jurnal menopause

8/15/2019 Jurnal Menopause

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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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