REVIEW

CURRENT
OPINION Women, the menopause, hormone replacement
therapy and coronary heart disease
Thomas F. Whayne Jr a and Debabrata Mukherjee b

Purpose of review
Cardiovascular disease considerations are associated with the menopause. Despite a misconception that
women have a minimal risk for coronary heart disease (CHD), it is the major cause of female deaths. This
review highlights issues of hormone replacement therapy (HRT) and CHD in women.
Recent findings
A woman under age 60 who suffers a myocardial infarction (MI) has a 2-year post-MI mortality of 28.9%;
it is 19.6% in men. CHD and MI in women are subtle. In addition, female mortality from CHD increases
after the menopause. The increased inflammatory risk factor status of women plays a role in development
of atherosclerosis, before and after the menopause. Until after the menopause, women overall have a
lower CHD mortality rate. Menopause is associated with unique symptoms, especially vasomotor ones;
preexisting cardiovascular disease further exacerbates problems associated with the menopause. Use of
HRT after the menopause is a major issue. Early menopause at age 39 years or younger and late
menopause at age 56 years or older increase cardiovascular risk. HRT should not be prescribed for
cardiovascular risk prevention, but when less than 10 years from menopause at a normal age, women can
be reassured that cardiovascular risk from HRT is very low.
Summary
Prescription of HRT should never be made only for cardiovascular risk reduction. However, when symptom-
related and other indications are present, HRT is appropriate and well tolerated in the early years after
menopause with onset at a normal age.
Keywords
cardiovascular risk, coronary heart disease, oestrogens, hormone replacement, inflammation, menopause,
thrombosis

INTRODUCTION cardiovascular death compared with men of the

Specific differences between women and men
include: women develop a first myocardial infarc-
tion (MI) at an older age, coronary heart disease
(CHD) events occur more after the menopause,
and, overall, women are less likely than men to
die of CHD [1]. Nevertheless, the major medical
problem women face is CHD and other cardiovas-
cular disease; breast cancer is much less of a lethal
problem. The lay press has hit on the idea that
women have more CHD than men, possibly because
of the reality that if a relatively young woman has a
CHD event, their mortality is higher [1]. Women
with cardiovascular disease tend to have more hy-
pertension and diabetes mellitus at the presentation
of acute coronary syndrome (ACS); on the contrary,
men at presentation of ACS are more likely to be
tobacco smokers [2]. Young women under the age
of 40 years with ACS are at the greatest risk of
same age; this disadvantage then decreases as
women age [2]. A problem in evaluating CHD in
women is their underrepresentation in clinical trials
[3]. Enrolment in randomized trials has improved
but is still low compared with the overall female
disease incidence [4]. Despite improved evidence-
based treatments in recent years, there is a gap in the
use of such treatments in both older and younger
a
Division of Cardiovascular Medicine, Gill Heart Institute, University of
Kentucky, Lexington, Kentucky and bDivision of Cardiovascular Medicine,
Texas Tech University HSC, and Paul Foster School of Medicine, El Paso,
Texas, USA
Correspondence to Thomas F. Whayne, Jr, MD, PhD, 326 Wethington
Building, 900 South Limestone Street, Lexington, KY 40536-0200, USA.
Tel: +1 859 218 5332; fax: +1 859 323 6475; e-mail: twhayn0@uky.edu
Curr Opin Cardiol 2015, 30:432–438
DOI:10.1097/HCO.0000000000000157

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 Women, menopause, hormone therapy, and coronary heart disease Whayne et al.
KEY POINTS
 Coronary heart disease is the major cause of death in
women before, during and after the menopause.
 Hormone replacement therapy is not indicated if given
solely for any possible cardiovascular risk benefit.
 The use of hormone replacement therapy in the early
years after a normal menopause is associated with
neutral or low cardiovascular risk.
women [5]. The purpose of this review is to clarify
some of these issues and possible explanations,
mechanisms and differences. Consideration of the
anatomical, hormonal, inflammatory and meta-
bolic status of women appears to offer possible
clarification of female cardiovascular risk. Treat-
ment of cardiovascular disease in women involves
specific problems, especially revascularization of
coronary arteries, which, when stenosed, appear
to offer unique challenges and differences.
CORONARY HEART DISEASE
DIFFERENCES IN WOMEN
In spite of previous thinking that women have a
minimal CHD risk and the failure of some clinicians
to pay proper attention to early CHD symptoms, the
reality is that a young woman has increased risk
from CHD if an acute event occurs. In a study of
6826 patients who were MI survivors from 1975 to
1995, Vaccarino et al. [6] found that the overall
2-year mortality rate was 28.9% in women com-
pared with 19.6% in men, and for each decrease
in age by decade, the 2-year female mortality
increased by 15.4% [95% confidence interval
(95% CI), 4.3–27.6] compared with men. Younger
women, defined as under age 60 years, were found to
have an increased risk for death after MI compared
with age-matched male counterparts [6].
In 2009, Shaw et al. [7] commented on the evolv-
ing knowledge of CHD in women and discussed
how women have a lower incidence of anatomical
CHD but when CHD is present, cardiovascular risk is
higher than in men, and women have more symp-
toms, evidence of ischemia and unfavourable out-
comes. The paradox may be from an increased
coronary reactivity in women, including microvas-
cular dysfunction [7]. Also, there appears to be a lower
incidence of obstructive CHD in women, but, if
present, CHD in a woman is associated with a higher
incidence of unfavourable outcomes after acute MI
[8]. Ischaemic heart disease may be a more appropri-
ate term for CHD in women due to the spectrum of
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
obstructive CHD, coronary microvascular dysfunc-
tion and endothelial dysfunction [8]. In addition, the
size of coronary arteries in women is relevant, as these
arteries are smaller [9] and may be a factor in
decreased benefit from invasive management. Due
to smaller body surface area, smaller left ventricular
mass and smaller coronary artery size, Kang et al. [10]
noted that reduced myocardial territory size may
account for a higher fractional flow reserve (FFR)
for a specific coronary artery stenosis than in men.
This is relevant to surgical benefit in women, in
whom Desai et al. [11] provided data that small
coronary target vessel size has an adverse effect on
coronary artery bypass graft (CABG) patency, modi-
fied favourably to increase graft patency in the pres-
ence of more severe proximal stenoses with also a
significantly increased benefit of a radial artery
CABG conduit.
Unique symptoms of CHD in women must be
considered. This was discussed by Albarran et al. [12]
after evaluating 12 female patients postacute MI.
They concluded that distribution and presentation
of symptoms of female patients failed to follow the
pattern associated with a traditional acute MI pres-
entation. Presentation may be with nonspecific
symptoms around the chest, making recognition
difficult for both patients and health team person-
nel [12]. In an extensive review, Bozkurt [13] con-
sidered statistics involving women in the United
States and emphasized that far more women die of
cardiovascular disease than cancer; there are nearly
250 000 cardiovascular deaths in women each year,
and, despite the lower prevalence of cardiovascular
disease in women, the absolute cardiovascular disease
death rate in women is higher than in men due to a
longer female life span. The fact that cardiovascular
disease mortality in women remains high, as com-
pared with improvement in survival trends in men,
may be related to multiple factors such as in the ACS,
wherein the following occur: women delay calling for
professional help, which results in a sicker patient at
the time of diagnosis; they present with more atypical
symptoms; there is decreased recognition of a prob-
lem by caregivers, including a bias against the pres-
ence of CHD in women; and women are less likely to
receive optimal cardiovascular risk control or referral
for cardiac catheterization and coronary interven-
tional procedures, with an eight-fold higher referral
rate in men [13]. This serves to emphasize the import-
ance of a commitment to explain and account for any
chest pain at any age and never dismiss it as irrelevant
until evaluated. Thus far, women are managed less
frequently than men with percutaneous coronary
intervention (PCI) and the use of evidence-based
cardiovascular disease management is less frequent
&
[14 ].
www.co-cardiology.com 433
Lipids and emerging risk factors
CHARACTERISTIC PROBLEMS OF THE
MENOPAUSE
The menopause is associated with some bothersome
symptoms, most characteristic of which are those
related to vasomotor abnormalities, mood swings
and quality-of-life symptoms [15]. Increased haemo-
stasis risk is associated with oestrogen use, with also
an increased risk with early or late menopause. In a
report of 426 women with a first episode of venous
thromboembolism (VTE), including 294 events
not associated with a procedure, Canonico et al.
&
[16 ] found that women with early menopause
(age <40 years) or late menopause (age >55 years)
had a significant increase in risk for VTE (hazard
ratio 1.8, 95% CI 1.2–2.7 and hazard ratio 1.5, 95%
CI 1.0–2.4, respectively). Stress associated with the
menopause may be a relevant cardiovascular risk
factor, with an apparent relationship with increased
C-reactive protein (CRP) and inflammation, not
seen in men [17].
Problems that women have with the menopause
are significantly worsened by associated cardio-
vascular diseases such as diabetes mellitus. Postme-
nopausal women with diabetes mellitus have an
increased cardiometabolic risk, with a special
emphasis on inflammation [18]. The same applies
to hypertension, in that after the menopause loss of
oestrogen protection may contribute to the occur-
rence of a female population more susceptible to
hypertension as a part of their increased cardio-
vascular risk [19].
ISSUES OF HORMONE REPLACEMENT
THERAPY IN WOMEN
There are multiple options for HRT. Oestrogen-only
administration should be considered only when no
uterus is present [20]. A summary of the options for
HRT can be made as follows [21]. Oestrogen admin-
istration can involve the following routes: oral,
transdermal, vaginal and injection. Progestins can
be given orally or transdermally (the transdermal
form involves an oestrogen-progestin patch).
Progestin-only use is for women with vasomotor
symptoms in whom oestrogen is contraindicated.
There is also a vaginal progesterone gel used every
second day to promote stable endometrial activity
of progesterone, although there is only a minimal
systemic effect. Raloxifene is an oral selective
oestrogen receptor modulator intended for asymp-
tomatic postmenopausal women to prevent and
treat osteoporosis. Tibolone is in tablet form and
is a derivative of norethynodrel consisting of some
oestrogenic, progestogenic and androgenic activity.
It has appeal as treatment for menopausal symp-
toms with a single medication [21].
434 www.co-cardiology.com
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Relief of menopausal symptoms appears to be
the major reason for HRT. Because of extensive
usage, it appears indicated to define bioidentical
hormones, which are also frequently administered,
as molecular compounds essentially identical in
structure to human hormones [22]. Appropriate
usage of HRT involves assessment of balance
between benefits and risks [23]. Both an older age
and an increased time since menopause predict
increased HRT risk. Women initiating HRT within
10 years of menopause and under age 60 were
reported to have reduced CHD risk compared with
initiation of HRT more distant from the menopause
[24]. In general, the smallest effective dose of HRT
should be used as briefly as possible with evaluation
each year to assess the benefits of HRT continuation
[20]. Other mitigating factors in favour of HRT
include low-risk plasma lipids, absence of metabolic
syndrome, absence of factor V Leiden genotype [25],
no history of VTE or pulmonary embolus, and no
history of breast cancer, where HRT use can be com-
plex [26]. Key components in favour of HRT include
increased severity of menopausal symptoms, individ-
ual patient preferences, presence of any HRT contra-
indications, patient age, time from menopause [23]
and route of administration. In a comparison of data
from a community pharmacy in postmenopausal
women where essentially 100% received progester-
one, Ruiz and Daniels [15] found that topical oestro-
gens did not relieve postmenopausal symptoms as
much as sublingual administration of oestrogens.
Ultimately, discontinuation of HRT is important
and Newton et al. [27] found that, in a study of
2328 postmenopausal women, advice by their physi-
cian as well as symptom resolution, especially
improvement in mood swings and depression and
improved sense of well being as well as quality of life
[28], led to successful HRT cessation.
Enhanced tendency for haemostasis and
increased risk of thrombosis appear to be hallmarks
of oestrogen use. A review of the effects of oestrogen
on haemostasis reported that there was an imbal-
ance in haemostasis with oral oestrogens, including
a decrease in inhibitors of coagulation and an
increase in activation of coagulation with a resultant
enhancement of production of thrombin [29]. Use
of transdermal oestrogen was not associated with
increased haemostasis or coagulation. Oestrogen
also increases risk for ischaemic strokes [28].
The issue of any increased cancer risk with HRT
must be considered. Oestrogen in HRT is in a high
enough concentration to cause endometrial pro-
liferation, hyperplasia and increased endometrial
cancer risk. A review found that after 10–15 years
of oestrogen use there was a 10-fold increase in risk
for endometrial cancer, but fortunately the resultant
Volume 30  Number 4  July 2015
 Women, menopause, hormone therapy, and coronary heart disease Whayne et al.
cancers were usually low grade, low stage, and
carried a good prognosis, and association of a
progestin with the HRT for at least 10 days per
month eliminated the endometrial cancer risk
[30]. A moderate increase in breast cancer risk
(relative risk of 1.3–1.5) was also found, with a
greater risk in subgroups associated with family
history, benign proliferative disease or late occur-
rence of natural menopause, with no decreased risk
associated with the use of a progestin [30]. However,
there did not appear to be any definite contraindi-
cation to oestrogen use from this standpoint,
although a relative risk as small as 1.2 could increase
the risk of breast cancer from 1 in 250 to 1 in 200.
The role played by female hormones in CHD has
been associated with much confusion and has major
implications. Despite the accepted cardiovascular
benefits of exercise, studies of amenorrheic female
athletes suggest an increased risk for early cardio-
vascular disease [31], whereas reports from observa-
tional studies have suggested that HRT decreases
cardiovascular mortality in postmenopausal women
[32]. However, the large randomized trial with
placebo control, Heart and Estrogen/progestin
Replacement Study (HERS), found that women with
known cardiovascular disease had increased cardio-
vascular disease events during the first year of HRT
use despite reported favourable benefit from
randomized trials of HRT on total cholesterol (C),
lipoproteins [increased high-density lipoproteins
(HDLs) and decreased low-density lipoproteins
(LDLs)], vasodilatation and reduced inflammation
[32]. In studies of any inflammatory effect of oes-
trogen, it has been shown that oestrogen at physio-
logical levels, at pregnancy levels and with HRT
inhibits secretion of pro-inflammatory cytokines,
stimulates synthesis and secretion of anti-inflam-
matory cytokines and also decreases cell responses
to lipopolysaccharide-induced inflammation [33].
However, such a beneficial effect on high cardiovas-
cular risk markers is not universal. A study of 76
early postmenopausal women found continuous
oral HRT and sequential transdermal HRT had no
significant effect on decreasing serum monocyte
chemoattractant protein-1 or homocysteine levels
[34]. The oestrogen vasodilatation effect also carries
over to the lung, wherein oestrogen has been shown
to cause pulmonary arterial vasodilatation and
attenuate vasoconstriction, such as from hypoxia
[35]. In the Women’s Health Initiative (WHI), Hsia
et al. [36] found that various trials have shown HRT
with conjugated equine oestrogens (CEEs) com-
bined with medroxyprogesterone acetate does not
protect postmenopausal women from CHD, and
questions have been raised about some increased
risk. These authors also found that CEE alone offered
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no significant protection from MI or CHD death in
women who were healthy, postmenopausal and
followed for 7 years, although there was a suggestion
of decreased CHD risk in women aged 50–59 years at
onset of use. In a cross-sectional study of HRT effects
performed by Prelevic et al. [37], occurrence of
different effects on some markers of cardiovascular
risk was noted. These authors found significantly
increased high-sensitivity CRP (hsCRP) levels in
women receiving CEE and tibolone compared with
women on no HRT. They also found that glycated
haemoglobin was significantly decreased with
transdermal oestrogens and tibolone vs. no HRT.
Tibolone resulted in a significantly increased SBP
compared with women on no HRT. These variable
effects on cardiovascular risk factors from different
forms of HRT may have clinical importance [37].
The issue of HRT replacement in the postmeno-
pausal female remains unresolved, but it appears
well validated to state that HRT should not be
prescribed for cardiovascular disease risk preven-
tion, but, when symptom-related and other indica-
tions are present in a female patient with fairly
recent menopause, that patient can be reassured
that cardiovascular risk from HRT is quite low.
INFLAMMATION
Inflammation appears to be a major mechanism for
development of CHD. Triggers of low-grade inflam-
mation and augmented autoimmune reactions
include thyroid-stimulating hormone (TSH), plate-
let-activating factor acetylhydrolase, acylation-
stimulating protein, lipoprotein (a), asymmetric
dimethylarginine and creatinine [38]. In an assess-
ment of biomarkers of CHD risk in postmenopausal
women, Spoletini et al. [39] found a consistent
association with CRP (usually specified as hsCRP),
interleukin-6 and lipoprotein(a). However, they
commented on lack of proof for a specific link
between such biomarkers and the occurrence of
CHD, and the need for such studies. In a review of
various inflammatory markers (additional markers
not already mentioned include metallic metallopro-
teinase-9, monocyte chemotactic protein-1, lipopro-
tein-associated phospholipase A2 and tumour/tissue
necrosis factor alpha) and their occurrence with
coronary artery calcification (CAC), Hamirani et al.
[40] found a weak association with CAC, mainly in
women and by univariate analysis, the association of
which was lost after obesity and BMI corrections.
Nevertheless, such an observation is consistent with
association of increased inflammation and CHD in
women. It was stated by Krintus et al. [41] that the
complex multifactorial cause of CHD goes beyond
inflammatory risk factors to include factors such as
electrocardiogram results, lipid profile, renal
www.co-cardiology.com 435
Lipids and emerging risk factors
function, and imaging and clinical parameters.
Favourable modification of inflammatory risk factors
is of major interest, and Soares and de Sousa [42]
reviewed 15 selected articles with women as the
protagonists and found that 12 of 15 articles showed
decreased inflammatory biomarkers in association
with exercise. Inflammatory risk status was the major
factor in the Justification for the Use of statins in
Primary prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER) trial. JUPITER’s findings
centred on patients with hsCRP at least 2 mg/l and
LDL-C less than 130 mg/dl with no perceived cardio-
vascular risk indication for a statin; these patients had
a higher probability of being female [43], consistently
with a greater association of inflammation with CHD
in women. In these JUPITER patients, including
women, rosuvastatin use resulted in a significant
decrease in the occurrence of major cardiovascular
events [44]. Observations contributing further to the
importance of inflammation in women involve
inflammatory bowel disease, which, in a review by
Singh et al. [45], was shown to have a modest associ-
ation with an increase in cardiovascular morbidity
risk from stroke and CHD, especially in women.
LIPIDS, LIPOPROTEINS AND THE
MENOPAUSE
Statins and other lipid-lowering medications play a
major role in CHD revascularization regarding
plaque stability and even regression. Although there
has been some controversy regarding statin benefit
in women, there is ample evidence to support their
use along with the lowering of LDL-C in the woman
at a high cardiovascular risk. In the Scandinavian
Simvastatin Survival Study (4S), the reduction of C
by simvastatin resulted in similar decreases in
relative risk as for men regarding the occurrence
of major CHD events [46]. In the Air Force/Texas
Coronary Atherosclerosis Prevention (AFCAPS/Tex-
CAPS) study, lovastatin decreased risk for a first
major CHD event in both men and women with
average total C levels, average LDL-C levels and
below-average HDL-C levels [47]. In an analysis of
multiple trials of statins, Wenger [48] reported on
the decrease in elevated LDL-C by statins in women
with elevated CHD risk and found decreased inci-
dence of revascularization procedures, CHD death
and nonfatal MI. She found no alteration in total
mortality in women, probably because there were
too few women in the trials assessed. She com-
mented on the apparent underutilization of statins
in women as a chance to improve their cardio-
vascular outcomes [48]. In JUPITER, rosuvastatin
decreased cardiovascular events in women similarly
to what resulted in men [49]. A meta-analysis by
Bukkapatnam et al. [50] showed that treatment with
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
statins along with diet and exercise in women with a
moderate elevation in plasma lipids and no prior
clinical cardiovascular disease resulted in a signifi-
cant benefit for the prevention of CHD events. The
Pravastatin or Atorvastatin Evaluation and Infection
Therapy-Thrombolysis in Myocardial Infarction 22
(PROVE IT-TIMI 22) trial also found that women as
well as men were benefited by intensive statin
administration after ACS [51]. A 2015 meta-analysis
of 27 trials of statin therapy, published in The Lancet
by the Cholesterol Treatment Trialists’ (CTT)
Collaboration, found that the decrease in major
cardiovascular events, as compared with the same
reduction in LDL-C, was the same for men and
&&
women, regardless of vascular risk or outcome [52 ].
THROMBOSIS AND THE MENOPAUSE
Risk of thrombosis and arterial disease has been
looked at in several trials, with some studies
suggesting that delayed menopause and longer
exposure to endogenous oestrogens protect against
cardiovascular diseases [53–55]. A large meta-
analysis, however, suggested that there was no con-
vincing relationship between postmenopausal sta-
tus and cardiovascular disease [56].
In the HERS, Grady et al. [57] reported that being
52 years or older at the last menstrual period was
independently associated with a higher risk of
thromboembolism. Similar findings were reported
by Simon et al. [58] in a case–control study of
idiopathic thromboembolism and demonstrated
that, independently of BMI, women with late men-
opause had a higher thrombotic risk than did
women with menopause at a normal age. One recent
study, however, showed a U-shaped association
between age at menopause and the risk of nonpro-
cedure-related thromboembolism among postme-
nopausal women who had never had a history of
&
thrombosis [16 ]. After adjustment for potential
confounders, women who experienced menopause
at 39 years or younger or at 56 years or older had
increased thrombotic risk as compared with women
with age at menopause between 40 and 49 years
&
[16 ]. Mechanistically, oestrogens have many differ-
ent effects on the coagulation system, which include
increases in the levels of procoagulant factors VII, X,
XII and XIII and reductions in the anticoagulant
factors protein S and antithrombin, leading to a
prothrombotic state [59].
SPECIFIC RECOMMENDATIONS
REGARDING CORONARY HEART DISEASE
RISK AND HORMONE REPLACEMENT
THERAPY
Several randomized clinical trials of HRT in women
with and without CHD have found no benefit of
Volume 30  Number 4  July 2015
 Women, menopause, hormone therapy, and coronary heart disease Whayne et al.
HRT in decreasing cardiovascular events [60]. In
fact, the WHI study and the HERS reported an
association between HRT and increased cardio-
vascular events [61,62]. A meta-analysis of all
randomized trials of HRT to estimate cardiovascular
event rates reported that HRT use is not associated
with reduced death, MI, or revascularization rate,
and HRT is not an effective agent for cardiovascular
disease prevention [60].
The United States Preventive Services Task Force
(USPSTF) recommends that administration of a
combination consisting of oestrogens and pro-
gesterone for management of postmenopausal
women should not be advised, and this was also
stated in the Evidence-Based Guidelines for Cardio-
vascular Disease Prevention in Women [63]. The
administration of HRT has been noted as Class D,
as the USPSTF has found sufficient evidence proving
that HRT has not been effective, and that potential
complications exceed possible benefits [63]. The
American College of Cardiology/American Heart
Association (ACC/AHA) guidelines state that there
is no basis for adding or continuing oestrogens in
postmenopausal women with clinically evident
CHD or cerebrovascular disease in an effort to
prevent or retard progression of their under-
lying disease [64]. At this time, HRT should not be
administered for either primary or secondary
prevention of cardiovascular disease. If HRT is indi-
cated for control of other symptoms or for other
indications, its use should be decided for each
woman based on symptoms, health status, personal
beliefs, expectations and individual risk–benefit
analysis.
CONCLUSION
CHD is the major cause of female mortality, both
before and after the menopause, with a marked
increase in risk from CHD when the young woman
under age 60 years suffers an MI. Presentation of
CHD and MI in women is more subtle and occult.
Early menopause (age 39 years) and late meno-
pause (age 56 years) exacerbate cardiovascular and
thrombotic risk. The use of HRT after menopause
is a major issue and it remains unresolved.
Nevertheless, it can be specifically stated that
HRT solely for cardiovascular risk prevention is
contraindicated. However, the female patient less
than 10 years from menopause and at a normal age
for menopause can be reassured that any cardio-
vascular risk from HRT is quite low. Therefore,
when symptom-related and other noncardiovascu-
lar indications are present, HRT appears appropri-
ate, well tolerated and beneficial following the
menopause.
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 30  Number 4  July 2015