METABOLISM
CLINICAL
AND
EXPERIMENTAL
62
(2013)
S15 -S19
Available online at www.sciencedirect.com
Metabolism
www.metabolismjournal.com
The role of personalized medicine in identifying appropriate
candidates for menopausal estrogen therapy
JoAnn E. Manson⁎
Brigham and Women's Hospital, Harvard Medical School
ARTICLE INFO
ABSTRACT
Keywords:
Menopausal estrogen therapy has a complex balance of benefits and risks and is no longer
Personalized medicine
routinely recommended for the majority of women during or after the transition to menopause. Recent findings
Menopausal hormone therapy
from the Women's Health Initiative (WHI) and other studies suggest that a woman's clinical and biological
Estrogen
characteristics may modify her health outcomes on hormone therapy (HT) and that some women may be more
Progestogen
appropriate candidates for therapy than others. An emerging body of evidence suggests that it may be possible to
Genomics
identify women who are more likely to have favorable outcomes and less likely to have adverse events on HT, as
Risk stratification
well as to tailor the optimal dose, formulation, and route of delivery of treatment, by the use of individual risk
Clinical decision making
stratification and a personalized approach. Several clinical characteristics that have been proposed for this
purpose include a woman's age, time since menopause, symptom severity, baseline vascular health, risk for
breast cancer, biomarker levels, and genetic predisposition. The underlying rationale for personalized medicine,
that each person has a unique biologic profile that can help to guide the choice of therapy, applies well to HT
decision making and holds promise for improved treatment efficacy and safety. This report, which focuses on
vascular health, reviews the evidence on the role of such markers in tailoring the use of hormone therapy to
appropriate candidates, with the ultimate goal of developing a personalized risk:benefit prediction model that
takes into account clinical
and genetic factors, "patient-centered" outcomes including sense of well being and quality of
life, and other variables. The proposed personalized approach to HT decision making has the
potential to improve the quality of health care.
© 2013 Published by Elsevier Inc.
1.
Background
fits for many women [2,3]. Estrogen therapy (ET), as well as
combination estrogen and progestin therapy (EPT), has
complex biological effects that vary according to the clinical
More than 70% of women have vasomotor symptoms during
characteristics of the woman [1,4]. Thus, several clinical factors,
the menopause transition and 15%-20% have moderate-tosevere symptoms that interfere with sleep and impair quality
including a women's age, time since menopause, baseline vascular health,
of life [1-3]. Estrogen therapy was once the mainstay of
treatment for women with menopausal symptoms but recent
randomized clinical trials have demonstrated that risks of menopausal
to modulate her
hormone therapy (HT) may outweigh the bene-
several other studies provide strong support for this concept.
risk for breast cancer, biomarker levels, and genetic predisposition appear
health outcomes on hormone therapy [1,3,5-9]. Recent
findings from the Women's Health Initiative (WHI) and
Publication of this article was supported by the Collège International de Recherche Servier (CIRS).
⁎ Corresponding author. Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth
Avenue East, Boston, Massachusetts 02215. Tel.: +1 617 278 0871; fax: +1 617 731 3843.
E-mail address: jmanson@rics.bwh.harvard.edu.
0026-0495/$ - see front matter © 2013 Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.metabol.2012.08.015
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METABOLISM CLINICAL AND EXPERIMENTAL 62 (2013) S15 -S19
Thus, an emerging body of evidence suggests that it may be possible to
identify women who are better candidates for HT,
i.e., those more likely to have favorable outcomes and less likely to have
2.
Cardiovascular outcomes related to
menopausal hormone therapy
adverse events, by the use of individual risk stratification and a
personalized approach. Moreover, it may be possible to use this
In the overall WHI study population, women randomized to estrogen-
information to tailor decision making about the type of HT, including the
progestin were 24% more likely to develop CHD
optimal dose, formulation, and route of delivery, to the individual patient.
unique biologic profile that can help to guide the choice of therapy, applies
(defined as myocardial infarction or coronary death), 30%40% more likely to develop stroke, and at least twice as likely
to develop pulmonary embolism as women assigned to placebo [11,13].
well to clinical decision making regarding HT and holds promise for
Women assigned to 6.8 years of estrogen alone had a neutral risk for CHD,
improved treatment efficacy and safety.
a nearly 40% increase in stroke, and a nonsignificant increase in
The underlying rationale for personalized medicine, that each person has a
This report reviews the evidence from the WHI and other studies,
pulmonary embo- lism, as compared with women assigned to placebo
including work in progress, on the role of clinical characteristics,
[12,14]. Recent research has elucidated several clinical characteris- tics,
serum/plasma biomarkers, genomic markers,
personal risk factors, and biochemical and genetic biomarkers that
and gene-environment interactions, in helping to identify
good versus poor candidates for HT use, with a focus on
cardiovascular outcomes. This article addresses personalized care and risk
indicate higher vs lower risk of adverse cardiovascular disease (CVD)
stratification for hormonal interventions only among women with a clinical
CVD risk while taking HT and that appear to help identify better vs worse
indication for systemic HT, including vasomotor symptoms severe enough
candidates for HT use are: age, time since menopause onset, LDL
to interfere with sleep or impair quality of life, in conjunction with her
cholesterol and other lipid levels, metabolic syndrome, and Factor V
personal interest in receiving this treatment. The ultimate goal is the
Leiden genotype [3,7,15]. Moreover, emerging evidence suggests that
development and validation of a personalized risk: benefit prediction model
women at elevat- ed thrombotic risk should either avoid systemic HT or
for HT use that takes into account
choose
clinical and genetic factors, "patient-centered" outcomes such
as subjective sense of well being and quality of life, personal
preference for behavioral vs pharmacologic therapy, and other
a transdermal, rather than oral, route of delivery [1-3,16].
outcomes, including CHD, stroke and venous thromboembolism (VTE),
while taking HT. The strongest factors that have been found to modify
2.1.
Influence of age and time since menopause
variables to determine appropriateness of treatment, as well
as guiding the selection of dose, formulation, and route of hormone
delivery.
As most of the research relevant to this report derives from the WHI, a
WHI analyses suggest that age or time since menopause
influences the relation between HT and CHD. In analyses pooling data
across both trials, HT-associated RRs for CHD
brief summary of the study design follows. The WHI HT trials included
were 0.76 (95% CI 0.50-1.16), 1.10 (95% CI 0.84-1.45), and 1.28
more than 27,000 healthy postmeno- pausal women aged 50 to 79 (mean
(95% CI 1.03-1.58) among women who were <10, 10-19, and 20 years past the
age, 63) [10]. In the
menopausal transition at study enrollment, respectively (p, trend=0.02) [5] Among
estrogen-progestin trial, 16,608 women with a uterus were
randomized to daily oral estrogen plus progestin (0.625 mg of
women aged 50-59,
estrogen alone was associated with significant reductions in
conjugated equine estrogens [CEE] plus 2.5 mg of medroxy- progesterone
the secondary endpoint of coronary revascularization (RR=
acetate [MPA]) or a placebo [11]. In the estrogen- alone trial, 10,739
women with hysterectomy (41% also had oophorectomy) were randomized
0.55; 95% CI 0.35-0.86) and a composite endpoint of MI,
coronary death, or coronary revascularization (RR=0.66; 95%
to daily oral estrogen alone (0.625 mg of CEE) or a placebo [12]. The main
CI 0.44-0.97), but CHD risk reductions were not seen for ages
outcome of interest was coronary heart disease (CHD), so older women
60-69 or 70-79 [14]. Overall, HT appeared to have a beneficial
or neutral effect on CHD in women closer to menopause (who
are likely to have healthier arteries) but a harmful effect in later years
were targeted for enrollment because their higher baseline
coronary risk led to improved study power. The estrogenprogestin trial was terminated 3 years early (after an average
of 5.6 years of treatment) because of an unfavorable risk-
[6,8,9].
Analysis of the entire follow-up period (i.e., intervention plus post-
benefit ratio associated with estrogen-progestin in the overall
study population (increased risk of CHD, stroke, and venous
thromboembolism [VTE]) and a significant increase in breast cancer risk)
intervention phases) of the estrogen-alone trial also found more favorable
[11]. The estrogen-alone trial was terminated ~1 year early (after 6.8 years)
alone were
because of an elevated risk for stroke that was not offset by a reduced risk
0.54 (0.34-0.86), 1.05 (0.82-1.35) and 1.23 (0.92-1.65) for ages 50-
for CHD in the hormone group [12]. Although both regimens lowered the
59, 60-69, and 70-79, respectively (p, interaction=0.007) [17].
Results were similar for CHD [17].
risk for osteoporotic fracture and estrogen-alone was also associ- ated with
an unexpected borderline significant reduction in breast cancer risk, the
effects for myocardial infarction (MI) and CHD in younger, compared with
older, women. For MI, the RRs associated with randomization to estrogen
For stroke, no effect modification was apparent by age.
risks appeared to outweigh the benefits for a large segment of the WHI
Women assigned to either estrogen-progestin or estrogen
study population. Cardiovas- cular health outcomes in the trials and
alone were 30%-40% more likely to experience stroke than
those assigned to placebo, irrespective of age [5,11,12,18].
quality of life parameters are the focus of the discussion below.
Baseline age, time since menopause, and other clinical characteristics did
not clearly identify women at higher vs lower risk of stroke on HT.
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METABOLISM CLINICAL AND EXPERIMENTAL 62 (2013) S15 -S19
Table 1 - CHD Risk in the WHI HT Trials (E+P and E-Alone)
According to Baseline Levels of Biomarkers.
assignment to HT was associated with a 40% lower risk for CHD, while
Biomarker OR (95% CI) for HT Treatment Effect P-Value
ratio >2.5), assignment to HT resulted in a 73% higher risk (p-value for
among women with an adverse cholesterol profile at baseline (LDL/HDL
interaction =0.002) [7]. Baseline hsCRP levels were marginally predictive of
LDL-Cholesterol (mg/dl)
<130
0.66 (0.34-1.27)
CHD risk on HT [7].
0.03
130
1.46 (1.02-2.10)
LDL/HDL Cholesterol Ratio
<2.5
0.60 (0.34-1.06)
2.5
1.73 (1.18-2.53)
hs-CRP (mg/dl)
<2.0
1.01 (0.63-1.62)
2.0
1.58 (1.05-2.39)
0.002
0.16
Source: Bray PF, et al. Am J Cardiol 2008; 101:1599.
Although several other biomarkers were predictive of CHD risk
in the WHI, including lipids (high LDL cholesterol, low HDL
cholesterol, high triglycerides) and higher levels of interleukin6, matrix metalloproteinase 9, D-dimer, factor VIII, von Willebrand factor, leukocyte count, homocysteine, and fasting
insulin [20], only the lipid abnormalities described above significantly
modified the effect of HT on CHD and helped to
identify women more or less likely to have CHD events on HT. Other
biomarkers are currently being studied (see Table 2 for listing of selected
biomarkers under study in the WHI and other randomized trials and/or
Regarding pulmonary embolism, compared with those in
the placebo group, women in the estrogen-progestin group
experienced a statistically significant doubling of risk [15].
Assignment to estrogen alone appeared to raise the risk by 37%; this
increase was not statistically significant [19]. No clear effect modification
by age or time since menopause was apparent. Lower absolute baseline risks
observational studies). Extensive arrays of biomarkers are also under study
for identification of women at high versus low risk of other outcomes on
hormone therapy, including cancer, diabetes, cognitive decline, and
autoimmune disorders, among others. Whether or not these
biomarkers enhance risk stratification will be known soon.
of CHD, stroke, VTE,
and other adverse events in younger vs older women, however, translated
2.3.
Genetic markers
into much lower absolute excess risks
associated with HT use in the former group.
Factor V Leiden was strongly predictive of pulmonary embolism and
other VTE events and the genetic polymor-
2.2.
Biomarkers
phism glycoprotein IIIa leu33pro predicted CHD events in WHI [15,20].
Factor V Leiden also interacted with HT to augment
Lower LDL cholesterol and lower LDL/HDL ratios were strongly
predictive of more favorable CHD outcomes on HT, again consistent with
VTE risk [15]. However, glycoprotein IIIa leu33pro did not clearly modify
better outcomes among women with lower baseline cardiovascular risk
have been linked to VTE, CHD, stroke, and other cardiovascular events,
[7,13] (Table 1). Among participants with a better cholesterol profile at
but it remains unclear if these genetic factors interact with HT to amplify
baseline (LDL/HDL ratio <2.5),
risk [21]. In the WHI, estrogen receptor polymorphisms were
Table 2 - Selected biomarkers under study to aid risk
stratification for hormone therapy decision making.
the effect of HT on vascular risk [20]. Gene variants in ABO blood group
found to reduce the effect of HT on plasmin-antiplasmin, a
marker of coagulation and fibrinolysis [22]. Analyses of other
promising genetic markers are under study and results are expected soon
(Table 2). These include gene variants related to sex hormone biosynthesis,
metabolism, and signaling. Ge- nome-wide association studies (GWAS) are
Biochemical Markers:
• Lipids (serum LDL cholesterol, LDL/HDL ratios, triglyceride levels,
Lp(a), 27-OH-Cholesterol, apolipoprotein levels)
also in progress and will aid with discovery of gene variants that may
modify risks of vascular events and other outcomes on HT.
• Inflammatory markers (high-sensitivity C-reactive protein
[hsCRP], interleukin-6, tumor necrosis factor alpha, leukocyte
count)
• Adipokines (adiponectin, leptin, retinol binding protein-4 [RBP4])
• Endothelial markers (E-selectin, P-selectin, ICAM, VCAM)
• Glucose tolerance markers: fasting glucose, insulin, HOMA-IR,
3.
Menopausal symptoms and quality of life
IGF-1, and biomarkers of metabolic syndrome
• Matrix metalloproteinases
• Hemostatic markers (D-dimer, factor VIII, von Willebrand
Women with menopausal symptoms, including hot flashes,
night sweats, disrupted sleep, and vaginal or genital dryness, are more
factor, homocysteine, fibrinogen, tissue factor pathway
likely to derive quality-of-life benefits from HT than
inhibitor or acquired activated protein C resistance)
women without such symptoms. In the WHI [23-25], among
• Sex steroid hormone levels, sex hormone binding globulin level
Genetic Markers:
• Factor V Leiden
• Glycoprotein IIIa leu33pro
• Gene variants in ABO blood group
• Estrogen and progesterone receptor polymorphisms
• Gene variants related to sex hormone biosynthesis • Gene
variants related to sex hormone metabolism
• Gene variants related to sex hormone signaling
• Genome-wide association studies (GWAS) and exome sequencing
for gene discovery
women who were symptomatic at baseline, estrogenprogestin provided significantly greater relief than placebo at
1 year for hot flashes (RR=4.40; 95% CI, 3.40-5.71), night sweats
(RR=2.58; 2.04-3.26), vaginal or genital dryness (RR=2.40; 1.90- 3.02), joint
pain or stiffness (RR=1.43; 1.24-1.64), and general aches or pains (RR=1.25;
1.08-1.44). However, HT also had
adverse effects including an increased risk of vaginal bleeding
and need for dilation and curettage procedures or hysterecto- my,
headaches, breast tenderness, and urinary incontinence
[23-25]. A similar pattern was seen for estrogen-alone [26,27].
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METABOLISM CLINICAL AND EXPERIMENTAL 62 (2013) S15-S19
Research is ongoing to identify the clinical characteristics that predict a net
favorable effect of HT on quality-of-life outcomes.
Conflict of interest
The author has nothing to disclose.
4.
Dose, formulation, and route of
hormone delivery
REFERENCES
Using lower doses, bioidentical vs synthetic formulations, and the
transdermal, rather than oral, route of administration of estrogens and
progestogens may result in a lower risk of side
effects and adverse events [1-4]. Differences would be
expected due to avoidance of the first-pass hepatic effects of
oral estrogen and differences in hormone concentrations in the blood
achieved by varying doses and routes of delivery. With transdermal
therapy, it may be possible to avoid the increased synthesis of clotting
factors, the increase in tri- glycerides, changes in C-reactive protein levels,
and increases in sex hormone-binding globulin that may lower free testosterone levels and adversely affect libido. Observational evidence, although
limited, suggests that transdermal estro- gen therapy may be associated
with a lower risk of venous thromboembolism and stroke than oral
administration [1,2,16]. Randomized clinical trial evidence, however, is
lacking. Women with an increased propensity for thrombosis and higher
baseline risk of vascular disease should avoid oral estrogen. It may be
possible to use risk prediction models based on clinical characteristics,
baseline biomarkers, and gene variants to identify women most likely to
benefit from low-dose therapy or transdermal delivery, as compared with
oral HT in conventional doses, or who should be advised to avoid any form
of estrogen therapy.
5.
Conclusions
Menopausal HT has a complex balance of benefits and risks
that can vary according to the clinical and biological charac- teristics of the
woman. An emerging body of evidence suggests that it may be possible to
identify women who are better candidates for HT, i.e., those more likely to
have favorable outcomes and less likely to have adverse events, as well as to
tailor the optimal dose, formulation, and route of delivery of HT, by the
use of individual risk stratification and a person- alized approach. The
WHI and other studies suggest an important role of clinical characteristics,
serum biomarkers,
genomic markers, and gene-environment interactions to
attain this goal. The development of a personalized risk:
benefit prediction model for HT use that takes into account
clinical and genetic factors, "patient-centered" outcomes such
as subjective sense of well being and quality of life, personal
preference for behavioral vs pharmacologic therapy, and other variables,
hold promise for improving clinical decision making and the quality of
health care.
Acknowledgment
The author is greatful to shari Bassuk and Philomena Quinn for expert
assistance.
[1] North American Menopause Society. Estrogen and
progestogen use in postmenopausal women: 2010 position statement of
The North American Menopause Society.
Menopause 2010;17:242-55.
[2] Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N,
Braunstein GD, et al. Postmenopausal hormone therapy: an
Endocrine Society scientific statement. J Clin Endocrinol
Metab 2010;95:S1-66.
[3] Manson JE, Bassuk SS. The menopause transition and
postmenopausal hormone therapy. In: Longo DL, Fauci AS,
Kasper DL, Hauser SL, Jamison JL, Loscalzo J, eds. Harrison's principles of
internal medicine: McGraw-Hill, 2011.
[4] International Menopause Society. Aging, menopause,
cardiovascular disease and HRT. International Menopause
Society Consensus Statement. Climacteric 2009;12:368-77.
[5] Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei
VM, Ko M, LaCroix AZ, Margolis KL, Stefanick ML. Effects of
postmenopausal hormone therapy on cardiovascular
disease by age and years since menopause. JAMA 2007;297:
1465-77.
[6] Manson JE, Bassuk SS. Invited commentary. Hormone
therapy and risk of coronary heart disease: why renew the
focus on the early years of menopause? Am J Epidemiol
2007;166:511-7.
[7] Bray PF, Larson JC, Lacroix AZ, Manson J, Limacher MC,
Rossouw JE, Lasser NL, Lawson WE, Stefanick ML, Langer RD,
Margolis KL. Usefulness of baseline lipids and C-reactive
protein in women receiving menopausal hormone therapy as predictors of
treatment-related coronary events. Am J Cardiol
2008;101:1599-605.
[8] Mendelsohn ME, Karas RH. Molecular and cellular basis
of cardiovascular gender differences. Science 2005;308:
1583-7.
[9] Grodstein F, Clarkson TB, Manson JE. Understanding the
divergent data on postmenopausal hormone therapy. N Engl J
Med 2003;348:645-50.
[10] Women's Health Initiative Study Group. Design of the
Women's Health Initiative clinical trial and observational
study. The Women's Health Initiative Study Group. Control
Clin Trials 1998;19:61-109.
[11] Writing Group for the Women's Health Initiative
Investigators. Risks and benefits of estrogen plus progestin in healthy
postmenopausal women: principal results from the Women's Health
Initiative randomized controlled trial. JAMA
2002;288:321-33.
[12] Women's Health Initiative Steering Committee. Effects of
conjugated equine estrogen in postmenopausal women with
hysterectomy: the Women's Health Initiative randomized
controlled trial. JAMA 2004;291:1701-12.
[13] Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser
NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong
ND, Crouse JR, Stein E, Cushman M. Estrogen plus progestin and the risk
of coronary heart disease. N Engl J Med
2003;349:523-34.
[14] Hsia J, Langer RD, Manson JE, Kuller L, Johnson KC, Hendrix
SL, Pettinger M, Heckbert SR, Greep N, Crawford S, Eaton CB, Kostis JB,
Caralis P, Prentice R. Conjugated equine estrogens and the risk of coronary
heart disease: the Women's Health
Initiative. Arch Intern Med 2006;166:357-65.
METABOLISM CLINICAL AND EXPERIMENTAL 62 (2013) S15 -S19
[15] Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM,
Stafford RS, Sidney S, Rosendaal FR. Estrogen plus
progestin and risk of venous thrombosis. JAMA 2004;292:
1573-80.
[16] Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Levesque
H, Trillot N, Barrellier MT, Wahl D, Emmerich J, Scarabin PY.
Hormone therapy and venous thromboembolism
among postmenopausal women: impact of the route of
estrogen administration and progestogens: the ESTHER study.
Circulation 2007;115:840-5.
[17] LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson
KC, Martin L, Margolis KL, Stefanick ML, Brzyski R, Curb JD,
Howard BV, Lewis CE, Wactawski-Wende J. Health outcomes
after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a
randomized controlled trial. JAMA 2011;305:1305-14.
[18] Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G,
Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE, Aragaki
A, Safford M, Stein E, Laowattana S, Mysiw WJ.
Effect of estrogen plus progestin on stroke in postmenopausal women: the
Women's Health Initiative: a randomized trial.
JAMA 2003;289:2673-84.
[19] Curb JD, Prentice RL, Bray PF, Langer RD, Van Horn L, Barnabei
VM, Bloch MJ, Cyr MG, Gass M, Lepine L, Rodabough RJ, Sidney
S, Uwaifo GI, Rosendaal FR. Venous thrombosis and
conjugated equine estrogen in women without a uterus. Arch
Intern Med 2006;166:772-80.
[20] Rossouw JE, Cushman M, Greenland P, et al. Inflammatory,
lipid, thrombotic, and genetic markers of coronary heart
disease risk in the Women's Health Initiative trials of
hormone therapy. Arch Intern Med 2008;168:2245-53.
[21] Carpeggiani C, Cocean M, Landi P, et al. ABO blood
group alleles: a risk factor for coronary artery
S19
disease. An angiographic study Atherosclerosis 2010;211: 461-6.
Rossouw JE, Bray P, Liu J, et al. Estrogen receptor
[22] polymorphisms and the vascular effects of hormone therapy.
Arterioscler Thromb Vasc Biol 2011;31:464-9.
Barnabei VM, Cochrane BB, Aragaki AK, Nygaard I, Williams
[23] RS, McGovern PG, Young RL, Wells EC, O'Sullivan MJ, Chen B,
Schenken R, Johnson SR. Menopausal symptoms and treatmentrelated effects of estrogen and progestin in
the Women's Health Initiative. Obstet Gynecol 2005;105:
1063-73.
Ockene JK, Barad DH, Cochrane BB, Larson JC, Gass M,
[24] Wassertheil-Smoller S, Manson JE, Barnabei VM, Lane DS,
Brzyski RG, Rosal MC, Wylie-Rosett J, Hays J. Symptom
experience after discontinuing use of estrogen plus progestin.
JAMA 2005;294:183-93.
Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE,
[25] Patterson RE, Aragaki AK, Shumaker SA, Brzyski RG, LaCroix AZ, Granek
IA, Valanis BG. Effects of estrogen plus progestin
on health-related quality of life. N Engl J Med 2003;348:
1839-54.
Brunner RL, Gass M, Aragaki A, Hays J, Granek I, Woods N,
[26] Mason E, Brzyski R, Ockene J, Assaf A, LaCroix A, Matthews K, Wallace R.
Effects of conjugated equine estrogen on healthrelated quality of life in postmenopausal women with
hysterectomy: results from the Women's Health Initiative
Randomized Clinical Trial. Arch Intern Med 2005;165:1976-86.
Brunner RL, Aragaki A, Barnabei V, Cochrane BB, Gass M,
[27] Hendrix S, Lane D, Ockene J, Woods NF, Yasmeen S, Stefanick
M. Menopausal symptom experience before and after
stopping estrogen therapy in the Women's Health Initiative
randomized, placebo-controlled trial. Menopause 2010;17:
946-54.