Occurring across the time period of

the menopause.

Unopposed estrogen: Estrogen used alone.

Urethra: A passage through which urine is discharged

from the bladder to the exterior of the body.

Urinary stress incontinence: Involuntary escape of urine

due to strain on the orifice of the bladder, as in

coughing or sneezing.

Urodynamics: A process that evaluates characteristics of

the urine stream and the pelvic musculature, and the

activity of the bladder.

Uterus: The hollow muscular organ in the female in

which the fertilized ovum normally becomes embedded and in which the developing embryo and fetus are

nourished. Its cavity opens into the vagina below and

into a uterine tube on either side.

Vagina: The canal in the female, from the vulva to the

cervix uteri, that receives the penis in copulation and

is the birth canal.

Vaginal atrophy: The wasting or diminution in size of

the vagina.

Vascular tree: The tree-like structure of the blood

vessels.

Withdrawal bleeding: Bleeding associated with combined hormone therapy caused by the stimulation of

the endometrium by progestin.
Index
Index

Alcohol, Drug Abuse, and Mental Health Administration

(ADAMHA) (U.S.), 76

National Institute on Drug Abuse (NIDA), 93

National Institute of Mental Health (NIMH), 93

Office of Science, 76

research on the menopause, 93-94

Amenorrhea, 18

American College of Obstetrics and Gynecology, guidance on

hormone therapy, 46

American College of Physicians, guidance on hormone

therapy, 46

. Animal models for research, 88

Arteriosclerosis Research Center, 88

Baltimore Longitudinal Study of Aging (BLSA), 76

Bellergal, 47

Beta-blockers, 47

Bilateral oophorectomy

and breast cancer, 40, 82

as cancer preventative, 20

and cardiovascular disease, 20, 26, 27,40, 77

and estrogen use, 49

and hysterectomy, 20, 22

indications for, 21

and menopausal symptoms, 19

and mortality, 78

and osteoporosis, 20,40, 85

research needs, 85-86

Bioequivalence, for estrogen, 67

Biofeedback, for menopausal symptoms, 48

Bowman Gray School of Medicine, 88

Breast cancer

estrogen, role in, 4,41-43,79-80,86

mortality rates for, 24

research needs, 86

risks for, 79-80

and Tamoxifen, 42

California, hormone prescribing practices in, 69

Cardiovascular disease

and bilateral oophorectomy, 20, 26, 27

and cholesterol, 26, 27,77-79

and estrogen, 4,5,24, 3940,76-77

and hysterectomy, 20

and lipid profiles, 77-79

and menopause, 26

morbidity and disability from, 26

mortality rates for, 24, 26, 27

and progestin, 5

research, in women, 26

and research needs as related to the menopause, 87-89

risk factors for, 40, 80

treatment of, 26

Catapress transdermal patch, 47

Change of life; see Menopause

Cholesterol, high-density lipoprotein (HDL)

and cardiovascular disease, 26, 27

effects of estrogen on, 77-81, 87-89

Cholesterol, low-density lipoprotein (LDL)

and cardiovascular disease, 26, 27

effects of estrogen on, 77-81, 87-89

CIBA, 54,63,71

Climacteric, definition of, 3,4

Combined hormone therapy

administration of, 36-38,70

alternatives to, 46-48, 106

and calcium intake, 39

compliance, 50

definition of, 5n.2

effects on weight gain, 90

FDA advice on, 66, 106

prescribing criterion for, 5

prescribing practices for, 4849,66-70

prevalence of use of, 48-50

professional guidelines for use of, 46

and progestin, 5

refining risks and benefits of, 103-104

side effects of, 37

user of, 49

Comparative Medicine Clinical Research Center, 88

Curetab, 71

Demographics

of menopausal women, 3

Depression, menopausal, 22-23,28,35

Diethylstilbestrol (DES), 92,95

Drug Efficacy Study Implementation (DESI) program, 63

Dyspareunia, 19

Dysuria, 19

Education, need for concerning the menopause and hormone

therapy, 106

Endometrial cancer, 64

and estrogen therapy, 4,36,38,40-41,64

and progestin, 5,36-37

Epidemiology

and menopause research, 81-84

and selection bias, 82-83

Estraderm

approved use for, 64, 106

marketing of, 71

Estradiol

ovarian secretion of, 24

receptors for, 22

Estratab, 71

Estratest, 71

Estrogen

and bone loss, 24

and breast cancer, 4

and cardiovascular disease, 24, 27

and endometrial cancer, 4

and hypertriglyceridemia, 27

and low-density lipoprotein cholesterol, 27

production of, 3, 18

protective effects of, 27

receptors for, 24

–123–
124 . The Menopause, Hormone Therapy, and Women’s Health

tissues affected by, 17,36

and vaginal dryness, 22

and very low density lipoprotein, 27

Estrogen replacement therapy (ERT); see Estrogen therapy

Estrogen Therapy (ET)

alternatives to, 46-48

approved use for, 64

bioequivalence for, 67

and breast cancer, 4,41-43,79-80, 83, 86

cardioprotective effect of, 35-36,3940,65,77-81, 87-89

and compliance, 50

contraindications to use, 36, 65

drug labeling for, 63-65, 105-106

and endometrial cancer, 4, 36, 38,40-41

and hepatobiliary disease, 43

and hot flashes, 4, 35

and lipid profiles, 35,37,3940,77-79, 87

marketing of, 70-71

and menopausal symptoms, 4, 35

opposed vs. unopposed, 4

and overall mortality, 39,78

prescribing practices for, 4849,66-70

prescriptions of, 67-70

and prevention of bone loss, 38-39,79, 89-90

and renal function, 90

routes of administration for, 36

sales figures for, 63

and triglyceride levels, 35,79

and weight gain, 90

Exercise and menopause, 39,48,91

Follicle-stimulating hormone (FSH), in reproductive cycle, 17,

18

Food and Drug Administration (U. S.)

Division of Epidemiology and Surveillance, 68

Fertility and Maternal Health Drugs Advisory Committee,

64-65,66

Generic Drugs Advisory Committee, 67

guidance regarding generic estrogens, 66

guidance regarding osteoporosis, 53

and women’s health issues, 5

Food, Drug, and Cosmetic Act, 63

Framingham Study, 76-77

General Accounting Office (U.S.), 75

Generic estrogens, 66

Ginseng, 48

Glucose metabolism and the menopause, 86-87

effects of progestin on, 87

Goldman, L., 105

Gonadotropin-releasing hormone (GnRH), in reproductive

cycle, 18

Healthy user effect, 82

Healthy Women Study, 77-78,83

Herbal treatments, 47-48

Hormone replacement therapy (HRT); see Combined hormone

therapy

Hormone therapy

definition of, 4n.2

weighing risks and benefits of, 5,49-50, 105

Hot flashes

incidence of, 18

treatment of, 4,64-66

vasomotor symptoms of, 19

Hypermenorrhea, 18

Hypertriglyceridemia, 27

Hypomenorrhea, 18

Hysterectomy

age at, 21-22, 22

and bilateral oophorectomy, 20, 22

and bone loss, 20, 85

and breast cancer risk, 82

and cardiovascular disease, 20, 77

indications for, 21, 22

and mortality, 78

prevalence of, 19-20,20,21

and psychiatric symptoms, 23

research needs on, 85-86

IMS, America, Ltd., 67 Inderal, 47

International Consensus Conference on progestin use, 46

International Menopause Society, 51

Involutional melancholia see Depression, menopausal

Japan, the menopause in, 111-112

Leisure World Study, 78

Lipids

effects of estrogens on, 77-81, 87-89

Lipid Research Clinic Mortality Followup Study, 39,78

Lipid Research Clinic Prevalence Study, 78

Los Angeles County Obstetrics and Gynecology Society, 69

Luteinizing hormone (LH), in reproductive cycle, 18

Massachusetts Women’s Health Study, Part 2, 13,23,48,

49,79,83

Menopause

age at, 3, 17

attitudes toward, 11, 13, 14-15, 16, 23

biology of, 15-17,22

and cholesterol levels, 26-27

clinics, 50-5 2

and cultural factors, 13

definition of, 3,4, 15, 101

and educational materials, 55

effects of smoking on, 77

ethnicity and, 92

factors affecting onset of, 77

historical medical perspectives on, 11, 12-13

hormone levels in, 18

as “medical” condition, 14

mood and behavioral changes in, 22-23

myths regarding, 14

nutritional requirements and, 90

patient and professional education regarding, 52

and psychiatric syndromes, 22

relationship with diseases of aging, 101-102

research needs, 11, 15, 82, 84-91, 102

and roles of women, 11, 14-15, 16

and sexuality, 23

and smoking, 17-18

symptomatology of, 11, 15, 18-19

timing of, 17

Menopause, surgical; see Hysterectomy; Bilateral

oophorectomy

Menorrhagia, 18
Index . 125

Menstruation, study of, 81

Metrorraghia, 18

National Cancer Institute, 42,94

National Center for Nursing Research, 94

National Center for Research Resources, 94

National Disease and Therapeutic Index, 67

National Heart, Lung, and Blood Institute, 42,76,77,78,80,94

National Institute for Dental Research, 94

National Institute on Aging, 76,79,94

National Institute of Arthritis and Musculoskeletal and Skin

Diseases, 80,94

National Institute of Child Health and Human Development,

80,94

National Institute of Diabetes and Digestive and Kidney

Diseases, 80,94

National Institute of Environmental Health Sciences, 81

National Institutes of Health

Computer Retrieval of Information on Scientific Projects

(CRISP), 92

Office of Research on Women’s Health, 75-76

research on menopause, 92-94

research on women’s health, 5, 6,75

National Osteoporosis Foundations, 42

National Prescription Audit, 67

National Surgical Adjuvant Breast and Bowel Project, 42

Nurses’ Health Study, 5,40,42,79-80,83

Oligomenorrhea, 18

Oral contraceptives

and postmenopausal hormone use, 102

risks of use of, 39, 80

Osteoporosis

and age, as factor in etiology of, 24

and bilateral oophorectomy, 20

and bone mass, 25-26

definition of, 24

and fractures, 24-25

in hysterectomized women, 24

incidence of, 24, 25

major sites of, 24

and ovarian hormones, 4, 24, 25

research needs, 89-90

risk factors for, 26,40, 90

Ovary, research needs on, 85-86

Pennsylvania State University, 81

Perimenopause

attitudes toward, 23

definition of, 3,4, 101

symptomatology of, 17, 27

Pharmacology, and hormone therapy, 91

Physician’s Desk Reference, 64,65,66

Physician’s Health Study, 84

PMB-200, 64

PMB-400, 64

Postmenopausal Estrogen Progestin Intervention (PEPI) Trial,

69,80-81,83,84,87,92, 103

Premarin

approved use of, 63-65

bioequivalence for, 67

cost of, 106

marketing of, 54,70

prescriptions of, 68

sales of, 63, 106

use in research participants, 77, 80, 87

Premature ovarian failure, definition of, 17

Premenstrual syndrome (PMS), as psychiatric syndrome, 22

Progesterone

and bone mass, 25

receptors for, 22

in reproductive cycle, 18

Progestins

alternatives to, 46-47

approved use of, 65-66

and breast cancer, 43

and cardiovascular disease, 5, 37, 77, 87

and combined hormone therapy, 5, 36-38

and compliance, 50

contraindications of, 66, 70

and endometrial cancer, 5, 36

and glucose metabolism, 87

and hot flashes, 37,46

labeled indications for, 65-66

marketing of, 70

prescribing practices for, 68-70

side effects of, 37

Provera, 63,80,87

Public Health Service (U.S.)

agenda for women’s health, 75

Healthy People 2000,94

investment in menopausal and related research, 92-94

Task Force on Women’s Health Issues, 73

Randomized trials

of estrogen, 81-82,83

need for, 102-103

Reid-Rowell, 71

Research

estrogen use, 77-81

Federal investment in, 92-94

gender-specific perspective in, need for, 3

menopause, 11, 15,81-92

methodologic considerations in, 81-84

needs, 84-91

women’s health, 75

Risk perception, 49-50, 104-105

Smoking, and menopause, 17-18

Symptoms, menopausal, and bilateral oophorectomy, 19

Tamoxifen, 42

Tosteson, A.N.A., 105

Tremin Trust Research Program on Women’s Health, 81

Tubal ligation, 86

United States Pharmacopoeia 67

University of California, San Diego, 54

University of Minnesota, 81

University of Utah, 81

Upjohn, 63

Urinary stress incontinence, 19

Vaginal atrophy, 18, 19

Veralipride, 47

Very low density lipoprotein (VLDL), and estrogen, 27

Vitamins, 47
126. The Menopause, Hormone Therapy, and Women’s Health

Waist-to-hip ratio, 76 Women’s Health Initiative Trial, 84

Women’s health World Health Organization, 115

congressional interest in, 5-6 Wyeth-Ayerst, 53,63,65,66,71

legislation, in 102nd Congress, 6