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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
Volume 189, Number 5Am J Obstet Gynecol
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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