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Early Menopause Predicts Future Coronary Heart Disease and Stroke: The
Multi-ethnic Study of AtherosclerosisMelissa Wellons, MD, NCMP, Pamela Ouyang, MBBS, Pamela J. Schreiner, PhD, David M.
Herrington, MD, Dhananay !aidya, PhD Oct "#, $%"$
&uthors ' Disclosures
Meno(ause. $%"$)"#*"%+"%-""%-/. 0 $%"$ 1he North &merican Meno(ause Society
Abstract and Introduction
Abstract
Objective: Cardiovascular disease is the number one killer of women. Identifying
women at risk of cardiovascular disease has tremendous public health
importance. Early menopause is associated with increased cardiovascular
disease events in some predominantly white populations, but not consistently.
Our objective was to determine if selfreported early menopause !menopause at
an age "#$ y% identifies women as at risk for future coronary heart disease or
stroke.
Methods: &he study population came from the 'ultiEthnic (tudy of
Atherosclerosis, a longitudinal, ethnically diverse cohort study of )( men and
women aged #* to +# years enrolled in ----- and followed up until --+.
&he association between a personal history of early menopause !either natural
menopause or surgical removal of ovaries at an age "#$ y% and future coronary
heart disease and stroke was assessed in ,*- women !ages #*+# y/ +0
white, 112 Chinese, $#2 black, and **- 3ispanic% from the 'ultiethnic (tudy
Atherosclerosis who were free of cardiovascular disease at baseline.
Results: Of ,*- women, $1 !+4% reported either surgical or natural early
menopause. In survival curves, women with early menopause had worse
coronary heart disease and strokefree survival !log rank 5 6 -.--+ and 5 6
-.-2*+%. In models adjusted for age, race7ethnicity, 'ultiethnic (tudy
Atherosclerosis site, and traditional cardiovascular disease risk factors, this risk
for coronary heart disease and stroke remained !ha8ard ratio, .-+/ *4 CI,
2.201.0-/ and ha8ard ratio, .2/ *4 CI, 2.22#.1, respectively%.
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Conclusions: Early menopause is positively associated with coronary heart
disease and stroke in a multiethnic cohort, independent of traditional
cardiovascular disease risk factors.
Introduction
Cardiovascular disease !C9:% is the leading cause of death in )( women. ;2
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mostly white or European populations and may not be generali8able to )(
women not of European origin. &herefore, we investigated whether early
menopause !menopause before age #$ y% was associated with C3: and stroke
in a multiethnic population of )( women. @e further investigated whether thisrelationship was independent of traditional C9: risk factors.
'ethods
Design Overview, Setting, and Participants
&he 'ultiethnic (tudy Atherosclerosis !'E(A% is a multicenter, longitudinal
cohort study of the prevalence and correlates of subclinical C9: and the factors
that influence its progression. ;2+
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lood pressure !5%, weight, and height were measured using standardi8ed
protocols.;2+,-
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to early menopause. &his was because all 'E(A women were at least age #*
years of age at enrollment.
Among all 'E(A women !n 6 1,$-2%, 2,$2 !1*4% reported hysterectomy. &his
prevalence of hysterectomy appears consistent with a previously published
report from the ational @omens 3ealth Information Center that one third of
women aged $- years in the )nited (tates have undergone hysterectomy. ;
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C#D and Stro$e Outco%es
&he 'E(A cohort has been followed for incident cardiovascular events for a
median of *0.1 months !range, 2.101. months%. &he primary means of
identifying possible events in 'E(A is participant selfreport via postbaseline
contacts !followup calls% conducted by telephone. =ield center staff may also
learn of potential events in other waysD participants may notify the clinic when
they eperience an event/ a 'E(A eamination may identify a possible event/
investigation of one event may identify another event/ ational :eath Inde
search could identify a death/ or field center staff may learn of a participants
death through an obituary or other public notice.
At intervals of to 2 months, a telephone interviewer contacted each participant
regarding hospital admissions, cardiovascular outpatient diagnoses, and deaths.
&o verify selfreported diagnoses, copies of all death certificates and medical
records for hospitali8ations and outpatient cardiovascular diagnoses were
re?uested. =or outofhospital cardiovascular deaths, netofkin interviews were
performed. Jecords on an estimated +4 of reported hospitali8ed cardiovascular
events and some information on *4 of reported outpatient diagnostic
encounters were obtained. &wo physicians independently reviewed and classified
C9: events and assigned incidence dates. If they disagreed, they adjudicated
their differences via discussion.
5eriodically, the Coordinating Center will search the ational :eath Inde for
participants with whom the study has lost touch. &he =ield Centers will then be
notified of these deaths so that additional information can be obtained and so
that the death can go to physician review. Criteria for events are available on the'E(A @eb site !httpD77www.mesanhlbi.org7'esaInternal7manuals.asp% and are
described in published 'E(A manuscripts.;1<
Jeviewers classified an 'I as definite or probable if either abnormal cardiac
biomarkers !two times upper limits of normal% regardless of pain or ECK findings/
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evolving L waves regardless of pain or biomarker findings/ or a combination of
chest pain and (&& evolution or new left bundle branch block and biomarker
levels one to two times the upper limits of normal was present. Jeviewers
classified a resuscitated cardiac arrest as present when a subject hadsuccessfully recovered from a full cardiac arrest through cardiopulmonary
resuscitation !including cardioversion%. &he reviewers classified C3: death as
present or absent based on hospital records and interviews with families. :efinite
fatal C3: re?uired an 'I within + days of death, chest pain within 0 hours
before death, or a history of C3: and the absence of a known nonatherosclerotic
or noncardiac cause of death. eurologists reviewed and classified stroke as
present if there was a focal neurologic deficit lasting # hours or until death, witha clinically relevant lesion on brain imaging and no nonvascular cause.
=or this report, we defined incident C3: as definite or probable 'I, resuscitated
cardiac arrest, or definite C3: death. Incident stroke included fatal and nonfatal
stroke. =ollowup was from the baseline eamination until the first C9: event,
loss to followup, death, or October 2#, --+, whichever came first.
Statistical Anal&ses
&he association between early menopause and incident C3: and stroke was
eamined in Maplan'eier survival analyses and Co proportional ha8ard
models. 5roportional ha8ard models were first adjusted only for age. &he models
were then adjusted for demographics !race7ethnicity and 'E(A site% and
traditional C9: risk factors !hypertension, ever smoking, diabetes mellitus, and
total and 3:> cholesterol%. Additional models included 'I and family history of
C3:. (econdary analyses included adjustment for 3& use and type of menopause !natural vs surgical%. Interactions between early menopause and !2%
3& use, !% type of menopause, and !1% ever smoking were performed after
adjustment for age, race7 ethnicity, and 'E(A site. @e also performed sensitivity
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analyses that included adjustment for education as a proy for socioeconomic
status.
&o assess discrimination of a model including traditional C9: risk factors only
!hypertension, ever smoking, diabetes mellitus, and total and 3:> cholesterol%
versus a model that also includes early menopause, we performed multiple
statistical tests. 3a8ard ratios !3Js% were estimated for each regression model.
&he incremental statistical significance of early menopause when added to the
traditional C9: risk factor model was evaluated with the @ald test of significance
of the N coefficient. :iscrimination was assessed using the area under the
receiver operator characteristic curve !Cstatistic%. &he Cstatistic for each model
was compared with the Cstatistic for the baseline model using a binomial test
!'ann@hitney U test%. All statistical analyses were performed with (tata version
+.- !(tataCorp, Austin, &/ httpD77 www.stata.com% with significance set
at P "-.-* !two tailed%.
Jesults
'able !" Characteristics o( )o%en )ith and )ithout *arl& Menopause +n -,./01
Characteristic *arl& %enopause +n 2031 4o earl& %enopause +n !,5!21 P
Age, y -.--2
#**# 2$ !1% 1$+ !-%
**$# 2+ !0% *01 !1%
$*0# -$ !1-% $2* !1#%
0*+# 21$ !-% $- !2#%
Education -.1#
"3igh school 2* !% $+ !-%
graduate
P3igh school *10 !0% 2,##1 !+-%
graduate
Jace7ethnicity
@hite #2 !1*% 0#$ !#2% "-.--2
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Chinese *$ !+% 0* !2*%
lack 21 !12% #+ !#%
3ispanic 2+1 !$% 1$0 !-%
>ive births, median 1 !2#% 1 !#% -.12
!ILJ%
5regnancies, 1 !*% 1 !*% -.#-
median !ILJ%
&ype of menopause "-.--2
atural ##$ !$#% 2,$1 !+%
(urgical #0 !1$% 21 !22%
3ormone therapy -.--$
Ever use 1$ !*1% +10 !#0%
ever use 12 !#0% #$ !*1%
:ata are presented as n !4%, unless otherwise indicated.ILJ, inter?uartile range
&able 2 includes the baseline characteristics of participants with early
menopause !n 6 $1% versus no early menopause !n 6 2+2$%. Compared with
participants without early menopause, a greater percentage of women with early
menopause were black or 3ispanic, 0* to +# years old at baseline, surgically
menopausal, and had ever used 3&.
'able -" C6D Ris$ actors o( )o%en )ith and )ithout *arl& Menopause +n -,./01
*arl& 4o earl&
C6D ris$ (actors %enopause %enopause
+baseline e7a%ination1 +n 2031 +n !,5!21 P
(moking
ever 1+- !**% 222-!$2% "-.--2
5ast - !1-% *1 !%
Current 2-# !2*% 20# !2-%
&otal cholesterol, mg7d> -1 Q 10 -2 Q 1$ -.1$
3:> cholesterol, mg7d> *$ Q 2* *0 Q 2* -.##
:iabetes, 4a 0 !2#% 2* !22% -.-2
(ystolic blood pressure, 2 Q * 2+ Q 1 -.
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mm 3g
:iastolic blood pressure, $ Q 22 $ Q 2- -.$+
mm 3g
3ypertension, 4b 110 !#% +$1 !#+% -.*
=amily history of C9: 11 !*-% +22 !#0% -.1
'I +. Q $.1 +. Q $.- -.-1
:ata are presented as mean Q (: or n !4%.C9:, cardiovascular disease/ 3:>, highdensity lipoprotein/ 'I, body mass inde.a American :iabetes Association --1 definition;2
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igure -"
Maplan'eier (urvival Curves for Coronary 3eart :isease in @omen @ith and @ithout Early
'enopause
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igure 3"
Maplan'eier (urvival Curves for (troke in @omen @ith and @ithout Early 'enopause
*arl& Menopause as a Predictor o( C#D and Stro$e
Early menopause was an independent predictor of C3: and stroke after
adjustment for age, race7ethnicity, and 'E(A site !3J, .22/ *4 CI, 2.21.0*/
and 3J, .2-/ *4 CI, 2.-+#.-0%. It remained an independent predictor of C3:
and stroke after further adjustment for traditional C9: risk factors !3J, .-+/ *4
CI, 2.201.0-/ and 3J, .2/ *4 CI, 2.22#.1%. &he 3Js were attenuated after
adjustment for family history of C9: !3J, 2.+-/ *4 CI, -.1./ and 3J, 2.+/
*4 CI, -.+#.--%. =urther adjustment for 3& use did not alter the 3Js
appreciably !3J, 2.+*/ *4 CI, 2.-21.10/ and 3J, .-1/ *4 CI, 2.--
#.2-/ &able 1 %. In sensitivity analyses that also adjusted for education, the 3Js
were not significantly different.
Discri%ination (or C#D
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&he Cstatistic for the traditional C9: risk factors was -.$+ in our sample. @hen
the predicted ha8ard due to both early menopause and traditional C9: risk
factors was used, the Cstatistic was -.0- !5 6 -.** vs traditional C9: risk
factors alone%.
Secondar& Anal&ses
Adjustment for type of menopause did not alter the results significantly. Analyses
did not provide evidence for interactions between early menopause and the
covariates !2% 3& use, !% type of menopause, and !1% ever smoking. 3owever,
power was limited for these analyses.
:iscussion
Early menopause was a significant predictor of future C3: and stroke in our
populationbased sample of multiethnic )( women, independent of traditional
C9: risk factors. @e found that women with early menopause have
approimately a twofold increased risk of a future C3: or stroke event. Our
findings align with other largescale epidemiologic studies of early age at natural
menopause and C3:. 3owever, most of these studies assessed C3: mortality
and were predominantly in European or white cohorts. ;0,+,22,#
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menopause that occurred naturally or surgically before age #$ years. @e lacked
ade?uate power to test for interactions between type of menopause !natural vs
surgical% and early menopause and our C9: outcomes. >onger followup of the
'E(A cohort may provide sufficient power. &his could provide valuableinformation for women weighing the risks and benefits of hysterectomy and
oophorectomy. Currently, the risks and benefits of early hysterectomy and
oophorectomy are unclear. A recent study of the @omens 3ealth Initiative !@3I%
observational cohort found that in women who underwent hysterectomy at age
younger than #- years, oophorectomy is associated with a slightly lower risk of
ovarian and, possibly, breast cancer without an increased risk of C9:.;$<
*arl& Menopause and Stro$e
Our study showed that early menopause was associated with an increased risk
of stroke. 5rior studies have found a relationship between early menopause and
stroke, although not consistently. (tudies of a Bapanese cohort;0
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nonsmokers but remained in the smokers when these two groups were stratified.
@e did not have ade?uate power to test for an interaction between smoking
history and early menopause when assessing our C9: outcomes. >onger follow
up of the 'E(A cohort may provide us with this information in the future.
In our study, after adjustment for family history of C9:, early menopause was no
longer a statistically significant predictor of C9: events. &his may be because !2%
of insufficient power, !% family history of C9: is a better predictor of C9: than
early menopause, or !1% the variables are highly related. &he timing of
menopause and C9: both appear highly heritable. =amily history of premature
C3: is included in C9: risk algorithms developed for postmenopausal women.
;
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(tudies of precision of natural menopause recall from the urses 3ealth
(tudy;1+
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simple hysterectomy from our analyses, and our findings are not applicable to
this group.
Survival ias" 'E(A participants were C9:free at baseline at ages #* to +#
years. @omen in 'E(A may represent survivors of early menopause who did not
develop C3: or die before enrollment. &he true point estimate for the
relationship between early menopause and C9: may be larger than we
observed because of survival bias.
Strengths and I%plications" @e found that early menopause is a moderate
predictor of C3: and stroke, even after adjusting for traditional C9: risk factors
in a diverse population of )( women. &his may suggest that early menopause, if possible, should be avoided and that women with early menopause may be a
group to target for aggressive C9: prevention strategies. efore the @3I trial
findings were released, physicians recommended oral 3&, anticipating that this
therapy would negate any detrimental cardiovascular effects associated with
menopause. Kiven the lack of cardioprotective benefit and potential harms of
menopausal 3&,;2$,20
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from the @3I suggest that simple hysterectomy and hysterectomy with
oophorectomy carry e?uivalent C9: risks. ;$
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