A Dietary Intervention for Vasomotor Symptoms of Menopause: A Randomized,

Controlled Trial
Running title: Intervention for Vasomotor Symptoms
Neal D. Barnard, MD, FACC;1,2 Hana Kahleova, MD, PhD;2 Danielle N. Holtz, BS;2 Tatiana
Znayenko-Miller, MSHS;2 Macy Sutton, MS;2 Richard Holubkov, PhD;3 Xueheng Zhao, PhD;4
Stephanie Galandi, MS;4 Kenneth D. R. Setchell, PhD, FAASLD4,5

1. Adjunct faculty, George Washington University School of Medicine & Health Sciences,
Washington, DC, USA
2. Physicians Committee for Responsible Medicine, Washington, DC, USA
3. School of Medicine, University of Utah, Salt Lake City, UT, USA
4. Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH, USA
5. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
Sources of funding: The study was funded by the Physicians Committee for Responsible
Medicine.

Financial Disclosures/Conflicts of Interest: Dr. Barnard is an Adjunct Professor of Medicine at

the George Washington University School of Medicine. He serves without compensation as
president of the Physicians Committee for Responsible Medicine and Barnard Medical Center in
Washington, DC, nonprofit organizations providing educational, research, and medical services
related to nutrition. He writes books and articles and gives lectures related to nutrition and health
and has received royalties and honoraria from these sources. Dr. Kahleova, Ms. Holtz, Ms.
Znayenko-Miller, Ms. Sutton, and Dr. Holubkov received compensation from the Physicians
Committee for Responsible Medicine for their work on this study. Dr. Holubkov currently receives
funding from Pfizer for DSMB service and DURECT Corporation for biostatistical consulting. He has
received funding from Revance for DSMB consulting in the past. Dr. Setchell holds equity in Aliveris
s.r.l., Asklepion Pharmaceuticals, and Ausio Pharmaceuticals, and is a consultant to Travere and
Mirum Pharmaceuticals.

Findings from the first study cohort (n=38) were published in Menopause and have been
presented at scientific meetings. This manuscript, reflecting the findings of the full study, has not
been presented in any format at any national meeting.

Some of the findings from this clinical trial have been presented at the International Conference on
Nutrition in Medicine, Washington, DC, August 19, 2022

Corresponding author, from whom reprints may be requested: Neal Barnard, MD, FACC, 5100
Wisconsin Ave, NW, Suite 200, Washington, DC 20016, USA, 202-527-7303, fax: 202-527-
7403, nbarnard@pcrm.org.

Trial registration: ClinicalTrials.gov, NCT04587154, registered on Oct 14, 2020.

1
Abstract
Objective: Postmenopausal vasomotor symptoms disrupt quality of life. This study tested the
effects of a dietary intervention on vasomotor symptoms and menopause-related quality of life.
Methods: Postmenopausal women (n = 84) reporting ≥2 moderate-to-severe hot flashes daily
were randomly assigned, in 2 successive cohorts, to an intervention including a low-fat, vegan
diet and cooked soybeans (½ cup [86g] daily) or to a control group making no dietary changes.
Over a 12-week period, a mobile application was used to record hot flashes (frequency and
severity) and vasomotor, psychosocial, physical, and sexual symptoms were assessed with the
Menopause Specific Quality of Life questionnaire (MENQOL). Between-group differences were
assessed for continuous (t-tests) and binary (chi-squared/McNemar tests) outcomes. In a study
subsample, urinary equol was measured following consumption of ½ cup (86g) of cooked whole
soybeans twice daily for 3 days.

Results: In the intervention group, moderate-to-severe hot flashes decreased 88% (p<0.001),
compared with 34% for the control group (p<0.001; between-group P<0.001). At 12 weeks, 50%
of completers in the intervention group reported no moderate-to-severe hot flashes at all. Among
controls, there was no change in this variable from baseline (chi-squared test p<0.001). Neither
seasonality nor equol production status was associated with the degree of improvement. The
intervention group reported greater reductions in the MENQOL vasomotor (p=0.004), physical
(p=0.01), and sexual (p=0.03) domains.

Conclusions: A dietary intervention consisting of a plant-based diet, minimizing oils, and daily
soybeans significantly reduced the frequency and severity of postmenopausal hot flashes and
associated symptoms.
Trial Registration: ClinicalTrials.gov, NCT04587154
Keywords: menopause, hot flashes, diet, nutrition, soy, isoflavones, vegan, plant-based

Video Summary: http://links.lww.com/MENO/B32.

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Introduction

Postmenopausal vasomotor symptoms cause recurrent discomfort, disrupt sleep, and reduce

quality of life.1 A role for nutritional factors in vasomotor symptoms was suggested by their low

prevalence in areas (notably Japan, China, and rural Mexico) where traditional dietary staples

included grains, legumes, vegetables, and other plant-derived foods.2-6 As the Japanese diet

Westernized between the 1980s and the early 2000s,7 reports of hot flashes increased from

approximately 15% to more than 40% of menopausal women.8

A dietary intervention increasing whole grains, fruits, and vegetables and reducing

dietary fat proved modestly effective in a randomized trial including 17,473 Women’s Health

Initiative participants. The odds of becoming free of hot flashes at one year were increased by

14% (OR = 1.14; 95% CI 1.01-1.28) for those adhering to the intervention regardless of any

weight change and by 23% (OR=1.23; 95% CI 1.05 – 1.46) among those who lost ≥10% of body

weight.9 In addition, soy isoflavones, particularly daidzein and genistein, have proven modestly

effective in controlled trials.10-12 They have estrogen-agonist and -antagonist actions, with

selective affinity for estrogen receptor-β.

The possibility that a low-fat plant-based diet with daily soybeans might be more potent

against vasomotor symptoms comes from the fact that such diets are typically high in fiber and

low in fat, favor weight loss, and appear to foster the growth of gut bacteria capable of

converting daidzein to equol. The ability to produce equol is detected more frequently in

individuals following vegetarian diets than in omnivores and appears to have been more

prevalent in Japan prior to Westernization of the diet.13,14 It has been proposed as a factor in soy’s

apparent health benefits.15

3
 In an initial cohort of a controlled trial of a plant-based diet including soybeans,

moderate-to-severe postmenopausal hot flashes fell 84% in 12 weeks.16 For 59% of participants,

moderate-to-severe hot flashes ended altogether. There were also improvements in body weight

and in psychosocial, physical, and sexual domains.

However, the autumn timing of the study raised the question as to whether this

symptomatic improvement might have been attributable to cooler temperatures. Also, the study

did not assess equol production. These questions were addressed in a replication. The results of

the full study, including both cohorts, are reported here.

Methods

Participants were recruited in 2 cohorts (fall and spring) for a parallel-design, 12-week study

beginning in September 2020 and February 2021. The Advarra Institutional Review Board

approved the study on September 2, 2020 (Pro00045315).

Postmenopausal women aged 40-65y reporting ≥2 moderate-to-severe hot flashes per day

were recruited via social media notices. Criteria for inclusion were cessation of menstruation

>1y and <10y prior and willingness to consume a low-fat vegan diet with daily soybeans.

Criteria for exclusion were any cause of vasomotor symptoms other than natural menopause,

current use of a low-fat vegan diet including daily soy products, soy allergy, use of hormonal

medications in the preceding 2 months, smoking, substance abuse, eating disorder history,

weight-reducing medication use during the last 6 months, a current effort at weight loss, and

body mass index <18.5 kg/m2.

Within each cohort, volunteers meeting the above criteria who provided a practice dietary

record and gave informed consent were assigned, using a random-number table, to an

intervention or control group.

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Outcome Measures

Before and after the 12-week intervention period, the following outcomes were assessed, except

as noted:

Health Status. Participants were asked about any health issues and medications.

Height. Self-reported height was collected at baseline.

Body Weight. Weight was measured with self-calibrating digital scales (Renpho Model ES-

CS20M, Anaheim, CA).

Dietary Intake. Dietary intake for 2 weekdays and 1 weekend day was recorded by participants

and analyzed by the Nutrition Coordinating Center, University of Minnesota, using Nutrition

Data System for Research software version 2020.

Recent Physical Activity. Using the International Physical Activity Questionnaire, metabolic

equivalents for given activity levels were multiplied by the time (minutes) and frequency (days)

of these activities.17

Hot Flashes. For 7 days, the onset, cessation, and intensity of hot flashes were recorded upon

occurrence with a mobile application (My Luna, Blue Trail Software Holding, San Francisco,

CA). Nighttime hot flashes were to be registered the following morning. In cases where hot flash

frequency changed markedly, participants were contacted by telephone for confirmation.

Quality of Life. The effect of menopausal symptoms on quality of life was reported using the

Menopause Specific Quality of Life questionnaire (MENQOL) for 4 domains: vasomotor,

psychosocial, physical, and sexual.18,19

Urinary S-Equol and Isoflavone Analysis by Tandem Mass Spectrometry

(UHPLC-MS/MS)

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Urinary isoflavone concentrations were measured in a subset of participants following the

consumption of ½ cup (86g) of cooked whole soybeans twice daily for 3 days. The total

concentration of S-equol, daidzein, genistein and glycitein in urine (50 µL) was determined by

stable-isotope dilution tandem mass spectrometry after addition of [13C3]equol and [13C3]daidzein

and [13C3]genistein, as internal standards for quantification and enzymatic hydrolysis with a β-

glucuronidase (Kura β-glucuronidase, BG100, Red Abalone). The isoflavone aglycones released

were extracted on a solid phase octadecylsilane bonded silica cartridge (Strata C18-E,

Phenomenex) and the methanolic extracts evaporated, reconstituted in mobile phase and

isoflavones separated and analyzed by tandem mass spectrometry on a Waters Micro TQ-S

instrument coupled to an Acquity UPLC H Class chromatograph. The analytical approach was

based on previously published methods (add 3 refs below) with minor modifications, and the

assay was performed with quality controls. The intra- and inter-assay imprecisions (within 5-

15% CV for all analytes) were monitored throughout the analysis.20-22 Equol-producer status was

defined as a log10 urinary equol:daidzein concentration ratio above -1.75.

Dietary Intervention

Intervention group participants were asked to avoid animal-derived foods, minimize the use of

oils and fatty foods (e.g., nuts and avocados), and consume daily ½ cup (86 g) of cooked whole

non-genetically modified soybeans (Laura Soybeans, Corwith, IA), which were provided. No

other foods were provided. All participants (in either group) who did not own pressure cookers

were loaned them (Instant Pot, Instant Brands, Kanata, Ontario, Canada) to facilitate soybean

preparation for the intervention group and maintain an equitable intervention in the control

group. Control participants were free to use them or not as they saw fit.

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 Participants in the intervention group were invited to one-hour group meetings each

week, conducted via the Zoom Internet conference platform by a registered dietitian or research

staff members for information on food preparation and managing common dietary challenges,

and to discuss dietary adherence, although formal adherence assessment was done using 3-day

dietary records.

Participants in the control group were asked to continue their usual diets, report body

weight and symptoms weekly, and attend 4 1-hour group sessions to maintain engagement. The

sessions covered vasomotor symptoms, the study rationale, and study procedures and permitted

free discussion of participant experiences. After study completion, they were offered optional

instruction in the intervention diet. For all participants, alcoholic beverages were not to exceed

one drink daily.

Participants in both groups were provided with a 100-mcg vitamin B12 supplement and

asked to take it daily. They were asked to avoid other new dietary supplements and to not change

their exercise or medication regimens, except as requested by their personal physicians.

All data forms were identified with participant numbers only. Data were collected using

Qualtrics Survey Software (Qualtrics, Provo, UT) and were stored using a secure Qualtrics

account.

Statistical Procedures

Because no prior study, to the investigators’ knowledge, had examined the effects of a plant-

based diet with soybeans on vasomotor symptoms, there was no sound basis for a power

analysis. Planned enrollment was therefore set at ≤40 participants as an initial cohort, with one or

more replications (up to 120 total participants) thereafter to compensate for seasonality.

7
 Descriptive statistics for baseline variables were calculated. T-tests (continuous variables)

and chi-squared-type tests (categorical measures) assessed significance of baseline differences

between study groups.

Descriptive statistics were calculated for outcome measures. Because distributions did

not substantially depart from approximate normality, treatment effects were assessed with

parametric tests. Comparisons of treatment arms used t-tests for two independent samples on the

change scores over time. Key findings were also evaluated in the subgroup of participants

reporting ≥7 moderate/severe hot flashes per day at baseline. Linear regression models of

outcomes including main effects of treatment and cohort, along with a treatment-cohort

interaction, were used to assess evidence of a seasonality effect. Pearson correlations were used

to quantify magnitude of association between outcomes, with partial Pearson correlations

quantifying associations adjusted for energy intake. Between-group differences for binary

outcomes were assessed with chi-squared or Fisher’s exact tests. Within-group changes in such

outcomes were assessed with the exact McNemar’s test.

Results

Of 1,662 volunteers, 1,301 were excluded prior to individual interviews, and 361 proceeded to

telephone interviews (Figure 1). Of these, 84 were randomly assigned, in 2 cohorts, to the

intervention and control groups (Table 1). Thirteen participants failed to complete the study,

leaving 71 participants for the main data analysis.

Within the intervention group, mean reported fat, saturated fat, and cholesterol intake

diminished, while fiber intake increased (all P<0.0001, Table 2). There were no significant

nutrient changes in the control group. Mean body weight decreased by 3.6 kg in the intervention

group and 0.2 kg in the control group (P<0.001).

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 Total hot flash frequency in the intervention group decreased 78% (p<0.001) and 39%

(p<0.001) for the control group (between-group p=0.003). The decrease in moderate-to-severe

hot flashes in the intervention group was 88% (from 5.0/day to 0.6/day, p<0.001), compared with

34% (from 4.4/day to 2.9/day, p<0.001) among controls (between-group p<0.001, Figure 2).

Among participants with ≥7 moderate-to-severe hot flashes per day at baseline (intervention n=8;

control n=10), moderate-to-severe hot flashes decreased 93% (from 10.6/day to 0.7/day) in the

intervention group (p<0.001) and 36% (from 9.0/day to 5.8/day) in the control group (p=0.01,

between group p<0.001).

The number of intervention-group study completers who were free of moderate-to-severe

hot flashes, based on mobile application reports, increased from 1/38 at week 1 to 19/38 (50%) at

week 12. This variable remained unchanged among controls (1/33 [3%] at each time point,

p<0.0001 for chi-squared test comparing proportion free of moderate-to-severe hot flashes at

week 12). These changes, reported with the mobile application, were paralleled by changes in

MENQOL questionnaire findings (Table 2). Significant between-group differences were found

in the vasomotor (p=0.004), physical (p = 0.01), and sexual (p = 0.03) domains.

For both groups combined, after adjustment for energy intake, changes in frequency of

severe hot flashes correlated directly with changes in fat intake (r=0.33; p=0.01) and inversely

with changes in carbohydrate (r=-0.35; p=0.006) and fiber intake (r=-0.29; p=0.03). That is, the

greater the reduction in fat intake and the greater the increases in carbohydrate and fiber

consumption, the greater the reduction in severe hot flashes. Changes in frequency of moderate-

to-severe hot flashes correlated inversely with daidzein (r=-0.29; p=0.03) and genistein (r=-0.27;

p=0.04) intake.

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 Body weight changes correlated with changes in frequency of moderate-to-severe hot

flashes (r=0.36; p=0.002). A similar association was found for the participants with a BMI ≥25

kg/m2 at baseline (r=0.36; p=0.02). Seasonality had no apparent effect; the changes in moderate-

to-severe hot flashes per day among intervention-group participants were -4.3 (SD = 3.1) and -

4.5 (SD = 4.2) in the fall and spring cohorts, respectively (p=0.34). Reductions in moderate-to-

severe hot flashes did not differ by race (Black vs White: p=0.99).

In the equol-production substudy, there was no apparent association between equol-

producing ability and symptomatic changes. Of 15 intervention-group participants tested, 5

(33%) were equol producers at week 12. Moderate-to-severe hot flashes diminished strongly in

both producers (from 8.0 to 0.7 per day) and nonproducers (from 4.3 to 0.6 per day), p = 0.16 for

t-test comparing changes by producer status. Similarly, among 12 control-group participants

tested, equol-production status had no apparent effect on hot flashes.

Discussion

The dietary intervention led to clinically important reductions in menopausal symptoms. Of

particular note was the 88% reduction in moderate-to-severe vasomotor events among

intervention-group participants, accompanied by weight loss and improvements in physical,

psychosocial, and sexual domains.

Biological plausibility for the role of diet in vasomotor symptoms comes from the fact

that, in premenopausal women, increasing dietary fat increases circulating estradiol

concentrations, while dietary fiber reduces these concentrations,23-25 suggesting the possibility

that chronic elevations of estrogen levels during the reproductive years may increase

vulnerability to vasomotor symptoms at menopause. In addition, soy isoflavones modestly

reduce hot flashes, as noted earlier.

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 The correlations between the observed changes in vasomotor symptoms and both weight

changes and nutrient-intake changes confirm and extend the more modest findings of the

Women’s Health Initiative. However, these correlations were only moderate in magnitude. Thus,

a single factor cannot be specified that would sufficiently explain the observed improvements.

The present study extends the findings from the initial study cohort16 by providing a

larger sample, ruling out seasonality in the reduction in vasomotor symptoms, and providing

initial data regarding equol. The ½ cup (86g) servings of mature soybeans hold approximately

55-60mg of isoflavones—slightly more than the amounts (approximately 30-40 mg/d)

traditionally consumed in Japan or China.26,27 In the present study, the ability to convert daidzein

to equol did not appear to influence the intervention’s efficacy; both equol producers and

nonproducers reported marked symptom reductions. Small sample size may have limited power

to identify differences.

This study has several strengths. Because participants were not confined to a metabolic

ward and used widely available foods, rather than commercial products, the findings readily

translate to non-research settings. The mobile application permits more consistent registration of

vasomotor events than occurs with questionnaires or diaries and is less cumbersome than

ambulatory skin conductance monitors.28-30 The use of the MENQOL questionnaire permitted

confirmation of symptom reductions reported using the mobile application. Because plant-based

diets are associated with improvements in body weight, plasma lipids, blood pressure, and other

health measures31 and have been shown to be highly acceptable in research studies,32-34 and

because soy intake is associated with reduced breast cancer risk in some populations,35 health

benefits may reinforce continued adherence.

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 The design also had limitations. It was limited to 12 weeks, and most participants had at

least some college education. Participant blinding is not possible in trials of whole diets. Because

the study tested a combination intervention, the efficacy of its individual components was not

assessed. Placebo effects cannot be ruled out, although improvements were consistent between

mobile-application recording and questionnaire responses, and changes in these symptoms were

paralleled by weight changes. Inaccuracies can occur in reporting of food intake and menopausal

symptoms. The equol substudy merits repeating in a larger sample.

The inclusion criteria required ≥2 moderate-to-severe vasomotor events per day, fewer

than the 7-8 such events recommended by the U.S. Food and Drug Administration for

therapeutic trials. The present study may therefore be more informative for women with less

frequent events and less so for those with more frequent events. Nonetheless, a small subanalysis

of women with ≥7 events/day suggested that effects may be similarly robust in this

subpopulation.

Conclusion

A dietary intervention, combining a reduced-fat vegan diet and daily soybeans, was associated

with a marked reduction in postmenopausal vasomotor events, significant weight loss, and

reductions in physical and sexual symptoms.

Acknowledgments

The authors wish to thank the research participants, Blue Trail Software Holding (San Francisco,

USA) for providing the My Luna app, and Instant Brands (Kanata, Ontario, Canada) for pressure

cookers.

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Figure and Table Legends:

Figure 1. Participant Flow Through the Trial

[Abbreviation:] MENQOL: The Menopause Specific Quality of Life Questionnaire

Figure 2. Moderate-to-Severe Hot Flashes (Per Day, with 95% CI, Completers)

Table 1. Baseline Demographics, Nutrient Intake, and Clinical Measures in a Dietary

Intervention Trial for Vasomotor Symptoms

[Footnotes for Table 1:] SD = standard deviation; kcal/day = kilocalories per day; g/day = grams
per day; MET = metabolic equivalents; kg = kilograms; BMI (kg/m2) = body mass index as
reported in kilograms of body weight per meter height squared; MENQOL = Menopause
Specific Quality of Life questionnaire

Table 2. Clinical Measures at Baseline and 12 weeks

[Footnotes for Table 2:] kcal/day = kilocalories per day; g/day = grams per day; mg/day =
milligrams per day; MET = metabolic equivalents; kg = kilograms; BMI (kg/m2) = body mass
index as reported in kilograms of body weight per meter height squared; MENQOL =
Menopause Specific Quality of Life questionnaire. For within-group p-values, a = p<0.05; b =
p<0.01; c = p<0.001.

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