The Journal of Nutrition

Nutritional Epidemiology

ConsumptionofLow-FatDairyProducts
13
MayDelayNaturalMenopause
4
4 6
Jenny L. Carwi le,
W alter C. W illett,
a n d K ar i n B. M i4,6,7
c h*e l s
4

Department s oEp
f i d em io logy , Nut
a n rd i t ion, Harvard S chool of Publ ic Health, Boston,
ChMA;
an nin g Divi sio n of Network
7
Medicine, Departmen t of Medicine, and
Obstetrics and Gynecology Epidemiology C e n t er , D epar t m ent of O bste t r ics, Gynecology , a nd
Rep r o ductive Biol ogy , Bri g h a m and W o men s H o s p i tal , Harvard M e d ical Sch ool, B oston, MA

Abstract
Latermenopauseisariskfactorforbreastandendometrialcancer,yetfewstudieshaveinvestigateddietarypredictors
of this potentially modiable event. In particular, dairy contains hormones and growth factors that could potentially
affect menopausal timing. We therefore assessed the association between regular consumption of dairy foods and
relatednutrients andageatnaturalmenopause.Weconductedaprospectiveanalysiswithupto20yof follow-upin
46,059 participants in the Nurses
Health Study who were premenopausal in 1980. We observed 30,816 events of
naturalmenopauseover401,754person-years.Inthetotalpopulation,theestimatedmeanageatnaturalmenopause
was51.5yforwomenwhoconsumednolow-fatdairyand51.5,51.6,51.7,and51.8yforwomenwhoconsumed
0.11.0, 1.12.0, 2.13.0, and >3 servings of low-fat dairy daily, respectively. Premenopausal women <51 y of age
consuming>3servingsoflow-fatdairyperdaywere14%lesslikely(HR:0.86;95%CI:0.77,0.96;P-trend<0.0001)to
reportnaturalmenopauseinthenextmonthrelativetothoseconsuming0.11servings/d.Similarresultswereobtained
forskimmilk(for>6servings/wkvs.01servings/mo:HR:0.93;95%CI:0.89,0.97;P-trend<0.0001)butnotfortotal
high-fat dairy or whole milk. Dairy foods were not associated with age at menopause among $women
51 y of age.
Thesendingssupportthegrowingbodyofliteratureonthehormonallyactivenatureofmilkanddairyfoods.J.Nutr.
143:16421650,2013.

Introduction

cow m ilk ( 9 ,10) and may retain bioactivity a fter ingestion ( 1 1).
The mean age at natural menopause, the permanent cessation
of epidemiologic studies have linked m il k con sumption
Furthermore,
menstrual periods, in the United States is between 50 andto51
y
elevated
plasma concentrations of estradiol (12) and insulin(1,2). Later menopauseis protectiveagainstcardiovascular like g r o w t h f a c t o r 8I (1316).
( I G F - I The
)
decl ine in estrogen
disease (3) and osteoporosis (4) but positively associated beginning
with
around 2 y before the nal menstrual period has
development of breast (5) and endometrial cancer (6). Moreover
been well, documented (17,18 ). E ndogenous estrogen concenearlier age at menopause may be positively associatedtrations
with all-before and during t his period may be affected by d airy
causemortality(7,8). Many behavioraland socioeconomic consumpti on .
factorsappearto influencemenopausaltiming(1); however,
T o our knowledge, 6 studies have prospectively investigated
despite t he potential for foods and nutrien ts to alter th e hdi
ormon
al g e
eta nda
a tn a t urme
al n op a (1
u se
9 24o ),nl y2 of w hi ch
milieu,few s tud i haveassessed
es
di etarypex
red
i ctors
atural
a mi
nofedn d
ai ry co n su mp ti on (2 2, 24 ). In a c r o ss -s ec ti o na l a na l y si s
menop ause. Dairy food s, especi ally milk, are of particular interest,
of th e Ja pHe
anaNu
l t rs
h Sestu dy, mo re fr eq u en t mi lk a nd da ir y
because s teroid h ormon es and g rowth factors
aremendogenous
co n su
p ti on w asto
a ss o ci a te d wi th a re d uc ed l ik el i h o od o f ea rl y
1

me no pa us e ( 2 4) ; ho we v e r, i mp or ta nt de ta i l s a b ou t th i s un p ub li sh ed wo rk a re un kn ow n . In t he E PI C (E ur o pe a n P ro sp ec ti v e

TheNurses HealthStudyissupportedbygrantsCA87969andHL034594from
In by
vethe
st Breast
ig a t i on i nt o Ca nc er a nd Nu t ri ti on ) co ho rt in He id el be rg ,
the National Institutes of Health (NIH). J.L.C. was supported
ba se li d
na
e ir co
y n su mp ti onnwa
ot sa ss o ci wi
a te
thdin ci d en ce
Cancer Research Foundation; training grant T32ES007069 in Environmental
EpidemiologyfromtheNationalInstituteofEnvironmentalHealthSciences,NIH,
of me no p a us e, a f t e r ad j u st i ng fo r t o ta l en er g y in ta ke a n d o th er
and training grant T32HD060454 in Reproductive, Perinatal, and Pediatric
pr ed ic to rs o f na tu ra l me no p a us e (2 2) . In di vi du al a ss es sm en t o f
Epidemiology from the Eunice Kennedy Shriver National Institute of Child
lo w- an d hi gh -f at d ai ry wa s no t p er fo rm ed bu t ma y b e w ar ra nt ed .
HealthandHumanDevelopment,NIH.
2
Steroid hormones, including estrogen, are lipophilic; however,
Authordisclosures:J.L.Carwile,W.C.Willett,andK.B.Michels,noconflicts
onterest.
conjugated estrogens, which comprise up to 98% of estrogen
3
Supplemental Methods are available from the Online Supporting Material
linkintheonlinepostingofthearticleandfromthesamelinkintheonlinetableof
contents athttp://jn.nutrition.org.
8
* To whom correspondence should be addressed. E-mail: kmichels@research.
Abbreviations used: IGF-I, insulin-like growth factor I; NHS, Nurses
Health
bwh.harvard.edu.
Study;OC,oralcontraceptive.

1642

2013AmericanSocietyforNutrition.
ManuscriptreceivedMay13,2013.InitialreviewcompletedJune19,2013.RevisionacceptedJuly19,2013.
FirstpublishedonlineAugust14,2013;doi:10.3945/jn.113.179739.

1986FFQ and two 1-wk diet records in 191 women, the deattenuated
found in dairy products, partition into the aqueous component
correlation coefcient for calcium was 0.75 (29).
(9). Hence, the association between dairy consumption and
natural menopause may depend on the fat content of the dairy
consumed.W epredictedthat consumptionof low-fat dairy Assessment of menopausal status and age at menopause.
foods may elevate circulating estrogen concentrations,Menopau
support-sal status, dened here as the permanen t cessation of menses,
was at
self-reported at baseline in 1976 and biennially thereafter. W omen
ing periodic menstrual bleeding and resulting in a later age
who reported menopause were further queried on age at menopause (y)
menopause.
and type of menopause
(naturalmenopausesurgica
,
l,radiation,or
W e examined intake of dairy foods, including total high-fat
chemotherapy). The midpoi nt of the reported age at menopa use was
dairy ,total low-fat dairy ,skim and whole milk, and related
used in analyses. For this analysis, we dened surgical menopause as uninutrients, including dairy fat, dairy protein, calcium, vitamin D,
or bilateral oopherectomy and/or hysterectomy or menopause resulting
and lactose, in relation to age at natural menopause infrom
a large
radiation/ chemotherapy . T o reduce misclassication, we used only
cohort of women with up to 20 y of follow-up.
the rst reported age at natural menopause.
Self-repor ted
m enopa uss al
tatuswa sv a l ida tam
ed ong ar a n dom
sa mp le
o fw o meinn t h isc o h orwthor e p or tseudr gi cmael no p a us e
bet we en
1982 and 1984 b ycomparingse lf -re porthyste
e d re ct omy
an d / or o v a ri an s ur ge ry w it h m e d ic a l re c o rd s ( 30 ) . T h e re w as c o m p le t e
ParticipantsandMethods
con c o r dance between self-repor t a nd m edical r ec o r ds fo r a ll but 2 out
Study population. The NursesHealth Study (NHS) is a
o prospective
f 20 0 w ome n . The r epr o ducibility o f s elf-r e p orted n a tura l m e n opau s e
cohort study initiated in 1976, when 121,700 married, female nurses,
wa s as s es sbed
y com par i ng
repor t ed
m enopaus s
alt atus,a g eat
aged 30 to 55 y , responded to a detailed baseline questionnaire me
on men o pa uase
ndt
, y peo f me no p aubseet w et eh ne1978 a n d1980
dical, lifestyle, and other health-related information. Follow-up quesq uestionnair es.
M o r et han98% of wome nw ho r e ported
b e ing
tionnaires were mailed biennia lly to update information on
p orisk
s t factors
m e n o p a u sa l o n the 1978 questionnaire also reported being postand newly diagnosed diseases. The NHS was approved by the institumenopa usal
on the 1980 questionnaire.Among women reporting
tional reviewboard of the Brighamand W omen
s Hospital(Boston, natural menopause, 82% reported their age at menopause to within a
MA).
year of their previous report; within-person variation increased with age
Follow-up for the present study began in 1980, when diet was since
rst menopause .
assessed, and ended in 2000, when age at menopause was ascertained for
the nal time. For this analysis, women were included if they had <10
Assessment
of nondietary factors.Information on nondietary pretotal missing food items, total energy intake of 500 to 3500 kcal/d,
and
dictors
no diagnosis of cancer by 1980. After further restriction to women
who of age at natural menopause was collected on the 1980 questionnai re and updated whenever possible by using data from follow-up
were premenopausal at baseline and reported at least 1 status update
Age was calculatedby subtracti ng
the participant
s
during the study period, 46,059 women were eligible for analysis.question naires.
reported date of birth from the questionnai re return date. Age at menarche and height were assessed in 1976. Marital status was assessed in
Dietary assessment.D i e t w as as s e s se d b y u si n g a se l f - a d m i ni s t e re d
1980, 1992, and 1996. Information on parity and age at rst birth was
sem iqu antitative FFQ , w hic h wa s a dm i n is tered i n 198 0, 1984 , 1986,
assessed at baseline and updated every year until 1984; in 1996, women
1990, 199 4, and 1998. In 1980 , t he FFQ consis ted o f 6 1 f ood item s .
were asked to report their lifetime pregnancy history . W e collected data
The 198 4 FFQ wa s expa nded to in c l ude 126 foo ds p lus vita m i n and
on oral contraceptive (OC) use, which was reported until 1984. Infor mi n e r a l s up pl em en t s; 19 8 6, 1 9 9 0 , 19 94 , an d 1 99 8 qu es ti o nn a ir e s w e r e
mation on smoking habits and body weight were assessed at baseline
s im il ar
to th e1984 FF Q .Pa r ti ci p an
wets
reas ke do ,na ve r a ho
ge w
,
2
and biennially thereafter . Updated BMI (kg/m
) was calculated by using
fr eq ue n t l y th ey co ns um ed a ty p ic a l po rt i on s iz e of s pe ci e d fo od s ov er th e
weight reported at each cycle and height in 1976. Between 1980 and
pa s t y ea r. N in e po s s ib l e fr e q ue nc y re s po ns es w er e a va il ab le fo r e a ch fo od ,
1982, vigorousactivitywas denedas the weeklytime engagedin
r a n gi ng fr o m ne v er t o >6 ti m e s /d . Tot a l d ai r y wa s ca l cu la te d as th e s um o f
activity sufcient to work up a sweat; for 1986 and beyond the mean
th e fo l lo w in g : sk im a n d lo w -f at m il k, wh o le m il k , y og u rt , c o tt a g e ch ee se ,
weekly moderate to vigorous activity was calculated by summing the
s he r be t, cr ea m , s ou r cr ea m , ic e cr ea m , cr ea m ch ee s e, a nd o th er ch ee se . Th e
mean nu mbe r of hou rs p er we ek spe nt p arti ci pat ing i n 7 c ommon l ei sure l ow - f a t d ai ry fo od ca tego ry was c alcu lated by summing in take s of skim
t im e p h y sical a cti v it ies s u ch a s brisk w a lking , run ni ng , jog g in g , sw imm in g ,
( non fa t) and l ow- f at m il k, yo gurt , c ot ta ge c he e se, and s herb et ; t he hig h - fat
and tennis.
d a i r y f o o d c a t e g o r y included whole milk, cream, sour cream, ice cream,
cream cheese, other cheese, and butter. Red meat included beef, pork,
W e uanalysis.
s e d Co x pr o p or t i o na l ha z a r d s r e gr e s s i on t o
lamb, and hamburger. If a food item was left blank, consumption Statistical
was set
es tim ate H R
a nd
s 95 % C I s for the as sociation
b e tween cum u la tive
to zero (25).
D i e t a nryut ri e n
i nt t a kewse rec al c u l atbeydmu l t i pl
ay
v tin
erh g
ae g ed dai r y c onsu m p tion a nd the event of na tura l m enopa us e for
eu
n ni
agteosf 3
0 t. h
5e
yn
. Al
es
u nt
s e d a t i me s c a le o f c a l e n da r t i m e
f r e q ue nc y of c o n su m p t i o n o fweom
ac h
f o2.o5d6
by
utl ria en na tl cyson
te
of the s peciedpor tionsa nds u m m iang
croinsall
mo
s foods
n t h .N
s ;upter ri so
entn - mo n t h s w e re c al c u l at e d f o r p ar t i c i pa n t s f r o m t h e
com pos i t ion v alues f o r each food wer e obta ined f ro m t hetim
U SeDA
a tthe
andr eturn of t he 1980 quest i onna ir e to t he
a tna
timtural
e
other sour ces (26). T otal n utrient in t a ke was calcul
m enop
ated in
ause,
a simil
repor
ar t o f sur g i c a l m enopa use, dea th, Ju ne 2000, o r , if th ey
ma n ne r; h o w e v e r , i n t ak e f ro m v it am i n an d s up p l e
wme
e re
lnotst
ut of
s eowl las
ow
a l-tsuhed
op , a t oe ft hel a stre t u rn qu
e de s t i o nn a i re ,
ichever
amthe
e dai
r st
includ e d . To ca l cula t e da ir y fa t a n d dair y pr owh
t ein,
foodsc in
r y. W om en who r e por te d m enopa us e but wh o fa i led
g r o u p, as w e l l a s d a ir y i ng re di e n t s i n o t h e r f o o dsto, w
r ee por
r e ty
ct opeof
n sm
i denop
e r e aus
d .we
e r ecens o r ed,
a swere womenwith
sim
ngneenopa ussat la tus
Al.l a na lys were
es s tra t i ed
b ya g ein
T o tal ener g y i ntake was ca lculated from all f ood s . T o redu m
c eisextra
n dusted
qby
u e st io n n ai r e c yc l e , m a ki n g t h e t i me sc al e e q u iv a l e n t t o
ous va r i a tion
in nutrientintak e nu
, trientsw e mo
r ener
e nt hs
gy a-adj
u s i nt gh er e si d ufal
r om
s t her e gr e ssoi fonnut ri e inntt a kon
e t o t a l ag e i n m o n t h s.
ener g y in t a ke (27).
Cumulative averaged consumption of total dairy , total low-fat dairy ,
The validity of the 61-item FFQ was assessed among a sample
total
of 173
high-fat dairy , skim milk, and whole milk was calculated by using
NHS participants by comparing intakes assessed using the FFQ todat
theacolle cte bet
d wee 1980
n
a ndthe q uestio nnaire
beforenat ural
men opause. For example, the incide nce of nat ural me nopause from
mean intake assessed using four 1-wk diet records (28,29). Deattenuated
correlation coefcients between the FFQ and the mean intake assessed
1980
through
by 1984 (reported on the 1982 and 1984 questionnaires) was
relatedto intakefrom the 1980 questionnaire,
and the incidenceof
the diet records were 0.81 for skim and low-fat milk, 0.62 for whole
natural
milk, 0.94 for yogurt, 0.73 for ice cream, 0.80 for cottage cheese,
and menopause from 1984 to 1988 (reported on the 1986 and 1988
0.57for other (hard) cheeses (28). After a comparison of intakequestion
from thenaires) was related to the mean intake from the 1980 and 1984
Dairyconsumptionandageatnaturalmenopause1643

questionnaires. Questionnaires ascertained typical diet and attainment

(n = 447) died during the study period, and the remaining 17%
of natural menopause over the previous year; thus, relating menopause
was censored for reasons including incomplete data on age at
to diet reported on the previous questionnaire was necessa ry to or
minimize
typeof menopause
(n = 7676).W omenreportingnatural
reverse causation. T o reduce the impact of outliers and to avoid
mismenopause
were followed for a mean of 8.5 y and had a median
classication of dairy consumption, cumulative averaged consumption
unadjusted age at natural menopause of 51.5 y . Among women
was categorized into 5 groups and modeled by using indicator variables.
who remainedpremenopausal
in 1990, thoseconsuming>3
T o aid interpretation, consumption of total and individual dairy foods
servings
was reported in units of servings per day or week. For tests of linear
trend of total dairy per day were more likely to have children
amongparouswomen,had
m orec hildrenrelati v te o
across categories of dairy consumption, we assigne d the medianand,
value
to
n o dairy (Table 1). W omenc onsuming
each category and modeled the values as a continuous variable. womenconsuming
The
amounts of dairy foods also reported a higher energy
proportional hazards assumption was tested by using a likelihoodgreater
ratio
test comparing a model with cross-product terms for continuous age
intake,werelesslikely to be smokers,and engagedin more
in months and the indicator variables for the exposure to the model
physical activity than those reporting the lowest intake of dairy
containing the main effects only . The proportional hazards assump
tion
foods.
was violated in the total cohort; therefore, we stratied all models by age
$ 51and
at questionnaire return
(
<51 y). This cutoff was chosen because
Overall cohort.In the overall cohort, higher intake of low-fat
it represents the median age at natural menopause in the cohort.
dairy
, skim milk, dairy protein, dairy fat, vitamin D, and lactose
T o explore whether dietary calcium explained any of the associa tion
predicted
between dairy consumption and natural menopause, we examined the a later age at natural menopause. For example, women
consuming >3 servings of low-fat dairy daily reported reaching
association between dairy and age at natural menopause after adjustnatural
ment for calcium. Similar models were constructed for other nutrients
of menopause 3.6 mo later than those consuming no lowfatwas
dairy (estimated mean age at natural menopause: 51.8 vs.
interest. W e conducted sensitivity analyses in which the exposure
1) baseline (1980) diet and
2) diet from 51.5y) (Table 2). However , the proportional hazards assumpclassied in 2 additio nal ways:
1980to 1998 using simple updates. Similar results were obtained
using
tion
was violated for several exposures. Therefore, all additional
each approach; only results for cumulative averaged diet are presented,
analyses were stratied by age at questionnaire return (<51 or
as this method reflects long-term dietary intake and reduces measure$ 51 y).
ment error due to within-person variation over time (31). OC use during
the perimenopau sal period may prolong menstrual bleeding, resulting in
Women aged <51 y at the time of questionnaire return.
misclassication of menopausal status; therefore, we repeated analyses
women<51y of age (accruing16,557eventsover
after excluding women who reported OC use at any point during Among
the
357,498
study period. Some studies (20,32), but not all (33), suggest that heavier person-years), more frequent consumption of low-fat
womenexperienc later
e
naturalmenopause,
so we also investigated dairy and skim milk, but not high-fatdairy or whole milk,
$ 30 kg/m2 ) a t the predicted a later age at natural menopause (i.e., a lower rate of
whether associations differe d by BMI (<25, 2529.9,
time of questionnaire return.
naturalmenopause).
Specicallypremenopausal
,
womenwho
Skim milk and low-fa t dairy were similarly correlated with individual
consumed >3 servings/d of low-fat dairy were 18% less likely
r = 0.63; low-fat dairy and dairy(HR: 0.82; 95% CI: 0.73, 0.91;P-trend< 0.0001)to report
nutrients: skim milk and dairy protein,
r = 0.06; low-fat dairy and naturalmenopause
protein,r = 0.73; skim milk and dairy fat,
in the next monthrelativeto thoseconr = 0.71; low-fat dairy
dairy fat,r = 0.10; skim milk and dietary calcium,
suming 0.11 servings/d of low-fat dairy , holding total energy
r = 0.73; skim milk and dietary vitamin
r = D,
and dietary calcium,
0.68;
constantTable3).
(
Multivariable analyses yielded similar effect
low-fat dairy and dietary vitamin rD,
= 0.63; skim milk and lactose,
P-trend < 0.0001).
estimates
(HR:
0.86;
95% CI: 0.77, 0.96;
r = 0.69; and low-fat dairy and lactose,
r = 0.66.
Frequency of skim milk consumption also predicted a later age
The following variables were chosen for inclusion in multivariate
atth
natural
m od e l s on th e ba si s o f th ei r p ot en ti a l as s oc ia ti o ns wi
n at u rmenopause
a l m en op a(for
us e:01 servings/mo of skim milk vs. >6
P-trend < 0.0001).
0.93; 95% CI: 0.89, 0.97;
ag e at m en ar ch e (< 1 0, 1 0 12 $. 9,
151y 3
), a14
ge. 9,
a t r st b i r th servings/wkHR:
a nd
$ 25
pa ri ty (n u ll i pa ro us , < 25 y a nd 1 or 2 ch il dr en , <2
5 y a nd Intake
> 2 ch ilofd dairy
r e n ,protein, dairy fat, and lactose, but not total
y an d 1 o r 2 ch i $
ld25
r en
y an
, d > 2 ch il dr en ), ho ur s pe r w ee k cal
ofm
de
t e D, als o pre d icte d a marginally
c ioum
or rvaitamin
laterageat
to v ig or ou s a c t i v it y (q u in ti l e s ), h ei g ht (q ui nt il es natural
), B M I (<
21n, opause
2 1 22 .( 9i.e.,
, 23alower rate o f natural mTable
me
e n opause) (
24.9, 25 2 9.$930k
, g/ 2m ), O C us e (n ev er ; cu r r en t us er ; fo r4).
me
r us e r,to<5
y ; i n the lowest quintile of dair y protein intake,
Relative
those
fo r m er u $
s5
ey
r, ), s m ok in g (n ev e r ; fo rm er ; cu rr en t, 1 14 ci ga r et te s/ d;
premenopausal w omen in t h e h igh e s t quin tile o f intak e were 9%
$ 25
cu r re n t, 15 2 4 ci g a r et te s/ d;
a nd
c i gar
c u retret e
n st, / d ) , m ar i t al st a t u s
P-trend < 0 .0001) t o
less lik ely (HR: 0.91; 95% CI: 0.86 , 0.95;
(m ar r ie
ordno tm ar r ie to
d) ta
, en
l er gy
(k ca l /d
co, nt i nu ou
resdm
), ea t
reach
n
atural
menopa
u
s
e
i
n
t
he
next
mon
th, holding c o variates
co ns um p ti on (0 , 0 .1 1, 1. 1 2 , 2. 1 3, >3 se r v in g s /d ), an d eg g co ns um pt i on
con
t a/wntk)(ad
orgtoi nd
tali energy
onl y H R : 0.88 ; 95% CI : 0 .84 ,
(0 1/ m o , 1 .1 / m o 2/ w k, 2. 1 4 /w k , 4 .1 6/ w
k,s
>6
. Thj eusted
m is sf in
ca Corre s ponding gures were
0.94 for dairy fat (95 % CI:
to r m e th od w as us ed fo r co v a ri a t es wi th m is si ng da ta0.93).
.
P; d : 0 .0 2 ) and 0. 92 f o r lac to se (9 5% CI: 0 . 87,
-tren
Additionally , w e estimated multivariable-adjusted mean age 0.89,
at na-0 .99
tural menopause
in the intervalbetween33.5 and 60.5 y by using 0.97; P-trend: 0. 0004) (adju s t ed for total energy o nlyHR for
baseline survival probabilities
SupplementalMethods
(
).
dairy f at: 0 .95 ; 9 5% CI: 0.90, 1 .00; HR for lactose: 0 .9 1; 95% CI:
Statisticaltestswere 2-sidedand performedat the 0.05 levelof
0.86, 0.9 5).
signicance. W e used SAS (version 9.2; SAS Institute) for all analyses.

Women aged $ 51 y at the time of questionnaire return.

Among women$ 51 y (accruing14,259eventsover 44,256
person-years), dairy foods and nutrients did not predict age at
Results
natural menopause.
Of the 121, 700 wo men enrolled i n t he NHS, 46,0 59 were
premenopausal
at baselineand met other eligibilitycriteria. Sensitivity analyses.T o explore which, if any , component of
dairy might explain the association between low-fat dairy and
Over a total of 401,754 person-years of follow-up, two-thirds
(n = 30,816) of women reported their age at natural menopause,
natural menopauseobservedamongwomen<51 y of age,
were individually added to the original fully adjusted
13% (n = 6069) reported their age at surgical menopause,nutrients
2%
model(model2).
For modelsincludinglactose,dairy fat, or
(n = 1051) remained premenopausal at the end of follow-up,
1%
1644 Carwileetal.

TABLE 1 Age-standardized characteristics of the 17,238 women in the Nurses

Health Study who
1
remained premenopausal in 1990, across categories of 1990 milk consumption
2

Dairyconsumption
#1.0serving/d
(n =2875)
3,4

Age , y
Ageatmenarche,
y
Nulliparous,
%
Children(amongparouswomen),
n
Ageatrstbirth,
y
Oralcontraceptive%use,
Neveruser
Formeruser
, 5y
$5 y
Totalenergyintake,
kcal/d
Totalmeat,
servings/d
Redmeat,
servings/d
Eggs,servings/d
2
BMI,kg/m
Height,
cm
5
Cigarettesmoking
% ,
Never
Former
Current
114cigarettes/d
1524cigarettes/d
$ 25cigarettes/d
Moderatetovigorousactivity,
h/wk
Married,
%

1.12.0servings/d
(n =6957)

2.13.0servings/d
(n =4474)

. 3 servings/d
(n =2932)

48.56 3.1
12.46 1.6
5
2.76 1.1
24.56 2.7

48.36 3.0
12.36 1.6
5
2.76 1.1
24.66 2.8

48.36 3.0
12.36 1.6
4
2.76 1.1
24.86 2.9

48.26 3.0
12.36 1.7
4
2.86 1.2
24.96 3.0

26

26

28

31

68
6
14106 383
1.56 0.7
1.16 0.6
0.36 0.3
25.76 5.2
1636 6

68
6
16306 374
1.56 0.6
1.26 0.6
0.46 0.3
25.76 5.0
1646 6

67
5
18406 387
1.56 0.6
1.26 0.5
0.46 0.3
25.76 5.0
1646 6

65
4
20806 410
1.66 0.6
1.26 0.6
0.46 0.3
25.76 5.2
1656 6

44
36

47
38

51
37

51
36

7
8
5
2.66 2.0
92

5
6
3
2.86 2.0
93

5
5
3
3.06 2.0
93

4
5
4
3.06 2.1
93

Valuesare means6 SDsor percentagesandarestandardizedto theagedistributionof thestudypopulation.

Total dairy consumption was calculated from reported intake of skim and low-fat milk, whole milk, yogurt, cottage cheese, sherbet,
cream,sourcream,ice cream,andcreamcheese.
3
Valueswerenotage-adjusted.
4
For thistable,dataondemographicanddietaryvariableswereobtainedbetween1980and1990.
5
Total doesnotsumto 100due torounding.
2

dairy protein, the association between low-fat dairy and natural

consumption of low-fat dairy may increase circulating estrogen
menopause was attenuated but generally retained signicance
concentrations,delayingnatural menopause.However ,al(P-trend:0.007,<0.0001,and 0.03, respectively),
suggesting though we collected data on and adjusted for many potential
that the observed association was attributable to a component
confounders, observed effect estimates were modest and comof milk otherthan thesenutrients.When the associationbe- patible with residual confounding.
tweenskim milk and naturalmenopause
was examinedin a
P-trend:
corresponding fashion, HRs were similarly attenuated
( Biological mechanism.Cow milk contains various estrogen
metabolites,
including17b-estradiol,estrone,and estriol(9),
0.01, <0.0001, and 0.08, respectively).
~8098% of which are present in their conjugated form (9,34).
W e also assessed whether ndings persisted after restriction
Estrone
sulfate and other conjugated estrogens are hydrophilic
to the 40,6 84 women who d id not report m en opause duri
ng t heir
(unlike
and mightthereforebe exrst year in th e study or the 45, 973 women who never r ep
orted lipophilic free estrogens)
pected
to
be
present
in
the
highest
concentrations
in low-fat
using O Cs during f ol low-up. Resu lts were not material ly different
products, including skim milk (9). However , studies rein either of these s ubpopul atio ns (dat a not shown). Effectdairy
estimates
latingestrogen
and dairy fat contentin dairy
were material ly unchanged after c onsideration o f c rude ber
i ntake concentrations
foods have yielded mixed results (9,34,35). Conjugated estro(data not sh own). Final ly , results were not mod ied by o verweight
gensbypassrst-passhepaticmetabolism,and are therefore
or o besity s tatus ( data not shown).
considered to be the most biologically relevant in the context of
oral administration (36). The bioactivity of orally administered
conjugatedestrogensis demonstrated
by the effectiveness
of
Discussion
OCs and hormone replacement therapy .
In this prospective study of dairy consumption and age at natural
Limited evidencesupportsthe hypothesisthat frequent
consumption of milk increases circulating estrogen concentramenopause, more frequent consumption of total low-fat dairy
and skim milk, but not high-fat dairy or whole milk, predicted
tions.
a In rats, plasma estrone sulfate concentrations were 29%
modest delay in natural menopause among women aged higher
<51 y .in animals fed low-fat milk compared with those fed a
One potentialbiologicalrationalefor thesendingsis that macronutrient milk substitute (37). Similarly , dairy consumpDairyconsumptionandageatnaturalmenopause1645

TABLE2
Estimated mean age at natural menopause amongThis is compatiblewith the hypothesisthat a nonnutrient
1
46,059 women in the Nurses
Health Study, 19802000
component of dairy f oods account s for the observed associ-

a t i o n s w i t h a g e a t n a t u r a l m e n o p a u s e . T h e o b s e r v e d associaEstimatedmeanage
tion between skim milk, low-fat dairy , and natural menopause
2
atnaturalmenopause was restricted to women aged <51 y a t the time of questionnaire
yre tur n. T h i s s ug ges ts t ha t o nl y y o u ng e r w ome n m a y be s u s 3
ceptible t o d airy consumptio n, possibl y becaus e menopause
Low-fatdairy
has a lready been init iat ed t o a n i rreve rsible deg ree i n o lder
0 servings/d
51.5
women.
0.11serving/d
51.5
Dairy contains other hormones and nutrients that may in1.12servings/d
51.6
fluence timing of natural menopause, and we considered several
2.13servings/d
51.7
alternative hypotheses related to these possible mechanisms. W e
. 3 servings/d
51.8
4
hypothesized that dairy consumption may predict earlier natural
High-fatdairy
menopause
becausegalactose,a lactosemetabolite,has been
0 servings/d
51.5
posited as an ovarian toxin. W omen with galactosemia experi0.11serving/d
51.7
enceearlymenopause
(40) and womenwith low activityof
1.12servings/d
51.5
galactose-1-phosphate
uridyl transferase, an enzyme responsi2.13servings/d
51.5
ble
for
galactose
metabolism,
may reachmenopause
earlier
. 3 servings/d
51.6
than women with normal enzyme activity (41). However, we
Skimmilk
observedonly positiveassociations
betweendairy foods and
01serving/mo
51.5
related
nutrients,
including
lactose,
and age at natural meno1.1serving/mo2 servings/wk
51.4
pause.
Frequent
dairy
consumption
is
also associated with a 10
2.14servings/wk
51.5
20% increase in circulating IGF-I concentrations (1316), which
4.16servings/wk
51.5
could possibly stimulate the ovaries, postponing natural men. 6 servings/wk
51.6
opause. Circulating IGF-I concentrations decrease with age and
Wholemilk
may be involved in the menopausal transition, as suggested by
01serving/mo
51.5
studiesin rats, in which decreasedIGF-I signalingleadsto
1.1serving/mo2 servings/wk
51.5
disrupted
surges in luteinizing hormone similar to that observed
2.14servings/wk
51.4
du
ringrep
r o ductive
sen escence
(42 ) H
. owever t, h erelation
4.16servings/wk
51.4
between IGF-I and natural menopause is still unclear . Addition. 6 servings/wk
51.5
ally , intake of an unidentied component of low-fat dairy may
1
Dietwasassessedin 1980,1984,1986,1990,1994,and1998.Foodintakeswere
increase the frequency of anovulatory menstrual cycles (43), a
cumulativelyupdatedoverfollow-up.
hypothesized predictor of later age at natural menopause (44).
2
Valuesofquestionnairecycleandriskfactorsquantiedbyusingquantileswereset
Last, our results c ou ld be explai n e d by a dietary pattern character tothemediancategory,othercategoricalriskfactorsweresettotheobservedmode
inthestudypopulation,andcontinuousvariablesweresettotheirobservedmeanin ized by freq uent consump t ion of low-fat dairy .
thestudypopulation.
3
Total low-fat dairy intake was calculated from reported intake of skim and low-fat
Strengths and limitations. Major strengthsof this study
milk,yogurt,cottagecheese,andsherbet.
include the prospective design as well as detailed collection of
4
Totalhigh-fatdairyintakewascalculatedfromreportedintakeofwholemilk,cream,
dietary information using previously validated questionnaires.
sourcream,ice cream,creamcheese,othercheese,andbutter.

Dietary recall on FFQs is subject to both within- and betweenperson e rrors. Calculation of c umulative av erages c an r e duce meation has beenpositivelyrelatedto total and free estradiolsuremen t error d ue to wi th in-person vari ation (2 9), bu t ndi ngs
concentrations
in postmenopausal
women(12). In a cross- were materially unchanged when we instead examined baseline
sectional analysis of NHS participants, total and free estradiol
or recent diet. W e observed large variation in total energy , which
concentrations
were positivelyassociatedwith the W esternlikely resulted in part from the under - or overreporting of dietary
pattern, a dietary pattern characterized by consumption of
intake
high-by some women. W e accounted for this by adjusting for
fat dairy and red and processed meats, as well as rened total
grains,
energyintake(29); howeversystematic
,
under o
- r over sweets, and desserts (38). Serum estradiol
concentrations
reporting
o f d a i r y f did
o o not
d s m a y r e m a i n . W e r el a t e d n a t u r a l m e n o differ by treatment status in an 18-mo intervention inpause
whicht12o diet aver a ged over the pr e ceding q uestionnair e cycles,
y-old girls were randomly assigned to receive 568 mL (1 pint)
of it unlikely t hat menopaus al status influenced dietary
making
whole or reduced-fat milk per day or a usual diet (39). However
reporting.
,
Exposure misclassication unrelated to age at menovarian production of estrogens is relatively high in this group,
opause likely resulted in slightly attenuated ndings.
and circulating estrogen concentrations would therefore
be more
Misclass
i cation of t h e outc o m e was minimiz e d by using o nly
tightly regulated than in a population of older females,
the rs
in twhom
repor t ed a ge at me n o pause and by colle c ting d ata ever y
peripheral e strogen p rodu ction i s more a bundant.
Althou
y . Thus,
2 r e gh
porting er r or s in age of m e nopause ar e expec t ed to be
these studies suggest that, in certain populations, milk
n o consumn d i f f e re n t i a l w i th r es p e ct to d a i ry c o n su mp ti o n .
ption may increase circulating estrogen concentrations, whether
NHS participants are not a random sample of the general
the magnitude of this increase is sufcient to stimulate menstruUnited Statespopulation,but our resultsare likely widely
ation is uncertain.
generalizable because the biological mechanisms of interest are
On the basis of this evidence, we expected consumption
of
unlikely
to differ between our population and other women in
dairy , and, in particular, low-fat dairy foods, to increase estrogen
the United States or elsewhere. Moreover , circulating estrogen
concentrations,
postponingmenopause.
Associationsbetween concentrations are likely to vary with body size (45), activity
low-fat dairy , skim milk, and natural menopause could
(46),
not
d ietary
be
compos i t ion (38), and other f a ctors (47). The wome n
fully explained by intake of dairy protein, dairy fat, or lactose.
in our study reported considerable variability in these and other
1646 Carwileetal.

TABLE 3 HRs and 95% CIs for associations between dairy and milk consumption and natural
1
menopause among 46,059 women in the Nurses
Health Study, 19802000
Dairyconsumption

2
P-trend

3
. 3
Low-fatdairyservings/d
,
0
0.11.0
1.12.0
2.13.0
Age32.550.9y
Events/person-year1137/29,909 10,080/206,4783568/75,271 1428/36,613 344/9227
Model1
1.00(0.94,1.07) 1.00(ref)
0.94(0.90,0.97)0.87(0.82,0.92)0.82(0.73,0.91) , 0.0001
Model2
1.00(0.94,1.07) 1.00(ref)
0.96(0.92,1.00)0.90(0.85,0.95)0.86(0.77,0.96) , 0.0001
Age51.060.5y
Events/person-year 585/2047
8373/25,853 3628/11,062 1371/4304
302/991
Model1
0.86(0.79,0.94) 1.00(ref)
1.01(0.97,1.05)0.98(0.92,1.04)0.91(0.81,1.03) 0.74
Model2
0.95(0.87,1.04) 1.00(ref)
0.99(0.95,1.04)0.98(0.92,1.04)0.95(0.84,1.07) 0.41
4
. 3
High-fatdairy
servings/d
,
0
0.11.0
1.12.0
2.13.0
Age32.550.9y
Events/person-year 52/1563
7523/166,577 5112/105,816 2030/42,200 1840/41,341
Model1
0.83(0.63,1.09) 1.00(ref)
1.01(0.97,1.05)1.01(0.96,1.06)1.02(0.96,1.07) 0.46
Model2
0.85(0.64,1.12) 1.00(ref)
1.00(0.96,1.04)0.99(0.94,1.04)0.98(0.92,1.03) 0.39
Age51.060.5y
Events/person-year 49/138
6508/20,312 4535/14,033 1759/5431
1408/4342
Model1
1.05(0.78,1.40) 1.00(ref)
1.00(0.96,1.04)1.00(0.95,1.06)0.99(0.93,1.05) 0.79
Model2
1.18(0.88,1.58) 1.00(ref)
1.00(0.96,1.04)1.00(0.95,1.06) 0.99(0.93,1.06) 0.81
. 6/wk
Skimmilk,
servings
01/mo
1.1/mo2/wk
2.14/wk
4.16/wk
Age32.550.9y
Events/person-year4676/106,701 3134/58,221 2538/51,961 1541/28,143 4668/112,471
Model1
1.00(ref)
1.01(0.97,1.06)0.95(0.900.99)1.00(0.94,1.06)0.89(0.850.93), 0.0001
Model2
1.00(ref)
1.02(0.97,1.07)0.96(0.911.01)1.02(0.96,1.08)0.93(0.890.97), 0.0001
Age51.060.5y
Events/person-year2805/9079
2847/8680
2464/7601
1569/4863
4574/14,033
Model1
1.00(ref)
1.12(1.06,1.18)1.09(1.03,1.15)1.08(1.011.16)1.08(1.031.14) 0.23
Model2
1.00(ref)
1.04(0.98,1.10)1.02(0.97,1.09)1.01(0.941.08)1.03(0.981.08) 0.69
. 6/wk
Wholemilk,
servings
01/mo
1.1/mo2/wk
2.14/wk
4.16/wk
Age32.550.9y
Events/person-year8843/201,578 3907/72,775 1611/32,714
610/11,348 1586/39,083
Model1
1.00(ref)
1.04(1.00,1.08)1.08(1.02,1.14)1.12(1.03,1.22)1.04(0.98,1.10) 0.01
Model2
1.00(ref)
1.01(0.97,1.05)1.05(0.99,1.10)1.07(0.98,1.16)1.00(0.95,1.06) 0.34
Age51.060.5y
Events/person-year7381/23,073 3961/12,185 1292/3987
531/1631
1094/3381
Model1
1.00(ref)
1.03(0.99,1.08)1.00(0.94,1.07)1.04(0.94,1.13)1.00(0.93,1.07) 0.95
Model2
1.00(ref)
1.01(0.97,1.05)1.00(0.94,1.06)1.00(0.91,1.09)1.02(0.96,1.09) 0.67
1

Dietwasassessedin1980,1984,1986,1990,1994,and1998.Foodintakeswerecumulativelyupdatedoverfollow-up.Model1isaCox
proportional hazards model adjusted for total energy intake (continuous) and stratied by age in months and period. Model 2 is a Cox
, 10,1012.9,1314.9,$ 15y),ageatrstbirth
proportionalhazardsmodeladjustedasformodel1covariatesaswellasageatmenarche(
, 25 yand1or2children, , 25 yand . 2 children,$ 25 yand1or2children, $ 25 yand . 2 children),moderateto
andparity(nulliparous,
$ 30 kg/m2 ), oral contraceptive use (never;
vigorous activity (quintiles), 1980 height (quintiles),,BMI
21, (2122.9, 2324.9, 2529.9,
, 5 y; former user,$ 5 y), smoking (never; former; current, 114 cigarettes/d; current, 1524 cigarettes/d;
current user; former user,
. 3 servings/d),andegg
current,$ 25 cigarettes/d),maritalstatus(marriedornotmarried),redmeatconsumption(0,0.11,1.12,2.13,
. 6/wk).ref,reference.
consumption(01/mo,1.1/mo2/wk,2.14/wk,4.16/wk,
2
Calculatedby usingthemedianofeachcategoryas a continuousterm.
3
Total low-fatdairyconsumptionwascalculatedfromreportedintakeofskimandlow-fatmilk, yogurt,cottagecheese,andsherbet.
4
Totalhigh-fatdairyintakewascalculatedfromreportedintakeofwholemilk,cream,sourcream,icecream,creamcheese,othercheese,
andbutter.

characteristics, supporting the generalizability of our ndings

a slightly
to later natural menopause relative to women consuming
women with a range of circulating estrogen concentrations.
theseitemslessfrequently
The
A. 1-y increasein ageat natural
unweighted median age at natural menopause was 51.5menopause
y , which has been found to predict a 2.5% increase in risk of
is laterthan thosecalculatedin otherpopulations,especially breast cancer (48); therefore,the modestobservedeffect
after accounting for differences in denition of menopause
estimates
(1).
we report are unlikely to be of clinical signicance.
The baseline exclusion of women who had already experienced
However,our resultsare consistentwith a growingbody of
menopause likely resulted in a slight upward bias in reported
literature supporting the hormonally active nature of milk and
age at natural menopause; however , this would not affectother
the dairy foods (49). Continuedresearchon the health
validity of our reported effect estimates.
consequences of dairy consumption is especially critical in light
In conclusion, our ndings suggest that women <51 y of
of age
the current Dietary Guidelines for Americans recommendawho frequently consume low-fat dairy and skim milk experience
tion of$ 3 servings of low-fat dairy per day (50).
Dairyconsumptionandageatnaturalmenopause1647

TABLE4
HRsand95%CIsforassociationsbetweennutrientsandnaturalmenopauseamong46,059
1
women in the NursesHealth Study, 19802000
Q1

Q2

Dairyfat
Age32.550.9y
Events/person-year
3072/68,322 3280/71,810
Model1
1.00(ref)
0.98(0.93,1.03)
Model2
1.00(ref)
0.98(0.93,1.03)
Age51.060.5y
Events/person-year
2346/7369
2767/8642
Model1
1.00(ref)
1.00(0.95,1.06)
Model2
1.00(ref)
0.97(0.91,1.02)
Dairyprotein
Age32.550.9y
Events/person-year
3415/70,787 3,606/74,295
Model1
1.00(ref)
0.98(0.94,1.03)
Model2
1.00(ref)
0.98(0.94,1.03)
Age51.060.5y
Events/person-year
2571/8235
2949/8941
Model1
1.00(ref)
1.04(0.99,1.10)
Model2
1.00(ref)
1.00(0.95,1.06)
3
Calcium
Age32.550.9y
Events/person-year
3618/76,997 3721/77,414
Model1
1.00(ref)
0.99(0.94,1.03)
Model2
1.00(ref)
0.98(0.94,1.03)
Age51.060.5y
Events/person-year
2754/8987
3064/9663
Model1
1.00(ref)
1.03(0.97,1.08)
Model2
1.00(ref)
0.99(0.94,1.04)
3
VitaminD
Age32.550.9y
Events/person-year
3697/76,007 3558/74,258
Model1
1.00(ref)
0.98(0.93,1.02)
Model2
1.00(ref)
0.99(0.95,1.04)
Age51.060.5y
Events/person-year
2830/8984
3091/9527
Model1
1.00(ref)
1.03(0.97,1.08)
Model2
1.00(ref)
1.00(0.95,1.06)
Lactose
Age32.550.9y
Events/person-year
3468/67,633 3575/73,488
Model1
1.00(ref)
1.00(0.95,1.05)
Model2
1.00(ref)
1.00(0.95,1.05)
Age51.060.5y
Events/person-year
2784/8864
2929/8937
Model1
1.00(ref)
1.04(0.99,1.10)
Model2
1.00(ref)
1.01(0.96,1.07)
1

Q3

Q4

Q5

2
P-trend

3344/72,001 3467/72,933 3394/72,432

0.97(0.92,1.01) 0.97(0.92,1.02) 0.95(0.90,1.00)
0.96(0.92,1.01) 0.97(0.92,1.02) 0.94(0.89,0.99)

0.06
0.02

2979/9048
3137/9634
3030/9564
1.03(0.97,1.09) 1.01(0.96,1.07) 0.99(0.94,1.05)
0.99(0.94,1.05) 0.98(0.93,1.04) 0.98(0.92,1.03)

0.72
0.60

3457/73,712 3223/72,439 2856/66,265

0.96(0.91,1.00) 0.91(0.87,0.96) 0.88(0.84,0.93) , 0.00
01
0.97(0.92,1.02) 0.92(0.88,0.97) 0.91(0.86,0.95) , 0.00
01
2975/9174
3097/9400
2667/8506
1.03(0.97,1.09) 1.04(0.98,1.10) 1.00(0.94,1.05)
0.99(0.94,1.05) 1.01(0.95,1.06) 0.98(0.92,1.04)

0.69
0.49

3563/74,945 3124/69,297 2531/58,844

0.99(0.94,1.03) 0.98(0.93,1.03) 0.97(0.92,1.02)
0.99(0.94,1.04) 0.98(0.93,1.03) 0.97(0.92,1.03)

0.21
0.35

3151/9785
2949/8855
2341/6967
1.03(0.98,1.09) 1.05(1.00,1.11) 1.05(0.99,1.11)
0.98(0.93,1.03) 1.00(0.95,1.06) 0.99(0.93,1.05)

0.05
0.95

3505/73,661 3135/71,877 2662/61,695

0.99(0.94,1.03) 0.95(0.90,0.99) 0.94(0.89,0.99)
1.00(0.95,1.05) 0.96(0.92,1.01) 0.96(0.91,1.01)

0.00
7
0.07

3107/9310
2767/8587
2464/7849
1.04(0.99,1.09) 1.01(0.96,1.07) 0.97(0.92,1.03)
1.01(0.96,1.06) 0.99(0.93,1.04) 0.95(0.90,1.01)

0.10
0.06

3373/72,264 3258/73,509 2883/70,604

0.97(0.92,1.02) 0.96(0.91,1.01) 0.91(0.86,0.95) , 0.00
01
0.99(0.94,1.04) 0.98(0.93,1.02) 0.92(0.87,0.97) 0.0004
2946/9180
2958/8889
2642/8387
1.02(0.96,1.07) 1.05(0.99,1.10) 1.00(0.95,1.06)
0.99(0.94,1.05) 1.02(0.96,1.07) 0.99(0.93,1.04)

0.88
0.61

Dietwasassessedin1980,1984,1986,1990,1994,and1998.Nutrientintakeswerecumulativelyupdatedoverfollow-up.Model1isa
Coxproportionalhazardsmodeladjustedfortotalenergyintake(continuous)andstratiedbyageinmonthsandperiod.Model2isaCox
, 10,1012.9,1314.9,$ 15y),ageatrstbirth
proportionalhazardsmodeladjustedasformodel1covariatesaswellasageatmenarche(
, 25 yand1or2children, , 25 yand . 2 children,$ 25 yand1or2children, $ 25 yand . 2 children),moderateto
andparity(nulliparous,
$ 30 kg/m2 ), oral contraceptive use (never;
vigorous activity (quintiles), 1980 height (quintiles),,BMI
21, (2122.9, 2324.9, 2529.9,
, 5 y; former user,$ 5 y), smoking (never; former; current, 114 cigarettes/d; current, 1524 cigarettes/d;
current user; former user,
. 3 servings/d),andegg
current,$ 25 cigarettes/d),maritalstatus(marriedornotmarried),redmeatconsumption(0,0.11,1.12,2.13,
. 6/wk).Q,quintile;ref,reference.
consumption(01/mo,1.1/mo2/wk,2.14/wk,4.16/wk,
2
Calculatedbyusingthemedianof eachcategoryas a continuousterm.
3
TotalcalciumandvitaminD includeintakefromfoodandsupplements.

1648 Carwileetal.

in a populat ion-based
cohort of women.J Clin Endocrin olMetab.
Acknowledgments
2008;93:384 752.
The authors thank Donna Spiegelman, Ellen Hertzmark,
and
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JT, M atthewsKA, Kuller LH, Wing RR, Meilahn E N ,
Molin W ang of the Harvard School of Public Health for their
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designed the research; J.L.C. analyzed the data and wrote20.
theDorjgochoo T, Kallianpur A, Gao YT, Cai H, Y ang G , L i H , Zheng W,
manuscript; W.C.W. and K.B.M. provided important consulta- Shu XO. Dietary and lifes tyle predictor s of age at natural menopau se
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