INTRODUCTION

Menopause, a pivotal phase in a woman's life, marks the cessation of ovarian function
and the conclusion of reproductive capacity. Menopause, a natural biological transition in a
woman's life, marks the cessation of reproductive capabilities and signifies the onset of a new
phase of hormonal fluctuations. Alongside this biological milestone, a spectrum of distressing
symptoms, collectively known as menopausal symptoms, often emerges. These symptoms,
encompassing hot flashes, night sweats, mood swings, insomnia, and vaginal dryness, can
significantly affect a woman's quality of life and overall well-being. For decades, Hormone
Replacement Therapy (HRT) has stood as the conventional approach to manage these
symptoms, utilizing exogenous hormones to offset the decline in endogenous estrogen
levels.1
However, concerns surrounding the safety and long-term use of HRT, including
potential links to increased risks of cardiovascular disease, breast cancer, and
thromboembolic events, have led to a quest for safer and effective alternative therapies. In
light of these safety concerns, it has become imperative to emphasize careful consideration
and individualized assessment of risks and benefits before initiating HRT. Not all women are
suitable candidates for HRT, and safety management strategies are crucial to minimize
associated risks.1,2
Among the alternatives gaining attention is the use of isoflavones, plant-derived
compounds with structural similarity to estrogen. Isoflavones, naturally occurring
phytoestrogens found in abundance in soy-based products and certain legumes, have emerged
as a potential alternative. These plant-derived compounds possess estrogenic properties,
allowing them to potentially mimic the effects of estrogen in the body, thus alleviating
menopausal symptoms.3
Despite their promise, the integration of isoflavones into mainstream menopausal
symptom management is met with ambiguities and challenges. Diverse study outcomes,
varying methodological approaches, and conflicting evidence have contributed to the
uncertainty surrounding their efficacy and safety. This research endeavors to elucidate the
potential of isoflavones as a mainstream therapy for managing menopausal symptoms,
addressing the ambiguities that encircle their use, and devising strategies to surmount
challenges hindering their broader acceptance.4
This research aims to elucidate the potential of isoflavones as a mainstream therapy
for managing menopausal symptoms, addressing the ambiguities surrounding their use, and
exploring strategies to overcome challenges hindering their broader acceptance. By
thoroughly reviewing existing literature, consolidating evidence, and critically evaluating the
merits and limitations of isoflavone-based therapy, this study seeks to provide a
comprehensive understanding of their role in the management of menopausal symptoms.
Ultimately, this investigation strives to contribute to a clearer pathway for the integration of
isoflavones as a viable and safe alternative therapy for menopausal symptom relief,
advancing women's health and well-being during this significant life stage.5

METHODS
This study is a systematic review of the literature of relevant studies published from
1994 to 2022. The search method used as reference for the research was the PRISMA
“Preferred Reporting Items for Systematic Reviews and Meta-Analyses”. The literature
review conducted based on the search for scientific articles on the subject “Use of soy
isoflavones for the relief of symptoms in meopausal women as alternative/adjunctive therapy
to hormone replacement therapy” on the PubMed, EMBASE, and Web of Science databases,
in the English language. The descriptors, words, and combinations for searching for data
were “Menopausal symptoms” AND (Isoflavone∗ OR Hormone therapy∗ OR “Equol”). The
criteria for inclusion of articles were: (A) Studies on the metabolism of isoflavones; (B) Peri
or postmenopausal women; (C) Randomized controlled trials (RCTs) evaluating isoflavones
and/or hormone replacement therapy; (D) Articles with the objective of verifying the
influence or effects of isoflavones on additional health benefits in menopausal women; (E)
Systematic reviews and meta-analyses; (F) Consensus/guidelines. Exclusion criteria applied
were (G) women out of peri- or postmenopausal period, (H) some chronic associated illness,
and (I) research with outcomes that are different from those desired by the researcher,
literature in the form of review articles, case reports, case studies, and conference abstracts.
During the bibliographic search phase, the analysis of titles, reading of abstracts, exclusion of
duplicates, complete reading of articles of interest, and inclusion of the data in the review
were completed.
The search strategy yielded 24,676 abstracts. Based on the review process, 176
abstracts were reviewed, 56 excluded and 120 unique trial reports were identified that met the
study inclusion and exclusion criteria. Of these, 33 focused on RCTs, 16 on crossover studies,
46 on literature review, systematic review or meta-analyses, and 25 in vitro reports or animal
studies (Fig. 1).
 PubMed, EMBASE, and Web
of Science search strategy
yielded 24,676 abstracts

176 abstracts were reviewed

119 abstracts were excluded

57 studies were reviewed

and included

Randomized Literature and Systematic

Crossover Studies In Vitro/
Controlled Trial Review/
n=12 Animal Studies
(RCT) Meta-analysis/Guidelines n=7
n=18 n=20

Fig. 1. Results of literature search and review

DISCUSSION
I. Isoflavone
Isoflavones are composed of two benzene rings linked through a heterocyclic pyrane
C-ring at the 3 position, which distinguishes them from flavones. Being malonyl-glucoside
conjugates in chemical structures, the primary isoflavones in soybeans belong to the daidzein,
genistein and glycitein families. Each family comprises its respective aglycone, β-glucoside,
malonyl-glucoside and acetyl-glucoside. Malonyl-glucoside is the predominant form of many
isoflavones in unprocessed soybeans. Research has revealed that malonyl-glucoside is heat
sensitive and easily converted to its corresponding acetyl-glucoside and/or β-glucoside
according to the thermal conditions of preparation and processing [7]. Similarly, a study has
indicated that soy flour that had not been heat-treated mainly contained malonyl-β-glucoside
conjugates; by contrast, heated soy flour consisted of large amounts of acetyl-β-glucoside
conjugates, formed by means of heat-induced decarboxylation of the malonate group to
acetate. Analyzed using high- performance liquid chromatography (HPLC)-mass
spectrometry, isolated soy proteins and textured vegetable proteins were composed of a
mixture of all three types of isoflavone conjugates. Frying or baking of textured vegetable
proteins at 190 ◦C and baking of soy flour did not change the total content of isoflavones, but
there was a stable increase in β-glucoside conjugates at the expense of malonyl-β-glucoside
conjugated. Therefore, the chemical structures of isoflavones in foods should be considered
when evaluating the availability of isoflavones for absorption from the diet. Different
processing conditions produce soybean products with a variety of isoflavone composition and
content. Recently, research has shown that the chemical structures and abundance of
isoflavones in soybean foods have an important impact on their biological effects and
bioavailability.6,7,8

Figure 2. The chemical structures of isoflavones including daidzin and genistin and their
derivatives daidzein, genistein and S-equol (structurally similar to estrogen). daidzein,
genistein and S-equol (structurally similar to estrogen).9

II. Isoflavone And Menopause Symptoms

(Barnard, et al., 2023) (Level of evidence: 1A) A randomized controlled trial was
conducted to test the effects of a dietary intervention on vasomotor symptoms and
menopause-related quality of life. Postmenopausal women were randomly assigned to an
intervention including a low-fat, vegan diet and cooked soybeans or to a control group
making no dietary changes. The intervention group reported greater reductions in vasomotor,
physical, and sexual symptoms, and moderate-to-severe hot flashes decreased by 88%
compared with 34% for the control group.10
(Maliehe, et al., 2019) (Level of evidence: 1A) This article provides an overview of
meta-analyses on the effect of isoflavones and genistein on glucose metabolism in peri- and
post-menopausal women. The included meta-analyses found that treatment with isoflavones
and genistein had a significant beneficial effect on fasting insulin levels and insulin resistance
in peri- and post-menopausal women. Specifically, fasting insulin levels and homeostatic
model assessment of insulin resistance (HOMA-IR) values were significantly lower in
women treated with isoflavones and genistein compared to the control group. However, the
effect on fasting blood glucose levels was inconsistent, with some studies showing
improvement and others showing no significant difference. Overall, the meta-analyses
suggest that these compounds have a positive impact on glucose metabolism.11
(Najaf, et al., 2018) (Level of evidence: 1A) Providing high-quality welfare and
healthcare for menopausal women is important because menopausal women may experience
various sexual dysfunctions such as problems with desire, arousal, orgasm, and pain . In this
research, phytoestrogens isolated from Lepidium meyenii, Foeniculum vulgare, and maritime
pine bark as well as Trigonella foenum-graecum L. were found to significantly improve
sexual function in menopausal women. Complementary and alternative medicine that
involves natural compounds is being commonly used to overcome these problems, and
phytoestrogens are one of the approaches suggested by complementary and alternative
medicine.12
(Howes, et al., 2006) (Level of evidence: 1A) This article is a systematic review and
meta-analysis of randomized, controlled trials on the effectiveness of isoflavone therapy for
reducing menopausal hot flashes. The study found that isoflavone supplementation, either
from soy or red clover, was associated with a significant reduction in hot flashes. The
reduction in hot flashes was more apparent in women experiencing a high number of hot
flashes per day.
The recommended dose of isoflavone supplementation for reducing menopausal hot flashes
varies depending on the study. In the studies included in the systematic review and meta-
analysis, the doses ranged from 40 mg to 160 mg of isoflavones per day. In the studies
included in the systematic review and meta-analysis, isoflavone therapy was generally well-
tolerated with no significant adverse effects reported. However, it is worth noting that
individual responses to isoflavone supplementation may vary, and some individuals may
experience gastrointestinal symptoms such as bloating or diarrhea. In the studies included in
the systematic review and meta-analysis, treatment durations ranged from 4 weeks to 16
weeks. Some studies reported a reduction in hot flashes as early as 4 weeks, while others
showed a more significant reduction after 12 weeks of therapy. It is important to note that
individual responses may vary, and it is recommended to consult with a healthcare
professional for personalized advice on the duration of isoflavone therapy for reducing hot
flashes.13
(Thomas, et al., 2014) (Level of evidence: 1A) This article presents a systematic
review of 17 controlled clinical trials investigating the effects of isoflavones and amino acid
therapies on hot flashes and other symptoms reported by women during the menopausal
transition and early postmenopause. According to the clinical trials reviewed in this article,
red clover supplements showed the most promise in reducing hot flashes and cognitive
symptoms. Other isoflavones also showed significant reductions in hot flashes, with some
reducing other symptoms such as mood, sleep, pain, and cognitive function. Soy isoflavones
were also studied, with two preparations showing significant reductions in hot flashes, but no
other symptoms.14
(Verhoeven, et al., 2007) (Level of evidence: 1A) The study investigated the effects of
a supplement containing isoflavones and Actaea racemosa L. on hot flashes and quality of
life. The supplement did significantly reduce hot flashes and improve quality of life
compared to placebo. The study concluded that the supplement may be a safe and effective
alternative to hormone therapy for menopausal symptoms.15
(Hariri, et al., 2021) (Level of evidence: 1A) The study aims to investigate the effect
of soy isoflavones and the combination of soy isoflavones and soy protein on serum CRP
concentrations among postmenopausal women. The overall effect of soy isoflavones on
serum CRP concentrations was non-significant (WMD = 0.08 mg/L, 95 % CI: -0.08, 0.24; p
= 0.302).
The combination of soy isoflavones and soy protein also did not have a significant effect on
serum CRP concentrations (WMD= -0.02 mg/L 95 % CI: -0.12, 0.08; p = 0.715). Published
RCTs do not provide strong evidence of the beneficial effect of soy isoflavones or the
combination of soy isoflavones and soy protein on serum CRP concentration among
postmenopausal women.16
 (Chen, et al., 2014) (Level of evidence: 1A) Soy isoflavone intake has a protective
effect against breast cancer for both pre- and post-menopausal women. The protective effect
is influenced by study design and region. Pooled ORs of studies carried out in Asian countries
suggested that soy isoflavone's protective effect exists in both pre- and post-menopausal
women (OR=0.59, 95%CI: 0.48- 0.69 for premenopausal women; OR=0.59, 95%CI: 0.44-
0.74 for postmenopausal women). However, there are some differences between the results
pooled from different study designs for women in Asian countries (test for consistency,
P=0.04). Pooled OR of studies on postmenopausal women in Western countries suggested
that soy isoflavone intake has a marginally significant protective effect (OR=0.92; 95%CI:
0.83~1.00), but further analyses stratifying by study design found no statistically significant
association. Soy isoflavone intake could lower the risk of breast cancer for both pre- and
post-menopausal women in Asian countries. For women in Western countries, pre- or post-
menopausal, there is no evidence to suggest an association between intake of soy isoflavone
and breast cancer.17
(Setiawan, et al., 2022) (Level of evidence: 1A) The study analyzed the content of
antioxidant level and isoflavones (genistein and daidzein) in instant cream soup and their
effect on ovariohysterectomy (OVx) rats. The isoflavone content (genistein 370.86 g/100 g,
daidzein 185.61 g/100 g) was only present in the pumpkin instant cream soup with tempeh
(IPTS). IPTS has higher antioxidant levels (134.25 mg AEAC/100 g) than instant pumpkin
cream soup without tempeh (IPS). In vivo study, experimental rats showed that OVx
increased malondialdehyde (MDA) levels up to 5.85-6.07 nmol mL"1 as compared to control
(4.47 nmol mL-1). Instant pumpkin cream soup with tempeh treatments significantly
increased serum estradiol levels (2.37-3.63 ug) and superoxide dismutase (SOD) levels of
497.49-558.89 UmL-1. The study concluded that instant pumpkin cream soup and tempeh
contained isoflavone and antioxidant, and it increased estradiol serum and SOD level.18
(Kazama, et al., 2022) (Level of evidence: 1B) This study investigates the
relationship between headache and dietary consumption of a variety of nutrients. The study
used first-visit records of 405 women aged 40-59 years, and the frequency of headaches was
assessed using the Menopausal Health-Related Quality of Life Questionnaire. Of the 43
major nutrient intakes surveyed using the brief-type self-administered diet history
questionnaire, those that were not shared between women with and without frequent
headaches were selected. Multiple logistic regression analysis was used to identify nutrients
independently associated with frequent headaches. The estimated dietary intake of
isoflavones (daidzein + genistein) (mg/1000 kcal/day) was negatively associated with
frequent headaches (adjusted odds, 0.974; 95% confidence interval, 0.950-0.999). The
estimated isoflavone intake was not significantly associated with headache frequency in the
premenopausal group, whereas it significantly correlated with that in the peri- and post-
menopausal groups. Headache in peri- and post-menopausal women was inversely correlated
with the dietary intake of isoflavones.19
(Sathyapalan, et al., 2018) (Level of evidence: 1B) A double-blind randomized
parallel study was conducted involving 200 women in the early menopause who were
randomized to 15 g soy protein with 66 mg isoflavone (SPI) or 15 g soy protein alone
(depleted of all isoflavones; SP) given as a snack bar between meals daily for 6 months. Age,
diabetes, smoking, blood pressure and lipid profiles were used to calculate CVR using the
Framingham CVR engine. SPI treatment resulted in a significant reduction in the metabolic
parameters and systolic blood pressure compared to SP. There were no changes in fasting
lipid profile and diastolic blood pressure with either treatment. At 6 months, changes in these
parameters with SPI treatment were reflected in a calculated 27% reduction in 10-year
coronary heart disease risk, a 37% reduction in myocardial infarction risk, a 24% reduction in
cardiovascular disease and 42% reduction in cardiovascular disease death risk.
Supplementation with soy protein with isoflavones for 6 months significantly improved CVR
markers and calculated CVR at 6 months during early menopause compared to soy protein
without isoflavones. Soy isoflavones may act as selective estrogen receptor modulators and
may be beneficial for cardiovascular disease risk (CVR) in post-menopausal women.20
(Wong, et al., 2012) (Level of evidence: 2B) Nitric oxide (NO) plays an important
role in the vasodilatory capacity of menopausal women. Isoflavones found in soybeans have
chemical structures similar to estradiol and possess anticancer properties. The objective of
the study was to test the effect of soy isoflavone supplementation on nitric oxide production
and blood pressure in menopausal women with high normal blood pressure. A randomized,
double-blind, parallel, placebo-controlled 6-wk trial was conducted with 24 menopausal
women with 12 women per group. Daily supplementation with 80 mg soy hypocotyl
isoflavones over a 6-wk period had no effect on nitric oxide metabolism or blood pressure
and associated vascular hemodynamics in menopausal women with high normal blood
pressure. Changes in nitric oxide metabolism were assessed via a primed, constant-infusion
protocol with [15N]arginine and [13C]- and [2H]citrulline. Changes in blood pressure and
associated vascular hemodynamics were assessed via office and 24-h ambulatory blood
pressure monitoring, forearm blood flow, and indexes of arterial compliance. Improved
arterial compliance has been reported in menopausal women taking a daily dose of soy
isoflavones Infusion of genistein, a type of isoflavone, produced a dose-dependent increase in
forearm blood flow similar in potency to 178-estradiol in men and in premenopausal women,
and the genistein-induced forearm vasodilation is anticipated to be via the L-arginine/NO-
dependent pathway. When compared with placebo and after control for pretreatment values,
soy isoflavone supplementation had no effect on arginine flux, citrulline flux, nitric oxide
synthesis, blood pressure, forearm blood flow, or estimates of arterial stiffness. Daily
supplementation with 80 mg soy hypocotyl isoflavones over a 6-wk period had no effect on
nitric oxide metabolism or blood pressure and associated vascular hemodynamics in
menopausal women with high normal blood pressure.21
(Sacks, et al., 2006) (Level of evidence: 1A) In 22 randomized trials, isolated soy
protein with isoflavones, as compared with milk or other proteins, decreased LDL cholesterol
concentrations by an average of ~3%. No significant effects on HDL cholesterol,
triglycerides, lipoprotein(a), or blood pressure were evident in these trials. Among 19 studies
of soy isoflavones, the average effect on LDL cholesterol and other lipid risk factors was non.
Soy protein and isoflavones have not been shown to lessen vasomotor symptoms of
menopause, and results are mixed with regard to soy's ability to slow postmenopausal bone
loss. The efficacy and safety of soy isoflavones for preventing or treating cancer of the breast,
endometrium, and prostate are not established; evidence from clinical trials is meager and
cautionary with regard to a possible adverse effect. Use of isoflavone supplements in food or
pills is not recommended. Many soy products should be beneficial to cardiovascular and
overall health because of their high content of polyunsaturated fats, fiber, vitamins, and
minerals and low content of saturated fat. The FDA approved labeling for foods containing
soy protein as protective against coronary heart disease in 1999, based on clinical studies
showing that at least 25 g of soy protein per day lowered total and LDL cholesterol. The AHA
Nutrition Committee released a scientific advisory on soy protein and CVD in 2000,
recommending including soy protein foods in a diet low in saturated fat and cholesterol. The
committee decided to reevaluate the evidence on soy protein and CVD and update its
scientific advisory, leading to this current assessment.22
(Taku, et al., 2010) (Level of evidence: 1A) Bone turnover markers (BTMs) have
been considered as biomarkers for fracture risk along with BMD. The effects of soy
isoflavone supplements on BTMs remain unclear in menopausal women. A systematic review
and meta-analysis of 10 randomized controlled trials (RCTs) were conducted to evaluate the
effects of soy isoflavone supplements on urinary deoxypyridinoline (DPD), serum bone
alkaline phosphatase (BAP), and serum osteocalcin (OC) compared with placebo in
menopausal women. From 3740 identified relevant articles, a total of 10 RCTs with 887
participants, 10 RCTs with 1210 participants, and 8 RCTs with 380 participants were selected
for meta-analysis of effects on DPD, BAP, and OC, respectively, using Review Manager
5.0.22. Daily ingestion of an average 56 mg soy isoflavones (aglycone equivalents) for 10
weeks to 12 months significantly decreased DPD by 14.1% compared to baseline. The overall
effect of soy isoflavones on DPD compared with placebo was a significant decrease of -
18.0%. Subgroup analyses and meta-regressions revealed that isoflavone dose and
intervention duration did not significantly relate to the variable effects on DPD. Daily
supplementation of about 84 mg and 73 mg of soy isoflavones for up to 12 months
insignificantly increased BAP by 8.0% and OC by 10.3% compared with placebo,
respectively. Soy isoflavone supplements moderately decreased the bone resorption marker
DPD, but did not affect bone formation markers BAP and OC in menopausal women. The
effects varied between studies, and further studies are needed to address factors relating to the
observed effects of soy isoflavones on DPD and to verify effects on other bone turnover
markers.23
(Kanadys, et al., 2021) (Level of evidence: 1A) A total of 1114 women who ingested
mean daily doses of 98.2 mg (30.9 to 300) of soy isoflavones for 3 to 24 months were
compared to 1081 subjects who used a placebo. Ten, eighteen, eight, and fourteen comparison
studies were finally selected for an estimation of the effects on osteocalcin (OC), bone
alkaline phosphatase (BAP), pyridinoline (PYD), and deoxypyridinoline (DPD), respectively.
The meta-analysis revealed that soy isoflavones intake is associated with a trend in increased
levels of OC and BAP, as well as a trend in reduced levels of PYD and DPD, but these
observations were statistically insignificant. The summary of the results of intervention was
as follows: 4.16%, 95% CI: - 7.72-16.04, p = 0.49 for OC; 5.50%, 95% CI: - 3.81-14.82, p =
0.25 for BAP; - 12.09%, 95% CI: - 25.37-1.20, p = 0.07 for PYD; and -7.48%, 95% CI: -
15.37-0.41, p = 0.06 for DPD. Soy isoflavones may have a beneficial effect on bone
formation markers, but this requires extensive multi-center research.24
(Wei, et al., 2012) (Level of evidence: 1A) The study aimed to analyze the effects of
isoflavones from Glycine max (L.) Merr (soy) used topically as a vaginal gel on the induction
of vascularization of the vaginal tissue in postmenopausal women. A placebo-controlled,
randomized, double-blind trial was conducted with 22 postmenopausal women, randomly
allocated for treatment with Glycine max (L.) Merr isoflavone 4% vaginal gel daily for 12
weeks or with placebo gel for the same period. Vaginal microbiopsies were collected before
and after the 12-week treatment. Immunohistochemistry analyses were performed to provide
a blood vessel count per field in the vaginal tissue, pre and post-intervention. The isoflavone
group exhibited a significant increase in blood vessels per field relative to baseline, whereas
the placebo group showed no difference compared to baseline. There was a significant
difference in the increase of the number of blood vessels between the isoflavone and placebo
groups. The results showed that local administration of Glycine max (L.) Merr isoflavone gel
promoted a significant improvement in the number of blood vessels in the vaginal tissue of
postmenopausal women. The decline in secretion of sex hormones in the climacteric,
particularly estrogens, promotes a series of signs and symptoms involving the vascular and
urogenital systems collectively called genitourinary syndrome of menopause (GSM).
Estrogens exert effects on tissue neovascularization, maintaining or restoring endothelial
function and modulating the production of angiogenic factors to promote tissue
neovascularization. The specific molecular mechanisms by which estrogens are able to
modulate angiogenesis remain unclear. However, it is known that estradiol induces
endothelial cell proliferation and migration through stimulation of vascular endothelial
growth factor receptors found in the endothelium.25
(Sun, et al., 2022) (Level of evidence: 1A) Investigating the therapeutic effect of
genistein (Gen) on postmenopausal senile vaginitis (SV) and its mechanism of action. Adult
SPF female Wistar rats were selected to establish a bilateral ovariectomized animal model
(OVX), which simulated senile vaginitis dominated by estrogen deficiency in ovarian
dysfunction. After 14 days of continuous treatment, the morphology of vaginal epithelial
tissue was observed and various types of epithelial cells were counted, and the body mass and
uterine and vaginal index of rats were measured. the levels of vaginal tissue secretion,
microorganism, hormone and glycogen in each group were measured and the reproductive
health was evaluated clinically. The protein expression and mRNA expression of epidermal
growth factor (EGF) and E-cadherin (E-cadherin) in vaginal tissues were detected by
immunohistochemistry and RT-PCR, respectively. Result showed that Genistein lowered
vaginal pH, increased vaginal index and vaginal health score, thickened epithelial layers and
improved vaginal tissue atrophy after administration. Genistein also increased the contents of
glycogen and Lactobacillus in vagina, and promoted the expression of EGF, E-cadherin
protein and mRNA. To sum up, there is no significant change in serum E2 and FSH levels,
indicating that genistein has no effect on hormone levels in rats. Genistein promoted the
proliferation of vaginal epithelial cells, thickened epithelial layers and the vaginal wall, which
improved the resistance of vaginal epithelium, the recovery of self-cleaning ability and
healed the vaginal wound and erosive surface to improve atrophy.26
 (Takahashi, et al., 2022) (Level of evidence: 1B) Equol Production Associated with
Lower Prevalence of Metabolic Syndrome in Japanese Women in their 50s-60s. Metabolic
syndrome (METS) prevalence increases in postmenopausal women. Estrogen deficiency after
menopause is a major cause of METS in women. Equol is produced from soy isoflavones by
gut bacteria. Equol acts as either an estrogen receptor agonist or antagonist. Equol has
beneficial effects on hormone-dependent conditions such as menopausal symptoms,
osteoporosis, and cardiometabolic risk factors. A cross-sectional study was conducted on
1,345 women aged 50 to 69 years who underwent health checkups in Fukushima, Japan.
Equol producers were defined as those with a urinary equol concentration of 1.0 uM or more.
METS was defined based on Japanese diagnostic criteria including abdominal obesity,
atherogenic dyslipidemia, elevated blood pressure, and glucose intolerance. Of the 1,345
women, 378 (28.1%) were equol producers. The proportion of women who had METS was
significantly lower in the equol-producing group than in the non-producing group.
Multivariable logistic regression analysis revealed that equol production was significantly
associated with METS. Equol production was associated with a lower prevalence of METS
among women aged 50 to 69 years.27
(Garrido, et al., 2006) (Level of evidence: 1A) Soy Isoflavones and Platelet
Thromboxane A2 Receptor Density in Menopausal Women. The study aims to examine the
effect of a 12-week soy isoflavone supplementation on lipoprotein status and platelet
thromboxane A2 receptor density in menopausal women. 29 healthy postmenopausal women
were invited to take part in a randomized study to receive either 100 mg/day isoflavone
supplement or identical placebo capsules. Blood samples obtained at baseline and after 12
weeks were analyzed for isoflavones, total cholesterol, high-density lipoprotein cholesterol,
triglycerides, glucose, insulin, estradiol, testosterone, gonadotrophins, sex hormone-binding
globulin, and platelet thromboxane A2 receptor density. Blood pressure measurements, BMI,
subcutaneous fat at entrance, and at the end of treatment were also registered. Changes in
variables between groups were compared by ANOVA for repeated measures. The results
show that blood pressure, BMI, subcutaneous fat, insulin, serum lipoprotein, sex hormones,
and SHBG did not differ among groups. However, platelet thromboxane A2 receptor density
declined significantly in the experimental group, remaining mostly unchanged in the placebo
group. The change in platelet thromboxane A2 receptors correlated negatively with
isoflavones serum concentration. The study demonstrates that the beneficial effects of
isoflavones in menopausal women could be more related to platelet function than to
improving classical cardiovascular risk factors.28
 (Schult, et al., 2004) (Level of evidence: 1B) Effect of Isoflavones on Lipids and
Bone Turnover Markers in Menopausal Women. The study was conducted to compare the
effects of two dietary supplements derived from red clover to placebo on lipids and bone
turnover markers in symptomatic menopausal women. The study was a 12-week randomized,
double-blind, placebo-controlled trial. 252 menopausal women aged 45-60 years
experiencing ≥35 hot flashes per week were randomly assigned to Promensil® (82 mg total
isoflavones), Rimostil® (57.2 mg total isoflavones), or placebo. Primary outcome measures
were mean absolute changes for HDL-cholesterol, serum osteocalcin, and urinary N-
telopeptide. Secondary outcome measures were mean changes of total cholesterol, LDL-
cholesterol, the ratio of HDL- to LDL-cholesterol, and triglycerides. Women taking
Rimostil® or Promensil® compared to those taking placebo had greater mean increases in
HDL-cholesterol; however, this change was small in magnitude (<2 mg/dl) and did not reach
significance. There was a significant decrease in triglyceride levels among women taking
Rimostil® (14.4 mg/dl, P = 0.02) or Promensil® (10.9 mg/dl, P = 0.05) compared to those
taking placebo. The decrease was primarily among women with elevated baseline triglyceride
levels (P for interaction = 0.009). There were no differences in mean changes of total
cholesterol, LDL-cholesterol, or the ratio of HDL- to LDL-cholesterol among treatment
groups. There were no statistically significant differences among treatment groups for bone
turnover markers. Both of the supplements containing isoflavones decrease levels of
triglycerides in symptomatic menopausal women compared to placebo, but the effect is small
in magnitude.29
(Cancellieri, et al., 2007) (Level of evidence: 2B) Herbal product containing
isoflavones and plant extracts for menopausal symptoms and plasma lipids. The study aims to
evaluate the effectiveness of an herbal product containing isoflavones and plant extracts
(BIO) on menopausal symptoms and plasma lipids. The study was a randomized, double-
blind, placebo-controlled clinical investigation with 125 menopausal women treated for 6
months.
Primary endpoint: Kupperman Menopause Index (KI) variations; secondary endpoint:
activity on plasma lipids profile and clinical global impression (CGI) on efficacy and
tolerability by investigators and patients. The BIO group showed a significant decrease in KI
compared to placebo after 4 and 6 months of treatment. The LDL cholesterol showed a
borderline but not significant reduction in the BIO group compared to placebo, while
triglyceride showed a significant decrease. The investigator's and patient's CGI on BIO group
were superior as compared to placebo. Clinical tolerability was good in both groups. The
study suggests that BIO can be considered one of the possible alternative therapies for
conventional HRT.30
 Table 1. A brief summary of current evidence of studies regarding the preventive and therapeutic effects of isoflavones in menopause symtpoms

Studies (Ref. No) Study Design Contents Main Preventive (P) and Therapeutic (T) Effects
Hot Flusches
[31] St Germain RCT soy T no difference
[32] Tice RCT isoflavone tablets T no difference
[30] Cancellieri RCT isoflavone from herbal supplement T isoflavones more effective than placebo
[33] Cheng prospective study isoflavones extracted from soya bean T isoflavones more effective than placebo
[34] Welty RCT, crossover soy nut T soy more effective than placebo
[14] Thomas systematic review natural vs. synthetic isoflavones T synthetic or combination isoflavones more effective than natural
[35] Washburn randomized crossover trial soy protein T soy
[36] Khaodhiar RCT daidzein-rich isoflavone aglycones T soy protein more effective than placebo
[37] Cianci observational prospective study calcium, vitamin D3, inulin, soy isoflavones T daidzein-rich isoflavone aglycones more effective than placebo
[38] Carmignani RCT soy vs. hormone replacement therapy (HRT) T soy supplement + inulin effective
[39] Bolanos-Diaz meta-analysis soy extracts vs. HRT T HRT more effective than soy; both are superior to placebo HRT
[40] Amato multicenter RCT aglycone hypocotyl soy isoflavone T more effective than soy extracts; both are superior to placebo
[41] Daily systematic review, meta-analysis soy isoflavone and equal T no difference
[38] Newton observational study equol-producer status T equal or isoflavone in equol-producers more effective than placebo
[42] Lambert RCT red clover extracts T soy in equol-producers more effective than non-producers
red clover extracts more effective than placebo
Hormone Related Osteoporosis
[43] Ma meta-analysis isoflavone T increase spinal bone mineral density (BMD)
[40] Amato multicenter RCT aglycone hypocotyl say isoflavone T slow BMD loss
[42] Lambert systematic review and meta-analysis isoflavone aglycone T preserve BMD

Urogential tract
[44] Reed RCT black cohosh or dietary soy T no effect on vaginal cytology
[46] Waetjen prospective cohort study dietary intake of isoflavones T no effect on stress or urge incontinence
[45] Vitale prospective, randomized, placebo-controlled isoflavones, calcium, vitamin D, inulin T May improve sexual function
[47] Ribeiro study isoflavone T failed to yield an estrogenic effect on the urogenital tract and to
RCT relieve the vulvovaginal symptoms
Metabolic syndrome
[48] Stuenkel randomized clinical trial. isoflavone supplements T loss of weight and fat mass, but interpretation difficult
[49] Mueller in vitro study PPARY binding and transactivational activity T red clover extracts may be used to treat metabolic syndrome
Cardiovascular Disease
[50] van der prospective study food phytoestrogens P low dose phytoestrogen not protective
Schouw randomized crossover trial purified soybean extract T may improve systemic arterial compliance
[51] Nestel prospective study isoflavones extracted from soya bean T no difference in lipoprotein lipids
[33] Cheng RCT soy hypocotyl isoflavones T no effect on nitric oxide metabolism or blood pressure
[21] Wong animal study soy protein T HRT+soy harmful, soy or HRT not beneficial
[57] Suparto double-blind randomized study T soy protein with isoflavones improved cardiovascular markers
[20] Sathyapalan compared to soy protein alone
[52] Ma 3 prospective cohort studies soy protein +/- soy isoflavone P higher intake of isoflavones and tofu was associated with a
moderately lower risk of developing coronary heart disease
Cognitive function and neuromuscular systems
[54] Clement systematic review isoflavones and soy T may improve cognition
[53] Greendale cohort study dietary phytoestrogens. T better processing speed but worse verbal memory
[55] Miyake cross-sectional study soy products and isoflavones T independent inverse relationships between intake of soy products
and isoflavones and depressive symptoms during pregnancy
[56]Tabata Animal study isoflavone aglycone T significantly modulated muscle atrophy after denervation in mice,
probably due to the decrease in apoptosis-dependent signaling
Cancer risk
[58] Hirose case-control study soy products as part of daily intake P lower risk of breast cancer in premenopausal women
[59] Alipour case-control study soy extracts soy extracts may cause benign changes in breast
[61] Kang cohort study dietary intake of soy isoflavones P lower recurrence of estrogen- and progesterone-receptor positive
breast cancers receiving anastrazole therapy after surgery
[62] Shin case-control study dietary soyfood and isoflavone intake P reduced risk for overall colorectal cancer
[60] Zhao meta-analysis soy foods P a high dietary intake of soy foods may reduce breast cancer risk
[63] Budhathoki prospective study soy food and isoflavone were not associated with the risk of endometrial cancer.
[64] Quaas double-blind RCT isoflavone soy protein no effect on the rates of endometrial hyperplasia and cancer
[65] Ollberding prospective study isoflavone, daidzein and genistein intake P are associated with a reduced risk of endometrial cancer
[66] Wada population-based prospective study total soy and isoflavones P are associated with a decrrssed risk of bladder cancer
CONCLUSION
The systematic review presented in this study synthesizes the current body of
evidence regarding isoflavone-based therapies for managing menopausal symptoms and
addresses the ambiguities and challenges inhibiting their mainstream acceptance. The
analysis underscores the potential of isoflavones, phytoestrogens found in various plant
sources, as a promising therapy for alleviating menopausal symptoms, including hot flashes,
mood disturbances, and vaginal dryness.
However, despite the potential benefits of isoflavones, this review highlights the need
for further research to standardize dosing regimens, optimize treatment durations, and
enhance understanding of potential adverse effects. The existing literature demonstrates
substantial heterogeneity in study designs, outcomes, and reporting, which necessitates a
concerted effort to establish a consensus on evaluating isoflavone efficacy.
To propel isoflavone-based therapies into mainstream menopausal symptom
management, robust randomized controlled trials with rigorous methodologies and long-term
follow-up are imperative. Furthermore, addressing safety concerns and potential interactions
with other therapies is essential for fostering confidence among healthcare professionals and
women undergoing menopause.
In conclusion, while isoflavones hold promise as a mainstream therapy for
menopausal symptom relief, overcoming the current ambiguities and challenges demands a
coordinated research agenda, standardized clinical approaches, and concerted efforts to build
a strong evidence base. The successful integration of isoflavone-based therapies into
mainstream menopausal care has the potential to significantly improve the quality of life for
women during this critical life stage.

Conflicts of Interest: The authors declare no conflict of interest.

REFERENCES
1. Hill, D.A.; Crider, M.; Hill, S.R. Hormone therapy and other treatments for symptoms
of menopause. Am. Fam. Physician 2016, 94.
2. Croden, J.; Ross, S.; Yuksel, N.; Sydora, B.C. A survey of the availability in Canadian
pharmacy chains of over-the-counter natural
3. health products for menopause symptoms. BMC Complement. Altern. Med. 2015, 15,
86.
4. United Nations Conference on Trade and Development: Soy Beans. Available online:
https://unctad.org/en/PublicationsLibrary/ INFOCOMM_cp10_SoyaBeans_en.pdf
5. Russell, L.; Hicks, G.S.; Low, A.K.; Shepherd, J.M.; Brown, C.A. Phytoestrogens: A
viable option? Am. J. Med. Sci. 2002, 324,185–188.

6. Johnson, L.A.; White, P.J. Soybeans: Chemistry, Production, Processing, and

Utilization, 1st ed.; Galloway, R., Ed.; AOCS Press: Urbana, IL, USA, 2008; pp. 1–
850.
7. Kurosu, M. Chapter 10-Biologically Active Molecules from Soybeans. In Soybean
and Health, 1st ed.; El-Shemy, H., Ed.; InTech: Rijeka, Croatia, 2011; pp. 207–230
8. Ligor, M.; Ratiu, I.A.; Kiełbasa, A.; Al-Suod, H.; Buszewski, B. Extraction
approaches used for the determination of biologically active compounds (cyclitols,
polyphenols and saponins) isolated from plant material. Electrophoresis 2018, 39,
1860–1874.
9. Chen, L. R., & Chen, K. H. (2021). Utilization of isoflavones in soybeans for women
with menopausal syndrome: An overview. International journal of molecular sciences,
22(6), 3212.
10. Barnard, N. D., Kahleova, H., Holtz, D. N., Znayenko-Miller, T., Sutton, M.,
Holubkov, R., ... & Setchell, K. D. (2023). A dietary intervention for vasomotor
symptoms of menopause: a randomized, controlled trial. Menopause (New York,
NY), 30(1), 80.
11. Maliehe, A., Ghahremani, S., Kharghani, S., Ghazanfarpour, M., Shariati, K., Kazemi,
M., & Khadivzadeh, T. (2019). Effect of isoflavones and genistein on glucose
metabolism in peri-and post-menopausal women: An overview of meta-
analysis. Journal of menopausal medicine, 25(2), 69-73.
12. Najaf Najafi, M., & Ghazanfarpour, M. (2018). Effect of phytoestrogens on sexual
function in menopausal women: a systematic review and meta-
analysis. Climacteric, 21(5), 437-445.
13. Howes, L. G., Howes, J. B., & Knight, D. C. (2006). Isoflavone therapy for
menopausal flushes: a systematic review and meta-analysis. Maturitas, 55(3), 203-
211.
14. Thomas, A. J., Ismail, R., Taylor-Swanson, L., Cray, L., Schnall, J. G., Mitchell, E. S.,
& Woods, N. F. (2014). Effects of isoflavones and amino acid therapies for hot flashes
and co-occurring symptoms during the menopausal transition and early
postmenopause: a systematic review. Maturitas, 78(4), 263-276.
15. Verhoeven, M. O., Teerlink, T., Kenemans, P., Zuijdgeest-van Leeuwen, S. D., & van
der Mooren, M. J. (2007). Effects of a supplement containing isoflavones and Actaea
racemosa L. on asymmetric dimethylarginine, lipids, and C-reactive protein in
menopausal women. Fertility and sterility, 87(4), 849-857.
16. Hariri, M., Ghasemi, A., Baradaran, H. R., Mollanoroozy, E., & Gholami, A. (2021).
Beneficial effect of soy isoflavones and soy isoflavones plus soy protein on serum
concentration of C-reactive protein among postmenopausal women: An updated
systematic review and meta-analysis of randomized controlled trials. Complementary
Therapies in Medicine, 59, 102715.
17. Chen, M., Rao, Y., Zheng, Y., Wei, S., Li, Y., Guo, T., & Yin, P. (2014). Association
between soy isoflavone intake and breast cancer risk for pre-and post-menopausal
women: a meta-analysis of epidemiological studies. PloS one, 9(2), e89288.
18. Setiawan, B., Aulia, S. S., Sulaeman, A., Kusharto, C. M., & Handharyani, E. (2022).
Isoflavone and Antioxidant of Instant Cream Soup Made from Pumpkin and Tempeh
and Their Active Compound in Ovariohysterectomy Rat-Induced Alzheimer’s
Disease. International Journal of Food Science, 2022.
19. Kazama, M., Terauchi, M., Odai, T., Kato, K., & Miyasaka, N. (2022). The inverse
correlation of isoflavone dietary intake and headache in peri-and post-menopausal
women. Nutrients, 14(6), 1226.
20. Sathyapalan, T., Aye, M., Rigby, A. S., Thatcher, N. J., Dargham, S. R., Kilpatrick, E.
S., & Atkin, S. L. (2018). Soy isoflavones improve cardiovascular disease risk
markers in women during the early menopause. Nutrition, Metabolism and
Cardiovascular Diseases, 28(7), 691-697.
21. Wong, W. W., Taylor, A. A., Smith, E. O. B., Barnes, S., & Hachey, D. L. (2012).
Effect of soy isoflavone supplementation on nitric oxide metabolism and blood
pressure in menopausal women. The American journal of clinical nutrition, 95(6),
1487-1494.
22. Sacks, F. M., Lichtenstein, A., Van Horn, L., Harris, W., Kris-Etherton, P., & Winston,
M. (2006). Soy protein, isoflavones, and cardiovascular health: an American Heart
Association Science Advisory for professionals from the Nutrition
Committee. Circulation, 113(7), 1034-1044.
23. Taku, K., Melby, M. K., Kurzer, M. S., Mizuno, S., Watanabe, S., & Ishimi, Y. (2010).
Effects of soy isoflavone supplements on bone turnover markers in menopausal
women: systematic review and meta-analysis of randomized controlled
trials. Bone, 47(2), 413-423.
24. Kanadys, W., Barańska, A., Błaszczuk, A., Polz-Dacewicz, M., Drop, B., Malm, M.,
& Kanecki, K. (2021). Effects of soy isoflavones on biochemical markers of bone
metabolism in postmenopausal women: A systematic review and meta-analysis of
randomized controlled trials. International Journal of Environmental Research and
Public Health, 18(10), 5346.
25. Wei, P., Liu, M., Chen, Y., & Chen, D. C. (2012). Systematic review of soy isoflavone
supplements on osteoporosis in women. Asian Pacific journal of tropical
medicine, 5(3), 243-248.
26. Sun, Y., Wang, L., Wang, B., Meng, Y., & Wang, W. (2022). Genistein Up-Regulates
the Expression of EGF and E-Cadherin in the Treatment of Senile
Vaginitis. Molecules, 27(8), 2388.
27. Takahashi, A., Kokubun, M., Anzai, Y., Kogre, A., Ogata, T., Imaizumi, H., ... &
Ohira, H. (2022). Association between equol production and metabolic syndrome in
Japanese women in their 50s-60s. Menopause, 29(10), 1196-1199.
28. Garrido, A., De la Maza, M. P., Hirsch, S., & Valladares, L. (2006). Soy isoflavones
affect platelet thromboxane A2 receptor density but not plasma lipids in menopausal
women. Maturitas, 54(3), 270-276.
29. Schult, T. M. K., Ensrud, K. E., Blackwell, T., Ettinger, B., Wallace, R., & Tice, J. A.
(2004). Effect of isoflavones on lipids and bone turnover markers in menopausal
women. Maturitas, 48(3), 209-218.
30. Cancellieri, F., De Leo, V., Genazzani, A. D., Nappi, C., Parenti, G. L., Polatti, F., ...
& Nichelatti, M. (2007). Efficacy on menopausal neurovegetative symptoms and
 some plasma lipids blood levels of an herbal product containing isoflavones and other
plant extracts. Maturitas, 56(3), 249-256.
31. St Germain, A.; Peterson, C.T.; Robinson, J.G.; Alekel, D.L. Isoflavone-rich or
isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks
of treatment. Menopause 2001, 8, 17–26.

32. Tice, J.A.; Ettinger, B.; Ensrud, K.; Wallace, R.; Blackwell, T.; Cummings, S.R.
Phytoestrogen supplements for the treatment of hot flashes: The Isoflavone Clover
Extract (ICE) Study: A randomized controlled trial. JAMA 2003, 290, 207–214.
33. Cheng, G.; Wilczek, B.; Warner, M.; Gustafsson, J.-A.; Landgren, B.M. Isoflavone
treatment for acute menopausal symptoms. Menopause 2007, 14, 468–473.
34. Welty, F.K.; Lee, K.S.; Lew, N.S.; Nasca, M.; Zhou, J.R. The association between
soy nut consumption and decreased menopausal symptoms. J. Womens Health
(Larchmt) 2007, 16, 361–369.
35. Washburn, S.; Burke, G.L.; Morgan, T.; Anthony, M. Effect of soy protein
supplementation on serum lipoproteins, blood pressure, and menopausal symptoms in
perimenopausal women. Menopause 1999
36. Khaodhiar, L.; Ricciotti, H.A.; Li, L.; Pan, W.; Schickel, M.; Zhou, J.; Blackburn,
G.L. Daidzein-rich isoflavone aglycones are potentially effective in reducing hot
flashes in menopausal women. Menopause 2008, 15, 125–132.
37. Cianci, A.; Colacurci, N.; Paoletti, A.M.; Perino, A.; Cicinelli, E.; Maffei, S.; Di
Martino, M.; Daguati, R.; Stomati, M.; Pilloni, M.; et al. Soy isoflavones, inulin,
calcium, and vitamin D3 in post-menopausal hot flushes: An observational study.
Clin. Exp. Obstet. Gynecol. 2015, 42, 743–745.
38. Carmignani, L.O.; Pedro, A.O.; Costa-Paiva, L.H.; Pinto-Neto, A.M. The effect of
dietary soy supplementation compared to estrogen and placebo on menopausal
symptoms: A randomized controlled trial. Maturitas 2010, 67, 262–269.
39. Bolaños-Díaz, R.; Zavala-Gonzales, J.-C.; Mezones-Holguín, E.; Francia-Romero, J.
Soy extracts versus hormone therapy for reduction of menopausal hot flushes:
Indirect comparison. Menopause 2011, 18, 825–829.
40. Amato, P.; Young, R.L.; Steinberg, F.M.; Murray, M.J.; Lewis, R.D.; Cramer, M.A.;
Barnes, S.; Ellis, K.J.; Shypailo, R.J.; Fraley, J.K.; et al. Effect of soy isoflavone
supplementation on menopausal quality of life. Menopause 2013, 20, 443–447.
41. Daily, J.W.; Ko, B.S.; Ryuk, J.; Liu, M.; Zhang, W.; Park, S. Equol decreases hot
flashes in postmenopausal women: A systematic review and meta-analysis of
randomized clinical trials. J. Med. Food 2019, 22, 127–139.
42. Lambert, M.N.T.; Thorup, A.C.; Hansen, E.S.S.; Jeppesen, P.B. Combined Red
Clover isoflavones and probiotics potently reduce menopausal vasomotor symptoms.
PLoS ONE 2017, 12, e0176590
43. Ma, D.-F.; Qin, L.-Q.; Wang, P.-Y.; Katoh, R. Soy isoflavone intake increases bone
mineral density in the spine of menopausal women: Meta-analysis of randomized
controlled trials. Clin. Nutr. 2008, 27, 57–64.
44. Reed, S.D.; Newton, K.M.; LaCroix, A.Z.; Grothaus, L.C.; Grieco, V.S.; Ehrlich, K.
Vaginal, endometrial, and reproductive hormone findings: Randomized, placebo-
controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor
symptoms: The Herbal Alternatives for Menopause (HALT) Study. Menopause 2008,
15, 51–58.
45. Vitale, S.G.; Caruso, S.; Rapisarda, A.M.C.; Cianci, S.; Cianci, A. Isoflavones,
calcium, vitamin D and inulin improve quality of life, sexual function, body
composition and metabolic parameters in menopausal women: Result from a
prospective, randomized, placebo-controlled, parallel-group study. Prz.
Menopauzalny 2018, 17, 32–38.
46. Waetjen, L.E.; Leung, K.; Crawford, S.L.; Huang, M.-H.; Gold, E.B.; Greendale,
G.A. Study of women’s health across the nation relationship between dietary
phytoestrogens and development of urinary incontinence in midlife women.
Menopause 2013, 20, 428–436.
47. Ribeiro, A.E.; Monteiro, N.E.S.; Moraes, A.V.G.; Costa-Paiva, L.H.; Pedro, A.O. Can
the use of probiotics in association with isoflavone improve the symptoms of
genitourinary syndrome of menopause? Results from a randomized controlled trial.
Menopause 2018, 26, 643–652
48. Stuenkel, C.A. Isoflavones and cardiovascular risk in postmenopausal women: No
free lunch. Menopause 2007, 14, 606–608.
49. Mueller, M.; Jungbauer, A. Red clover extract: A putative source for simultaneous
treatment of menopausal disorders and the metabolic syndrome. Menopause 2008, 15,
1120–1131.
50. Van der Schouw, Y.T.; Kreijkamp-Kaspers, S.; Peeters, P.H.M.; Keinan-Boker, L.;
Rimm, E.B.; Grobbee, D.E. Prospective study on usual dietary phytoestrogen intake
and cardiovascular disease risk in Western women. Circulation 2005, 111, 465–471.
51. Nestel, P.J.; Yamashita, T.; Sasahara, T.; Pomeroy, S.; Dart, A.; Komesaroff, P.;
Owen, A.; Abbey, M. Soy isoflavones improve systemic arterial compliance but not
plasma lipids in menopausal and perimenopausal women. Arterioscler. Thromb.
Vasc. Biol. 1997, 17, 3392–3398.
52. Ma, L.; Liu, G.; Ding, M.; Zong, G.; Hu, F.B.; Willett, W.C.; Rimm, E.B.; Manson,
J.E.; Sun, Q. Isoflavone intake and the risk of coronary heart disease in US men and
women: Results from 3 prospective cohort studies. Circulation 2020, 141, 1127–
1137.
53. Greendale, G.A.; Huang, M.-H.; Leung, K.; Crawford, S.L.; Gold, E.B.; Wight, R.;
Waetjen, E.; Karlamangla, A.S. Dietary phytoestrogen intakes and cognitive function
during the menopausal transition: Results from the study of women’s health across
the nation phytoestrogen Study. Menopause 2012, 19, 894–903.
54. Clement, Y.N.; Onakpoya, I.; Hung, S.K.; Ernst, E. Effects of herbal and dietary
supplements on cognition in menopause: A systematic review. Maturitas 2011, 68,
256–263.
55. Miyake, Y.; Tanaka, K.; Okubo, H.; Sasaki, S.; Furukawa, S.; Arakawa, M. Soy
isoflavone intake and prevalence of depressive symptoms during pregnancy in Japan:
Baseline data from the Kyushu Okinawa Maternal and Child Health Study. Eur. J.
Nutr. 2018, 57, 441–450.
56. abata, S.; Aizawa, M.; Kinoshita, M.; Ito, Y.; Kawamura, Y.; Takebe, M.; Pan, W.;
Sakuma, K. The influence of isoflavone for denervation-induced muscle atrophy.
Eur. J. Nutr. 2019, 58, 291–300.
57. Hirose, K.; Imaeda, N.; Tokudome, Y.; Goto, C.; Wakai, K.; Matsuo, K.; Ito, H.;
Toyama, T.; Iwata, H.; Tokudome, S.; et al. Soybean products and reduction of breast
cancer risk: A case–control study in Japan. Br. J. Cancer 2005, 93, 15–22.
58. Alipour, S.; Afshar, S.; Moini, A.; Dastjerdi, M.; Saberi, A.; Bayani, L.; Eslami, B.;
Hosseini, L. Clinical and ultrasonographic changes of the breast after use of soy
isoflavones. APJCP 2012, 13, 6093–6095.
59. Shike, M.; Doane, A.S.; Russo, L.; Cabal, R.; Reis-Filho, J.S.; Gerald, W.; Cody, H.;
Khanin, R.; Bromberg, J.; Norton, L. The effects of soy supplementation on gene
 expression in breast cancer: A randomized placebo-controlled study. J. Natl. Cancer
Inst. 2014, 106, dju189.
60. Zhao, T.T.; Jin, F.; Li, J.G.; Xu, Y.Y.; Dong, H.T.; Liu, Q.; Xing, P.; Zhu, G.L.; Xu,
H.; Miao, Z.F. Dietary isoflavones or isoflavone-rich food intake and breast cancer
risk: A meta-analysis of prospective cohort studies. Clin. Nutr. 2019, 38, 136–145.
61. Kang, X.; Zhang, Q.; Wang, S.; Huang, X.; Jin, S. Effect of soy isoflavones on breast
cancer recurrence and death for patients receiving adjuvant endocrine therapy. CMAJ
2010, 182, 1857–1862
62. Shin, A.; Lee, J.; Lee, J.; Park, M.S.; Park, J.W.; Park, S.C.; Oh, J.H.; Kim, J.
Isoflavone and soyfood intake and colorectal cancer risk: A case-control study in
Korea. PLoS ONE 2015, 10, e0143228.
63. Budhathoki, S.; Iwasaki, M.; Sawada, N.; Yamaji, T.; Shimazu, T.; Sasazuki, S.;
Inoue, M.; Tsugane, S.; JPHC Study Group. Soy food and isoflavone intake and
endometrial cancer risk: The Japan Public Health Center-based prospective study.
BJOG 2015, 122, 304–311.
64. Quaas, A.M.; Kono, N.; Mack, W.J.; Hodis, H.N.; Felix, J.C.; Paulson, R.J.; Shoupe,
D. Effect of isoflavone soy protein supplemen-tation on endometrial thickness,
hyperplasia, and endometrial cancer risk in postmenopausal women: A randomized
controlled trial. Menopause 2013, 20, 840–844.
65. Ollberding, N.J.; Lim, U.; Wilkens, L.R.; Setiawan, V.W.; Shvetsov, Y.B.;
Henderson, B.E.; Kolonel, L.N.; Goodman, M.T. Legume, soy, tofu, and isoflavone
intake and endometrial cancer risk in postmenopausal women in the multiethnic
cohort study. J. Natl. Cancer Inst. 2012, 104, 67–76.
66. Wada, K.; Tsuji, M.; Tamura, T.; Konishi, K.; Goto, Y.; Mizuta, F.; Koda, S.; Uji, T.;
Hori, A.; Tanabashi, S.; et al. Soy isoflavone intake and bladder cancer risk in Japan:
From the Takayama study. Cancer Epidemiol. Biomark. Prev. 2018, 27, 1371–1375.