European Journal of Clinical Nutrition (2019) 73:1501–1511
https://doi.org/10.1038/s41430-019-0398-9

ARTICLE
Epidemiology

Soy intake and vasomotor menopausal symptoms among midlife
women: a pooled analysis of ﬁve studies from the InterLACE
consortium
Yashvee Dunneram 1 Hsin-Fang Chung2 Janet E. Cade1 Darren C. Greenwood 1 Annette J. Dobson2
Ellen S. Mitchell3 Nancy F. Woods4 Eric J. Brunner5 Toyoko Yoshizawa6 Debra Anderson7 Gita D. Mishra2
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Received: 21 September 2018 / Revised: 3 January 2019 / Accepted: 16 January 2019 / Published online: 4 February 2019
© Springer Nature Limited 2019

Abstract
Background/objectives Phytoestrogen rich-foods such as soy may be associated with less frequent/severe vasomotor
menopausal symptoms (VMS), although evidence is limited. We thus investigated the associations between the consumptionof soy products and soy milk and the frequency/severity of VMS.
Subjects/methods We pooled data from 19,351 middle-aged women from ﬁve observational studies in Australia, UK, USA,and Japan that contribute to the International Collaboration for a Life course Approach to reproductive health and Chronic
disease Events (InterLACE). Information on soy consumption, VMS and covariates were collected by self-report. We
included 11,006 women who had complete data on soy consumption, VMS and covariates at baseline for the cross-sectional
analysis. For the prospective analysis, 4522 women who were free of VMS at baseline and had complete data on VMS atfollow-up were considered. Multinomial logistic regression and binary logistic regression models were used.
Results No statistically signiﬁcant evidence of an association was found between soy products (relative risk ratio (RRR):
0.92, 95% CI: 0.76–1.11) or soy milk (RRR: 1.24, 95% CI: 0.93–1.65) and the likelihood of reporting frequent or severe
VMS cross-sectionally. Prospective results indicated that frequent consumption of soy products (odds ratio (OR): 0.63, 95%
CI: 0.45–0.89) but not soy milk (OR: 1.11, 95% CI: 0.85–1.45) was associated with lower likelihood of reporting subsequent
VMS, after adjustment for socio-demographic and reproductive factors.
Conclusions These are the ﬁrst ever ﬁndings from pooled observational data of association between consumption of soy
products and VMS.

Introduction
Sources of support: Commonwealth Scholarship, Australian National
Health and Medical Research Council project grant (APP1027196 &APP1121844)
Supplementary information The online version of this article (https://doi.org/10.1038/s41430-019-0398-9) contains supplementarymaterial, which is available to authorised users.
* Yashvee Dunneram
fsyd@leeds.ac.uk
1

Nutritional Epidemiology Group, School of Food Science andNutrition, University of Leeds, Leeds, UK

2

School of Public Health, The University of Queensland,
Brisbane, Queensland, Australia

3

Family and Child Nursing, School of Nursing, University ofWashington, Seattle, WA, USA

Menopause, a natural event marking the end of the reproductive life of women, is often accompanied by menopausal
symptoms. Vasomotor menopausal symptoms (VMS),
including hot ﬂushes and night sweats, are the most common symptoms which arise as a consequence of a decline inendogenous oestrogen levels, in particular during the4

Biobehavioral Nursing and Health Systems, School of Nursing,
University of Washington, Seattle, WA, USA

5

Department of Epidemiology and Public Health, University
College London, London, UK

6

Department of Women’s Health Nursing, Tohoku University
Graduate School of Medicine, Sendai, Japan

7

Menzies Health Institute Queensland, Grifﬁth University,
Gold Coast, Queensland, Australia

1502

perimenopausal and early postmenopausal phases [1, 2].
The frequency and severity of VMS usually, decrease overtime, but this varies by individual with symptoms subsiding
after a year for some or persisting for over 30 years in others[3]. The frequency/severity of VMS have been linked tovarious chronic diseases, including cardiovascular disease,osteoporosis and cognitive decline [4, 5].
Phytoestrogen rich-foods such as soy have been associated with less frequent and less severe menopausal
symptoms, although evidence is limited [6, 7]. Epidemiological studies which investigated the association between
soy intake and the frequency/severity of VMS also
demonstrated conﬂicting results [8, 9]. Moreover, according
to a review of 43 randomised controlled trials (RCTs) [1],the positive effect of phytoestrogen supplements on thefrequency/severity of hot ﬂushes and night sweats in perior postmenopausal women is still inconclusive given thesmall sample size and potential high risk of bias of the
included trials. However, the same review suggested thatthe effect of genistein (a soy derived isoﬂavone) was promising [1].
While dietary intake of phytoestrogens is usually, in theform of soy bean, soy bean curd, tofu, tempeh, soy milk andother soy products, most studies have investigated theeffects of soy supplements and extracts [10–12]. This study
thus sought to elucidate the cross-sectional and prospective
associations between soy intake and VMS among peri andpostmenopausal women across ﬁve studies contributing to
the International Collaboration for a Life course Approachto reproductive health and Chronic disease Events (InterLACE) consortium.

Subjects and methods
Ethical approval
Written consent was obtained from all participants. All thecohort studies included in the InterLACE consortium havebeen previously granted ethical approval by the respective
ethical committees [13].

Study participants
The InterLACE consortium includes individual data fromten countries. It involves around 230,000 participants from
20 observational studies with data on women’s health (12 ofwhich provided longitudinal data). Further detailed information on InterLACE has been published elsewhere[13, 14]. For the current study, ﬁve studies that had information on soy intake (the exposure) and hot ﬂushes and/ornight sweats (the outcome) were included: AustralianLongitudinal Study on Women’s Health (ALSWH) [15],Y. Dunneram et al.

Healthy Ageing of Women Study (HOW)—Australia,
Whitehall II study (WHITEHALL)—UK [16], Seattle
Midlife Women’s Health Study (SMWHS) [17] and Japanese Midlife Women’s Health Study (JMWHS) [18] (Supplementary Table 1). For the cross-sectional analysis, datafrom 11,006 women who reported VMS (either frequency
or severity), consumption frequency of soy products and soy
milk and had complete information on confounders (listed
below) were included in the analysis. The prospective analysis included data from three studies (ALSWH, HOW and
WHITEHALL) (n = 10,082). Excluding 5560 women who
reported VMS at baseline and those with missing data on
VMS, menopausal status and use of hormone therapy atfollow-up, 4522 women were considered for the prospective
analysis (Supplementary Figure 1).

Main outcome and exposure variables
VMS was deﬁned as the presence of hot ﬂushes and/ ornight sweats. Response options for the frequency of hot
ﬂushes and night sweats (over the last 12 months) were‘never, rarely, sometimes, and often’ in ALSWH. For theother four studies, the severity of VMS over a shorter period
was recorded; HOW, WHITEHALL and JMWHS considered the current severity of VMS, while SMWHS considered the severity of VMS in the last 1–3 months. For
example, in HOW and JMWHS the response options for theextent of symptoms were ‘not at all, a little, quite a bit, andextremely’ and for WHITEHALL the response options were‘not at all, a little, somewhat, and a lot’. The degree ofseverity was harmonised as ‘never, mild, moderate andsevere’ over a shorter period of time. Since the frequency of
VMS was assessed in ALSWH and severity in theremaining four studies, results were presented separately.
VMS were further coded dichotomously as ‘absent’ (neverand rarely if reporting frequency; never and mild if
reporting severity) and ‘present’ (sometimes and often if
reporting frequency; moderate and severe if reporting
severity) for the study-speciﬁc and prospective analysis.
Soy products such as tofu, soy beans, tempeh, and soy
milk were commonly reported in the ﬁve studies. The soy
products were combined based on their phytoestrogencontents. Thus, tofu, soy beans, tempeh and soy ﬂour
having a high phytoestrogen content were grouped under
the soy products category, while soy milk was consideredseparately [19, 20].
In ALSWH, there were ten consumption frequency
options: ‘never, less than once per month, 1–3 times permonth, 1 time per week, 2 times per week, 3–4 times per
week, 5–6 times per week, 1 time per day, 2 times per day
and 3 or more times per day’. In the WHITEHALL study,nine consumption frequency options were provided; ﬁve in
SMWHS and four response categories in HOW andSoy intake and vasomotor menopausal symptoms among midlife women: a pooled analysis of ﬁve studies. . .

JMWHS. Therefore for this study, studies having more thanfour categories were collapsed into four frequency categories: ‘never/rarely’, ‘monthly’, ‘weekly’ and ‘daily’. They
were further coded dichotomously as ‘less frequent’ (never/rarely and monthly) and ‘frequent’ (weekly and daily) given
the small number of observations for ‘weekly’ and ‘daily’
intake for the prospective analysis.

Covariates
Categorical variables in the InterLACE study were collapsed into the simplest categories possible so as to include
data from as many studies as possible [13]. For example,
education level was collated into three categories as ≤10years, 11–12 years and >12 years. Smoking status wasgrouped as never smokers, past smokers and current smokers. Based on gynaecological surgery and menstrual
bleeding patterns, menopausal status was collated into ﬁve
categories to include (1) hysterectomy/oophorectomy, (2)unknown due to hormone use (menopausal hormone therapy or oral contraceptive hormones before reaching menopause), (3) premenopause (regular menstruation in the last 3
and 12 months), (4) perimenopause (menses in the past
3 months and changes/irregularity in menstrual patterns in
the past 12 months; or no menses in the previous 3 months
but menses in the preceding 11 months) and (5) natural
postmenopause (amenorrhoea for at least 12 months).
Current use of menopausal hormone therapy (e.g., oestrogen) was categorised as yes and no.

Statistical analysis
As the result of different assessments (frequency or severity) and different recall periods (in the past 12 months or ina more recent period) for VMS, studies were grouped as: (1)frequency of VMS in the past 12 months (ALSWH) and (2)severity of VMS over a shorter time period (HOW,
WHITEHALL, SMWHS and JMWHS). The associations
between soy consumption and VMS were ﬁrst examined
separately for the two different designs, followed by theoverall estimates.
Multinomial logistic regression models with four categories of outcome for VMS (never, rarely/mild, sometimes/
moderate and often/severe) were used to investigate thecross-sectional associations between frequency of consumption of soy products and soy milk with frequency/
severity of VMS at baseline. The VMS category ‘never’was used as the reference group for the outcome, and thesoy consumption category ‘never’ was used as the referencegroup for the exposure. Relative risk ratios (RRR) and 95%
conﬁdence intervals (CI) were estimated. According to theminimally sufﬁcient set of adjustments, smoking status,
education level, menopausal status and race/ethnicity were1503

identiﬁed as confounders using a directed acyclic graph(DAG) (Supplementary Figure 2) and were adjusted for in
the regression models. However, race/ethnicity was notincluded in the model as participants from ALSWH(96.5%), HOW (95.1%), WHITEHALL (88.1%) and
SMWHS (88.1%) were mainly Caucasians, and in JMWHS
all the participants were Japanese. Concurrent menopausal
hormone therapy use was included in the model given its
potential effect on the frequency/severity of VMS [21]. The
models were thus adjusted for menopausal status and concurrent menopausal hormone therapy use (model 1) andadditionally adjusted for other potential covariates including
education level and smoking status (model 2). ‘Study’ wasincluded as a ﬁxed effect to account for differences in levelsof VMS between studies and as a stratiﬁcation variable toaccount for correlation of individuals within studies.
Due to small numbers of participants in the four categories of exposure and outcome in individual studies,dichotomised soy consumption (frequent and less frequent)and dichotomised VMS (presence and absence) were used
for the study-speciﬁc and prospective analyses. To examine
between-study heterogeneity in the effect size estimates,
study-speciﬁc logistic regression and random-effects metaanalysis were used with the estimates adjusted for all thecovariates in model 2.
For the prospective analysis based on three studies(ALSWH, HOW and WHITEHALL), logistic regression
models with the binary outcome for VMS (presence andabsence) were ﬁtted, adjusted for all the covariates in model
2. In addition, a sensitivity analysis was conducted toinvestigate the association between soy consumption andsubsequent risk of VMS at follow-up with all the women
included (n = 10,082), but adjusting for their baseline
VMS, given that a large proportion of women were excluded in the prospective analysis due to the presence of VMS
at baseline. Analyses were performed using STATA 14(StataCorp LP, College Station, TX). All statistical tests
were two sided.

Results
A total of 11,006 women reported their consumption frequency of soy and VMS, and also had complete data on thecovariates. The median age of the women at baseline was
52 years (interquartile range: 51–54) (Supplementary
Table 1). Table 1 shows the baseline characteristics of theparticipants in each study. The majority of the participants
were Caucasians-Australians/New-Zealanders (57.5%), had
10 years or less of education (46.3%), and never smoked(60.9%). Nearly, 30% of the women were naturally postmenopausal, and 26.5% were currently using menopausal
hormone therapy. Across HOW, WHITEHALL, SMWHS

1504

Y. Dunneram et al.

Table 1 Baseline characteristics of participants
CharacteristicsnOverall
11,006

ALSWH
7373

HOW
563

WHITEHALL
2146

SMWHS
174

JMWHS
750

Caucasian-Australian/
New Zealand6323 (57.5)

5853 (79.4)

470 (83.5)

0 (0.0)0 (0.0)0 (0.0)

Caucasian-European

3163 (28.7)

Caucasian-American/
Canadian

202 (1.8)

1207 (16.4)

65 (11.6)

1891 (88.1)

0 (0.0)0 (0.0)54 (0.7)

0 (0.0)0 (0.0)148 (85.1)

0 (0.0)Japanese
Chinese and other
Asians756 (6.9)

6 (0.1)0 (0.0)0 (0.0)0 (0.0)750 (100.0)

166 (1.5)

144 (2.0)

7 (1.2)0 (0.0)15 (8.6)

0 (0.0)

Others396 (3.6)

109 (1.5)

21 (3.7)

255 (11.9)

11 (6.3)

0 (0.0)Race/ethnicity

Birth year (n = 11,002)<1940

856 (7.8)

N/A

N/A

855 (39.8)

1 (0.6)

N/A

1940–1949

7354 (66.8)

5410 (73.4)475 (85.0)1034 (48.2)

81 (46.6)354 (47.2)≥1950

2792 (25.4)

1963 (26.6)

84 (15.0)257 (12.0)

92 (52.9)396 (52.8)

Education level≤10 years

5096 (46.3)

3568 (48.4)

286 (50.8)

1171 (54.6)

0 (0.0)71 (9.5)

11–12 years

2177 (19.8)

1269 (17.2)

92 (16.3)

345 (16.1)

24 (13.8)

447 (59.6)>12 years

3733 (33.9)2536 (34.4)

185 (32.9)

630 (29.4)

150 (86.2)

232 (30.9)

Married7927 (77.5)

6028 (82.0)

427 (76.3)

1357 (63.3)

115 (66.1)

N/A

Separated/divorced/
widowed1597 (15.6)

1099 (15.0)

106 (18.9)340 (15.9)

52 (29.9)

N/A

Single701 (6.9)

221 (3.0)

27 (4.8)446 (20.8)

7 (4.0)

N/A

Normal weight (<25kg/m²)

5071 (48.6)

3048 (43.9)

233 (43.3)

1068 (52.7)

90 (51.7)

632 (85.8)

Overweight (25–29.9
kg/m²)

3259 (31.3)

2297 (33.1)

165 (30.7)654 (32.3)

47 (27.0)

96 (13.0)

Obese (≥30 kg/m²)

2095 (20.1)

1604 (23.1)

140 (26.0)

305 (15.1)

37 (21.3)

9 (1.2)

Never

6707 (60.9)4505 (61.1)

356 (63.2)

1108 (51.6)

89 (51.2)

649 (86.5)

Past smoker

2704 (24.6)

1782 (24.2)

158 (28.1)

667 (31.1)

67 (38.5)

30 (4.0)

Current smoker

1595 (14.5)

1086 (14.7)

49 (8.7)371 (17.3)

18 (10.3)

71 (9.5)

Hysterectomy/
oophorectomy

2598 (23.6)

2001 (27.1)

165 (29.3)

344 (16.0)

6 (3.5)82 (10.9)

Unknown due tohormone use

1721 (15.6)

1346 (18.3)

46 (8.2)

265 (12.4)

47 (27.0)

17 (2.3)

Premenopause

1315 (12.0)

636 (8.6)

22 (3.9)463 (21.6)

44 (25.3)

150 (20.0)

Perimenopause

2090 (19.0)1484 (20.1)

76 (13.5)

390 (18.2)

53 (30.5)87 (11.6)

Natural menopause

3282 (29.8)

1906 (25.9)

254 (45.1)

684 (31.9)

24 (13.8)414 (55.2)

Marital status (n = 10,225)

Body mass index (n = 10,425)

Smoking status

Menopausal status

Current use of menopausal hormone therapyNo8085 (73.5)5043 (68.4)

369 (65.5)

1813 (84.5)

134 (77.0)

726 (96.8)

Yes2921 (26.5)2330 (31.6)

194 (34.50

333 (15.5)

40 (23.0)

24 (3.2)

Frequency or severity of hot ﬂushes
Never4443 (40.4)

2249 (30.5)

323 (57.4)

1344 (62.6)

118 (67.8)

409 (54.5)

Rarely or mild

2009 (18.3)

1183 (16.1)

160 (28.4)

388 (18.1)

29 (16.7)

249 (33.2)

2608 (23.7)

2241 (30.4)

59 (10.5)233 (10.9)

15 (8.6)

60 (8.0)

Soy intake and vasomotor menopausal symptoms among midlife women: a pooled analysis of ﬁve studies. . .

1505

Table 1 (continued)
CharacteristicsnOverall
11,006

ALSWH
7373

HOW
563

WHITEHALL
2146

SMWHS
174

JMWHS
750

Sometimes ormoderate
Often or severe

1946 (17.7)

1700 (23.1)

21 (3.73)

181 (8.4)

12 (6.9)32 (4.3)

Frequency or severity of night sweats
Never5510 (50.1)

2996 (40.6)

358 (63.6)

1458 (67.9)

137 (78.7)

561 (74.8)

Rarely or mild

1813 (16.5)

1157 (15.7)

136 (24.2)

339 (15.8)

22 (12.6)

159 (21.2)

Sometimes ormoderate

2183 (19.8)

1914 (26.0)

52 (9.2)

190 (8.9)5 (2.9)22 (2.9)

Often or severe

1500 (13.6)

1306 (17.7)

17 (3.0)159 (7.4)

10 (5.8)8 (1.1)2034 (27.6)

285 (50.6)

1251 (58.3)

112 (64.4)

367 (48.9)

Frequency or severity of vasomotor symptomsa
Never4049 (36.8)

Rarely or mild

2099 (19.1)

1212 (16.4)

184 (32.7)

388 (18.1)

31 (17.8)284 (37.9)

Sometimes ormoderate

2728 (24.8)2312 (31.4)

66 (11.7)

269 (12.5)

15 (8.6)

66 (8.8)

Often or severe

2130 (19.4)

1815 (24.6)

28 (5.0)238 (11.1)

16 (9.2)

33 (4.4)

Consumption frequency of soy products
Never/rarely

9239 (84.0)

6590 (89.4)

475 (84.4)

2047 (95.4)

127 (73.0)

0 (0.0)Monthly491 (4.5)357 (4.8)

50 (8.9)62 (2.9)

0 (0.0)22 (2.9)

Weekly820 (7.5)

357 (4.8)

34 (6.0)35 (1.6)

36 (20.7)358 (47.7)

Daily

456 (4.1)

69 (0.9)

4 (0.7)2 (0.1)

11 (6.3)

370 (49.3)

Consumption frequency of soy milk (n = 10,954)
Never/rarely

9860 (90.0)6634 (90.0)

460 (85.2)

2103 (98.2)

147 (84.5)

516 (70.8)

Monthly156 (1.4)

29 (0.4)

21 (3.9)

17 (0.8)

0 (0.0)89 (12.2)

Weekly237 (2.2)

110 (1.5)

11 (2.0)

19 (0.9)

13 (7.5)

84 (11.5)

Daily

701 (6.4)

596 (8.1)

48 (8.9)

3 (0.1)14 (8.1)

40 (5.5)

Data are presented as n (%); N/A—not applicablea

Vasomotor menopausal symptoms were deﬁned as having hot ﬂushes, night sweats, or bothand JMWHS which measured the severity of VMS,
WHITEHALL had the highest percentage of women who
reported ‘severe’ VMS (11.1%), while JMWHS (Japanese)
had the lowest percentage (4.4%). In the ALSWH study,
24.6% reported ‘often’ for the frequency of VMS. In thispredominantly Caucasian population, 80–90% of thewomen reported that they never consumed soy products or
soy milk. Across the individual studies, JMWHS had thelargest percentage of women who reported ‘daily’ and‘weekly’ soy product consumption (49.3% and 47.7%,
respectively) (Table 1). Comparing baseline characteristics
of women included in the prospective analysis and those
excluded due to loss to follow-up, the excluded women
were less educated and more likely to be obese and current
smokers at baseline. They were more likely to be postmenopausal and less likely to report frequent/severe VMS
compared to women with complete follow-up data (Supplementary Table 2).
For the cross-sectional analysis, women with ‘weekly’and ‘daily’ consumption of soy products were less likely toreport frequent/severe VMS compared to those with ‘never/rarely’ consumption (11.7% vs. 20.5% and 6.4% vs. 20.5%,
respectively) (Table 2). However, after adjusting for covariates and study differences, no clear evidence of an
association was found between soy product consumption
and the degree of VMS. Similarly, there was no clear evidence of an association observed for ALSWH or the otherfour studies. For soy milk consumption, women with a daily
consumption were more likely to report frequent/severe
VMS compared to women who reported ‘never/rarely’
consumption (RRR: 1.56, 95% CI: 1.24–1.96). A similar
pattern for ‘daily’ consumption and risk of frequent/severe
VMS was observed in ALSWH (RRR: 1.39, 95% CI: 1.10–1.77) and the other four studies (RRR: 3.09, 95% CI: 1.47–
6.50).
When using dichotomised exposure and outcome variables for the study-speciﬁc analysis, the pooled estimate of
association between frequent soy product consumption andthe presence of VMS was 0.92 (95% CI: 0.76–1.11), withno statistically signiﬁcant heterogeneity between studies,Never Rarely/
mild

357

69

Weekly

Daily

20.3

33.3

33.1

29.4

31.4

Sometimes/
moderate463

387

Weekly

Daily

456

Daily

110

596

Weekly

Daily

24.7

22.7
15.3

19.1

13.8

34.5

29

Monthly

38.4

16.5

44.5

43.4

Never/rarely 6634 27.9

ALSWH (n = 7369)

Soy milk

820

Weekly

24.0

17.5

491

Monthly

35.6

17.8

41.6

Never/rarely 9239 35.9

OVERALL (n = 11,006)

47.3

52.3

31.3

24.6

134

Monthly

53.0

20.7

Never/rarely 2649 57.3

30.7

35.5

41.4

31.3

10.8

20.9

24.6

25.8

6.7

11.5

11.9

12.1

HOW, WHITEHALL, SMWHS, JMWHSc (n = 3633)

29.0

31.9

14.6

14.9

357

Monthly

29.1

16.6

Never/rarely 6590 27.3

ALSWHc (n = 7373)

Soy products

Soy consumption frequencyn

VMS (hot ﬂushes and night sweats) (%)

29.4

22.7

10.3

24.3

6.4

11.7

22.2

20.5

4.4

5.0

10.5

9.9

17.4

20.5

26.6

24.8

Often/
severeRarely/mild

Reference 1.02 (0.78–
1.34)

Reference 1.41 (0.79–
2.54)

Reference 0.68 (0.21–
2.17)

Reference Reference

Reference 1.11 (0.79–
1.56)

Reference 0.81 (0.63–
1.05)

Reference 0.85 (0.65–
1.12)

Reference Reference

Reference 1.33 (0.81–
2.19)

Reference 1.01 (0.65–
1.56)

Reference 0.97 (0.63–
1.51)

Reference Reference

Reference 1.13 (0.57–
2.26)

Reference 0.72 (0.52–
1.02)

Reference 0.81 (0.58–
1.14)

Reference Reference

Never

1.08 (0.86–1.36)

1.38 (0.83–2.32)

1.05(0.45–2.48)

Reference

0.77 (0.51–1.16)

0.95 (0.75–1.20)

0.89 (0.69–1.14)

Reference

0.77 (0.38–1.55)

1.22 (0.71–2.09)

1.08 (0.60–1.93)

Reference

0.97 (0.52–1.79)

0.85 (0.65–1.11)

0.84 (0.63–1.11)

Reference

Sometimes/
moderate

Model 1a RRR (95% CI)

1.33 (1.05–
1.68)

1.17 (0.66–
2.08)

0.34 (0.09–
1.25)

Reference

0.65 (0.40–
1.05)

0.70 (0.53–
0.93)

1.03 (0.79–
1.35)

Reference

0.86 (0.37–
2.02)

0.86 (0.42–
1.75)

1.45 (0.76–
2.70)

Reference

0.64 (0.31–
1.33)

0.66 (0.49–
0.90)

0.96 (0.71–
1.29)

Reference

Often/severe

1.03 (0.78–
1.35)

1.42 (0.79–
2.56)

0.69 (0.21–
2.20)

Reference

1.18 (0.85–
1.65)

0.85 (0.66–
1.09)

0.87 (0.66–
1.13)

Reference

1.41 (0.86–
2.32)

1.05 (0.68–
1.63)

1.02 (0.65–
1.59)

Reference

1.11 (0.56–
2.21)

0.71 (0.51–
1.00)

0.80 (0.57–
1.13)

Reference

Rarely/mild

1.09 (0.87–1.37)

1.41 (0.84–2.36)

1.08 (0.46–2.54)

Reference

0.85 (0.57–1.28)

1.03 (0.81–1.30)

0.93 (0.72–1.20)

Reference

0.89 (0.44–1.80)

1.35 (0.79–2.31)

1.23 (0.68–2.21)

Reference

0.98 (0.53–1.81)

0.86 (0.66–1.13)

0.85 (0.64–1.13)

Reference

1.39 (1.10–
1.77)

1.27 (0.71–
2.26)

0.37 (0.10–
1.38)

Reference

0.78 (0.49–
1.24)

0.82 (0.62–
1.09)

1.14 (0.88–
1.49)

Reference

1.00 (0.43–
2.34)

0.95 (0.46–
1.95)

1.70 (0.90–
3.21)

Reference

0.69 (0.33–
1.43)

0.73 (0.53–
0.99)

1.03 (0.76–
1.38)

Reference

Model 2b RRR (95%CI)
Sometimes/moderate Often/severe

Table 2 Cross-sectional association of soy products and soy milk consumption frequency with the frequency/severity of vasomotor menopausal symptoms at baseline

1506
Y. Dunneram et al.

Soy intake and vasomotor menopausal symptoms among midlife women: a pooled analysis of ﬁve studies. . .

1507

Fig. 1 Forest plot of study-speciﬁc effect estimates of the crosssectional association between consumption frequency of soy products
and the presence of vasomotor menopausal symptoms at baseline. Soy
product consumption was coded dichotomously as ‘frequent’ (weekly
and daily) and ‘less frequent’ (never/rarely and monthly) and vasomotor symptoms as ‘present” (sometimes and often if reporting frequency; moderate and severe if reporting severity) and ‘absent’ (neverand rarely if reporting frequency; never and mild if reporting severity)
given the small number of observations in each study. Odds ratios(ORs) a presented on a log scale. Effect estimates were adjusted formenopausal status, current use of menopausal hormone therapy, education level, and smoking status. VMS – vasomotor menopausal
symptoms

Fig. 2 Forest plot of study-speciﬁc effect estimates of the crosssectional association between consumption frequency of soy milk andthe presence of vasomotor menopausal symptoms at baseline. Soy
milk consumption was coded dichotomously as ‘frequent’ (weekly anddaily) and ‘less frequent’ (never/rarely and monthly) and vasomotor
symptoms as ‘present” (sometimes and often if reporting frequency;
moderate and severe if reporting severity) and ‘absent’ (never andrarely if reporting frequency; never and mild if reporting severity)
given the small number of observations in each study. Odds ratios(ORs) a presented on a log scale. Effect estimates were adjusted formenopausal status, current use of menopausal hormone therapy, education level and smoking status. VMS – vasomotor menopausal
symptoms

test for heterogeneity: P = 0.49, I2 = 0% (Fig. 1). For the
association between frequent consumption of soy milk andthe presence of VMS, the pooled OR estimate was 1.24
(95% CI: 0.93–1.65) with no statistically signiﬁcant heterogeneity between the studies (test for heterogeneity: P =0.24, I2 = 26.6%) (Fig. 2).
For the prospective analysis, the overall estimates suggest that women who had frequent soy product consumption were less likely to report the incidence of VMS atfollow-up (OR: 0.63, 95% CI: 0.45–0.89) (Table 3). A
consistent pattern was observed in ALSWH (OR: 0.63, 95%
CI: 0.44–0.90) and the other four studies (OR: 0.60, 95%
CI: 0.18–1.97). There was no clear evidence of an

association between frequent consumption of soy milk andincident VMS at follow-up (OR: 1.11, 95% CI: 0.85–1.45).
The sensitivity analysis with all the women included
demonstrated a similar or weaker association between soy
consumption and subsequent VMS, even after adjusting forbaseline VMS (Table 4).

Discussion
This pooled study demonstrated no clear evidence of an
association between consumption frequency of soy products
and VMS in the cross-sectional analysis. However, in the1508
Table 3 Prospective associationof soy product and soy milk
consumption frequency with thepresence of vasomotor
menopausal symptoms at thefollow-up survey

Y. Dunneram et al.

Soy consumptionnaVMS (%)Crude
OR (95% CI)

Model 1bOR (95% CI)

Model 2c
OR (95% CI)

Soy products
ALSWH (n = 2,852)
Less frequentd

2688

35.5

Reference

Reference

Reference

Frequent

164

26.2

0.65 (0.45–0.92)

0.63 (0.44–0.91)

0.63 (0.44–0.90)

HOW, WHITEHALL (n = 1670)
Less frequent

1625

12.4

Reference

Reference

Reference

Frequent

45

6.7

0.56 (0.17–1.85)

0.58 (0.18–1.91)

0.60 (0.18–1.97)

Less frequent

4313

26.8

Reference

Reference

Reference

Frequent

209

22.0

0.64 (0.45–0.90)

0.63 (0.45–1.88)

0.63 (0.45–0.89)

Less frequent

2608

34.9

Reference

Reference

Reference

Frequent

241

35.7

1.04 (0.79–1.37)

1.05 (0.79–1.38)

1.04 (0.79–1.38)

OVERALL (n = 4522)

Soy milk
ALSWH (n = 2849)

HOW, WHITEHALL (n = 1655)
Less frequent

1614

12.2

Reference

Reference

Reference

Frequent

41

17.1

2.01 (0.85–4.78)

2.08 (0.86–4.99)

2.18 (0.91–5.23)

Less frequent

4222

26.2

Reference

Reference

Reference

Frequent

282

33.0

1.09 (0.84–1.43)

1.10 (0.84–1.43)

1.11 (0.85–1.45)

OVERALL (n = 4504)

Logistic regression models were used to estimate odds ratios (OR) and 95% conﬁdence intervals (95% CI).
a

VMS was deﬁned as ‘presence of VMS’ for ‘never’ and ‘rarely/mild’ VMS and ‘absence of VMS’ for‘sometimes/moderate’ and ‘often/severe’ VMSbModel 1 was adjusted for menopausal status and current use of menopausal hormone therapy at follow-upcModel 2 was adjusted for model 1 along with other covariates including smoking status, and education leveld

Soy consumption frequency was deﬁned as ‘frequent’ for ‘daily’ and ‘weekly’ consumption and ‘lessfrequent’ for ‘monthly’ and ‘never/rarely’ consumption

prospective analysis, women with frequent consumption ofsoy products were less likely to report subsequent VMS.
Furthermore, there was no evidence of an association
between consumption of soy milk and frequency/severity of
VMS both cross-sectionally (Figs. 1 and 2) and prospectively (Table 3).
Our prospective analysis showed an association between
frequent consumption of soy products and decreased odds of
VMS at follow-up, though this was attenuated when baseline
VMS was taken into account. Similarly, a Japanesecommunity-based study in which women were followed for
6 years found that soy products intake alleviated hot ﬂushes[9]. Several RCTs have investigated the association between
some type of substance containing dietary soy (e.g., soy
extract in capsule or tablet form, soy powder or soy protein
added to diets) and its effect on hot ﬂushes. While somedemonstrated a reduction in the frequency/severity of hot
ﬂushes [10, 22–24], others have shown contradictory ﬁndings [25, 26]. According to a review study, the dose ofgenistein, in particular, was associated with a reduction of

the symptoms rather than total isoﬂavone [27]. The
oestrogen-like properties of soy food due to the isoﬂavones
content have been linked to the protective effect on VMS. A
decrease in the number of ovarian follicles and consequent
fall in oestrogen level could be the underlying hormonal
aetiology of VMS [28, 29]. However, the effect of phytoestrogens in reducing VMS remains unclear [30]. One ofthe possible mechanism of action is the structural similarityof isoﬂavones to that of oestradiol could confer oestrogenicor anti-oestrogenic effects depending on the circulatingoestrogen level by binding to oestrogen receptors [31, 32].
The relative decline in oestrogen level leads to higher circulating norepinephrine levels and an upregulation of serotonin receptors which mediate hot ﬂushes in menopausal
women. By binding to oestrogen receptors, isoﬂavones help
to restore the oestrogen level, and causes subsequent changes in norepinephrine and serotonin levels, thus reducing thepropensity of hot ﬂushes [33].
Our pooled data did not show a clear association between
soy milk consumption and frequency/severity of VMS. The

Soy intake and vasomotor menopausal symptoms among midlife women: a pooled analysis of ﬁve studies. . .
Table 4 Sensitivity analysis forthe prospective association
between soy consumption andlikelihood of reporting
vasomotor symptoms at followup

Soy consumptionn

VMSa (%)

Soy products
ALSWH (n = 6603)
Less frequente6235 54.8
Frequent
368
48.6
HOW, WHITEHALL (n = 2251)
Less frequent
2194 21.4
Frequent
57
19.3
OVERALL (n = 8854)
Less frequent
8429 46.1
Frequent
425
44.7
Soy milk
ALSWH (n = 6599)
Less frequent
5970 54.1
Frequent
629
57.6
HOW, WHITEHALL (n = 2233)
Less frequent
2175 21.2
Frequent
58
31.0
OVERALL (n = 8832)
Less frequent8145 45.3
Frequent
687
55.3

1509

Crude
OR (95% CI)

Model 1bOR (95% CI)

Model 2c
OR (95% CI)

Model 3d
OR (95% CI)

Reference
0.78 (0.63–0.96)

Reference
0.76 (0.62–0.94)

Reference
0.79 (0.64–0.98)

Reference
0.79 (0.63–1.00)

Reference
1.05 (0.54–2.07)

Reference
0.99 (0.50–1.97)

Reference
1.05 (0.53–2.08)

Reference
1.04 (0.54–1.99)

Reference
0.80 (0.65–0.98)

Reference
0.78 (0.63–0.96)

Reference
0.81 (0.66–1.00)

Reference
0.81 (0.65–1.01)

Reference
1.15 (0.97–1.36)

Reference
1.15 (0.97–1.36)

Reference
1.17 (0.99–1.38)

Reference
1.06 (0.89–1.27)

Reference
2.63 (1.43–4.84)

Reference
2.44 (1.29–4.60)

Reference
2.65 (1.40–5.00)

Reference
2.10 (1.07–4.13)

Reference
1.21 (1.03–1.43)

Reference
1.20 (1.01–1.41)

Reference
1.22 (1.04–1.44)

Reference
1.10 (0.92–1.32)

Logistic regression models were used to estimate odds ratios (OR) and 95% conﬁdence intervals (95% CI).
a

VMS was deﬁned as ‘presence of VMS’ for ‘never’ and ‘rarely/mild’ VMS and ‘absence of VMS’ for‘sometimes/moderate’ and ‘often/severe’ VMSbModel 1 was adjusted for menopausal status and current use of menopausal hormone therapy at follow-upcModel 2 was adjusted for model 1 along with other covariates including smoking status and education leveldModel 3 was adjusted for model 2 along with baseline VMS

eSoy consumption frequency was deﬁned as ‘frequent’ for ‘daily’ and ‘weekly’ consumption and ‘lessfrequent’ for ‘monthly’ and ‘never/rarely’ consumption

source of dietary isoﬂavones may also contribute to theobserved effect since processing methods tend to alter thephytoestrogen contents of soy products [34]. For instance,
the total isoﬂavone content in soy beans (103 mg per 100 g),
tempeh (18 mg per 100 g) and tofu (27 mg per 100 g) ismuch higher than that in soy milk (3 mg per 100 g) [20].
The overall low-consumption frequency of soy milk among
the participants and its low isoﬂavone content could possibly explain this ﬁnding.
The main drawback of our study is the variation inassessments used by the different studies. Soy consumption
was measured as frequency, with no information on quantities. Moreover, for the consumption of soy milk, the crosssectional nature of some of the studies and lack of evidenceof a signiﬁcant association from the prospective analysis,mean that we cannot conﬁrm a temporal relationshipbetween soy milk consumption and VMS. There also might
be possibility of residual confounding, e.g., by factors notmeasured in the studies. One weakness of data harmonisation is the collapsing of the variables of interest into thesimplest level of detail in order to incorporate informationfrom as many studies as possible, leading to loss ofstatistical power as well as potential misclassiﬁcation of thedegree of VMS and frequency of soy consumption. For
instance, studies like ALSWH and WHITEHALL had ten
and nine frequency options respectively for consumption ofsoy that were collapsed to four categories for this analysis.
In addition, the frequency of VMS was reported in ALSWH
over a longer period of time (12 months), and the other fourstudies recorded the severity of VMS over a shorter periodthat limited our ability to pool data. Despite these limitations the pooled results showed considerable homogeneity
as shown in the forest plots and the low values for thestatistic I2.
Furthermore, our study had several strengths that ranged
from the inclusion of a large number of women acrossdifferent geographic regions and cultures that allowed
greater generalisability of the results. This is also, to ourknowledge, the ﬁrst pooled study consisting of women’s
health studies from four different countries examining an
association between soy products and soy milk with frequency/severity of VMS. We also included women who hada hysterectomy, oophorectomy, and/or were currently using
hormones that could provide a better estimate of the1510

prevalence of VMS. In addition, the individual data available in the InterLACE enabled harmonisation of the variables of interest using common deﬁnitions, coding and cut
points not normally possible with meta-analyses of published results. Harmonisation of the data further reduces the
between-study heterogeneity. A consistent approach toconfounder adjustment was used for the regression models
along with careful selection of the confounders using a
DAG, thus reducing the probability of the results being
affected by uncontrolled confounders.
While menopause is an inevitable phenomenon in awoman’s life cycle, the frequency and severity of VMS
show marked variations [35]. VMS are reported by around
75% of postmenopausal women globally, with a minority
reporting severe symptoms [36, 37]. Findings from thisstudy provide some evidence that frequent consumption ofsoy products (e.g., soy beans, tofu and tempeh) as partof the usual diet may be associated with a reduced risk ofsubsequent VMS. However, frequent consumption of soy
milk did not appear to be associated with subsequent VMS.
As justiﬁed by potential mechanisms in previous studies,
our ﬁndings could prompt RCTs testing the effects of
dietary soy intake in particular on VMS as opposed toearlier RCTs which have mainly considered the effects ofsoy extracts and supplements.
Acknowledgements The data on which this research are based weredrawn from ﬁve observational studies. The research included datafrom the ALSWH, the University of Newcastle, Australia, and the
University of Queensland, Australia. We are grateful to the AustralianGovernment Department of Health for funding and to the women who
provided the survey data. SMWHS was supported in part by grants
from the National Institute of Nursing Research. HOW and JMWHS(also called Australian and Japanese Midlife Women’s Health Study)
were supported by the Queensland University of Technology Early
Career Research Grant and the JSPS Grant-in-aid for ScientiﬁcResearch. The Whitehall II study is supported by grants from theMedical Research Council (K013351), British Heart Foundation (BHF
RG/16/11/32334) and US National Institutes on Aging(R01AG013196 and R01AG034454). All study teams would like tothank the participants for volunteering their time to be involved in therespective studies. The ﬁndings and views in this paper are not thosefrom the original studies or their respective funding agencies.
Funding InterLACE project is funded by the Australian National
Health and Medical Research Council project grant (APP1027196).
GDM is supported by the Australian National Health and Medical
Research Council Principal Research Fellowship (APP1121844). YD
is in receipt of a scholarship from the Commonwealth Scholarship
Commission, UK. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of themanuscript.
Author contributions The authors’ responsibilities were as follows—
GDM: conceived the study; YD, HFC and GDM: designed theresearch and had primary responsibility for the ﬁnal content; JEC,
DCG, AJD, ESM, NFW, EJB, TY and DA: contributed to the data;
YD: performed the statistical analysis and wrote the manuscript; HFC,
DCG, JEC, AJD and GDM: provided statistical input, helped with

Y. Dunneram et al.
interpretation of the results and reviewed the manuscript for important
intellectual content; and all authors: read and approved the ﬁnal
manuscript.

Compliance with ethical standards
Conﬂict of interest JEC is the director of a university spin out company, Dietary Assessment Ltd. The remaining authors declare that they
have no conﬂict of interest.
Publisher’s note: Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional afﬁliations.

References
1. Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J,
Brown J. Phytoestrogens for menopausal vasomotor symptoms.
Cochrane Database Syst Rev. 2013:Cd001395.
2. Gold EB, Colvin A, Avis N, Bromberger J, Greendale GA, Powell
L, et al. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: study of women’s health across the nation. Am J Public
Health. 2006;96:1226–35.
3. Rapkin AJ. Vasomotor symptoms in menopause: physiologic
condition and central nervous system approaches to treatment. Am
J Obstet Gynecol. 2007;196:97–106.
4. Pines A. Vasomotor symptoms and cardiovascular disease risk.
Climacteric. 2011;14:535–6.
5. Biglia N, Cagnacci A, Gambacciani M, Lello S, Maffei S, Nappi
RE. Vasomotor symptoms in menopause: a biomarker of cardiovascular disease risk and other chronic diseases? Climacteric.
2017;20:306–12.
6. Levis S, Griebeler ML. The role of soy foods in the treatment of
menopausal symptoms. J Nutr. 2010;140:2318s–2321s.
7. Baber R. Phytoestrogens and post reproductive health. Maturitas.
2010;66:344–9.
8. Sievert LL, Morrison L, Brown DE, Reza AM. Vasomotor
symptoms among Japanese-American and European-American
women living in Hilo, Hawaii. Menopause. 2007;14:261–9.
9. Nagata C, Takatsuka N, Kawakami N, Shimizu H. Soy productintake and hot ﬂashes in Japanese women: results from acommunity-based prospective study. Am J Epidemiol.
2001;153:790–3.
10. Carmignani LO, Pedro AO, Costa-Paiva LH, Pinto-Neto AM. The
effect of dietary soy supplementation compared to estrogen andplacebo on menopausal symptoms: a randomized controlled trial.
Maturitas. 2010;67:262–9.
11. Khaodhiar L, Ricciotti HA, Li L, Pan W, Schickel M, Zhou J,
et al. Daidzein-rich isoﬂavone aglycones are potentially effective
in reducing hot ﬂashes in menopausal women. Menopause.
2008;15:125–32.
12. Ye YB, Wang ZL, Zhuo SY, Lu W, Liao HF, Verbruggen M,
et al. Soy germ isoﬂavones improve menopausal symptoms but
have no effect on blood lipids in early postmenopausal Chinese
women: a randomized placebo-controlled trial. Menopause.
2012;19:791–8.
13. Mishra GD, Chung HF, Pandeya N, Dobson AJ, Jones L, Avis
NE, et al. The InterLACE study: design, data harmonization andcharacteristics across 20 studies on women’s health. Maturitas.
2016;92:176–85.
14. Mishra GD, Anderson D, Schoenaker DA, Adami HO, Avis NE,
Brown D, et al. InterLACE: A New International Collaboration
for a Life Course Approach to Women’s Reproductive Health andChronic Disease Events. Maturitas. 2013;74:235–40.

Soy intake and vasomotor menopausal symptoms among midlife women: a pooled analysis of ﬁve studies. . .
15. Lee C, Dobson AJ, Brown WJ, Bryson L, Byles J, Warner-SmithP, et al. Cohort Proﬁle: the Australian Longitudinal Study on
Women’s Health. Int J Epidemiol. 2005;34:987–91.
16. Marmot M, Brunner E. Cohort Proﬁle: the Whitehall II study. Int J
Epidemiol. 2005;34:251–6.
17. Mitchell ES, Woods NF. Cognitive symptoms during the menopausal transition and early postmenopause. Climacteric.
2011;14:252–61.
18. Anderson D, Yoshizawa T, Gollschewski S, Atogami F, Courtney
M. Menopause in Australia and Japan: effects of country ofresidence on menopausal status and menopausal symptoms. Climacteric. 2004;7:165–74.
19. Nutrient Data L. USDA database for the isoﬂavone content of
selected foods, release 2.0. Beltsville, Md: U.S. Department ofAgriculture; 2008.
20. Thompson LU, Boucher BA, Liu Z, Cotterchio M, Kreiger N.
Phytoestrogen content of foods consumed in Canada, including
isoﬂavones, lignans, and coumestan. Nutr Cancer. 2006;54:184–201.
21. Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH,
Pinkerton JV, et al. Treatment of symptoms of the menopause: an
Endocrine Society Clinical Practice Guideline. J Clin Endocrinol
Metab. 2015;100:3975–4011.
22. Welty FK, Lee KS, Lew NS, Nasca M, Zhou JR. The association
between soy nut consumption and decreased menopausal symptoms. J Women’s Health. 2007;16:361–9.
23. Cheng G, Wilczek B, Warner M, Gustafsson JA, Landgren BM.
Isoﬂavone treatment for acute menopausal symptoms. Menopause. 2007;14:468–73.
24. Nahas EA, Nahas-Neto J, Orsatti FL, Carvalho EP, Oliveira ML,
Dias R. Efﬁcacy and safety of a soy isoﬂavone extract in postmenopausal women: a randomized, double-blind, and placebocontrolled study. Maturitas. 2007;58:249–58.
25. Burke GL, Legault C, Anthony M, Bland DR, Morgan TM,
Naughton MJ, et al. Soy protein and isoﬂavone effects on vasomotor symptoms in peri- and postmenopausal women: the Soy
Estrogen Alternative Study. Menopause. 2003;10:147–53.
26. Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Viganó
P. Effect of soy-derived isoﬂavones on hot ﬂushes, endometrial

1511

thickness, and the pulsatility index of the uterine and cerebral
arteries. Fertil Steril. 2003;79:1112–7.
27. Williamson-Hughes PS, Flickinger BD, Messina MJ, Empie MW.
Isoﬂavone supplements containing predominantly genistein
reduce hot ﬂash symptoms: a critical review of published studies.
Menopause. 2006;13:831–9.
28. Sturdee DW. The menopausal hot ﬂush—anything new? Maturitas. 2008;60:42–49.
29. Pachman DR, Jones JM, Loprinzi CL. Management of
menopause-associated vasomotor symptoms: current treatment
options, challenges and future directions. Int J Women’s Health.
2010;2:123–35.
30. Moreira AC, Silva AM, Santos MS, Sardão VA. Phytoestrogens
as alternative hormone replacement therapy in menopause: what isreal, what is unknown. J Steroid Biochem Mol Biol. 2014;143:61–
71.
31. Rietjens I, Louisse J, Beekmann K. The potential health effects of
dietary phytoestrogens. Br J Pharmacol. 2017;174:1263–80.
32. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der
Saag PT, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology.
1998;139:4252–63.
33. Morrow PKH, Mattair DN, Hortobagyi GN. Hot ﬂashes: a review
of pathophysiology and treatment modalities. Oncologist.
2011;16:1658–64.
34. Setchell KDR, Cole SJ. Variations in isoﬂavone levels in soy
foods and soy protein isolates and issues related to isoﬂavone
databases and food labeling. J Agric Food Chem. 2003;51:4146–
55.
35. Luoto R. Hot ﬂushes and quality of life during menopause. BMC
Women’s Health. 2009;9:13.
36. Monteleone P, Mascagni G, Giannini A, Genazzani AR,
Simoncini T. Symptoms of menopause—global prevalence,physiology and implications. Nat Rev Endocrinol. 2018;
14:199–215.
37. Woods NF, Mitchell ES. Symptoms during the perimenopause:
prevalence, severity, trajectory, and signiﬁcance in women’s lives.
Am J Med. 2005;118(Suppl 12B):14–24.