Brief Reviews

Menopause and Hypertension

An Age-Old Debate
Megan Coylewright, Jane F. Reckelhoff, Pamela Ouyang

P remenopausal women (pre-MW) have lower blood pres-

sure (BP) than age-matched men, and women have higher
rates of hypertension than men as they age.1 These findings
suggest that gender or sex hormones have a prominent role in
hypertension. Determining the role of sex hormones in the
pathogenesis or progression of hypertension is complex given
the effects of aging on the cardiovascular system and its
relationship to other powerful risk factors such as body
weight and cholesterol level.2 Longitudinal and cross-
sectional studies report conflicting results concerning the role
of menopause in the pathogenesis of hypertension. Large
randomized trials of hormone replacement therapy (HRT)
have called into question the long assumed protective effect
of estrogen in heart disease risk.3,4 There are excellent
reviews on the effects of gender and sex hormones on
vascular tone and pathophysiologic abnormalities associated
with hypertension in animals.5,6 This review focuses on
studies in postmenopausal women (PMW), the relationship
between menopause and hypertension, factors contributing to
hypertension in PMW, and discussion of identification and
treatment of hypertension in PMW.
Relationship Between Gender, Menopause,
and Hypertension
Studies Indicating Menopause Leads to
Increasing Hypertension
Cross-sectional studies suggest a relationship between meno-
pause and both hypertension and serum cholesterol7 (Table).
Both systolic and diastolic BP are reported to be related to
menopause independent of age, body mass index (BMI),
pulse rate, and HRT, and PMW had greater odds of being
hypertensive than pre-MW (OR 2.2, P0.03).8 In addition,
the association between BP and age is steeper in PMW.
Longitudinal cohort studies also demonstrated a relation-
ship between menopause and hypertension. In a study of 315
women and age- and BMI-matched men followed for 5 years,
PMW had higher systolic BP at baseline and systolic BP
increased by approximately 5 mm Hg over 5 years of
follow-up only in the peri- and PMW. The rise exclusively
involved systolic pressure suggesting underlying decreased
arterial compliance.9
The association between BP and use of HRT was assessed
in PMW who had never used HRT and 77 who had received
continued HRT. Age at first examination, time in the study,
and HRT predicted change in BP during 5.7 years of
follow-up. Systolic and diastolic BP decreased to a lesser
extent among HRT-users compared with nonusers with the
greatest difference in older women,10 indirectly supporting a
role for ovarian senescence in the development of
hypertension.
Studies Indicating No Relationship Between
Menopause and Hypertension
Other studies suggest that the apparent relationship between
menopause and hypertension is explained by other factors
including age (Table). An epidemiological study including
568 pre- and PMW, evaluated at 2 time periods separated by
16 years, showed that the higher systolic BP and cardiovas-
cular morbidity and mortality seen in PMW was accounted
for by age.11
A study examining the relationship between BP and
menopause in both African-American and White women also
reported no difference in BP change over a 6-year period
among women who transitioned to menopause compared
with pre-MW.12
Whether menopause is surgically induced or natural may
influence subsequent risk of coronary heart disease. Bilateral
oophorectomy without subsequent HRT, but not natural
menopause or oophorectomy with subsequent HRT, has been
associated with an increased risk of coronary heart disease.13
One longitudinal study suggested that in healthy normoten-
sive women ovarian senescence protects against increasing BP
with a negative association between years after menopause and
systolic and diastolic BP.14 Aging was associated with a non-
significant increase in systolic BP only; however, increased BMI
was associated with hypertension. The study participants were a
select group: only 10% of the eligible cohort of more than 4000
responded to invitation to participate, and of those, 402 were
excluded because of medications that impacted BP, metabolism

Received December 2, 2007; first decision December 21, 2007; revision accepted January 3, 2008.
From the Department of Medicine (M.C., P.O.), Johns Hopkins University School of Medicine, Baltimore, Md; and Physiology and Biophysics (J.F.R.),
University of Mississippi Medical Center, Jackson.
This paper was sent to Ernesto L. Schiffrin, consulting editor, for review by expert referees, editorial decision, and final disposition.
Correspondence to Pamela Ouyang MBBS, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, Baltimore, MD 21224. E-mail
pouyang@jhmi.edu
(Hypertension. 2008;51:952-959.)
2008 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.107.105742

952
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 Coylewright et al Menopause and Hypertension 953

Table. Studies Describing Relationship Between Menopausal Status and Blood Pressure or Cardiovascular Events
Study Menopause
Author, Publication Year Population Status Study Design Association/Conclusion Strengths Limitations
Menopause associated with HTN
Weiss 19727 897 women; Pre- and Cross-sectional Increasing DBP is related US HES cohort. Questionnaire
age 4051 postmenopausal to menopause, for menopause.
years independent of age; no Limited
effect of time since accounting of
menopause confounders
e.g. BMI, race.
Average of only
3 BP
measurements.
Staessen 19898 462 women; Pre- and Cross-sectional After stratifying by age Stratified by 3 age Questionnaire
age 3559 postmenopausal and BMI, odds of groups and 2 strata of for menopause.
years hypertension for BMI. BP from average of
postmenopausal women 10 measurements.
compared to
premenopausal women
was 2.2 (95% CI
1.14.4, P0.03).
Relation between SBP
and age steeper in
menopausal than
premenopausal women
Owens 199379 34 women and Pre- and Cross-sectional Postmenopausal women Ambulatory BP monitor Small size of
15 men; age postmenopausal had higher and standardized mental sample
4055 years stress-induced SBP and and physical challenges
DBP rises than
premenopausal women
or men. Diastolic BP was
higher in
post-menopausal women
and men compared to
pre-menopausal women
Zanchetti 200515 18,326 women; Pre-, peri-, and Cross-sectional SBP and DBP higher in Large cohort. The 2- Three BP
age 4659 postmenopausal postmenopausal women, year span subgroups measurements
years association evident only reduce age difference in 505 general
among women in the among pre-, peri- and practitioners
younger age groups post-menopausal groups. offices
(4649 years);
P0.0001
Staessen 19979 315 women, 166 pre-, 44 Prospective SBP rose nearly Median follow-up of 5.2
matched to 315 peri-, 105 5 mm Hg per decade years. Ambulatory
men by age postmenopausal more (Por0.05) in 24-hour monitoring used
and BMI; age peri- and in the follow-up
3070 years postmenopausal than in measurement. FSH levels
premenopausal women. at follow-up
These trends were not
found in DBP in women,
or in SBP or DBP in
men.
Scuteri 200110 226 women; Pre-, peri-, and Prospective Postmenopausal women Well characterized cohort Predominantly
mean age 64 postmenopausal on HRT have a smaller within Baltimore white, educated
10 years evaluating increase in SBP over Longitudinal Study of volunteers.
association with time; most pronounced Aging (BLSA) Observational
use of HRT among older women study so there
may be
unaccounted
differences
between HRT
users and
non-users
(Continued )

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954 Hypertension April 2008 Part II

Table. Continued
Study Menopause
Author, Publication Year Population Status Study Design Association/Conclusion Strengths Limitations

No association between Menopause and Hypertension or Cardiovascular events

Casiglia 199611 568 Italian Pre- and Prospective After controlling for age, Time span of 16 years. Only last of 3
women: At postmenopausal there is no difference Age-adjusted data office BP
follow-up: between pre- and presented. Age-matched measurements
pre-menopausal postmenopausal women cohort showed similar used.
mean age 40 in relation to lack of association
4 years; hypertension or between menopause and
post- cardiovascular risk hypertension. Only
menopausal natural menopause
mean age 61 considered, none on
8 years HRT.
Luoto 200012 3,800 women; Peri- and Prospective Looking specifically at ARIC cohort followed for
age 4564 postmenopausal the peri-menopausal 6 years. Both White and
years period, SBP did not differ African-Americans
from postmenopausal included.
women
Pearson 199780 1307 men and Pre-, peri-, and Prospective There was not a greater BLSA cohort are No data on role
333 women. postmenopausal increase in BP rise over well-characterized. of menopause.
Men aged time compared to men Predominantly
1797 years; white, highly
women aged educated and
1893 years health
conscious group
of volunteers
Colditz 198713 121,700 Pre- and Prospective Naturally 16-year follow-up with Observational
women; age postmenopausal postmenopausal women, biannual questionnaires study. Cannot
3055 years after controlling for age for cardiovascular exclude
and smoking, were not outcomes. Adjudicated unaccounted
at greater risk for medical records review. differences
coronary heart disease; between women
those with surgical with and
menopause did have a without
higher risk (RR 2.2) but oophorectomy
this was eliminated with
HRT

Menopause associated with lower BP

van Beresteyn 198914 193 women; Pre- and Prospective SBP and SBP were Seven-year follow-up. Highly selected
age 4954 postmenopausal negatively associated small cohort of
years; all pre- with years from healthy
or 2 years menopause (SBP: normotensive
post- 1.34 mm Hg per year women
menopausal and DBP: 0.63 mm Hg
per year)
BMI indicates body mass index; CVD, cardiovascular disease; SBP, systolic blood pressure; DBP, diastolic blood pressure. HRT, hormone therapy; RR, risk ratio;
FSH, Follicle stimulating hormone; US HES, United States Health Examination Survey of adults; ARIC, Atherosclerosis Risk In Communities.

of calcium, or timing of menopause. Careful selection of healthy
normotensive individuals may reduce confounding, but inclu-
sion of these individuals may introduce other biases and reduce
the generalizability of the findings.
Relative Contribution of Menopause or Aging to
Hypertension in PMW
Conflicting findings may result from differences among
cohorts, including sample size, age ranges, length of time
postmenopause, use of datasets not designed to study meno-
pause, and reliance on questionnaires.11 Surgically PMW
were often included, without considering the hormonal dif-
ferences in natural and surgical menopause. Finally, both
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cross-sectional and longitudinal analyses are subject to con-
founding; the former because of inability to assess temporal
relationships and the latter because of environmental changes
or changes in medical management over time.
Given these inconsistencies, a cross-sectional analysis was
done in more than 18 000 Italian women, aged 46 to 59 years,
that found a significant, but clinically small, increase in both
systolic and diastolic BP of 3.4/3.1 mm Hg among PMW,
which was independent of age, BMI, smoking, or contracep-
tion or HRT, and was only evident at younger menopausal
age.15 The difference in BP may be underestimated given the
higher prevalence of treated hypertension in PMW (35%)
compared with pre-MW (20%). However, menopausal effects
 Coylewright et al
appear to be small and may be masked by age-related changes
that increase BP. Careful large longitudinal studies may add
further information.
Factors Contributing to Hypertension
in PMW
We review major data on mechanisms postulated to contrib-
ute to the development of hypertension after menopause
(Figure 1) and discuss mechanisms by which sex hormone
changes related to menopause may contribute to postmeno-
pausal hypertension (Figure 2).
Figure 2. Sex hormones and postmenopausal hypertension.
Menopause is associated with a reduction in estradiol and a
decrease the estrogen to testosterone ratio. This results in en-
dothelial dysfunction and increases in body weight (body mass
index [BMI]) or type II diabetes, which causes an increase in
sympathetic activation, which is common in PMW. Sympathetic
activation can result in increased renin release and increases in
angiotensin II (Ang II). Endothelial dysfunction is accompanied
by reductions in NO and increases in endothelin, which both
contribute to salt sensitivity of BP, which is common in PMW.
The increase in Ang II and endothelin and the reduction in NO
may all lead to increased oxidative stress. An increase in vaso-
constrictors, Ang II, and endothelin, and a reduction in NO and
increase in oxidative stress, all contribute to increases in renal
vasoconstriction that will cause hypertension.
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Menopause and Hypertension 955
Figure 1. Factors contributing to hyper-
tension in postmenopausal women.
Genetic factors, environmental factors,
and change in sex hormone levels have
each been implicated in the development
of hypertension. Interactions between gen-
der, the genetic background, environmen-
tal factors, and changes in sex hormones
have been described. eNOS indicates NO
synthase.
Endothelial Dysfunction
Endothelial dysfunction, with reduction in vasodilators
modulating vascular tone, is associated with diseases
including hypertension and atherosclerosis, and may be one
mechanism by which estrogen deficiency may result in
hypertension. In a prospective study of 952 PMW, followed
for 3.6 years, each one-unit decrease in flow-mediated dila-
tion (FMD), measured by high resolution ultrasound, in-
creased the risk of developing hypertension by 16%.16 In a
second study endothelium-dependent vasodilation to acetyl-
choline decreased with age in hypertensive subjects, with a
slower decline in pre-MW, compared with men.17 The great-
est rate of decline in FMD occurred in PMW when compared
with men (P0.01) and pre-MW (P0.001). The endotheli-
um-independent (nitroprusside) response did not differ by sex
or menopausal status. In normotensive women, age-related
impairment of endothelial function was only seen after
menopause.
Men and PMW may have less endogenous nitric oxide
(NO) production, shown by less vasoconstriction following
inhibition of NO synthase by L-N-monomethyl-arginine (L-
NMMA), than pre-MW. After estrogen therapy, L-NMMA
resulted in greater constriction consistent with estrogen re-
storing vascular NO activity to levels seen in pre-MW.18
Other studies have shown improvement in endothelial func-
tion with estrogen therapy with a greater improvement in
hypertensive PMW.19
Treatment of postmenopausal hypertension can improve
FMD and is associated with a better cardiovascular out-
come.20 Hypertensive PMW who experienced a significant
increase in FMD (10% baseline) after nearly 6 years of
antihypertensive therapy experienced fewer cardiovascular
events than those without FMD improvement (3.5 per 100
person-years versus 0.51, P0.0001). Thus, impaired FMD
may identify particularly high-risk hypertensive PMW.
Acute estrogen deprivation after oophorectomy in healthy
women results in impaired endothelium-dependent vasodila-
tion as a result of reduced NO availability.21 Estrogen therapy
improves endothelium-dependent vasodilation after oopho-
956 Hypertension April 2008 Part II
rectomy and also natural menopause.22 However, among a
broader sample of PMW, HRT results in improved FMD only
among women with no cardiovascular risk factors.23,24
Arterial Stiffness
Increased arterial stiffness coincides with menopause. In a
random sample of more than 300 women and 300 men, PMW
showed higher carotid-femoral pulse wave velocity (PWV)
and larger common carotid artery diameters after adjustment
for age, BMI, and smoking, indicating increased arterial
stiffness which may explain the greater rise in systolic
pressure among PMW.25 A study of 3149 women, ages 21 to
94 years, evaluated the relationship between age, menopause,
and arterial stiffness assessed by brachial-ankle PWV.
Women, aged 45 to 56 years, who were 6 years from
menopause, were most likely to be in the highest tertile of
PWV; this was independent of age and other cardiovascular
risk factors.26 However, other investigators have not found
sex differences in arterial wall properties with aging.27
Renin-Angiotensin System
The renin-angiotensin (RAS) system is an important regulator
of BP and fluid and electrolytes. Estradiol may provide
cardiovascular protection by controlling components of the
RAS, including decreasing AT1 receptor expression in vessels
and kidney28 and reducing the activity of angiotensin
1-converting enzyme (ACE).29
The role of the RAS in hypertension in PMW is less clear
than in animal studies. A placebo-controlled study of 2 years
of estrogen therapy found no correlation between BP and
plasma renin activity (PRA). PRA increased during oral, but
not transdermal, estradiol administration.30 Other small stud-
ies have shown similar results,31 though some show decreased
ACE activity with oral HRT.32
The regulation of the prorenin and renin may be affected by
gonadal hormones. Ovarian production of prorenin in re-
sponse to gonadotropins has been reported.33,34 The effect of
estrogen on prorenin and renin appear complex. Studies in
hypertensive individuals may be complicated by antihyper-
tensive drugs that inhibit the RAS.35
Oxidative Stress
An increase in oxidative stress can result from increased
production of reactive oxygen species (ROS) or decreased
ability to neutralize these reactive molecules. Gender differ-
ences in oxidative stress have been found with higher levels
in males.36 Gonadectomy decreased urinary H2O2 excretion in
male SHR and increased H2O2 excretion in females, suggest-
ing that testosterone increases whereas estrogen suppresses
total body oxidative stress.37 In vitro and animal models have
shown that estrogen modulates prooxidant and antioxidant
enzyme expression and activity, including NAD(P)H oxidase
and superoxide dismutase, inhibiting production of ROS. It is
postulated that the postmenopausal estrogen-deficient state is
associated with increased ROS contributing to vasoconstric-
tion and hypertension.38,39
Whether increased ROS is present with menopause has not
been unequivocally demonstrated. Increased nitrotyrosine, a
marker of endogenous peroxynitrite, and decreased nitroso-
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thiols, consistent with less NO bioavailability, were reported
in PMW compared with pre-MW.40 However, the contribu-
tion of menopause could not be distinguished from that of
age. Another oxidative stress marker is F2-isoprostane,
produced by free radicalinduced peroxidation of arachidonic
acid and has been considered a marker of in vivo ROS.41
Recently, investigators reported F2-isoprostanes were not
elevated in PMW compared with pre-MW, and, contrary to
expectations, were positively associated with levels of me-
tabolites of estradiol.42
Estrogens, including estradiol and estrogen metabolites,
decrease ROS by scavenging free radicals.43,44 Whether HRT
in PMW protects against oxidative stress-associated diseases
is unknown.
Salt Sensitivity
Salt sensitivity increases with age in both sexes and is likely
mediated by impaired vasodilation of the renal circulation,
possibly because of reduced NO availability, increased vaso-
constriction response to angiotensin II, or attenuation of the
conversion of L-arginine to NO in the renal vasculature
endothelium.29,45,46
PMW appear to be more salt sensitive than pre-MW,47 and
surgical menopause is associated with development of salt
sensitivity.48 Salt sensitivity of systolic BP in healthy PMW
not receiving HRT may be related to reduced bioavailability
of NO associated with increased levels of the NO synthase
antagonist, asymmetrical dimethyl-L-arginine.49 Treatment
with transdermal estradiol in PMW was associated with a
decrease in salt sensitivity of BP.50
Low sodium diets decrease BP in experimental and real-
world settings. Thus lifestyle behaviors including low sodium
diet and exercise are recommended for individuals with
hypertension.
Obesity
A large cross-sectional study showed an independent associ-
ation between BMI and hypertension in women, aged 46 to
59 years.15 In a Finnish prospective population-based study of
9485 perimenopausal women not on antihypertensive ther-
apy, predictors of hypertension over 5-year follow-up in-
cluded baseline weight, weight increase, and PM status at
baseline.51 Overweight has a stronger association with hyper-
tension in pre-MW, whereas age has a stronger association in
PM non hormone users.52
The mechanisms by which obesity is associated with
hypertension include increased sympathetic overactivity that
appears closely associated with abdominal visceral fat.53
Greater sympathetic activity increases renin release and
angiotensin II formation, which in turn increases adrenal
aldosterone production with resultant sodium retention. In-
creased visceral fat is associated with increased inflammatory
mediators, increased oxidative stress, and decreased endothe-
lial vasodilation.
It is not clear whether menopause itself results in an
increase in BMI. Although perimenopausal women and those
with surgical menopause have been found to have higher
BMI than pre-MW when controlling for age, physical activity
and race/ethnicity were much stronger predictors of BMI.54
 Coylewright et al
Genetic Factors Influencing Hypertension
Genetic factors account for 30% to 50% of interindividual
variability in BP.55,56 Hypertension is most likely a polygen-
etic disorder with each of the genes contributing modestly to
BP. It is possible that menopause might provide the environ-
mental trigger for the expression of certain genetic suscepti-
bilities. Polymorphisms affecting a number of pathways
involved in hypertension have been studied. While this is not
an exhaustive review of the literature on genetics and hyper-
tension, a few pertinent studies are reviewed.
Sex-specific determinants of genetic susceptibility that are
distinct from sex hormonemediated attenuation of sex-
common determinants have been found.57 Several investiga-
tors have reported sex specific associations between human
hypertension and polymorphisms of components of the
RAS,58,59 aldosterone synthase,60 and NO synthase,61 al-
though not in all populations studied.62 A study evaluating the
relationship between the extremes of BP with 35 loci that
have physiological roles in the regulation of BP described
several gene-by-gender interactions. In women, polymor-
phism at the 1-adrenergic receptor and 2A adrenergic
receptor contributed to BP, and in men polymorphism of
2-adrenergic receptor and angiotensinogen were associat-
ed.63 Polymorphism of genes regulating sodium reabsorption,
such as adducin-1, have been associated with BP and hyper-
tension.64 Gene-environment interactions have been shown
including BMI65 and salt intake.66
Other studies have also focused on pathways that might be
implicated in sex hormonerelated associations with hyper-
tension.67 Gender-specific contributions of estrogen-related
genes to BP variation have been described. Inactivating
mutations in the follicle-stimulating hormone (FSH) receptor
(FSHR) gene may cause hereditary hypergonadotropic ovar-
ian failure. Polymorphisms in the human FSHR gene have
been linked to essential hypertension in women.68 Other
candidates in the testosterone-estradiol pathway have been
investigated. In a case-control study of hypertension, associ-
ations between aromatase CYP19A1 gene variants and hy-
pertension were found only in women, and this association
was dependent on BMI. No association with menopause was
found, suggesting that the effect of CYP19A1 variants on BP
may be mainly related to aromatase activity in adipose
tissue.69
Gene-gender and gene-environment interactions impact
hypertension in women. Menopause may provide an impor-
tant environmental trigger resulting in genetic influences that
mediate hypertension in women. These findings also raise the
potential that antihypertensives may have different efficacy
based on the gender and genetic background.70
Current Clinical Issues
Most women will develop hypertension in their lifetime, and
women who develop hypertension at a younger age are at
higher risk of adverse cardiovascular events. The prevalence
of hypertension rises more steeply in women than men after
middle age. A study of women aged 45 years or older and
initially free of cardiovascular disease showed that one third
of women who were normotensive at baseline developed
hypertension during the 10 year follow-up. Half the women
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Menopause and Hypertension 957
with high-normal BP (130/85 to 138/89 mm Hg) developed
hypertension within 5 years, and two-thirds progressed to
hypertension within 10 years. Women with hypertension at
baseline had the highest age-adjusted rate of cardiovascular
events (4.32/1000 person-years) followed by women with
high-normal BP (2.92/1000 person-years), compared with
normotensive women (1.62/1000 person-years).71 Diastolic
hypertension is more prevalent among younger patients, but
for those older than 50, systolic hypertension is a better risk
predictor of cardiovascular events.72
Treatment of systolic hypertension in men and women
reduces stroke, myocardial infarction, heart failure, and
death.73,74 Lifestyle changes, such as low sodium diets,
decrease BP in experimental and real-world settings.75,76
Strategies to delay the development of hypertension among
women could have a significant public health benefit. Unfor-
tunately, women are less likely to have controlled hyperten-
sion despite medication. During the 1990s, undiagnosed
hypertension and poorly treated hypertension increased
among women whereas hypertension among men decreased;
these differences were not explained by age. Womens
cardiovascular health, by survey data, may be deteriorating
compared with mens health.77
Inadequate Recognition of Hypertension in PMW
Inadequate recognition and control of hypertension remain
major obstacles in reducing adverse cardiovascular outcomes
for women. Among the 93 676 women enrolled in the
WHI-OS, 32% were hypertensive though with no known
cardiovascular disease. Of these, 52% were on antihyperten-
sive medications, yet only 36% were at BP goal of less than
140/90 mm Hg. Among diabetic women only 21% of patients
reached goal pressures. These results appear related to insuf-
ficiently therapy, as the majority of women were only on 1
antihypertensive agent.78 Multi-drug therapy may be neces-
sary to control hypertension as women age and should be
combined with lifestyle modifications, such as a low-sodium
diet and an exercise regimen.
Future Directions
Hypertension in PMW is a major medical problem. Further
understanding of the basic mechanisms leading to hyperten-
sion in postmenopausal women may promote or guide more
effective and rational choices of antihypertensive treatment.
Future research should focus on strategies to increase public
awareness of the association of hypertension with age among
both women and men, including high risk minority groups, to
educate about and improve adherence to lifestyle modifica-
tions and to implement evidence-based medical practice.
Sources of Funding
J.F.R. is funded by the National Institutes of Health HL51971,
HL69194, and HL66072. P.O. is funded by National Institutes of
Health RR023561, HL074406, and DK062368.
Disclosures
None.
958 Hypertension April 2008 Part II
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 Menopause and Hypertension: An Age-Old Debate
Megan Coylewright, Jane F. Reckelhoff and Pamela Ouyang

Hypertension. 2008;51:952-959; originally published online February 7, 2008;

doi: 10.1161/HYPERTENSIONAHA.107.105742
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