Decision analysis of hormone replacement therapy after the

Women’s Health Initiative

Catherine Kim, MD, MPH,a,b and Yeong S. Kwok, MDa

Ann Arbor, Mich

OBJECTIVES: The purpose of this study was to estimate the quality-adjusted life expectancy with and

without hormone replacement therapy.

STUDY DESIGN: We compared the quality-adjusted life expectancy with and without combination hormone

replacement therapy in three cohorts of women with menopausal symptoms over a 20-year period using

a Markov decision-analysis model. Women were either at high or low risk for breast cancer and coronary

heart disease or at high risk for osteoporosis.

RESULTS: Hormone replacement therapy decreases life expectancy slightly compared with no hormone

replacement therapy if menopausal symptoms are not considered. However, if relief from menopausal

symptoms is considered and the usefulness of life with symptoms is worth < 0.996 compared with life without

symptoms, then 5 years of hormone replacement therapy provides equivalent quality-adjusted life-years.

CONCLUSION: Combination hormone replacement therapy decreases life expectancy if quality of life with

menopausal symptoms is not considered. However, the benefit of hormone replacement therapy can

exceed the risk for women with menopausal symptoms. (Am J Obstet Gynecol 2003;189:1228-33.)

Key words: Estrogen, progestin, menopause

After the publication of the Heart Estrogen/Progestin

Replacement Study (HERS) results,1 recommendations

for hormone replacement therapy (HRT) use changed

dramatically. Experts advocated HRT only in women with

menopausal symptoms or in women with documented

osteoporosis or osteopenia who were at relatively low risk

for breast cancer.2 Recently, the Women’s Health Initiative

(WHI) study results demonstrated that combination

estrogen/progestin increased the risk of coronary heart

disease (CHD) and breast cancer in women with and

without known CHD.3 Subsequently, medical organi-

zations including the American College of Obstetrics

and Gynecology have recommended against the use of

HRT for primary or secondary prevention of CHD

and recommend alternate therapies be considered for

osteoporosis.4

It is unclear how to weigh the menopausal symptom

relief provided by HRT against its risks of CHD, breast

cancer, pulmonary embolus, and stroke. HRT risks and

benefits will vary between women because women have

Supplementary data associated with this article can be found atdoi:10.1067/S0002-9378(03)00778-6.From the Departments of Internal Medicinea and Obstetrics andGynecology,b University of Michigan.Received for publication December 16, 2002; revised February 22, 2003;accepted June 12, 2003.Reprints not available from the authors.� 2003, Mosby, Inc. All rights reserved.0002-9378/2003 $30.00 + 0doi:10.1067/S0002-9378(03)00778-6

1228

widely varying experiences of menopause5 and the risks

of disease change with the duration of therapy and with

the baseline risks and the age of the woman.3

Decision analysis is a technique that allows for the

mathematic modeling of likely outcomes, given known

probabilities.6 Decision analysis can provide likely

answers through mathematic modeling in cases in which

direct data are not available. Using decision analysis, we

can take the quality of life of a given condition into

account, which is an important consideration given that

menopausal symptoms are primarily a quality-of-life

issue. There are two commonly used measures to ascer-

tain the quality of life or usefulness with a given disease

state: the standard gamble and the time trade-off tech-

niques. In the standard gamble, subjects are asked how

high of a risk of death they would be willing to accept

for a procedure that will rid them of the disease. In

the time trade-off, subjects are asked to express their

preferences toward treatment by comparing a period of

ill health with a shorter period with a higher quality of

life. For example, if someone with a given disease is

willing to undergo an operation that has a maximum

10% mortality rate in return for a cure or if they are

willing to only live 9 years disease free instead of 10 years

with the disease, then that disease state has a utility of 0.9

or 90%.6 This method has been used to determine the

‘‘utility’’ of disease states (such as allergies), with a utility

of 0.97 (97%), which means that on average someone

would be willing to undergo a procedure that would cure

Volume 189, Number 5Am J Obstet Gynecol

Kim and Kwok 1229

their allergies as long as the risk of death was less than

3%.7

Previous decision analyses have modeled the risks and

benefits of HRT but were limited by an inability to

incorporate randomized controlled trial data and did not

address the issue of menopausal symptom relief.8,9

Therefore, we conducted a decision analysis that in-

corporated WHI randomized controlled trial results. Our

objectives were to estimate life expectancy with and

without HRT, by adjusting for quality-of-life for disease

states, and the degree to which HRT would need to

improve a woman’s quality of life to outweigh its risks.

Material and methods

Decision model. Using Excel (Microsoft Corporation,

Redmond, Wash), we created a Markov state transition

model to simulate morbidity and mortality rates of disease

states that are affected by HRT. We included the following

disease states: breast cancer, CHD, stroke, pulmonary

embolism, colon cancer, and hip fracture. The key

assumptions of the model are outlined in Table I. We

modeled three hypothetical cohorts of 50-year-old women,

all with menopausal symptoms, and varied their baseline

risk of adverse events. The first cohort of women included

healthy women at low risk of adverse events (ie, at low risk

for breast cancer and CHD). The second cohort included

women at relatively high risk of osteoporosis (ie, with

a weight of < 57 kg and a family history of postmenopausal

fracture). The third cohort included women at high risk

for adverse events (ie, women with diabetes mellitus and

two first-degree relatives with breast cancer).

Each year women could have breast cancer, CHD

events, stroke, pulmonary embolism, hip fracture, colon

cancer, or a combination of these diseases, or they could

die of any of the diseases that are mentioned. Three

simulations were run for each cohort: no HRT use, HRT

use for 5 years, and HRT use for 15 years. The model was

run for 20 years, 5 years more than the maximum length

of modeled HRT, and near the maximum likely HRT use

in the population.10 We did not include endometrial

cancer as an outcome because we assumed that women

used progestin and estrogen, and this combined regimen

was not associated with an increased risk of endometrial

cancer in WHI.3 Discounting is a method to place a higher

value on current life than future life and is commonly

used in decision analyses. We used a discount rate of 3%

per year for our primary analyses but also examined

outcomes without discounting.

We assumed that HRT consisted of combination con-

jugated equine estrogen 0.625 mg per day and medroxy-

progesterone acetate 2.5 mg per day because this was the

drug regimen reported in the WHI. We compared out-

comes at 20 years between women with no HRT use and

women with HRTuse for 5 years and HRTuse for 15 years.

We assumed that HRT use alleviated menopausal

Table I. Model assumptions

Disease state Assumption

Annual incidence of diseaseCHD

Women at low risk* 0.001 for 50-59 y; 0.002 for 60-69 yWomen at high risky 0.0029 for 50-59 y; 0.006 for 60-69 y

Breast cancerWomen at low riskz 0.0012 for 50-54 y; 0.0016 for

55-59 y; 0.0018 for 60-65 y; 0.0022for 65-69 y

Women at high risk§ 0.0085 for 50-54 y; 0.010 for55-59 y; 0.013 for 60-65 y; 0.015for 65-69 y

StrokeWomen at low risk* 0.000754 for 50-59 y; 0.00151 for

60-69 yWomen at high risky 0.0022 for 50-59 y; 0.0044 for 60-69 y

Pulmonary embolism 0.0000495 for 50-59 y; 0.00088 for60-69 y

Hip fractureWomen at low riskk 0.0003 for 50-54 y; 0.0005 for

55-59 y; 0.0009 for 60-64 y; 0.0018for 65-69 y

Women at high risk{ 0.001 for 50-54 y; 0.002 for 55-59 y;0.004 for 60-64 y; 0.0079 for 65-69 y

Colon cancer 0.0005 for 50-54 y; 0.0009 for55-59 y; 0.0014 for 60-65 y; 0.002for 65-70 y

Annual mortality rateCHD

Women at low risk* 0.0002 for 50-59 y; 0.0004 for 60-69 yWomen at high risky 0.00058 for 50-59 y; 0.0012 for 60-69 y

Breast cancer 0.00013, rising annually 0.0001Stroke

Women at low risk* 0.000113 for 50-59 y; 0.0002265for 60-69 y

Women at high risky 0.000328 for 50-59 y; 0.000657for 60-69 y

Pulmonary embolism 0.00001Hip fracture

Women at low riskk 0.000075 for 50-54 y; 0.00015for 55-59 y; 0.0003 for 60-64 y;0.0006 for 65-69 y

Women at high risk{ 0.00033 for 50-54 y; 0.00067 for55-60 y; 0.0013 for 60-64 y;0.00263 for 65-69 y

Colon cancer 0.000032 for 50 y, rising by 0.000007annually until 60 y, then rising by0.0000134 annually

Relative risks of estrogen/progestin#Coronary heat disease 1.29 (1.02-1.63)Breast cancer 1.26 (1.00-1.59)Stroke 1.41 (1.07-1.85)Pulmonary embolism 2.13 (1.39-3.25)Hip fracture 0.66 (0.45-0.98)Colon cancer 0.63 (0.43-0.92)

Quality of life estimates#Myocardial infarction 0.729 (0.628-0.871)Breast cancer 0.660 (0.546-0.864)Stroke 0.880 (0.120-0.980)Pulmonary embolism 0.978 (0.682-0.984)Hip fracture 0.95 (0.613-0.990)Colon cancer 0.88 (0.74-0.93)

*No diabetes mellitus, systolic blood pressure 140 mm Hg,total cholesterol 200 mg/dL, no cigarette use.yDiabetes mellitus with risk factor profile.zNo relatives with breast cancer and no breast biopsies.§Two first-degree relatives with breast cancer and no breast

biopsies.kWeight >57 kg and no family history of postmenopausal fracture.{Weight <57 kg and family history of postmenopausal fracture.#Figures in parentheses indicate the ranges used in sensitivity

analyses.

November 2003Am J Obstet Gynecol

1230 Kim and Kwok

symptoms and that women with symptoms have similar

disease rates to the overall population. In the instances of

cardiovascular disease, pulmonary embolism, and

fractures, we modeled HRT effects to begin when therapy

was initiated and to cease when therapy was discon-

tinued.3,11,12 In the instance of breast and colon cancer,

we modeled HRT effects to begin 4 years after therapy

initiation.3,13,14

Data sources for disease incidence and mortalityestimates. References for data sources that are listed in

Table I are available in the reference list for on-line

publication. We derived the risk of developing breast

cancer by applying the proportional hazards model that

was obtained from the Breast Cancer Detection Demon-

stration Project, commonly known as the Gail model. We

derived breast cancer mortality rates from National

Center for Health Statistics publications. To model the

increased risk of breast cancer in a woman with two first-

degree relatives with breast cancer, we assumed that the

mortality rate from the disease was increased by a factor of

2.93.15 Because the WHI study follow-up was not long

enough to assess breast cancer mortality rate differences,

it is unclear whether the breast cancer on HRT is asso-

ciated with a different prognosis than the more poorly

differentiated tumors seen without HRT, so breast cancer

outcomes were modeled similarly for women with and

without HRT use.

To predict the annual risk of CHD events (defined as

the development of myocardial infarction or sudden

cardiac death), we applied the model that was derived

from the Framingham Heart Study. To model the

increased risk of CHD events that are caused by diabetes

mellitus, we also assumed that the risk of CHD in a woman

with diabetes mellitus was increased by a factor of 2.90.16

Stroke risk was also derived from the Framingham Heart

Study. Stroke mortality rate was obtained from the

Framingham Heart Study and WHI. We did not model

the effect of HRT on the development of subclinical CHD

because such population-based information is not yet

Table II. Quality-adjusted life-years with and without

HRT, without adjustment for quality of life with

menopausal symptoms and with 3% annual discounting

Duration of HRT use

None 5 Y 15 Y

Women at low riskfor CHD and breast cancer

14.88 14.87 14.84

Women with lowweight and family historyof postmenopausal fracture

14.86 14.85 14.83

Women with diabetesmellitus and twofirst-degree relatives withbreast cancer

14.11 14.07 13.92

available and the initial manifestation of CHD in women is

commonly a cardiac event rather than diagnostic testing

or symptoms.17 Because there were no increases in actual

CHD or stroke mortality rate in the WHI, it is unclear

whether the thrombotic events that are caused by HRT

carry the same mortality rates as these events in the

general population; therefore, CHD outcomes were

modeled similarly for women with and without HRT use.

We predicted the risk for the development of hip fractures

on the basis of the proportional hazards model from the

Study of Osteoporotic Fractures Research Group and

derived hip fracture mortality rates from population-

based estimates of hip fractures. We obtained pulmonary

embolism incidence rates from population-based esti-

mates and pulmonary embolism mortality rates from

National Center for Health Statistics data. We obtained

colon cancer incidence rates from the Surveillance,

Epidemiology, and End Results registry. We obtained the

hazard ratios for the above diseases caused by HRT use

from the WHI Randomized Controlled Trial. We assumed

that the HRT hazard ratios would be identical across

women in the same subgroups of age, regardless of risk

factors for specific diseases, because of similar hazard

ratios that were obtained in the WHI subgroup analyses

for CHD and breast cancer.

Quality of life. Published quality-of-life estimates vary

widely for the diseases in our model. For our base-case

analyses, we used previously published utilities from

surveys from population-based cohorts when available

and then varied these simultaneously in sensitivity

analyses, using results reported in the literature. For

menopausal symptoms, we assigned a value of 1 to the

state of taking HRT. We then determined the relative

decline in quality of life from symptoms that were needed

to equal the losses in quality-adjusted life years because of

HRT.

Sensitivity analyses. We conducted one-way sensitivity

analyses on the rates of disease by varying the rates of

disease from one half to twice the point estimate. We

conducted one-way and multiway sensitivity analyses on

the quality-of-life estimates for the disease states. We also

conducted one-way and multiway sensitivity analyses on

the hazard ratios of the disease states that are associated

with HRT. Finally, we calculated quality-adjusted life-years

with and without discounting.

Results

No adjustment for quality of life with menopausalsymptoms. Without adjustment for symptoms, HRT is

associated with fewer years of life than no HRT for all

cohorts of women (Table II). However, the differences

in quality-adjusted life expectancy are slight between

HRT users and non-HRT users for low-risk women with

short-term use. This is consistent with WHI results that

demonstrated risks of disease that were slightly, but

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Kim and Kwok 1231

significantly, increased with HRT. For women at low risk of

CHD and breast cancer, the use of HRT for only 5 years is

associated with 4 fewer days of quality-adjusted life over 20

years. For women who are at high risk from osteoporosis

or the women who are most likely to benefit from HRT,

the use of HRT for 5 years is still associated with 4 fewer

days of quality-adjusted life over 20 years.

For women who are at high risk of breast cancer and

CHD, the use of HRT for 5 years is associated with 15 fewer

days of quality-adjusted life over 20 years.

As the duration of HRT use increases, the quality-

adjusted life expectancy decreases for all women (Table

II). For women who are at low risk of CHD and breast

cancer, the use of HRT for 15 years is associated with 15

fewer days of quality-adjusted life over 20 years. For women

who are at high risk of osteoporosis, the use of HRT for 15

years is associated with 11 fewer days of quality-adjusted

life over 20 years. For women who are at high risk of CHD

and breast cancer, the use of HRT for 15 years is associated

with 69 fewer days of quality-adjusted life over 20 years.

Adjustment for quality of life with menopausalsymptoms. We then calculated how much HRT would

have to improve the quality of life of a woman with

symptoms to make HRT beneficial (Table III). To make

life expectancy with HRT equivalent to life expectancy

without HRT, women who use HRT need only slight

improvements in their quality of life because of symptoms.

For women with a low risk of breast cancer and CHD, the

use of HRT for 5 years is associated with equivalent or

better quality-adjusted life than no HRTuse, if the quality-

of-life with symptoms is < 0.996. If the time trade-off

interpretation is used, women must be willing to give up

0.4% of their remaining life (about 1.5 days per year) with

symptoms to live without menopausal symptoms to make

HRT beneficial. For women with a high risk of breast

cancer and CHD, the use of HRT for 5 years is associated

with equivalent or better quality-adjusted life than no

HRT use, if the quality-of-life with symptoms is < 0.988. If

the standard gamble interpretation is used, women must

be willing to risk a 1.2% chance of death to accept

a procedure that would rid them of symptoms. Finally, for

women who are at high risk for osteoporosis, the use of

HRT for 5 years results in equivalent quality-adjusted life

expectancy, if the quality of life with symptoms is < 0.997.

The degree of relief from menopausal symptoms that is

required for equivalent quality of life for longer use is

similar to short-term use. The improvement in the quality

of life with symptoms over a longer time period balances

the increased risk of breast cancer and cardiovascular

disease. For women with a low risk of breast cancer and

CHD, the use of HRT for 15 years is associated with similar

life expectancy than no HRT use, if the quality of life with

symptoms is < 0.996. For women with a high risk of breast

cancer and CHD, the use of HRT for 15 years is associated

with similar life expectancy than no HRTuse, if the quality

of life with symptoms is < 0.981. For comparison purposes,

the quality of life with allergies has been estimated at 0.97

in women.7

When we eliminated discounting, the degree of

symptom relief needed from HRT to compensate for

increased mortality and morbidity rates decreased slightly

(Table III) because the benefits of HRT are experienced

immediately although the costs mostly come later.

However, the differences were slight.

Sensitivity analyses. We examined how these estimates

changed because of uncertainty or disagreement

surrounding the quality-of-life estimates for the various

disease states and the estimates for the risks that are

associated with HRT. For all women, the risks of HRT

exceeded the benefits of HRT when symptoms were not

considered. The quality of life with menopause that was

needed to justify HRT use varied primarily depending on

the woman’s baseline risk of disease and the relative risks

of HRT and to a lesser extent on the estimates for the

quality of life. All one-way sensitivity analyses led to

minimal changes and only minimally affected the results,

never changing the quality of life with HRT needed for

equivalence by >0.002. We present two extreme scenarios,

one biased in favor of HRT and one biased against HRT.

For women who are at high risk for osteoporosis, when the

quality of life with breast cancer, CHD, stroke, and

pulmonary embolus were at the highest estimate (Table

I), the relative risks for these diseases were at the lowest

estimate (Table I), and when the quality of life estimates

and relative risks for hip fracture and colon cancer were at

the lowest estimates, the HRT use provided 0.01 addi-

tional quality adjusted life years for 5 years of use and 0.03

Table III. Quality of life with menopausal symptoms

with which HRT would provide greater benefit than

no therapy

Duration of symptomsand HRT use

5 Y 15 Y

With annual discountingWomen at low risk for coronary

heart disease and breast cancer0.996 0.996

Women with low weight andfamily history ofpostmenopausal fracture

0.997 0.997

Women with diabetes mellitusand 2 first-degree relativeswith breast cancer

0.988 0.981

Without annual discountingWomen at low risk for coronary

heart disease and breast cancer0.997 0.997

Women with low weight andfamily history ofpostmenopausal fracture

0.998 0.997

Women with diabetes mellitusand 2 first-degree relativeswith breast cancer

0.991 0.985

November 2003Am J Obstet Gynecol

1232 Kim and Kwok

for 15 years of use compared with no HRT use. In other

words, even without considering symptom improvement,

women gained 4 days of life after using HRT for 5 years

and 11 days of life after using HRT for 15 years.

At the other extreme, for women with a high risk of

breast cancer and diabetes mellitus, when the quality of

life with breast cancer, CHD, stroke, and pulmonary

embolus were at the lowest estimate (Table I), the relative

risks for these diseases were at the highest estimate (Table

I); when the quality of life and the relative risks with hip

fracture and colon cancer were high, the quality of life

with symptoms had to be < 0.933 to justify HRT use for 5

years and 0.915 to justify HRT use for 15 years. Although

this figure is the lowest estimate of the equivalence utility

that is needed from menopausal symptoms, it is com-

parable to utility estimates for sleep disorder, which

using the time trade-off method is estimated at 0.908.7

Comment

Our model predicts that HRT decreases a woman’s life

expectancy over a period of 20 years, with adjustment for

reduced quality of life with CHD, breast cancer, stroke,

pulmonary embolus, and hip fracture. However, when

relief from menopausal symptoms is taken into account,

women who use HRT can have equivalent or greater life

expectancy than women who do not use HRT. The degree

of benefit because of HRT depends on the severity of

a woman’s symptoms and impact on her quality of life.

The overall risks and benefits of HRT are determined by

a woman’s baseline risk of disease, the severity of

a woman’s symptoms, and the duration of HRT use.

Our findings do not apply to women taking unopposed

estrogen or estrogen and cyclic progesterone because we

based relative risk changes from WHI data that only

examined women who were taking continuous estrogen

and progestins. We also assumed that HRT provided relief

from menopausal symptoms and that our results would

apply only to women taking HRT who had relief from

symptoms. Women need not obtain complete relief from

symptoms with HRT use as long as they obtain a relative

benefit compared with not taking HRT. In HERS, HRT

improved quality of life primarily in women with flushing

but not without flushing, although improvements were

expressed in mood and other symptoms.18 In the WHI,

women with moderate-to-severe symptoms reported

improvements in vasomotor symptoms and had reduced

sleep disturbance, although no such benefit was found in

women without symptoms.19,20 Symptoms may be associ-

ated with different incidence and mortality rates of

disease that are not accounted for in our model; however,

these incidences are not available, and we assumed that

women with symptoms have disease rates similar to those

of the overall population. We were unable to assess

outcomes such as dementia that have not yet been

reported in WHI. Our analysis also used estimates that

are based on disease incidences and utilities in non-

Hispanic white women; it is possible that different disease

rates and utilities in nonwhite women would lead to

different results. We do not address the impact of the

initiation of HRT in women who were younger or older

than 50 years at the time that they initiated HRT, and our

baseline incidence and mortality rates of CHD and other

outcomes may not necessarily pertain to these age groups.

We used mortality and event rates from other sources

aside from the WHI; ideally, results would be available

from the WHI, but 15 more years will elapse before 20-year

outcome data are available; therefore, we used best

estimates for disease from other population-based studies.

Our model also does not adjust directly for the fact that

breast cancers that develop in hormone users may carry

a more benign prognosis than those that develop in none-

users, but we did vary the death rates by a 2-fold margin in

our sensitivity analyses without a substantial change in our

results. Finally, our model does not assess the impact of

compliance.

Before the release of the HERS and WHI publications,

recommendations for estrogen/progestin use had ex-

tended to prevention of chronic disease.21 However, these

randomized trials demonstrated that the HRT did not

have a beneficial effect on CHD outcomes. In addition,

other screening and treatment modalities, such as

colonoscopy and bisphosphonates, exist for colon cancer

and osteoporosis. Consequently, publications after WHI

emphasized the inappropriateness of HRT for chronic

disease prevention22 and previous confounding by

socioeconomic status.23

However, the risks associated with HRT were low;

for every 10,000 women who were taking combination

estrogen/progestin, 38 women had breast cancer each

year compared with 30 women who were not taking HRT,

and 37 women had a myocardial infarction each year

compared with 30 women who were not taking HRT.3 Our

results confirmed that slight but significant risk with HRT

use, by demonstrating that HRT reduced life expectancy

on the order of several days.

In comparison, symptoms may affect 50% to 75% of

menopausal women in the United States,24,25 and estro-

gen replacement is still the most effective therapy for

relief of symptoms that are associated with menopause.25

The effect of menopausal symptoms on a woman’s quality

of life should be considered along with the risks of therapy

in the decision to use HRT. Our analysis found that a

woman’s quality of life with menopausal symptoms could

affect the life expectancy with HRT. For women who use

HRT for < 5 years, symptoms would need to affect only

a woman’s quality of life slightly to make HRT use bene-

ficial. A woman’s quality of life with menopausal symp-

toms need only be slightly decreased, less than the

decrease in the quality of life with seasonal allergies, to

justify HRT use. Our analysis can help women and their

Volume 189, Number 5Am J Obstet Gynecol

Kim and Kwok 1233

clinicians balance their value of quality of life with

symptoms against their risk of chronic disease to decide

whether HRT is an option for them.

We thank Laurence F. McMahon, Jr, and Nancy Reamefor their helpful comments on the manuscript drafts.

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