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Soy isoflavone supplements for the treatment of menopausal hot flashes: the Women’s Isoflavone Soy Health (WISH) trial

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Soy isoflavone supplements for the treatment of menopausal hot flashes: the Women’s Isoflavone Soy Health (WISH) trial

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Content SOY ISOFLAVONE SUPPLEMENTS FOR THE TREATMENT OF MENOPAUSAL
HOT FLASHES: THE WOMEN’S ISOFLAVONE SOY HEALTH (WISH) TRIAL

by

ChunJu Chien

——————————————————————————————

A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOSTATISTICS)

December 2010

Copyright 2010 ChunJu Chien
ii

ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to my committee chair, Dr. Wendy
Mack, for her illuminating guidance, insights, and kindly support throughout the duration
of this research. Without her invaluable help, this thesis could not be completed. I also
want to express my sincere gratitude to my committee members, Dr. Stanley Azen and
Dr. Roksana Karim, for their insightful comments and enthusiastic help. I would also like
to acknowledge all the help and support from my family: Mom, Dad, Shirley and Allison
for their understanding and unwavering support over the years.
iii

TABLE OF CONTENTS

ACKNOWLEDGEMENTS ii
LIST OF TABLES iv
ABSTRACT v
CHAPTER I: INTRODUCTION 1
CHAPTER II: METHODS
Study Population
Flushing Sub-Study
Trial Procedures
Flushing Assessment
Flushing Trial Outcomes
Statistical Analysis
3
3
4
4
5
5
6
CHAPTER III: RESULTS
Participants
Flushing Outcomes
Association of Plasma Concentrations of Isoflavone with Soy Treatment (ISP)
Association of Isoflavone Levels with Flushing
Treatment Group Comparisons on Flushing and Plasma Concentrations of
Isoflavone by Equol-Producer Status
Sensitivity Analysis
9
9
14
20
22
25

25
CHAPTER IV: DISCUSSION 27
REFERENCES 34
ALPHABETIZED REFERENCES 39

iv

LIST OF TABLES

Table 1: Baseline Participants Demographics and Other Characteristics 12
Table 2: Association of Number of Daily Hot Flash, Composite Scores, and
Changes with Soy Treatment (ISP) Over Trial Follow-up 16
Table 3: Number of Daily Hot Flash and Composite Score at Baseline and
Each Trial Follow-up Visit 17
Table 4: Hot Flashes per Day and Composite Score at Baseline and Over
Trial Follow-up by BMI Group 19
Table 5: Plasma Concentrations of Isoflavones by ISP Treatment Over Trial
Follow-up 21
Table 6: Pearson Correlation between Change in Plasma Isoflavones and
Change in Hot Flashes Over Trial Follow-up 23
Table 7: Association between Hot Flashes and Soy Treatment (ISP) by
Change in Plasma Glycitein 24
Table 8: Treatment Group Comparisons on Flushing and Plasma Isoflavone
Concentrations by Equol-Producer Status Over Trial Follow-Up 26

v

ABSTRACT

Background: Isoflavone soy protein (ISP) is used as an alternative to steroidal hormone
therapies for alleviating menopausal hot flash symptoms; however, the reported efficacy
of soy isoflavones on hot flashes is inconsistent. Objective: The primary aim of the study
was to compare the efficacy of 25 g of isoflavone soy protein versus placebo twice per
day in altering hot flash frequency and severity among postmenopausal women. Design,
Setting, and Participants: This is an ancillary analysis among a subset of 101
postmenopausal women participanting of the Women’s Isoflavone Soy Health (WISH)
trial, who experienced 5 or more hot flashes per week at baseline. WISH was a
randomized, double-blind, placebo-controlled, single center trial including 350 healthy
postmenopausal women.designed to evaluate the effect of isoflavon soy on the carotid
artery intima-media thickness (CIMT). The study participants were between the ages of
44 to 72 years with no clinically evident ardiovascular disease (CVD). Intervention:
Participants were randomly assigned to 25 g soy isoflavone product containing 85 mg of
isoflavones (45 mg genistein, 35 mg daidzein and 5 mg glycitein) or milk protein
matched placebo (0 mg isoflavones) daily for 2.5-3 years. Main Outcome Measures:
Among the 101 participants with ≥5 weekly flashes at baseline, the primary endpoints
were the frequency of hot flashes and hot flash composite scores calculated from the
product of the daily frequency and severity rating using flushing diaries completed over
the trial. Secondary outcome measures included the change in hot flashes number and
composite scores from baseline. Results: Of the 101 postmenopausal women, 53 subjects
vi

were randomly assigned to isoflavone soy protein (ISP) and 48 subjects were assigned to
placebo. The treatment groups did not significantly differ on the daily number of hot
flashes, composite scores, or the change in hot flash frequency or composite scores over
the trial. The reduction in mean hot flash frequency from baseline to 30 months was
similar for the ISP (1.33/day) and the placebo group (1.33/day). Among ISP-treated
women, the change in plasma glycitein from baseline was inversely associated with the
change in hot flash severity (  = -0.35, p=0.02); this association was not observed in the
placebo group. ISP-treated women who were consistent equol-producers significantly
differed on the on-trial mean change of hot flash frequency, plasma genistein, plasma
gaidzein, and plasma glycitein from the placebo-treated women (all p<0.05).
Conclusions: These randomized clinical trial data indicate that ISP do not alleviate hot
flash symptoms in postmenopausal women. Subgroup and ancillary analyses suggested
an association between achieved glycitenin concentrations and reduction of hot flashes.
1

CHAPTER I
INTRODUCTION

Vasomotor hot flashes are the most common symptom of menopause and more than
half of women experience them for several years after menopause [1-2]. While some
women tolerate menopausal flushing without treatments, many women seek medical and
other therapies to relieve the symptoms which interrupt their activities or sleep [3].
Over the last seventy years, estrogenic hormone therapy (HT) has been the standard
therapy for women experiencing menopausal flushing. There are currently no other
effective therapies for treating flushing [4-5]. However, the results of the Women’s
Health Initiative (WHI) trial [6] and other studies raised concern about possible adverse
effects of HT including thrombosis, cardiovascular disease, Alzheimer’s disease, breast
cancer and unpleasant mood swings [7-11]. Following publication of WHI trial results,
the U.S. Food and Drug Administration (FDA) recommended HT only for short-term
treatment of menopausal symptoms at the lowest effective dose [12]. Therefore,
alternative effective treatments for menopausal symptoms are of interest.
The proportions of postmenopausal women experiencing vasomotor flushing in the
East Asian countries are lower than those in the Western countries [13, 17]. It is
speculated that diets rich in soybeans or Chinese medicine may contribute to fewer
complaints and even absence of menopausal vasomotor symptoms in those women [13-
16]. For example, more than 75% of Japanese peri- and postmenopausal women reported
not experiencing hot flashes [17]. Of note, Japanese populations consume a great deal of
2

soybean products, including tofu, soymilk, and Miso. Soy isoflavones containing
genistein, daidzein and glycitein could be considered alternative treatment for
menopausal symptoms. Due to the similar chemical structure of isoflavones and estrogen
and estrogen receptor- binding capacities of isoflavones, it is possible that isoflavones
may ease menopausal symptoms [18-20].
We utilized data from the Women’s Isoflavone Soy Health (WISH) Trial to determine
whether soy isoflavone supplements can effectively relieve hot flashes in postmenopausal
women.
3

CHAPTER II
METHODS

Study Population
The Women’s Isoflavone Soy Health (WISH) Trial was a single-center, randomized,
double-blind, placebo-controlled trial designed to test the hypothesis that isoflavone soy
protein (ISP) reduces the progression of subclinical atherosclerosis in postmenopausal
women. Recruitment was based on a 5-year trial which included a 2-year recruitment
period and 2.5 years of randomized treatment. The study was administered through the
academic clinical research site, the Atherosclerosis Research Unit, University of Southern
California. Subjects were screened through initial telephone screening followed by a
clinic screening visit (if the subject passed telephone screening).
Eligible subjects were healthy postmenopausal women aged 30 years or older with no
clinical symptoms of cardiovascular disease. Postmenopausal status was defined as at
least 12 months of amenorrhea and serum estradiol level <20 pg/ml. Exclusion criteria
were: fasting plasma triglycerides >500 mg/dL, serum creatinine >2.0 mg/dL, diabetes
mellitus, uncontrolled hypertension, untreated thyroid disease, life threatening disease
with prognosis <5 years, alcohol intake >5 drinks per day, and soy, nut or related food
allergies. Participants provided written informed consent, and the study protocol was
approved by the Institutional Review Board of the University of Southern California.
350 subjects were randomized in the WISH study, 175 of them received ISP and 175
received placebo.
4

Flushing Sub-Study
While the primary trial outcome was progression of carotid artery intima–media
thickness measured at baseline and 6-month intervals, the outcomes of the flushing sub-
study were frequency of hot flushes and hot flush composite scores calculated from the
product of daily frequency and severity rating from flushing diaries completed over the
trial. To be included in this WISH flushing sub-study, randomized women also must have
reported at least five hot flashes per week at baseline using a hot flash diary. A total of
101 randomized participants (n=53 ISP, n=48 placebo, 29% of randomized) were
included in this sub-study.
Trial Procedures
Eligible postmenopausal women were randomly assigned to receive 25 g isoflavone
soy protein (ISP) or a milk protein matched placebo twice daily in the form of powder or
bars. The soy protein product contained 45 mg genistein, 35 mg daidzein and 5 mg
glycitein (aglycone weights). The formulated percentages of isoflavones were 50% to
55% genistein, 40% to 45% daidzein, and 5% to 10% glycitein for daily soy supplement.
The placebo contained 0% isoflavones. Compliance was assessed by envelope and bar
count at each clinic visit.
Over the trial follow-up, participants returned to the clinic every month for the first 6
months, and every two months thereafter. At each clinic visit, data collection included
product compliance (envelope and bar counts), dietary intake, vital signs, non-study
medications, and nutritional supplements. The occurrence of adverse events were also
queried at each visit. Fasting blood and urine samples for measurement of isoflavones
5

and lipids, and carotid ultrasonography for determination of carotid artery intima-media
thickness (CIMT) were obtained every six months. Participants fasted at least 8 hours
before sample collections. The isoflavone concentrations (genistein, daidzein, glycitein,
and equol, a metabolism of daidzein) were assessed from overnight fasting urine and
blood samples. Plasma lipids were measured using an enzymatic method under the CDC
Standardization Program [21]. Depressed mood was assessed every six months using the
Center for Epidemiological Studies Depression (CES-D) Scale [22].
Flushing Assessment
Hot flash diaries were used to document the frequency and severity (mild, moderate,
or severe) of hot flashes, any food, beverages, or activities associated with flashes, and
any other symptoms (complaints) due to hot flash. Diaries were completed at home
before randomization and at each clinic visit over the trial. Subjects were asked to record
the number of mild, moderate, and severe hot flashes experienced daily and return diaries
at their next clinic visit. The definition of mild hot flash was a feeling of warm sensation,
no perspiration, and no disruption of activity. Moderate hot flash was defined as a warm
sensation with perspiration and no disruption of activity. A severe hot flash was a hot
sensation with perspiration and disruption of activity.
Flushing Trial Outcomes
The end points for this sub-study were the number of hot flashes per day and the hot
flash composite score calculated from the product of the daily frequency and severity
rating. The number of hot flashes per day was calculated as the mean over six month
periods after baseline. The composite score was calculated by assigning a number to the
6

severity of the hot flash (mild=1, moderate=2, severe=3) and multiplying by the number
of hot flashes experienced at that severity level. The three resulting numbers were then
added for a total score, and each mean daily composite score was averaged over six
months. Other end points included the change in isoflavone concentrations of plasma
genisten, plasma daidzein, and plasma glycitein.
Statistical Analysis
The primary hypothesis of this WISH trial sub-study is that soy isoflavones will be
more effective than placebo in reducing hot flashes among postmenopausal women
reporting at least 5 hot flashes per week. The sample size of 101 postmenopausal women
provided 80% power to detect a difference of 1.7 hot flashes per day with the pooled
standard deviation of 2.9 units per day and α(2)=0.05.. The pooled standard deviation was
computed from the 101 women as follows:
       
2 2 2 2
1 1 2 2
12
1 1 53 1 (2.8) 48 1 (3.0)
2.9
53 48
pooled
n s n s
S
nn
     
  

, where
1
s and
2
s represent the standard deviation in ISP and placebo groups; and
1
n and
2
n represent the sample size respectively. The Cohen’s effect size d was 0.59 (effect size
d=1.7/2.9=0.59).
Baseline characteristics were summarized by treatment group using the two-sample t-
test for continuous variables and the Chi-square test for categorical variables. The
Kruskal-Wallis test was used for variables with non-normal distributions.
The primary analysis compared the mean change within each subject from baseline to
2.5 years in the daily number of hot flashes and composite score among women
7

randomized to ISP versus placebo. All randomized women meeting the inclusion criteria
for this sub-study were included in an intent-to-treat analysis. Due to the repeated
measurements across subjects, the analysis used a generalized linear mixed model
(GLMM, PROC GLIMMIX procedure, 2005, SAS Institute Inc, Cary, NC) with a
compound-symmetry covariance structure. Using the minimum Akaike Information
Criterion (AIC) to select the covariance structure, the compound-symmetry covariance
structure was adopted, that fits a common correlation between all pairs of measures. A
random intercept model was used to specify the subject-specific variability in mean hot
flashes or composite scores at baseline. The model also included treatment group and
follow-up time as fixed effects, with the interaction term, treatment × follow-up time, to
test the consistency of treatment effect over time on the flushing endpoints. The
regression coefficient associated with treatment group represents the mean difference in
hot flash between ISP and placebo groups. Follow-up time (months since randomization)
was specified as a continuous variable, and the regression coefficient associated with
follow-up time represents the change in hot flash endpoints or plasma isoflavones per
month. Baseline covariates were included that were known to be associated with hot
flash, including age, BMI, and race. In addition, all change variables were computed as
the difference between the values at every six months follow-up visit with baseline value.
Subgroup analyses were also performed to identify whether certain groups of
postmenopausal women might particularly benefit from soy isoflavone supplementation.
Women were categorized based on body mass index (BMI<25 or BMI

25), vitamin E
use at baseline, depression (CES-D <16, or CES-D >16), time since menopause (<5yrs,
8

5-10 yrs,>10yrs), and type of menopause (natural or surgical). In addition, the equol-
producer status was defined among ISP participants. Women were stratified by equol-
producer status which was determined by the plasma equol levels at post-randomization
visits (non-equol-producer (equol concentrations never >20 nmol/L), intermittent equol-
producer (equol concentrations >20 nmol/L at some visits), or consistent equol-producer
(equol concentrations > 20 nmol/L at all visits)). Equol is produced through metabolism
of daidzein by gut flora. It has been suggested that beneficial soy outcomes may be
enhanced among equol-producers.
The plasma concentrations of genistein, daidzein, and glycitein were compared
between ISP and placebo groups using a GLMM model. In addition, Pearson correlation
was used to assess the association of the change from baseline in hot flash number and
composite scores with the change from baseline in plasma isoflavone concentrations. The
change of plasma concentrations (genistein, daidzein, and glycitein) and hot flash
outcomes were classified as low, medium, and high based on the tertile distribution of the
average change for each subject over the trial follow-up. The on-trial means were the
average of the hot flash frequency, composite scores, or plasma concentrations measured
every six months after baseline. A sensitivity analysis excluding women taking estrogen
or antidepressants during the trial was performed. All analyses were performed using
SAS version 9.2. Hypothesis testing were considered statistically significant at two-sided
P-value <.05.
9

CHAPTER III
RESULTS

Participants
Among 1063 women screened by telephone and clinic visit (Figure 1), 574 women
were screened out (ineligible or refused to enroll) by telephone. Of the 489 women clinic
screened,,86 women were ineligible and 53 chose not to participate. The principal
reasons for ineligibility included estradiol >20 pg/ml (n=20), using current hormones
therapies for menopause (n=15), and symptoms of cardiovascular disease (n=14). 350
women were randomized in the Women’s Isoflavone Soy Health (WISH) trial., Of the
350 WISH participants, only 101 women who had reported 5 or more hot flashes at
baseline were included in this sub-study; 53 randomized to soy isoflavone and 48 to
placebo. Forty one (77% completion rate) ISP-treated women and 34 (71% completion
rate) placebo-treated women completed the trial from baseline to trial end. The mean
follow-up time was 25.7 months (median: 30 months; range: baseline to 30 months) for
the ISP group, and 23.6 months (median: 30 months; range: 6 months to 30 months) for
the placebo group.
Participant characteristics at baseline are summarized in Table 1. The total sample of
101 postmenopausal women had a mean age of 57.5 years, were 69.3% non-Hispanic
whites, and on average reported 3.3 hot flashes per day. The majority of women were
married, were non-smokers, and had experienced a natural menopause. The treatment
groups did not differ on age, BMI, waist-hip ratio, CES-D, time since menopause, or past
10

use of hormone therapy. The groups did differ on race (p=0.01). There were 56.6% and
83.3% non-Hispanic whites in the ISP and placebo group, respectively. In addition,
20.8% of ISP-treated women and 4.2% of placebo-treated women were Hispanic.
11

Figure 1: Flow Diagram of The Women’s Isoflavone Soy Health (WISH) Trial-Flushing Sub-study.

Telephone Screened
for Eligibility
(n = 1063)
Clinic Screened
for Eligibility
(n =489)

Randomization
(n =350)
Ineligible (n=574)

Protocol-Specific Reasons (n=86)
5 Vaginal Bleeding
20 Estradiol ≥20 pg/ml
14 Cardiovascular Disease
1 TG >500mg/dL
2 Serum Creatinine >2.0mg/dL
21 Diseases (Diabetic, Thyroid)
15 Current Hormone Therapy
3 Food Allergies
3 Alcohol Intake >5 per Day
2 Others

Personal Reason for Refusal (n=53)
Assigned to Receive
25g Matched Placebo
(n=175)
Assigned to Receive
25 g Soy Isoflavone
(n=175)
In Sub-Study,
Assigned to Receive
25 g Soy Isoflavone
(n=53)
In Sub-Study,
Assigned to Receive
25g Matched Placebo
(n=48)
12

Table 1: Baseline Participants Demographics and Other Characteristics.
Variable
ISP
(n=53)
Placebo
(n=48)
P-value
1

Age, mean (range), (years) 56.8 (44-74) 58.2 (50-72) 0.25
Age Group, No. (%), (years) 0.07
40-49 7 (13.2) 0
50-59 29 (54.7) 31 (64.6)
60-69 16 (30.2) 15 (31.3)
>70 1 (1.9) 2 (4.2)
Body Mass Index, (
2
/ kg m ) 25.9 (4.5) 25.1 (3.9) 0.33
<25.0 25 (47.2) 25 (52.1) 0.62
≥25.0 28 (52.8) 23 (47.9)
Waist Hip Ratio 0.79 (0.05) 0.79 (0.06) 0.97
Race, No. (%) 0.01
White 30 (56.6) 40 (83.3)
Black 3 (5.7) 1 (2.1)
Hispanic 11 (20.8) 2 (4.2)
Asian 5 (9.4) 5 (10.4)
Other 4 (7.6) 0 (0.0)
Education Level, No. (%) 0.29
High school graduate or less 3 (5.7) 0 (0.0)
Some college 19 (35.9) 14 (29.2)
Bachelor degree 14 (26.4) 14 (29.2)
Post graduate or professional degree 17 (32.1) 20 (41.7)
Marital Status, No. (%) 0.49
Single 4 (7.6) 3 (6.3)
Married 35 (66.0) 37 (77.1)
Separated 1 (1.9) 0 (0.0)
Divorced 11 (20.8) 8 (16.7)
Widowed 2 (3.8) 0 (0.0)
Smoking Status, No. (%) 0.18
Never smoked 32 (60.4) 27 (56.3)
Former smoker 21 (39.6) 18 (37.5)
Current smoker 0 (0.0) 3 (6.3)
CES-D 6.5 (5.2) 7.5 (6.4) 0.38
Depression (CES-D >16), No. (%) 3 (5.7) 5 (10.4) 0.38
Type of Menopause, No. (%) 0.44
Natural 47 (88.7) 40 (83.3)
Surgical 6 (11.3) 8 (16.7)
Time Since Menopause (years) 8.3 (6.8) 9.5 (7.2) 0.38
< 5 years 25 (47.2) 19 (39.6) 0.74
5-10 years 13 (24.5) 14 (29.2)
> 10 years 15 (28.3) 15 (31.3)

13

Table 1: Continued
Variable
ISP
(n=53)
Placebo
(n=48)
P-value
1

Hot Flash at Baseline
3

Daily Hot Flash Frequency (# per day) 0.40
Mean (SD) 3.1 (2.8) 3.4 (3.0)
Median (IQR) 2.0 (2.8) 2.6 (2.5)
Range 0.7 – 12.7 0.7 - 16.5
Hot Flash Composite Score 0.61
Mean (SD) 5.0 (5.3) 6.0 (7.4)
Median (IQR) 2.8 (3.9) 3.2 (4.4)
Range 0.7 – 20.0 0.7 - 39.7
Relevant Medical History
Hysterectomy, No. (%) 10 (18.9) 15 (31.3) 0.15
Current Vitamin E Supplement, No. (%) 15 (28.3) 10 (20.8) 0.39
Past use of Hormone Therapy, No. (%) 34 (64.2) 37 (77.1) 0.16
Duration of Hormone Therapy (years) 7.9 (7.1) 6.7 (6.8) 0.46
Time since Last Used Hormone Therapy (years) 2.6 (2.5) 2.8 (2.6) 0.67
1

P-value from two-sample t-test (continuous variables) or Chi-square test (categorical variables).
2

Mean (SD) for continuous variables; n (%) for categorical variables.
3

P-values are obtained by the two-sided Kruskal-Wallis tests test.

14

Flushing Outcomes
At baseline, there were no significant differences in the number of hot flashes per day
or the flushing composite scores between ISP and placebo groups (Table 1). Treatment
effects for the flushing endpoints over the entire trial follow-up are indicated in Table 2.
The treatment groups did not significantly differ on the daily number of hot flashes,
composite scores, or mean change in hot flash frequency or composite scores over the
trial with adjustment for follow-up time, although the mean on-trial daily number of hot
flashes and composite score were lower in the ISP group compared to the placebo group.
The results were not altered with adjustment for follow-up time and race.
Comparisons of the mean on-trial and reduction from baseline in daily number of hot
flashes and composite score over trial follow-up are presented in Table 3. At baseline and
during the trial, none of the mean daily hot flashes counts and composite scores
significantly differed between groups. The mean reduction in hot flash frequencies from
baseline to 30 months was -1.33 (SE=0.27) for the ISP group, and -1.33 (SE=0.30) for
the placebo group. The mean reduction in composite scores from baseline to 30 months
was -2.02 (SE=0.54) for the ISP group, and -2.24 (SE=0.58) for the placebo group. The
reduction in daily number of hot flashes and composite scores from baseline to closeout
was significant for both groups (both p<0.05, data not shown). However, the mean
reductions in the ISP group were not statistically different from the placebo group at any
6 month-period during the trial (all p>0.05, data not shown). The interaction of
treatment follow-up time was not significant indicating that the treatment effect did not
differ over the trial (p>0.05). However, women assigned to the ISP group may have had a
15

faster decreasing rate in daily number of hot flashes and composite scores than the
placebo group for the first six months. In general, women in both groups were still
experiencing on average more than 1 hot flash per day and having nearly 3 units of
composite scores at the end of the 30-month period.
16

Table 2: Association of Number of Daily Hot Flash, Composite Scores, and Changes with Soy Treatment (ISP) Over
Trial Follow-up.
Variable

Treatment Group Comparison
Using On-trial Data Only
Treatment
β (SE)
Using All Visits
P-value
ISP
1

(n=53)
LS Mean (SE)
Placebo
(n=48)
LS Mean (SE)
P-value
for
differenc
e
Model I
2

Daily hot flash number -0.43 (0.49) 0.39 1.98 (0.35) 2.39 (0.36) 0.42
Hot flash composite score -0.97 (1.05) 0.36 3.27 (0.72) 4.10 (0.75) 0.43
Change in daily hot flash number -0.13 (0.30) 0.67 -1.14 (0.27) -1.02 (0.28) 0.75
Change in composite score
4

-0.04 (0.57) 0.94 -1.78 (0.52) -1.85 (0.54) 0.93
Model II
3

Daily hot flash number -0.53 (0.52) 0.31 2.09 (0.44) 2.49 (0.56) 0.46
Hot flash composite score -1.39 (1.11) 0.21 3.70 (0.93) 4.76 (1.18) 0.35
Change in daily hot flash number 0.11 (0.32) 0.73 -1.52 (0.34) -1.74 (0.43) 0.60
Change in composite score 0.42 (0.61) 0.49 -2.53 (0.66) -3.26 (0.84) 0.36
1
Isoflavone Soy Protein.
2
Association between hot flashes and soy treatment over trial follow-up were evaluated by GLMM (generalized linear
mixed model) with a compound-symmetry covariance structure. Model I included intercept as a random effect, and
treatment group, follow-up time as fixed effects. β was the regression coefficient representing change in daily hot
flash number, composite scores, and their reduction compared to baseline per unit change in independent variable
(treatment group, or per month for follow-up time). The on-trial means in hot flash endpoints were the average of
endpoints measured every six months over the trial follow-up after baseline.
3
Model II included the covariates in model I plus the additional adjustment for race.
4
Change variables computed at every six months follow-up visit=visit value-baseline value.
17

Table 3: Number of Daily Hot Flash and Composite Score at Baseline and Each Trial Follow-up Visit.
Measure
ISP
1
(n=53)
Placebo (n=48)
P-value
3

for
difference
LS Mean
2

(95% CI)
Reduction from
Baseline
LS Mean (SE)
LS Mean
(95% CI)
Reduction from
Baseline
LS Mean (SE)
Hot Flashes per Day
Baseline 3.12 (2.39-3.84) 3.42 (2.65-4.18) 0.58
6 months 2.25 (1.51-2.98) -0.88 (0.26) 2.90 (2.13-3.66) -0.52 (0.27) 0.23
12 months 2.08 (1.34-2.83) -1.01 (0.27) 2.59 (1.79-3.39) -0.81 (0.29) 0.37
18 months 1.81 (1.06-2.56) -1.28 (0.27) 2.06 (1.25-2.87) -1.34 (0.30) 0.66
24 months 1.77 (1.01-2.52) -1.33 (0.27) 2.20 (1.39-3.02) -1.17 (0.30) 0.44
30 months 1.74 (0.98-2.50) -1.33 (0.27) 2.07 (1.26-2.88) -1.33 (0.30) 0.56
Composite Score
4

Baseline 5.04 (3.51-6.57) 5.98 (4.37-7.60) 0.41
6 months 3.68 (2.14-5.23) -1.37 (0.50) 5.06 (3.45-6.67) -0.92 (0.51) 0.23
12 months 3.56 (1.99-5.13) -1.43 (0.52) 4.40 (2.71-6.08) -1.51 (0.57) 0.47
18 months 2.78 (1.22-4.35) -2.21 (0.52) 3.43 (1.73-5.13) -2.52 (0.58) 0.58
24 months 2.94 (1.35-4.52) -2.06 (0.53) 3.82 (2.11-5.53) -2.03 (0.59) 0.45
30 months 2.94 (1.34-4.53) -2.02 (0.54) 3.66 (1.96-5.36) -2.24 (0.58) 0.54
1

Isoflavone Soy Protein.

2
All means and reductions of hot flashes and composite scores at each visit during the trial were evaluated by GLMM
(generalized linear mixed model) with a compound-symmetry covariance structure. Model included intercept as a
random effect, and treatment group, follow-up time, and treatment×follow-up time as fixed effects. Follow-up time
was specified as a categorical variable. All reductions were relative to baseline.
3
P-values for the mean difference at each visit during the trial were evaluated by GLMM model.
4
Hot flash composite scores were obtained by multiplying the frequency per day by the severity grade.

18

Table 4 shows the association of hot flash counts per day and composite scores over
the trial follow-up by BMI groups (BMI<25.0
2
/ kg m and BMI≥25.0
2
/ kg m ). At
baseline, women below the median BMI (BMI<25.0
2
/ kg m ) had on average fewer hot
flashes per day (mean=3.00 vs. 3.51) and lower composite scores (mean=4.46 vs. 6.50)
compared to women above the median BMI (p-value for difference=0.33 and 0.07,
respectively). Among the thinner women (BMI<25.0
2
/ kg m ), the mean reduction in the
daily number of hot flashes from baseline to 12 months was -0.85 (SE=0.32, p<.0001) in
the ISP group, and -0.42 (SE=0.34, p>0.05) for women assigned to the placebo group.
The mean reduction in composite scores from baseline to 24 months was -1.61 (SE=0.63,
p<.0001) for thinner women assigned to the ISP group and -1.16 (SE=0.67, p>0.05) for
the placebo group. Among women above the median BMI (BMI  25.0
2
/ kg m ), the
mean change in daily numbers of hot flash or composite scores over the trial follow-up
significantly differed from baseline in both ISP and placebo groups (all p<0.05).
However, there was no statistically significant differences between ISP and placebo
groups in hot flash frequencies, composite scores, or their reductions from baseline
during the trial.
Table 4: Hot Flashes per Day and Composite Score at Baseline and Over Trial Follow-up by BMI Group.
Measure
1

BMI < 25.0 (n=50) BMI  25.0 (n=51)
ISP (n=25) Placebo (n=25)
P-value
2

for
difference
ISP (n=28) Placebo (n=23)
P-value
2

for
difference
LS Mean
(SE)
Reduction
from
Baseline
(SE)
LS Mean
(SE)
Reduction
from
Baseline
(SE)
LS Mean
(SE)
Reduction
from
Baseline
(SE)
LS Mean
(SE)
Reduction
from
Baseline
(SE)
Hot Flashes per Day
Baseline 2.89 (0.46) 3.11 (0.46) 0.73 3.32 (0.58) 3.75 (0.64) 0.63
6 months 2.23 (0.47) -0.67 (0.32)* 3.05 (0.46) -0.06 (0.32) 0.21 2.27 (0.58) -1.05 (0.39)* 2.73 (0.64) -1.02 (0.43)* 0.60
12 months 2.06 (0.47) -0.85 (0.32)* 2.69 (0.48) -0.42 (0.34) 0.35 2.10 (0.60) -1.16 (0.42)* 2.45 (0.69) -1.27 (0.49)* 0.71
18 months 1.64 (0.47) -1.27 (0.33)* 2.17 (0.48) -0.91 (0.35)* 0.44 1.97 (0.60) -1.29 (0.41)* 1.91 (0.69) -1.85 (0.49)* 0.95
24 months 1.52 (0.47) -1.37 (0.33)* 2.31 (0.48) -0.77 (0.35)* 0.24 2.03 (0.61) -1.25 (0.43)* 2.06 (0.70) -1.65 (0.50)* 0.97
30 months 1.53 (0.47) -1.37 (0.33)* 2.15 (0.48) -0.96 (0.35)* 0.36 1.96 (0.61) -1.27 (0.44)* 1.94 (0.70) -1.77 (0.50)* 0.99
Composite Score
Baseline 3.95 (0.90) 4.97 (0.90) 0.42 6.01 (1.26) 7.09 (1.40) 0.57
6 months 3.25 (0.91) -0.72 (0.62) 4.76 (0.90) -0.21 (0.60) 0.24 4.10 (1.26) -1.91 (0.76)* 5.39 (1.40) -1.70 (0.84)* 0.50
12 months 3.21 (0.91) -0.76 (0.62) 4.32 (0.93) -0.64 (0.65) 0.39 3.84 (1.31) -2.08 (0.82)* 4.37 (1.48) -2.58 (0.97)* 0.79
18 months 2.17 (0.92) -1.82 (0.63)* 3.34 (0.95) -1.54 (0.67)* 0.37 3.35 (1.30) -2.56 (0.81)* 3.46 (1.48) -3.66 (0.97)* 0.96
24 months 2.34 (0.92) -1.61 (0.63)* 3.73 (0.95) -1.16 (0.67) 0.29 3.48 (1.32) -2.48 (0.85)* 3.84 (1.50) -3.09 (0.99)* 0.86
30 months 2.43 (0.92) -1.53 (0.64)* 3.52 (0.94) -1.45 (0.66)* 0.41 3.38 (1.33) -2.49 (0.86)* 3.71 (1.50) -3.21 (0.99)* 0.87
1
All means and reductions of hot flashes and composite scores at each visit during the trial were evaluated by GLMM (generalized linear mixed model) with a compound-
symmetry covariance structure. Model included intercept as a random effect, and treatment group, follow-up time, and treatment×follow-up time as fixed effects. Follow-up time
was specified as a categorical variable. All reductions were relative to baseline.
2
P-value for the LS mean difference at each visit during the trial was evaluated by GLMM model.
3
* represents p-value < 0.05.
19
20

Association of Plasma Concentrations of Isoflavone with Soy Treatment (ISP)
The treatment effects for the plasma concentrations of isoflavone are summarized in
Table 5. The associations of plasma concentrations with soy treatment were examined
with generalized linear mixed model including intercept as a random effect, and
treatment group and follow-up time as fixed effects. Baseline levels of plasma
concentrations were equal between ISP and placebo groups. On-trial plasma
concentrations of genistein, daidzein, and glycitein were statistically significant higher
among ISP treated women over the trial follow-up.
An analysis was performed to test the ISP treatment effect on plasma isoflavone
progression using GLMM.(data not shown) The model included intercept as a random
effect and follow-up time as a fixed effect using data including all visits in the ISP group.
For ISP treated women, the change rate was 12.0±3.0 nM/month (p<.0001) for plasma
genistein, 9.3±2.3 nM/month (p<.0001) for plasma daidzein, and 0.17±0.08 nM/month
(p=0.03) for plasma glycitein.
21

Table 5: Plasma Concentrations of Isoflavones by ISP Treatment Over Trial Follow-up.
Variable

Treatment Group Comparison
Treatment
β (SE)
2

Using All Visits
P-value
Baseline
On-Trial
3

ISP
1

Mean
(SE)
Placebo
Mean
(SE)
P-value
ISP
Mean
(SE)
Placebo
Mean
(SE)
P-value
Genistein (nM) 336.5 (74.2) <.0001
58.4
(68.2)
56.3
(71.7)
0.98
540.3
(64.4)
106.6
(72.0)
<.0001
Daidzein (nM) 250.9 (58.7) <.0001
61.7
(52.1)
63.8
(54.7)
0.98
430.9
(49.5)
105.4
(55.3)
<.0001
Glycitein (nM) 6.8 (2.36) 0.004
6.0
(2.1)
6.5
(2.2)
0.86
16.4
(1.9)
7.9
(2.1)
0.003
1
Isoflavone Soy Protein.
2
Associations between plasma isoflavones and ISP treatment effect over trial follow-up were evaluated by GLMM
(generalized linear mixed model) with a compound-symmetry covariance structure. Model included intercept as a
random effect, and treatment group, follow-up time as fixed effects. β was the regression coefficient representing
change in plasma genistein, plasma daidzein, and plasma glycitein per unit change in independent variable (treatment
group, or per month of follow-up).
3
The on-trial means in plasma concentrations were the average of plasma concentrations measured every six months
over the trial follow-up after baseline.
22

Association of Isoflavone Levels with Flushing
The Pearson correlation between the change in plasma isoflavone concentration and
the change in hot flash activity over trial follow-up are displayed in Table 6. Among the
84 women with more than 1 measurement of plasma isoflavone, the change in daily hot
flash number was not significantly correlated with the change in plasma genisten,
daidzein, or glycitein (all p>0.05). A significant inverse association was observed
between the change in plasma glycitein and the change in hot flash composite scores (  =
-0.35, p=0.02) among women in the ISP group, but not in the placebo group (  = -0.07,
p=0.69).
An additional analysis was performed to test the association of change in plasma
glycitein with flushing endpoints (Table 7). The change in plasma glycitein was classified
as low (average glycitein change <2.28 nM), medium (2.28 nM ≤average glycitein
change <11.20 nM), and high (average glycitein change >11.20 nM) based on the tertile
distribution of the average change during the trial in the ISP group. The categorical
change in plasma glycitein was significantly associated with the change in daily hot flash
counts and composite scores (P-value for trend=0.05, and 0.01, respectively). For both
the change in hot flash frequency and the change in composite scores, the on-trial mean
difference between high and low change level in plasma glycitein was statistically
significant (p=0.03 and 0.02, respectively).
23

Table 6: Pearson Correlation between Change in Plasma Isoflavones and Change in Hot Flashes Over Trial Follow-up.
Pearson Correlation
ISP (n=46)
1

Placebo (n=38)

P-value

P-value
Change in Hot Flashes per Day
2

Change in Plasma Genistein
3

-0.16 0.29 -0.11 0.51
Change in Plasma Daidzein -0.04 0.69 -0.13 0.45
Change in Plasma Glycitein -0.25 0.10 -0.03 0.88
Change in Composite Scores
Change in Plasma Genistein -0.16 0.28 -0.26 0.11
Change in Plasma Daidzein -0.12 0.41 -0.12 0.47
Change in Plasma Glycitein -0.35 0.02 -0.07 0.69
1
In ISP group, the measurement of plasma isoflavones for 6 women and hot flashes diary for 1 woman only could be
found at baseline. In the placebo group, 10 women only had the measurement of plasma isoflavones at baseline.
Change variables computed at every six months follow-up visit=visit value-baseline value.
2
The change in hot flash number per day and composite scores were classified as low, medium, and high based on the
tertile distribution of the average change for each subject over the trial follow-up visit.
Change in hot flashes per day: Low=1 (< -1.41), Medium=2 (-1.41~-0.36), and High=3 (-0.36<);
Change in composite scores: Low=1 (< -1.94), Medium=2 (-1.94~-0.42), and High=3 (-0.42<).
3
The changes in plasma isoflavones (genistein, daidzein, and glycitein) were classified as low, medium, and high
based on the tertile distribution of the average change for each subject over the trial follow-up visit.
Change in plasma genistein: Low=1 (<28), Medium=2 (28~238), and High=3 (238<);
Change in plasma daidzein: Low=1 (<43), Medium=2 (43~216), and High=3 (216<);
Change in plasma glycitein: Low=1 (<0.58), Medium=2 (0.58~6.9), and High=3 (6.9<).
24

Table 7: Association between Hot Flashes and Soy Treatment (ISP) by Change in Plasma Glycitein.
On-Trial
ISP
1

(n=47)
Placebo
(n=48)
Change Levels of Plasma Glycitein
Mean(SE)
High
2

(n=15)
Mean (SE)
Medium
(n=17)
Mean (SE)
Low
(n=15)
Mean (SE)

P-value
3

for trend
Daily Hot Flash Number 1.75 (0.61) 1.61 (0.58) 1.67 (0.64) 0.88 2.46 (0.35)
Hot Flash Composite Score 2.55 (1.27) 2.62 (1.19) 2.56 (1.32) 0.99 4.22 (0.72)
Change in Daily Hot Flash Number -1.99 (0.48) -0.93 (0.45)
-0.52 (0.50)
4

0.05 -0.96 (0.28)
Change in Composite Score -3.51 (0.92) -1.48 (0.87)
-0.36 (0.96)
5

0.01 -1.74 (0.53)
1
In ISP group, 6 women had only baseline isoflavones measurements. Change variables computed at every six months
follow-up visit=visit value-baseline value.
2
The change levels of plasma glycitein were classified as low (average glycitein change<2.28 nM), medium (2.28
nM≤average glycitein change<11.20 nM), and high (average glycitein change≥11.20 nM) based on the tertile
distribution of the average change during the trial in the ISP group.
3
All on-trial means were evaluated by GLMM (generalized linear mixed model) with a compound-symmetry
covariance structure. Model included intercept as a random effect, and the change levels of plasma glycitein as a
fixed effect. The change level of plasma glycitein was specified as a continuous variable for trend test. The on-trial
mean in hot flash endpoints were the average of endpoints measured at every six months over the trial follow-up
after baseline.
4
Significant on-trial mean difference in the change of daily hot flash number between high and low change level in
plasma glycitein (P-value =0.03).
5
Significant on-trial mean difference in the change of composite score between high and low change level in plasma
glycitein (P-value=0.02).

25

Treatment Group Comparisons on Flushing and Plasma Concentrations of
Isoflavone by Equol-Producer Status
Table 8 shows the treatment group comparisons on hot flash endpoints and the
plasma isoflavones by equol-producer status. The majority of ISP-treated women were
not equol producers (n=29). Women who were consistent equol-producers had the
highest mean change in hot flash frequency and composite scores during the trial, and the
lowest on-trial mean change in hot flashes occurred among women who were not equol-
producers. Consistent equol-producers and non-equol-producers differed significantly on
the change of hot flash frequency and composite scores (p=0.01 and 0.03, respectively).
Consistent equol-producers also had the highest on-trial mean plasma isoflavones among
the three equol-producer groups. In addition, consistent equol-producers significantly
differed on the on-trial mean change of hot flash frequency (p=0.04), plasma genistein
(p<0.0001), plasma gaidzein (p=0.001), and plasma glycitein (p<0.0001) compared to
placebo-treated women.
Sensitivity Analysis
A sensitivity analysis excluding 9 postmenopausal women who took estrogens or
antidepressants during the trial showed results consistent with the primary results. Of 6
women assigned to the ISP group, one woman took conjugated estrogens (Premarin or
Prempro), and five women took antidepressants including fluoxetine, sertraline, and
venlafaxine over the trial follow-up. In the placebo group, two women took estradiol, and
one woman took venlafaxine during the trial.
26

Table 8: Treatment Group Comparisons on Flushing and Plasma Isoflavone Concentrations by Equol-Producer Status
Over Trial Follow-Up.
On-Trial
ISP
1

(n=47)

Placebo
(n=48)
Consistent
Equol-
Producer
(n=9)
Mean (SE)
Intermittent
Equol-
Producer
(n=9)
Mean (SE)
Non
Equol-
Producer
(n=29)
Mean (SE)
P-value
2

for trend
Mean(SE)
Daily Hot Flash Number 1.62 (0.80) 2.34 (0.80) 1.55 (0.46) 0.67 2.46 (0.35)
Hot Flash Composite Score 2.40 (1.66) 3.98 (1.65) 2.33 (0.94) 0.66 4.22 (0.73)
Change in Daily Hot Flash Number -2.39 (0.62) -1.40 (0.62) -0.60 (0.36) 0.02 -0.96 (0.28)
Change in Composite Score
3

-3.92 (1.22) -2.16 (1.22) -0.86 (0.70) 0.02 -1.74 (0.54)
Plasma Genistein 805.1 (142.0) 352.3 (142.0) 517.6 (81.0) 0.31 107.9 (70.5)
Plasma Daidzein 510.3 (111.5) 313.2 (111.5) 444.4 (63.6) 0.88 106.2 (55.3)
Plasma Glycitein 26.0 (4.1) 11.3 (4.1) 15.2 (2.3) 0.13 8.0 (2.0)
1
In ISP group, 6 women had only baseline plasma equol measurements.
2
All means over trial follow-up were evaluated by GLMM (generalized linear mixed model) with a compound-
symmetry covariance structure. Model included intercept as a random effect, and equol-producer groups as a fixed
effect. The equol-producer status was specified as a continuous variable for trend test.
3
Change variables computed at every six months follow-up visit=visit value-baseline value.
4
Significant on-trial mean difference in the change of hot flash number between consistent equol-producer with
placebo group and non equol-producer (p-value=0.04, 0.01; respectively);
Significant on-trial mean difference in the change of hot flash composite score between consistent equol-producer
and non equol-producer (p-value=0.03);
Significant on-trial mean difference in plasma genistein between consistent equol-producer with placebo group and
intermittent equol-producer (p-value= <0.0001, 0.02; respectively);
Significant on-trial mean difference in plasma daidzein between placebo group with consistent equol-producer and
non equol-producer (p-value= 0.001, <0.0001; respectively);
Significant on-trial mean difference in plasma glycitein between consistent equol-producer with non equol-producer,
intermittent equol-producer, and placebo group (p-value= 0.02, 0.01m <0.0001; respectively).
27

CHAPTER IV
DISCUSSION

Our data from the Women’s Isoflavone Soy Health (WISH) trial indicate no overall
evidence to support the use of isoflavone soy protein (ISP) treat hot flash symptoms in
healthy postmenopausal women. Over 30 months of randomized intervention, ISP and
placebo groups did not significantly differ on the daily hot flash and composite scores. A
significant inverse association was observed between plasma glycitein and hot flash
severity in ISP treated women. Thus women with higher plasma glycitein levels achieved
through ISP supplementation may find some benefit in relieving hot flash symptoms.
In previous trials, treatment duration was no more than one year, and most were less
than 3 months (range=4 weeks to 1 year). Crisafulli et al. examined the effect of genistein
(54 mg/day, n=30) or estradiol (1 mg 17beta-estradiol combined with 0.5 mg
norethisterone per day, n=30) compared to placebo (n=30) on hot flushes among 90
natural menopausal women who participated in a bone loss trial [31]. After 12 months of
treatment intervention, both genistein and estrogen treated women had significant
reductions from baseline in hot flash frequency (mean reduction: 24%, p<0.01; 54%,
p<0.001; respectively). Only estrogen-treated women had a significant reduction in hot
flash frequency compared to the placebo (mean difference: 24%, p<0.01). The reduction
in hot flash frequency in the estrogen group was also greater than that of the genistein
group (mean difference: 30%, p<0.05). The authors concluded that genistein might have
benefits on relieving flushing with no side effect on endometrial thickness. (similar to the
28

current study) The sample sizes in previous studies were less than 50 subjects per group.
Few trials investigated the treatment effect in plasma isoflavone concentrations or
considered subset analyses of equol-producers who generate greater responses from soy
isoflavone diets and may have more relief on flushing symptoms [47].
The reported effect of soy isoflavones on flushing was inconsistent in prior studies.
Several studies found no treatment benefit on hot flash frequency compared to placebo
with soy isoflavone (72 mg/day including 36 mg isoflavone and 48 mg soy
saponine)[23], 25 g soy tablet (medium dose of isoflavone 42 mg/day or higher dose of
isoflavone 58 mg/day )[24], or genistein and daidzein (50 mg/day)[25]. Although hot
flashes may be more troublesome in women who have survived breast cancer than in
postmenopausal women due to premature menopause from chemotherapy or drug
(tamoxifen) side effects, five trials of menopausal women with breast cancer treated with
soy isoflavones found no differences in hot flash frequency or severity scores compared
to placebo [26-30].
Three previous studies reported a benefit of soy isoflavone on hot flash frequency
[31-33], and two studies indicated significant group differences in severity scores
compared with placebo using soy capsules (83 mg three times daily including 50 mg soy
protein, 23 mg genistein, 6 mg diadzein, and 4 mg glycitein)[34], or genistein and
diadzein(50 mg/day))[33]. The mixed results may be due to the differences in
formulation of soy supplements, study design, duration of soy exposure, study
populations, and individual variation in isoflavone metabolism.
29

In WISH, both ISP and placebo groups showed a significant reduction in the number
of daily hot flashes and composite scores from baseline, that did not differ by treatment
group. One study comparing soy isoflavone (70 mg/day of genistein and daidzein) with
placebo indicated a significant reduction in hot flash frequency from baseline to 16 weeks
(p-value=0.01, 61% of isoflavone vs. 21% of placebo sample exhibited reduction from
baseline) [32]. Another study randomized women to soy isoflavone (50 mg/day of
genistein and daidzein) or placebo, and noted a significant reduction in hot flash
frequency from baseline to 6 weeks (p-value<0.05, 40% of isoflavone vs. 25% of placebo
sample exhibited reduction from baseline).[33] From these two studies, we may conclude
that women assigned to higher doses of soy isoflavone may have greater reductions in hot
flash frequency. In two recent meta-analyses, the group mean difference in daily number
of hot flashes was -1.1 between soy isoflavone- and placebo-treated group, and was -2.3
between hormone replacement therapy- and placebo-treated group [35-36].
The placebo effect may be another explanation for the equivalent reduction in
flushing between ISP and placebo group in our study. The improvement in self-reported
hot flash symptoms may be due to the expectation that taking medication will lead to
some beneficial effect, especially for motivated women. We could address this bias by
using objective measurement techniques such as monitoring skin conductance [37-38] or
use of a support vector machine (SVM) [49] to measure hot flashes. Alternatively, a more
detailed questionnaire or closer contact with patients may help to obtain more accurate
information about hot flashes. These results demonstrate the importance of blinding to
30

intervention and use of placebo controlled studies to evaluate interventions utilizing
somewhat subjective self-reported outcomes.
Several subgroup analyses were performed to investigate possible benefits from ISP
in our study. As expected, thinner women (BMI <25.0
2
/ kg m ) had a lower frequency of
hot flashes and composite scores compared to overweight women (BMI ≥25.0
2
/ kg m ) at
baseline. Previous studies noted that women with higher BMI may have a higher
frequency of hot flashes than women with lower BMI [39-40], although one study stated
that the BMI-related higher frequency of moderate and severe hot flashes only could be
found in younger (40 to 50 years old) or premenopausal women, not in older (51 to 60
years old) or postmenopausal women [41]. Among thinner women (BMI <25.0
2
/ kg m )
assigned to the placebo group, the mean reduction in hot flash frequency and composite
scores over 6-months trial periods were not significantly different from zero (p >0.05).
The relative lack of change in hot flashes among placebo-treated women with lower BMI
may also be due to a floor effect.
The on-trial plasma concentrations of genistein, daidzein, and glycitein were
significantly and markedly higher in the ISP group than the placebo group.(Table 5)
Furthermore, there was an inverse association between the levels of plasma glycitein and
the change in composite scores in ISP-treated women (p=0.02). Although the exact
mechanism of the hot flash is unknown, disruption of neural signals to the hypothalamus,
which controls body temperature, is likely involved [42-43]. Although glycitein has the
weakest estrogenic activity compared to genistein and daidzein [44], our results suggest
that postmenopausal women may reduce severe hot flashes when achieving higher level
31

of plasma glycitein through ISP supplementation. Further studies are warranted to
explore a possible benefit of glycitein in postmenopausal women.
Recent studies suggest that subjects who generate consistent levels of plasma equol
from the metabolism of soy isoflavone daidzein may achieve greater benefits than non
equol-producers [46-48]. Our data support the above hypothesis. Women who were
consistent equol-producers had the highest mean reduction in hot flash frequency and
composite scores during the trial (-2.39±0.62, -3.92±1.22; respectively, Table 8).
Conversely the lowest mean change in hot flash activities was observed among women
who were non equol-producers (-0.60±0.36, -0.86±0.70; respectively, Table 8).
Consistent equol-producers significantly differed from the placebo-treated women in the
change of daily hot flash number (p=0.04). However, the conclusion should be stated
with extreme caution due to the very small sample size for each equol-producer status in
our study. It is also unclear why the lowest plasma concentrations of genistein, diadzein,
and glycitein were observed among intermittent equol-producers.
Our trial, with a sample size of approximately 50 postmenopausal women per
treatment group and more than one year of treatment duration, has several limitations.
First, the Women’s Isoflavone Soy Health (WISH) Trial was not specifically designed to
investigate the treatment effect on hot flash symptoms. Such a trial would require
different inclusion or exclusion criteria for different study populations. The typical
inclusion criteria for trials testing a hot flash intervention are absence of periods for more
than 12 months or bilateral oophorectomy for more than 6 months, healthy
postmenopausal women aged at least 30 years old (range: 30 to 75 years old), and no
32

current medication for menopausal symptoms. The most important inclusion criterion is
the definition of bothersome hot flashes occurring prior to study entry. In previous
studies, women were experiencing at least 5 hot flashes per day (range: at least 2 to 7 hot
flashes per day). Second, our results may not apply to other populations, especially peri-
menopausal women who have higher frequency of hot flashes than postmenopausal
women or women with breast cancer who have a different mechanism of hot flashes.
Selective dropout may be an issue in our study, because the treatment effect of ISP
could differ between women who discontinue and women who remain in the trial. In the
first 12 months, 7 (13%) ISP-treated women and 10 (21%) placebo-treated women
dropped from the trial. Over the entire 30-month trial period, 12 (23%) ISP-treated and
14 (29%) placebo-treated women did not complete the trial. Women who dropped from
the trial were experiencing on average 3.9 hot flashes per day (median: 3.2 hot flashes)
and having 7.4 units of composite scores (median: 4.0 units) at baseline. In contrast,
women who remained in the trial were experiencing on average 3.0 hot flashes per day
(median: 2.2 hot flashes) and having 4.8 units of composite scores (median: 2.6 units). At
baseline, the mean difference on the hot flash frequency or composite scores was not
significant between women who discontinued and who remained in the trial (p=0.16 and
0.08; respectively). Thus, women with higher frequency of hot flash may feel more
uncomfortable and try to seek alternative therapies such as HT during the trial. How to
deal with the resulting missing values that are not missing at random would be a key
issue in trials testing a hot flash intervention.
33

In conclusion, data from the Women’s Isoflavone Soy Health (WISH) Trial showed
no significant treatment benefits of soy isoflavones on flushing. Our study provided new
information on the association between the levels of plasma glycitein and the reduction in
hot flash symptoms considering equol-producer status. Current evidence does not
indicate that soy isoflavones containing genistein, daidzein and glycitein may be an
alternative treatment for relieving menopausal symptoms. In the future, additional
randomized clinical trials or focused studies are needed to elucidate how plasma glycitein
may relieve the menopausal symptoms.
34

REFERENCES

[1]. Anne N, Jill M, Miranda W, Peggy N, et al. Complementary and Alternative
Therapies for the Management of Menopause-Related Symptoms. Archives of
Internal Medicine. 2006; 166(14): 1453-65.
[2]. Nelson HD. Commonly used types of postmenopausal estrogen for treatment of
hot flashes. JAMA. 2004; 291(13): 1610-11.
[3]. Oldenhave A, Jaszmann L, Haspels AA, Everaerd WT. Impact of climacteric on
well-being: a survey based on 5213 women 39 to 60 years old. American Journal
of Obstetrics and Gynecology. 1993; 168: 772-80.
[4]. Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal
hormone replacement therapy: scientific review.(Scientific Review and Clinical
Applications). JAMA. 2002; 288: 872-881.
[5]. Mary P. Gillam By J. Larry Jameson. Management of menopause-related
symptoms. Postgraduate Medicine. 2005; 118(4): 11.
[6]. Writing Group for the Women's Health Initiative Investigators. Risks and Benefits
of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results
From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002;
288(3): 321-333.
[7]. Utian W, Archer D, Bachmann G, Gallagher C, Grodstein F, Heiman J,
Henderson V, Hodis H, Karas R, Lobo R and others. Estrogen and progestogen
use in postmenopausal women: July 2008 position statement of The North
American Menopause Society. Menopause. 2008; 15:584-602.
[8]. Wassertheil SS, Hendrix S, Limacher M, Heiss G, Kooperberg C, et al. Effect of
Estrogen Plus Progestin on Stroke in Postmenopausal Women: The Women's
Health Initiative: A Randomized Trial. JAMA. 2003; 289(20): 2673-2684.
[9]. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix
SL, et al. Estrogen Plus Progestin and the Incidence of Dementia and Mild
Cognitive Impairment in Postmenopausal Women: The Women's Health Initiative
Memory Study: A Randomized Controlled Trial. JAMA. 2003; 289(20):2651-
2662.
35

[10]. Hays J, Ockene JK, Brunner RL, Kotchen JM, et al. Effects of Estrogen plus
Progestin on Health-Related Quality of Life. N Engl J Med. 2003; 348: 1839-
1854.
[11]. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, et al. Influence of
Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy
Postmenopausal Women: The Women's Health Initiative Randomized Trial.
JAMA. 2003; 289(24): 3243-3253.
[12]. Stephenson J. FDA Orders Estrogen Safety Warnings: Agency Offers Guidance
for HRT Use. JAMA. 2003; 289(5): 537.
[13]. Boulet MJ, Oddens BJ, Lehert P, Vemer HM, Visser A. Climacteric and
menopause in seven south-east Asian countries. Maturitas. 1994; 19(3): 157-176.
[14]. Coward L, Barnes NC, Setchell KD, Barnes S. Genistein, daidzein, and their
{beta}-glycoside conjugates: antitumor isoflavones in soybean foods from
American and Asian diets. Journal of Agricultural and Food
Chemistry. 1993; 41(11): 1961-1967.
[15]. Obermeyer, Makhlouf C. Menopause Across Cultures: A Review of the Evidence.
Menopause. 2000; 7: 184-192.
[16]. Grace W.K, Tang. The climacteric of Chinese factory workers. Maturitas. 1994;
19(3): 177-182.
[17]. Lock M. Encounters with aging: mythologies of menopause in Japan and North
America. University of California Press. 1993.
[18]. Setchell KD. Phytoestrogens: the biochemistry, physiology, and implications for
human health of soy isoflavones. American Journal of Clinical Nutrition. 1998;
68: 1333-46.
[19]. Setchell KD. Soy Isoflavones--Benefits and Risks from Nature's Selective
Estrogen Receptor Modulators (SERMs). J Am Coll Nutr. 2001; 20: 354-362
[20]. Kurzer MS, Xu X. Dietary phytoestrogens. Annu Rev Nutr. 1997; 17: 353-81.
[21]. Bethesda. Lipid Research Clinics Program. The Manual of laboratory Operations;
Lipid and Lipoprotein Analysis. National Institutes of Health. 1974; 75-628.
[22]. Radloff L. The CES-D scale: A self-report depression scale for research in the
general population. Applied Psychological Measurement. 1977; 1: 385-401.
36

[23]. Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Viganó P. Effect of soy-
derived isoflavones on hot flushes, endometrial thickness, and the pulsatility
index of the uterine and cerebral arteries. Fertil Steril. 2003; 79 (5): 1112-1117.
[24]. Burke GL, Legault C, 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(2): 147-153.
[25]. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor
symptom relief by soy isoflavone extract tablets in postmenopausal women: a
multicenter, double-blind, randomized, placebo-controlled study.
Menopause. 2000; 7(4): 236-242.
[26]. MacGregor CA, Canney PA, Patterson G, McDonald R, Paul J. A randomised
double-blind controlled trial of oral soy supplements versus placebo for treatment
of menopausal symptoms in patients with early breast cancer. European Journal of
Cancer. 2005; 41(5): 708-714.
[27]. Secreto G, Chiechi LM, Amadori A, Miceli R, Venturelli E, et al. Soy isoflavones
and melatonin for the relief of climacteric symptoms: a multicenter, double-blind,
randomized study. Maturitas. 2004; 47(1): 11-20.
[28]. Nikander E, Kilkkinen A, Metsä-Heikkilä A, Adlercreutz H, et al. A Randomized
Placebo-Controlled Crossover Trial With Phytoestrogens in Treatment of
Menopause in Breast Cancer Patients. Obstetrics & Gynecology. 2003; 101(6):
1213-1220.
[29]. Quella SK, Loprinzi CL, Barton DL, Knost JA, Sloan JA, et al. Evaluation of Soy
Phytoestrogens for the Treatment of Hot Flashes in Breast Cancer Survivors: A
North Central Cancer Treatment Group Trial. JCO. 2000; 18: 1068-1074.
[30]. Patten CLV, Olivotto IA, Chambers GK, Gelmon KA, Hislop TG, et al. Effect of
Soy Phytoestrogens on Hot Flashes in Postmenopausal Women With Breast
Cancer: A Randomized, Controlled Clinical Trial. JCO. 2002; 20(6): 1449-1455.
[31]. Crisafulli A, Marini H, Bitto A, Altavilla D, et al. Effects of genistein on hot
flushes in early postmenopausal women: a randomized, double-blind EPT- and
placebo-controlled study. Menopause. 2004; 11(4): 400-404.
[32]. Faure ED, Chantre P,Mares P. Effects of a standardized soy extract on hot
flushes: a multicenter, double-blind, randomized, placebo-controlled study.
Menopause. 2002; 9(5): 329-334.
37

[33]. Scambia G, Mango D, Signorile PG, Angeli RA, et al. Clinical Effects of a
Standardized Soy Extract in Postmenopausal Women: A Pilot Study. Menopause.
2000; 7(2): 105-111.
[34]. Han KK, Soares JM, Haidar MA, de Lima GR, et al. Benefits of Soy Isoflavone
Therapeutic Regimen on Menopausal Symptoms. Obstetrics & Gynecology.
2002; 99(3): 389-394.
[35]. Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, et al. Nonhormonal Therapies
for Menopausal Hot Flashes: Systematic Review and Meta-analysis. JAMA.
2006; 295(17): 2057-2071.
[36]. Nelson HD. Commonly Used Types of Postmenopausal Estrogen for Treatment
of Hot Flashes: Scientific Review. JAMA. 2004; 291(13): 1610-1620.
[37]. Freedman RR. Laboratory and Ambulatory Monitoring of Menopausal Hot
Flashes. Psychophysiology. 1989; 26(5): 573-579.
[38]. Freedman RR, Blacker CM. Estrogen raises the sweating threshold in
postmenopausal women with hot flashes. Fertil Steril. 2002; 77: 487-490.
[39]. Gold EB, Sternfeld B, Kelsey JL, Brown C , Mouton C, et al. Relation of
Demographic and Lifestyle Factors to Symptoms in a Multi-Racial/Ethnic
Population of Women 40–55 Years of Age. Am. J. Epidemiol. 2000; 152: 463-
473.
[40]. Freeman EW, Sammel MD, Grisso JA, Battistini M, el al. Hot Flashes in the Late
Reproductive Years: Risk Factors for African American and Caucasian Women.
Journal of Women's Health & Gender-Based Medicine. 2001; 10(1): 67-76.
[41]. Whiteman MK, Staropoli CA, Langenberg PW, Patricia McCarter RJ, et al.
Smoking, Body Mass, and Hot Flashes in Midlife Women. Obstetrics &
Gynecology. 2003; 101(2): 264-272.
[42]. Rossmanith WG, Ruebberdt W, et al. What causes hot flushes? The
neuroendocrine origin of vasomotor symptoms in the menopause. Gynecological
Endocrinology. 2009; 25(5): 303 – 314.
[43]. Website: http://www.breastcancer.org/tips/menopausal/facing/hot_flashes.jsp
[44]. Song TT, Hendrich S, Murphy PA. Estrogenic activity of glycitein, a soy
isoflavone. J Agric Food Chem. 1999; 47(4):1607-10.
38

[45]. Gutierrez-Zepeda A,, Santell R, Wu Z, et al. Soy isoflavone glycitein protects
against beta amyloid-induced toxicity and oxidative stress in
transgenic Caenorhabditis elegans. BMC Neuroscience. 2005; 6:54.
[46]. Setchell, KDR, Clerici, Carlo, Lephart, Edwin D, et al. S-Equol, a potent ligand
for estrogen receptor {beta}, is the exclusive enantiomeric form of the soy
isoflavone metabolite produced by human intestinal bacterial flora. Am J Clin
Nutr. 2005; 81: 1072-1079.
[47]. Setchell KDR, Brown NM, Lydeking-Olsen E. The clinical importance of the
metabolite equol-a clue to the effectiveness of soy and its isoflavones. J
Nutr. 2002; 132(12): 3577-84.
[48]. Setchell KD, Cole SJ. Method of defining equol-producer status and its frequency
among vegetarians. J Nutr. 2006; 136(8): 2188-93.
[49]. Thurston RC, Mattews KA, et al. Improving the performance of physiologic hot
flash measures with support vector machines. Psychophysiology. 2009; 46(2):
285–292.
39

ALPHABETIZED REFERENCES

[1]. Anne N, Jill M, Miranda W, Peggy N, et al. Complementary and Alternative
Therapies for the Management of Menopause-Related Symptoms. Archives of
Internal Medicine. 2006; 166(14): 1453-65.
[21]. Bethesda. Lipid Research Clinics Program. The Manual of laboratory Operations;
Lipid and Lipoprotein Analysis. National Institutes of Health. 1974; 75-628.
[13]. Boulet MJ, Oddens BJ, Lehert P, Vemer HM, Visser A. Climacteric and
menopause in seven south-east Asian countries. Maturitas. 1994; 19(3): 157-176.
[24]. Burke GL, Legault C, 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(2): 147-153.
[11]. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, et al. Influence of
Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy
Postmenopausal Women: The Women's Health Initiative Randomized Trial.
JAMA. 2003; 289(24): 3243-3253.
[14]. Coward L, Barnes NC, Setchell KD, Barnes S. Genistein, daidzein, and their
{beta}-glycoside conjugates: antitumor isoflavones in soybean foods from
American and Asian diets. Journal of Agricultural and Food
Chemistry. 1993; 41(11): 1961-1967.
[31]. Crisafulli A, Marini H, Bitto A, Altavilla D, et al. Effects of genistein on hot
flushes in early postmenopausal women: a randomized, double-blind EPT- and
placebo-controlled study. Menopause. 2004; 11(4): 400-404.
[32]. Faure ED, Chantre P,Mares P. Effects of a standardized soy extract on hot flushes:
a multicenter, double-blind, randomized, placebo-controlled study. Menopause.
2002; 9(5): 329-334.
[40]. Freeman EW, Sammel MD, Grisso JA, Battistini M, el al. Hot Flashes in the Late
Reproductive Years: Risk Factors for African American and Caucasian Women.
Journal of Women's Health & Gender-Based Medicine. 2001; 10(1): 67-76.
[37]. Freedman RR. Laboratory and Ambulatory Monitoring of Menopausal Hot
Flashes. Psychophysiology. 1989; 26(5): 573-579.
[38]. Freedman RR, Blacker CM. Estrogen raises the sweating threshold in
postmenopausal women with hot flashes. Fertil Steril. 2002; 77: 487-490.
40

[39]. Gold EB, Sternfeld B, Kelsey JL, Brown C , Mouton C, et al. Relation of
Demographic and Lifestyle Factors to Symptoms in a Multi-Racial/Ethnic
Population of Women 40–55 Years of Age. Am. J. Epidemiol. 2000; 152: 463-
473.
[16]. Grace W.K, Tang. The climacteric of Chinese factory workers. Maturitas. 1994;
19(3): 177-182.
[45]. Gutierrez-Zepeda A,, Santell R, Wu Z, et al. Soy isoflavone glycitein protects
against beta amyloid-induced toxicity and oxidative stress in
transgenic Caenorhabditis elegans. BMC Neuroscience. 2005; 6:54.
[34]. Han KK, Soares JM, Haidar MA, de Lima GR, et al. Benefits of Soy Isoflavone
Therapeutic Regimen on Menopausal Symptoms. Obstetrics & Gynecology.
2002; 99(3): 389-394.
[10]. Hays J, Ockene JK, Brunner RL, Kotchen JM, et al. Effects of Estrogen plus
Progestin on Health-Related Quality of Life. N Engl J Med. 2003; 348: 1839-
1854.
[20]. Kurzer MS, Xu X. Dietary phytoestrogens. Annu Rev Nutr. 1997; 17: 353-81.
[17]. Lock M. Encounters with aging: mythologies of menopause in Japan and North
America. University of California Press. 1993.
[26]. MacGregor CA, Canney PA, Patterson G, McDonald R, Paul J. A randomised
double-blind controlled trial of oral soy supplements versus placebo for treatment
of menopausal symptoms in patients with early breast cancer. European Journal of
Cancer. 2005; 41(5): 708-714.
[5]. Mary P. Gillam By J. Larry Jameson. Management of menopause-related
symptoms. Postgraduate Medicine. 2005; 118(4): 11.
[2]. Nelson HD. Commonly used types of postmenopausal estrogen for treatment of
hot flashes. JAMA. 2004; 291(13): 1610-11.
[4]. Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal
hormone replacement therapy: scientific review.(Scientific Review and Clinical
Applications). JAMA. 2002; 288: 872-881.
[35]. Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, et al. Nonhormonal Therapies
for Menopausal Hot Flashes: Systematic Review and Meta-analysis. JAMA.
2006; 295(17): 2057-2071.
41

[36]. Nelson HD. Commonly Used Types of Postmenopausal Estrogen for Treatment of
Hot Flashes: Scientific Review. JAMA. 2004; 291(13): 1610-1620.
[28]. Nikander E, Kilkkinen A, Metsä-Heikkilä A, Adlercreutz H, et al. A Randomized
Placebo-Controlled Crossover Trial With Phytoestrogens in Treatment of
Menopause in Breast Cancer Patients. Obstetrics & Gynecology. 2003; 101(6):
1213-1220.
[15]. Obermeyer, Makhlouf C. Menopause Across Cultures: A Review of the Evidence.
Menopause. 2000; 7: 184-192.
[3]. Oldenhave A, Jaszmann L, Haspels AA, Everaerd WT. Impact of climacteric on
well-being: a survey based on 5213 women 39 to 60 years old. American Journal
of Obstetrics and Gynecology. 1993; 168: 772-80.
[30]. Patten CLV, Olivotto IA, Chambers GK, Gelmon KA, Hislop TG, et al. Effect of
Soy Phytoestrogens on Hot Flashes in Postmenopausal Women With Breast
Cancer: A Randomized, Controlled Clinical Trial. JCO. 2002; 20(6): 1449-1455.
[23]. Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Viganó P. Effect of soy-
derived isoflavones on hot flushes, endometrial thickness, and the pulsatility
index of the uterine and cerebral arteries. Fertil Steril. 2003; 79 (5): 1112-1117.
[29]. Quella SK, Loprinzi CL, Barton DL, Knost JA, Sloan JA, et al. Evaluation of Soy
Phytoestrogens for the Treatment of Hot Flashes in Breast Cancer Survivors: A
North Central Cancer Treatment Group Trial. JCO. 2000; 18: 1068-1074.
[22]. Radloff L. The CES-D scale: A self-report depression scale for research in the
general population. Applied Psychological Measurement. 1977; 1: 385-401.
[42]. Rossmanith WG, Ruebberdt W, et al. What causes hot flushes? The
neuroendocrine origin of vasomotor symptoms in the menopause. Gynecological
Endocrinology. 2009; 25(5): 303 – 314.
[33]. Scambia G, Mango D, Signorile PG, Angeli RA, et al. Clinical Effects of a
Standardized Soy Extract in Postmenopausal Women: A Pilot Study. Menopause.
2000; 7(2): 105-111.
[27]. Secreto G, Chiechi LM, Amadori A, Miceli R, Venturelli E, et al. Soy isoflavones
and melatonin for the relief of climacteric symptoms: a multicenter, double-blind,
randomized study. Maturitas. 2004; 47(1): 11-20.
[18]. Setchell KD. Phytoestrogens: the biochemistry, physiology, and implications for
human health of soy isoflavones. American Journal of Clinical Nutrition. 1998;
68: 1333-46.
42

[47]. Setchell KDR, Brown NM, Lydeking-Olsen E. The clinical importance of the
metabolite equol-a clue to the effectiveness of soy and its isoflavones. J
Nutr. 2002; 132(12): 3577-84.
[46]. Setchell, KDR, Clerici, Carlo, Lephart, Edwin D, et al. S-Equol, a potent ligand
for estrogen receptor {beta}, is the exclusive enantiomeric form of the soy
isoflavone metabolite produced by human intestinal bacterial flora. Am J Clin
Nutr. 2005; 81: 1072-1079.
[48]. Setchell KD, Cole SJ. Method of defining equol-producer status and its frequency
among vegetarians. J Nutr. 2006; 136(8): 2188-93.
[19]. Setchell KD. Soy Isoflavones--Benefits and Risks from Nature's Selective
Estrogen Receptor Modulators (SERMs). J Am Coll Nutr. 2001; 20: 354-362
[9]. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL,
et al. Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive
Impairment in Postmenopausal Women: The Women's Health Initiative Memory
Study: A Randomized Controlled Trial. JAMA. 2003; 289(20):2651-2662.
[44]. Song TT, Hendrich S, Murphy PA. Estrogenic activity of glycitein, a soy
isoflavone. J Agric Food Chem. 1999; 47(4):1607-10.
[12]. Stephenson J. FDA Orders Estrogen Safety Warnings: Agency Offers Guidance
for HRT Use. JAMA. 2003; 289(5): 537.
[49]. Thurston RC, Mattews KA, et al. Improving the performance of physiologic hot
flash measures with support vector machines. Psychophysiology. 2009; 46(2):
285–292.
[25]. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor
symptom relief by soy isoflavone extract tablets in postmenopausal women: a
multicenter, double-blind, randomized, placebo-controlled study.
Menopause. 2000; 7(4): 236-242.
[7]. Utian W, Archer D, Bachmann G, Gallagher C, Grodstein F, Heiman J,
Henderson V, Hodis H, Karas R, Lobo R and others. Estrogen and progestogen
use in postmenopausal women: July 2008 position statement of The North
American Menopause Society. Menopause. 2008; 15:584-602.
[8]. Wassertheil SS, Hendrix S, Limacher M, Heiss G, Kooperberg C, et al. Effect of
Estrogen Plus Progestin on Stroke in Postmenopausal Women: The Women's
Health Initiative: A Randomized Trial. JAMA. 2003; 289(20): 2673-2684.
[43]. Website: http://www.breastcancer.org/tips/menopausal/facing/hot_flashes.jsp
43

[41]. Whiteman MK, Staropoli CA, Langenberg PW, Patricia McCarter RJ, et al.
Smoking, Body Mass, and Hot Flashes in Midlife Women. Obstetrics &
Gynecology. 2003; 101(2): 264-272.
[6]. Writing Group for the Women's Health Initiative Investigators. Risks and Benefits
of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results
From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002;
288(3): 321-333.

Abstract (if available)

Abstract Background: Isoflavone soy protein (ISP) is used as an alternative to steroidal hormone therapies for alleviating menopausal hot flash symptoms

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Asset Metadata

Creator Chien, ChunJu (author)

Core Title Soy isoflavone supplements for the treatment of menopausal hot flashes: the Women’s Isoflavone Soy Health (WISH) trial

School Keck School of Medicine

Degree Master of Science

Degree Program Biostatistics

Publication Date 11/07/2010

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag equol-producer,glycitein,hot flash,isoflavone,OAI-PMH Harvest,postmenopausal

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Mack, Wendy J. (committee chair), Azen, Stanley Paul (committee member), Karim, Roksana (committee member)

Creator Email chienchunju@gmail.com,chunjuc@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m3518

Unique identifier UC1261928

Identifier etd-CHIEN-4163 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-397902 (legacy record id),usctheses-m3518 (legacy record id)

Legacy Identifier etd-CHIEN-4163.pdf

Dmrecord 397902

Document Type Thesis

Rights Chien, ChunJu

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

Repository Location Los Angeles, California

Repository Email cisadmin@lib.usc.edu