CHAPTER 38

Isoflavones for Menopausal

Vasomotor Syndrome
RAFAEL BOLAÑOS DIAZ, MD, MSc*a AND
JUAN CARLOS ZAVALA GONZALES, MD, MScb
a
Calle 9, n1 241, Dpt. 101-A, Urb. Monterrico Norte, San Borja, Lima 41,
Lima, Peru; b Av. Angamos-Este, Cdra. 26, F 47, San Borja (Lima 41),
Lima, Perú
*Email: rbolanosd@correo.unmsm.edu.pe; rbolanosd@yahoo.es

38.1 Pharmacology Aspects

Isoflavones, coumestans, lignans and some resorcinol derivatives are con-
sidered to be phytoestrogens, molecules that perform important functions in
certain vegetables and share properties similar to human estrogens. Because of
this structural and functional similarity, they have been studied for many years
to establish their clinical usefulness to manage menopausal syndrome. Iso-
flavones and coumestans (coumestrol, metoxycoumestrol) are flavonoid com-
pounds, whereas lignans (enterodiol, enterolactone) and resorcinol derivatives
are non-flavonoids (Figure 38.1). The latter abound in grapes and in grape
products, such as wine. Greater emphasis has been placed on the study of this
type of phytoestrogen because soy (Glycine max) isoflavones are distributed in
many sources of human consumption and there are certain epidemiological
associations described in populations with a high consumption of these foods.
There are various types of isoflavones but those most studied in connection
with human health are genistein, daidzein and glycitein, which are the names
given to the non-glycosidic forms to distinguish them from the corresponding

Food and Nutritional Components in Focus No. 5

Isoflavones: Chemistry, Analysis, Function and Effects
Edited by Victor R Preedy
r The Royal Society of Chemistry 2013
Published by the Royal Society of Chemistry, www.rsc.org

627
628 Chapter 38

Ipriflavone Phytoestrogens

Genistein
Flavonoids Non-flavonoids

Isoflavones Coumestans Lignans Resorcinol

• Coumestrol derivatives
Enterodiol
• Metoxy-coumestrol Enterolactone Resveratrol

Soy “Red Clover” “Black Cohosh” (Cimicifuga racemosa)

(Glycine max) (Trifolium pratense) “Don Quay” (Angelica sinensis)
“Flaxseed” (Oenothera biennis)

Genistein
Daidzein
Biochanin …………..… Genistein
Equol Formononetin-A ..……. Daidzein ?
Glicitein

Figure 38.1 Chemical types of phytoestrogens.

glycosidic forms (linked to glucose): genistin, daidzin and glycitin. Other less
active forms, such as formononetin and biochanin A, are partially metabolized
by intestinal flora to obtain genistein and daidzein in a highly variable pro-
portion that depends on individual intestinal enzymatic capacity. A synthetic
form of isoflavone (ipriflavone) has been used in several clinical trials, as it is
estimated that its intestinal metabolism produces genistein in approximately
10% of the total load contributed by ipriflavone. These compounds generally
have a chemical structure based on two phenolic rings joined by a heterocyclic
ring (forming the basic structure of isoflavones) and with various hydroxyl
substitutions (-OH) at different points of the heterocyclic chain, generating a
specific chemical name for each isoflavone (Figure 38.2). The presence of these
hydroxyl radicals provides these compounds with a significant antioxidant
capacity (Button and Patel 2004; Palacios 2002; Yildiz 2006).
Trifolium pratense (red clover), a vegetable species used to feed equines but
not apt for human consumption, is a rich source of formononetin and bio-
chanin A. Nevertheless, the clinical efficacy of this source on menopausal
vasomotor syndrome has been evaluated for a long time, although the results
were non-conclusive due to the high heterogeneity of the studies. Other sources,
such as Cimicı´fuga racemosa (black cohosh), Angelica sinensis (dong quai) or
Oenothera bienis (evening primrose), have been described, but their benefits on
the climacteric syndrome are more based on experience than on formal scien-
tific evidence. However, the phytoestrogen composition in these sources has not
been well determined (Button and Patel 2004; Low Dog 2005).
Studies on phytoestrogens have accumulated enough evidence to support
their alternative use in the management of climacteric vasomotor symptoms,
Isoflavones for Menopausal Vasomotor Syndrome 629

Daidzein Genistein Glicitein

4'-7 dihidroxi-isoflavone 4'-5-7 trihidroxi-isoflavone (6-metoxi)-5-7-dihidroxi-isoflavone

HO
O

Equol Ipriflavone
7-isopropoxi-isoflavone

Figure 38.2 Chemical structures of isoflavones.

and such benefit seems to be supported by its isoflavone content. However, the
main sources (soy, T. pratense, C. racemosa and A. sinensis) differ in isoflavone
composition, and such difference may explain the heterogeneity in the results of
the studies when analyzed as a whole (Button and Patel 2004; Low Dog 2005;
Mahady 2003). Such heterogeneity can be minimized with subgroup analysis.
For this reason, it is important that studies with phytoestrogens determine the
exact composition of the intervention under study.
Genistein, daidzein and glycitein are the predominant isoflavones in soy
(G. max), in contrast with the composition of red clover (T. pratense) based on
formononetin and biochanin, its main flavonoids. Other sources, such as black
cohosh (C. racemosa) and dong quai (A. sinensis), are popularly used but there
is much uncertainty to their exact isoflavone composition (Mahady, 2003). For
this reason, the results of studies that evaluate the efficacy of all these sources
should not be extrapolated and it would more consistent to conduct separate
analyses. Moreover, considering that the proportion of isoflavones in soy may
vary in accordance with the preparation administered, we prefer to classify this
source into three types, ‘‘dietary isoflavone intake’’, ‘‘soy extract’’ and ‘‘soy
isoflavone concentrate’’ (genistein or daidzein), to try to reduce the hetero-
geneity observed in all the studies.
630 Chapter 38
The study of equol has been a focus of attention. This active intestinal
metabolite of daidzein and genistein has shown a significant biological activity.
The clinical response has been related to the intestinal enzymatic capacity for
generating equol. It is presumed that an important proportion of menopausal
women could not produce sufficient equol, which represents a disadvantage to
show a significant clinical result. This hypothesis is still under research and
ongoing studies would enable us to draw more definitive conclusions in
this regard. Other metabolites, such as O-desmethyl-angolensin (O-DMA)
(Atkinson et al. 2005; Jou 2008; Yuan et al. 2007) have been described, but they
do not perform an important biological function. Although it has been
proposed that intestinal enzymatic capacity to form equol in the metabolism of
phytoestrogens would be a plausible cause to predict the clinical response, some
clinical studies have not been able to prove this hypothesis. New trials on the
use of an equol concentrate are awaited to define the actual impact which the
metabolism of isoflavones would have on the predicted clinical efficacy.
Some pharmacokinetic aspects in the metabolism of isoflavones must be
highlighted. Although the intestinal absorption rate is still uncertain, pre-
liminary studies indicate that it would be approximately 0.5 mg kg–1 dose–1,
which would be consistent with most of the doses used in clinical trials. That
is, loads above 0.5 mg kg–1 dose–1 would progressively saturate intestinal
absorption receptors up to generating the fecal loss of the excess dose.
However, there is some population variability about the calculation of this
absorption rate, and today it is believed that the absorption range would be
broader than believed up to now (Setchell 2001).
Isoflavones have affinity for the estrogen receptors (ER) a and b, but, for
ERa, they behave like competitive antagonists, showing a blocking effect with
regard to ovarian estrogens. Nevertheless, they have an intense activity in ERb
and their biological effects are shown through them. The distribution of ERs
varies; thus, for example, ERa predominate in mammary and endometrial
tissue, while ERb predominate in bone, nervous and endothelial tissues.
However, this distribution of receptors varies among individuals. This would
(at least partially) explain the variability of their efficacy when evaluating the
clinical effect of these compounds. Vaginal tissue does not have a clear pre-
dominance of any type of these receptors, making uncertain the use of local
phytoestrogens to manage the vaginal dryness, dyspareunia or external dysuria
of the climacteric syndrome (Palacios 2002; Yildiz 2006).

38.2 Clinical Evidence

The number of studies published on the efficacy of isoflavones to manage
climacteric hot flushes has increased significantly since the 1990s (Usui 2006).
Synthesis evidence currently reveals a clear tendency in favor of the effect of
isoflavones on menopausal vasomotor syndrome, despite the existence of
studies that have not proven a significant difference from placebo. Various
hypotheses have been proposed to explain this difference in results, such as the
Isoflavones for Menopausal Vasomotor Syndrome 631
capacity for metabolizing equol, the type of isoflavones or the critical quantity
of some of them; however, new publications with better standardized sources of
these compounds are awaited to homogenize the combined results of the
studies. For instance, the meta-analysis by Williamson-Hughes et al. (2006)
established a critical threshold of genistein to predict the efficacy of these
phytoestrogens by observing that the trials which had found a significant
clinical response associated to the use of phytoestrogens contained an intake of
genistein above 15 mg/day in comparison with those studies in which the
intake of isoflavones was smaller (Figure 38.3). However, this hypothesis was
not strengthened by the observations of the Study of Women’s Health Across
the Nation (SWAN), which evaluated the relationship between vasomotor
symptoms and race during menopausal transition in 3198 women, and where
no relationship was found between the consumption of genistein and vaso-
motor symptoms (Gold et al. 2006).
Initially, the few trials that used T. pratense as sn isoflavone source did not
yield convincing results about the efficacy of isoflavones (Knight et al. 1999;
Tice et al. 2003); however, it is clear that the sources of these compounds may
greatly differ in their composition. Thus, for instance a standardized extract of
T. pratense (Promensils) has a very different isoflavone composition from a
standardized soy extract (the most currently used source in clinical trials). More
than 80% of the composition of the first one is based on formononetin and

Figure 38.3 Meta-analysis by Williamson-Hughes et al. (2006).

632 Chapter 38
biochanin A, whereas more than 90% of the composition of the latter is based
on genistein and daidzein. These differences in composition generate part of the
heterogeneity in published meta-analyses.
The importance and need to provide an appropriate treatment for meno-
pausal vasomotor syndrome has been well proven, not only for the deteriora-
tion it causes to the quality of life in women but also for its probable
association with other clinical conditions such as osteoporosis (Lee and Kanis
1994). The cumulative evidence proves the usefulness of isoflavones and their
role in the management of menopausal vasomotor syndrome. A brief review of
the main synthesis studies published in this regard is shown below.
The review of the Cochrane collaboration, in charge of Lethaby et al. (2007),
grouped the studies conducted with isoflavones according to the isoflavone
sources used. Thus, four groups of studies were analyzed: soy extract, dietary
soy, T. pratense (red clover), and ‘‘other phytoestrogens’’ (C. racemosa,
A. sinensis, etc.). A relevant aspect of this meta-analysis was the exclusion of
studies conducted with women with breast cancer background, under the
hypothesis that such background would alter hormonal physiology in some
way. The studies that compose the analysis of each one of these groups are
shown in Table 38.1, and those studies excluded from the analysis because of
the participants’ breast cancer background have been identified (Nahas et al.
2004; Nikander et al. 2005; Quella et al. 2000; Secreto et al. 2004; Van Patten
et al. 2002).
Due to the presence of an important heterogeneity in the studies with ‘‘soy
extract’’ (Bicca et al. 2004; Campagnolli et al. 2005; Duffy et al. 2003; Faure
et al. 2002; Han et al. 2002; Kaari et al. 2006; Khaodhiar et al. 2008; Penotti
et al. 2003; Upmalis et al. 2000), ‘‘dietary supplement’’ (Albertazzi et al. 1998;
Balk et al. 2002; Brzezinski et al. 1997; Burke et al. 2003; Colacurci et al. 2004;
Dalais et al. 1998; Knight et al. 2001; Kotsopoulos et al. 2000; Lewis et al. 2006;
Murkies et al. 1995; St Germain et al. 2002) and ‘‘other phytoestrogens’’
(Crisafulli et al. 2004; Dalais et al. 1998; Dodin et al. 2005; Heyerick et al. 2006;
Lewis et al. 2006; Woo et al. 2003), the Cochrane review only carries out the
meta-analysis for the group of studies developed with T. pratense (Baber et al.
1999; Jeri 2002; Knight et al. 1999; Tice et al. 2003; Van der Weijer and
Barentsen 2002), which shows a discrete tendency in favor of this isoflavone
source versus placebo in the efficacy to treat the menopausal vasomotor
syndrome (Figure 38.4). This result coincides with those of other published
meta-analyses (Howes et al. 2006; Nelson et al. 2006; Thompson et al. 2007).
Nevertheless, in this group of studies the heterogeneity reached 59.9%
(I2 ¼ 0.599), and in the subgroup analysis according to the isoflavone dose
(40 mg day–1 vs. 80 mg day–1) it showed a reduction in the statistical tendency
and an increase in heterogeneity (68.3% in the 40 mg day–1 subgroup). The trial
carried out by Atkinson et al. (2004) was not included in this analysis; although
nearly half of the women in each group of this study suffered from hot flushes,
this was not a requirement to participate in the trial. The authors also excluded
the trial by Hidalgo et al. (2005) from this analysis because they did not present
sufficient statistical data (did not report P-values or measures of variation).
Table 38.1 Meta-analysis by Lethaby et al. (2007). Grouping of studies according to isoflavone source.
Trifolium pratense Soy extract Dietary soy Other phytoestrogens Excluded studiesc
Baber et al. (1999) Bicca et al. (2004) Albertazzi et al. (1998) Crisafulli et al. (2004)b Nikander et al. (2005)
Jeri (2002) Campagnolli et al. (2005) Balk et al. (2002) Dodin et al. (2005) Van Patten et al. (2002)
Knight et al. (1999) Duffy et al. (2003) Brzezinski et al. (1997) Heyerick et al. (2006) Nahas et al. (2004)
Tice et al. (2003) Faure et al. (2002) Burke et al. (2003) Woo et al. (2003) Secreto (2004)
Van der Weijer and Han et al. (2002) Dalais et al. (1998) Dalais et al. (1998) Quella et al. (2000)
Barentsen (2002) Khaodhiar (2008) Knight et al. (2001) Lewis et al. (2006)
Atkinson et al. (2004)a Penotti et al. (2003) Kotsopoulos et al. (2000)
Isoflavones for Menopausal Vasomotor Syndrome

Hidalgo et al. (2005)a Upmalis et al. (2000) Lewis et al. (2006)

Kaari et al. (2006)a St Germain et al. (2001)
Colacurci et al. (2004)a
Murkies et al. (1995)a
a
Not considered in the analysis because of some exclusion criteria established by the authors.
b
Genistein concentrate was used as the isoflavone source.
c
Women had breast cancer antecedent.
633
 634

Figure 38.4 Meta-analysis of T. pretense by Lethaby et al. (2007).

Chapter 38
Isoflavones for Menopausal Vasomotor Syndrome 635
The prior meta-analysis by Nelson et al. (2006), which also grouped studies
by isoflavone source and administered dose, did not find statistically relevant
results in the group of studies that used T. pratense.
In the Cochrane review, five out of the eight studies that compared soy
extract with placebo reported significant differences with respect to the
frequency and severity of hot flushes (Bicca et al. 2004; Faure et al. 2002; Han
et al. 2002; Khaodhiar et al. 2008; Upmalis et al. 2000); three studies found a
reduction in the frequency of hot flushes (Bicca et al. 2004; Faure et al. 2002;
Khaodhiar et al. 2008); and two studies observed a reduction in the severity of
hot flushes (Han et al. 2002; Upmalis et al. 2000). The trial by Kaari et al.
(2006) was not analyzed within this group of studies because it had a com-
parative design between soy extract and hormonal therapy and did not report
significant differences between soy and estrogens in the decrease of hot flushes
(at 6 months, P ¼ 0.74, t test). The trial by Crisafulli et al. (2004) was not
analyzed within this group as well, although the source used was a genistein
concentrate; however, this decision from the authors contrasts with the matter
of including the study by Khaodhiar et al. (2008) within the group that used soy
extract, despite it used a daidzein concentrate (Table 38.1).
Crisafulli et al. (2004) had a parallel 3-arm design and contrasted the efficacy
of genistein and hormonal therapy versus placebo. Although both alternatives
surpassed the placebo, the effect of hormonal therapy was significantly better
than that of genistein. These results contrast with Kaari et al. (2006), who did
not find significant differences between soy and estrogen therapy. By combining
direct and indirect evidence, it was recently proven in a meta-analysis that the
effect of hormonal therapy is significantly distinguishable from that of soy
when the purpose of the study corresponds to menopausal vasomotor syn-
drome (Bolaños et al. 2011). However, it is possible that the differences between
both interventions shorten, depending on the effect studied; thus, for instance,
this same difference was not found in a recent indirect meta-analysis when the
effect evaluated was the risk of osteoporotic fracture (Bolaños et al. 2010-a).
Nelson et al. (2006) evaluated the studies conducted with soy under the
perspective of the time of duration of the intervention. The authors of this
meta-analysis made a separate evaluation of studies with durations of 4–6
weeks, 12–16 weeks and 24 weeks, but did not observe special changes in the
combined result favorable to soy in these subgroups. Without making a special
subgroup analysis, the meta-analysis by Thompson et al. (2007) found a
marginal benefit in favor of a short-term use of T. pratense.
Other meta-analyses have been subsequently conducted with the same pur-
pose of evaluating the efficacy of isoflavones versus placebo; however, the
perspective of each one of these meta-analyses is varied, for the purpose of
optimizing the analysis and not just updating the studies. Thus, the meta-
analysis by Howes et al. (2006) only includes published studies and does not
include those studies in which women with a breast cancer background have
participated. The meta-analysis by Bolaños et al. (2010-b) only focused on
published studies with soy or its by-products, regrouping them by the type of
by-product used: soy extract, dietary isoflavone intake or soy isoflavone
636 Chapter 38
concentrate. As well as the Cochrane study, this meta-analysis did not include
studies on women with a breast cancer background.
It is important to observe various studies included in each one of these meta-
analyses to explain the change in the trend of the results. For example, unlike
the Cochrane study, besides including studies on women with breast cancer
background (Nahas et al. 2004; Nikander et al. 2005; Quella et al. 2000; Secreto
et al. 2004; Van Patten et al. 2002), Howes et al. (2006) carries out subgroup
analysis according to the source used: T. pratense and soy by-products; and it
considers Atkinson et al. (2004), which was not included in the Cochrane meta-
analysis, whereas it does not include Baber et al. (1999), which was included in
the Cochrane meta-analysis. However, despite these modifications, the results
obtained the same trend in both meta-analyses (Figure 38.5). As it was to be
expected, Howes et al. (2006) includes a larger number of studies and their
combined results show an increase in the tendency observed in the review of the
Cochrane study for the group of studies with soy by-products. Another result
to be highlighted in the analysis by Howes et al. (2006) is the following rela-
tionship that exists between the frequency of hot flushes and the clinical result,
finding in the corresponding regression a higher clinical response in women
with Z4 hot flushes day–1 (Figure 38.6).
On the other hand, the meta-analysis by Bolaños et al. (2010-b) not only
includes two studies in addition (D’Anna et al. 2007; Cheng et al. 2007) to the
previously described studies, but it also has some peculiarities that distinguish it
from previous analyses. The authors only focus on studies conducted with soy
and its by-products and categorized these studies according to the isoflavone

Figure 38.5 Meta-analysis by Howes et al. (2006). Weighted regression analysis plot
for the number of baseline flushes as a predictor of the percentage fall
from baseline of flushes.
Isoflavones for Menopausal Vasomotor Syndrome 637

Figure 38.6 Meta-analysis by Howes et al. (2006).

source: soy extract, dietary isoflavone intake or soy isoflavone concentrate

(Figure 38.7). The results from Crisafulli et al. (2004) are also included in the
analysis (as this study used genistein concentrate), together with the trials by
Khaodhiar et al. (2008) and D’Anna et al. (2007), which used daidzein and
genistein concentrates, respectively. Similar to Howes et al. (2006), the authors
of this work also considered the studies of Colacurci et al. (2004) (subgroup
with soy extract) and Murkies et al. (1995) (subgroup with dietary isoflavone)
to be acceptable for the analysis. Both trials were excluded from the Cochrane
analysis.
The results of this meta-analysis are consistent with those of previous meta-
analyses. The trend of the combined results favors soy and its by-products
in the three subgroups analyzed; nevertheless, heterogeneity is important in
‘‘soy extract’’ and ‘‘dietary isoflavone intake’’ subgroups (42% and 56%,
respectively). However, the isoflavone concentrate subgroup, made up by three
 638
Chapter 38

Figure 38.7 Meta-analysis by Bolaños et al. (2010-b).

Isoflavones for Menopausal Vasomotor Syndrome 639
clinical trials (Crisafulli et al. 2004; D’Anna et al. 2007; Khaodhiar et al. 2008),
did not show a higher heterogeneity (0%). The global analysis of all the trials
reached 53% heterogeneity. The same as found by Howes et al. (2006), in this
study regression found a significant direct relationship between number of hot
flushes and the response to the treatment with isoflavones.
Since the meta-analysis by Bolaños et al. (2010-b), new randomized and
placebo-controlled trials have been published which have not been evaluated in
a new synthesis review (Borges and Salazar 2009; Ferrari 2009). In the near
future, this would provide higher statistical forcefulness to the results described
in this review. It is important that the new studies for this same purpose
standardize the main heterogeneity factors observed, such as isoflavone source,
duration of treatment and measurement scales for results. On the other hand
and taking into account that the updating of a meta-analysis may significantly
increase the type I error (even more than the known publication bias), Bolaños
et al. (2010-b) verified that including three additional studies to the analysis
(not included in previous meta-analyses) would lead to an increase in said error.
The P-value of the meta-analysis and the previously defined alpha value (0.05)
made the updating possible without increasing the type I error (Borm and
Donders 2009).
Although some meta-analyses exclude unpublished studies (unlike the
Cochrane study), it is important to observe that, in general, such studies do not
show the minimum methodological quality to include them in the final analysis.
Because of this reason, many experts consider it more worthwhile investing in
updating reviews than an exhaustive search for unpublished data. The authors
also included studies with small samples and low statistical power, which
increases the probability of obtaining non-significant results and reducing the
probability of being published; however, this situation does not detract from
the results, as the meta-analyses that include low power studies (50% on
average) closely agree with the ‘‘actual’’ difference in the effect size of the
intervention under study, even in presence of a publication bias. Previous
studies have proven that the results of small trial meta-analyses are very similar
to those of large trial meta-analyses on the same intervention. According to
Van Driel et al. (2009), the key question should not focus on the existence of a
publication bias but on the true impact of this bias.
It is important to observe some limitations in the synthesis studies published
until now, as they limit the interpretation of results. First, in accordance with
the current regulatory frame, a definite dose for dietary soy supplements has
not been established. This hinders the comparison of studies that use said
supplements without an appropriate standardization in their isoflavone com-
position. Besides, the role of intact soy protein on the effect size is still uncer-
tain, and it has not yet been defined whether the presence of soy protein
constitutes a heterogeneity factor across the studies. Second, despite the evi-
dence that suggests that an intestinal metabolic trait could have a significant
influence on the bioavailability and activity of isoflavones (a hypothesis that
involves the formation of equol), most of the studies do not evaluate the par-
ticipants’ intestinal metabolic pattern, which could also be a source of
640 Chapter 38
heterogeneity in the results. Third, the studies analyzed often use different
scores to measure the effect size (frequency and/or severity of hot flushes),
which could generate another additional heterogeneity factor.

38.3 Conclusions
Studie on isoflavones (a type of phytoestrogen) have accumulated enough
evidence to support their alternative use in the management of climacteric
vasomotor symptoms, and such a benefit seems to be supported by its isoflavone
content. However, the main sources of these compounds (soy, T. pretense and
C. racemosa) differ in isoflavone content, and such differences may explain the
heterogeneity in the results of the studies when analyzed as a whole.
Genistein, daidzein and glycitein are the predominant isoflavones in soy
(G. max), in contrast with the composition of red clover (T. pratense) based on
formononetin and biochanin A, its main flavonoids. Black cohosh (C. race-
mosa) is popularly used but evidence about its exact isoflavone content is
uncertain.
Considering that the proportion of isoflavones in soy may vary in accordance
with the preparation administered, this source could be classified into three
types: ‘‘dietary isoflavone intake’’, ‘‘soy extract’’ and ‘‘soy isoflavone con-
centrate’’ (genistein or daidzein), to try to reduce the heterogeneity observed in
all the studies.

Summary Points
 Isoflavones show a significantly higher efficacy than placebo on climacteric
vasomotor syndrome.
 There are apparent differences in efficacy associated with the evaluated
isoflavone source, as different sources vary in their isoflavone composition.
 The evidence does not support an effect equivalent to hormone therapy.
 A better response is obtained with isoflavones when the intensity of the
vasomotor syndrome is mild or moderate, and when the number (fre-
quency) of hot flushes is high (Z4 hot flushes day–1).
 The use of isoflavones is pertinent when the patient does not wish to or
cannot receive hormone therapy.
 Isoflavones show a safety level comparable with placebo.

Key Facts
 There has been some uncertainty about the true effect size of isoflavones.
For a long time they were considered to hold a placebo effect.
 The evidence has increased in the last 20 years and several meta-analyses
have demonstrated a significant effect size.
 Heterogeneity is still the key-point for the robustness of the conclusions,
so it is necessary to standarize some criteria as type of supplement, patients
follow-up and clinical scores to measure menopausal symptoms.
Isoflavones for Menopausal Vasomotor Syndrome 641
Definition of Words and Terms
Dietary isoflavone intake: Total amount of isoflavones that an individual
intakes in their diet every day.
Soy extract: A genistein, daidzein and glicitein mixture that is isolated from soy
plant.
Soy isoflavone concentrate: Total amount of genistein or daidzein administered
as a formula.

List of Abbreviation
ER estrogen receptor

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Balk, J.L., Whiteside, D.A., Naus, G., Deferrari, E., and Roberts, J.M., 2002.
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