MODERN TRENDS

Edward E. Wallach, M.D.

Associate Editor

Phytoestrogens in clinical practice: a review of the

literature
Clemens B. Tempfer, M.D.,a Eva-Katrin Bentz, M.D.,a Sepp Leodolter, M.D.,a Georg Tscherne, M.D.,b
Ferdinand Reuss, M.D.,b Heide S. Cross, Ph.D.,c and Johannes C. Huber, M.D., Ph.D.a
a
Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna; b Department of Obstetrics and Gynecology,
Medical University of Graz, Graz; and c Department of Pathophysiology, Medical University of Vienna, Vienna, Austria

Objective: To review clinical studies assessing the effect of phytoestrogen supplementation on the signs and symp-
toms of the climacteric syndrome and on the incidence of breast cancer, cardiovascular disease, and skeletal
fractures.
Design: Literature research using PubMed and the Cochrane controlled trials register.
Setting: None.
Patient(s): None.
Intervention(s): None.
Main Outcome Measure(s): None.
Result(s): Six systematic reviews and meta-analyses of 25 randomized, controlled trials (RCTs) assessing the use
of phytoestrogens for the treatment of the climacteric syndrome were identified. Systematic reviews of RCTs show
contradictory results, and meta-analyses demonstrate no statistically significant reduction of vasomotor symptoms
for phytoestrogens. Individual RCTs report significant reductions in vasomotor symptoms for red clover and soy
phytoestrogens. In selected patient populations, such as in women with early natural postmenopause and mild to
moderate vasomotor symptoms, a systematic review of five RCTs found a significant reduction of hot flashes in five
out of five RCTs. Twenty-two case-control and cohort studies examined the incidence of breast cancer among
women with and without a diet high in phytoestrogens. A meta-analysis of 21 studies found a significantly reduced
incidence of breast cancer among past phytoestrogen users. RCTs document beneficial effects of phytoestrogens on
surrogate parameters such as bone mineral density, vasodilation, platelet aggregation, insulin resistance, and serum
concentrations of triglycerides, high-density lipoprotein, and low-density lipoprotein. None of the available RCTs
documents a protective effect of phytoestrogens for the clinical end points of breast cancer, bone fracture, or car-
diovascular events.
Conclusion(s): Based on the available evidence, phytoestrogens should only be used in selected women, i.e., those
presenting with mild to moderate vasomotor symptoms in early natural postmenopause. None of the compounds
investigated so far have been proven to protect against breast cancer, bone fracture, or cardiovascular disease.
(Fertil Steril 2007;87:1243–9. 2007 by American Society for Reproductive Medicine.)
Key Words: Phytoestrogens, climacteric syndrome, hormone replacement, soy, red clover, alternative, review

Phytoestrogens have been widely used in various cultures and
time periods. Empirical data and epidemiologic research
indicate that the incidence of hormone-dependent diseases
is reduced in countries with a high dietary content of phytoes-
trogens (1, 2). Thus, modern clinical and molecular bio-
logical research has increasingly focused on plant-derived
phytoestrogens such as isoflavones, lignans, dihydrochal-
cones, and coumestans. The most widely studied phytoestro-
genic compounds are isoflavones found in red clover and
Received January 4, 2006; revised and accepted January 11, 2007.
Reprint requests: Clemens B. Tempfer, M.D., Department of Obstetrics
and Gynecology, Medical University of Vienna, Waehringer Guertel
18-20, A-1090, Vienna, Austria (FAX: þ43-1-40400-2911; E-mail:
clemens.tempfer@meduniwien.ac.at).
soy, such as genistein, formononetin, biochanin A, and daid-
zein (3).
The widely publicized and discussed results of the
Women’s Health Initiative (WHI) and the One Million
Women Study have considerably increased the interest in
the use of phytoestrogens. Because phytoestrogens interact
with the estrogen receptor, inducing agonistic as well as antag-
onistic effects, the primary preventive potential as well as the
oncologic safety of a prolonged use of phytoestrogens are of
considerable interest. We summarize the clinical and experi-
mental data on the use of phytoestrogens for the alleviation
of signs and symptoms of the climacteric syndrome. Numer-
ous randomized, controlled trials (RCTs) have investigated

0015-0282/07/$32.00 Fertility and Sterility Vol. 87, No. 6, June 2007 1243
doi:10.1016/j.fertnstert.2007.01.120 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
the therapeutic efficacy of phytoestrogens, allowing for an
evidence-based recommendation for clinical practice. In
addition, we summarize clinical evidence investigating the
effects of phytoestrogens on the skeletal system and the cardio-
vascular system, the incidence of breast cancer, and skin
health.
PHYTOESTROGENS AND THE CLIMACTERIC SYNDROME
A number of controlled and uncontrolled clinical studies have
indicated that a dietary increase in phytoestrogens in addition
to a regular diet (4) and phytoestrogen supplementation (5–9)
are associated with an increase in quality of life and a signif-
icant amelioration of the signs and symptoms of the climac-
teric syndrome, as summarized by the Kuppermann index
(10). On the other hand, several studies could not demonstrate
a clinical effect, especially with regard to hot flashes (11).
Several reasons may account for these and other discrep-
ancies between studies, among them differences in patient
selection, phytoestrogen content, and symptom assessment,
and variations in endogenous estrogen production, intestinal
resorption, and activation of orally ingested isoflavones.
Study Selection
We searched PubMed and the Cochrane controlled trials reg-
ister (January 06, 2006, for search terms: climacteric syn-
drome, hot flashes, phytoestrogens, isoflavones, treatment)
to identify RCTs, systematic reviews, and meta-analyses of
RCTs assessing the efficacy of phytoestrogens in women
with the climacteric syndrome. Studies were included if
they were published as complete reports in English. Studies
were eligible if they were RCTs comparing placebo or no in-
tervention with phytoestrogens in perimenopausal and/or
postmenopausal women with hot flashes. Phytoestrogens
were defined as substances with a defined amount of isofla-
vones, lignans, or coumestans. Studies investigating black
cohosh were not included in this review because the mecha-
nism of action of this botanical is unknown. Studies assessing
menopausal symptoms other than hot flashes were excluded.
Two reviewers assessed eligibility of the studies and
extracted data. Missing information and additional trials
were not sought from the investigators. To identify subgroups
of women selectively benefiting from phytoestrogen treat-
ment, we used criteria proposed by the U.S. Food and Drug
Administration (FDA) for the conduct of studies evaluating
hormone replacement therapies (12) and by Messina and
Hughes (13), who proposed to exclude women with iatro-
genic menopause after treatment for oncologic diseases in
the assessment of the efficacy of phytoestrogens.
Following criteria used in previous meta-analyses (11), we
recorded the adequacy of treatment allocation concealment
according to criteria published by Schulz et al. (14). Trials
were considered to have adequate concealment if they
described satisfactory procedures to conceal treatment allo-
cation such as coded identical containers or centralized
randomization. We also recorded blinding participants and
1244 Tempfer et al. Literature review
outcome assessors to treatment, use of intention-to-treat anal-
ysis, and the number of participants who withdrew or were
lost to follow-up evaluation. When possible, effect sizes
were calculated to provide a measure of the magnitude of
a treatment effect for each study. The effect sizes represent
the difference in mean hot flash frequency outcomes divided
by the standard deviation. Negative effect size values favor
placebo, and positive effect sizes favor phytoestrogen. In
the scale suggested by Cohen (15), cutoff values of 0.2,
0.5, and 0.8 reflect small, moderate, and large treatment
effects, respectively.
If possible, outcome data were pooled and analyzed using
the Cochrane Collaboration Review Manager (RevMan 4.2;
Update Software, Oxford, United Kingdom). Weighted
mean differences, the difference between treatment and con-
trol pooled means at end point, along with 95% confidence
intervals (CI), were calculated for continuous variables.
Efficacy of Phytoestrogens
We identified 25 RCTs (5–9, 16–35) and six systematic re-
views and meta-analyses of RCTs (3, 11, 36–39). In a system-
atic review and meta-analysis of 25 RCTs, red clover
products were not shown to be effective for the treatment
of hot flashes (weighted mean difference 0.60; 95% CI,
1.71–0.51). Of the five soy extract trials reporting hot flush
frequency, three trials, including the two largest trials, were
negative (11). In another systematic review of 29 RCTs of al-
ternative therapies for hot flashes and other menopausal
symptoms, the investigators identified 12 RCTs examining
soy or soy extracts (3). Only three of eight studies with treat-
ment phases >6 months showed a significant improvement in
hot flashes. The effects were modest, and most benefits disap-
peared after 6 weeks. This review cites two RCTs document-
ing no statistically significant benefit for red clover products.
Similarly, Huntley and Ernst (36) identified 10 RCTs assess-
ing soy preparations for the treatment of perimenopausal
symptoms and found four of 10 RCTs to be positive, suggest-
ing soy preparations are beneficial for perimenopausal symp-
toms. Six RCTs were negative, with one of the six showing
a positive trend.
Another review of botanical compounds for the treatment
of menopause-related symptoms identified RCTs investigat-
ing soy isoflavone extracts with varying compositions and
dosages of soy supplements. Results from five RCTs assess-
ing the efficacy of semipurified isoflavone red clover (Trifo-
lium pratense L.) leaf extracts were contradictory. The
largest study showed no benefit for reducing symptoms asso-
ciated with menopause for two different red clover isoflavone
products compared with placebo. No significant adverse
events were reported in the investigated studies (37). A
meta-analysis by Nelson et al. (38) investigated alternative
treatments for menopausal symptoms. The following com-
pounds were found to significantly reduce the number of
daily hot flashes compared with placebo: seven RCTs of se-
lective serotonin reuptake inhibitors (SSRIs) or serotonin
Vol. 87, No. 6, June 2007
norepinephrine reuptake inhibitors (SNRIs) (mean differ-
ence, 1.13; 95% CI, 1.70 to 0.57), four RCTs of cloni-
dine (0.95; 95% CI, 1.44 to 0.47), and two RCTs of
gabapentin (2.05; 95% CI, 2.80 to 1.30). In contrast,
the frequency was not reduced in a meta-analysis of 17
RCTs of red clover isoflavone extracts and soy isoflavone ex-
tracts (39). Kang et al. (39) identified seven RCTs, of which
five RCTs reported no beneficial effect on hot flashes of soy
protein. Two RCTs reported a significant reduction of hot
flashes in the group treated with soy product over placebo.
Hot flash frequency was reduced by 45% and 28%, respec-
tively, in these two trials, but the placebo effect was also
high, with reductions of 30% and 18%.
These data indicate that phytoestrogens have modest if any
effects, and that these effects may be limited to selected pa-
tient populations. Thus, in an effort to better define possible
patient subgroups who may selectively benefit from phytoes-
trogens, we tried to identify studies examining only early
postmenopausal women with natural menopause and mild
to moderate vasomotor symptoms using previously published
recommendations (12, 13).
We identified 25 RCTs examining phytoestrogens for the
treatment of hot flashes (5–9, 16–35). We excluded 20 studies
from further evaluation (16–35), leaving five RCTs with 411
early postmenopausal women with natural menopause (5–9).
Tables 1 and 2 show the study and participant characteristics
of this highly selected set of studies. All of the trials included
postmenopausal women and reported double-blinding. Two
of the five trials (5, 7) provided enough information to con-
firm adequate concealment of treatment allocation. Three
of the five trials (5–7) reported intention-to-treat analysis.
The minimal dose of isoflavones used in these studies was
40 mg per day, the maximal dose was 100 mg per day. The
phytoestrogens tested were soy in four trials (5–7, 9) and
red clover extract in one trial (8). The number of women
included in these studies varied between 30 and 122.
Table 3 shows the outcomes of trials and the symptom
score results. All of the five individual studies demonstrated
a statistically significant reduction of vasomotor symptoms.
Four of five trials reported continuous variables such as
mean percentage change of hot flashes per day or Kupperman
TABLE 1
Study characteristics and isoflavone dosages.
Cases Controls
Study (reference) (n) (n)
Albertazzi et al., 1998 (5) 51 53
Faure et al., 2002 (6) 39 36
Han et al., 2002 (7) 40 40
Jeri, 2002 (8) 15 15
Upmalis et al., 2000 (9) 59 63
a
Highest P value for improvement of symptoms.
Tempfer. Literature review. Fertil Steril 2007.
Fertility and Sterility
index (5, 7–9). Only one study (6) reported absolute numbers.
Therefore, a pooled analysis for the identification of mean
weighted differences was not performed. One study reported
sufficient data for the calculation of effect sizes (6). This
study favored placebo with a moderate effect size (0.53).
In summary, this meta-analysis of a predefined, selected
patient population indicates that the efficacy of isoflavones
as a treatment for the signs and symptoms of the climacteric
syndrome is reduced in women with idiopathic premature
ovarian failure, premature ovarian failure after cancer treat-
ment, after long-term hormone therapy, and when isoflavone
treatment is initiated >3 years after menopause (12, 13).
Consequently, phytoestrogens may be used most effectively
in early postmenopausal women with a natural menopause
and mild to moderate climacteric syndrome. Meta-analyses
of intervention studies with isoflavones without specific se-
lection criteria may thus underestimate the clinical efficacy
of this therapy. This may serve as a possible explanation
for contradictory results of RCTs in unselected patient popu-
lations (3, 11, 36–39). From a clinical perspective, phytoes-
trogens may be used most appropriately as first-line
treatment for women presenting with mild to moderate va-
somotor symptoms in early natural postmenopause. This is
also in accordance with the recommendations of the North
American Menopause Society (40).
PHYTOESTROGENS AND BREAST CANCER
In Vitro Data
In vitro experiments using benign breast cell lines, skeletal
muscle cell cells, and rodent models have found that phytoes-
trogens exert a proliferation-enhancing effect (41, 42).
Although these studies principally document that
phytoestrogens can lead to cell proliferation, other in vitro
and in vivo studies have demonstrated a concentration-depen-
dent biphasic antiproliferative effect of isoflavones (43).
Phytoestrogens can, under certain conditions, function as
antioxidants and protect against oxidant-induced DNA dam-
age (44). In vivo studies in rodents also indicate that low-dose
dietary isoflavones abrogate tamoxifen-associated mammary
tumor prevention (45). Thus, the experimental data available
so far are not conclusive. Epidemiologic data and prospective
case-control studies, on the other hand, clearly demonstrate
Isoflavone
Compound P valuea dosage
Isoflavone protein < .001 76 mg/day
Isoflavone capsules < .01 70 mg/day
Isoflavone capsules < .01 100 mg/day
Red Clover extract < .001 40 mg/day
Isoflavone tablets .03 50 mg/day
1245
 TABLE 2
Characteristics of studies and participants.
Participants Participant Study
Study (reference) (dropouts) Inclusion criteria characteristics duration
Albertazzi et al., 1998 (5) 104 (25) Amenorrhea R6 months or Italy; MA 53 years; 12 weeks
oophorectomy, or FSH MDM 3.9 years
>50 IU/L and E2
<35 pg/mL; R7 HF/day
Faure et al., 2002 (6) 75 (20) Amenorrhea R6 months or France; MA 53 years; 16 weeks
FSH >40 IU/L and E2
<35 pg/mL; R7 HF/day
Han et al., 2002 (7) 82 (2) Age 45–55 years and Brazil; MA 53 years; 4 months
amenorrhea R12 MDM 2.4yrs
months or FSH >25 IU/L
and E2 <35 pg/mL;
HF present
Jeri, 2002 (8) 30 (0) Age <60 years and Peru; MA 52 years; 14 weeks
amenorrhea >1 year MDM -
or FSH >30 IU/L; R5
HF/day
Upmalis et al., 2000 (9) 177 (55) Age >50 years and U.S.; MA 55 years; 12 weeks
amenorrhea R6 months MDM
or FSH >40 IU/L and E2
<25 pg/mL; R5 HF/day
Note: E2, estradiol; FSH, follicle-stimulating hormone; HF, hot flashes; MA, mean age; MDM, median duration after
menopause.
Tempfer. Literature review. Fertil Steril 2007.

that countries with a high dietary content of isoflavones have
lower incidence rates of breast and prostate cancer compared
with countries with a low dietary content of phytoestrogens,
which argues against a principally cell-proliferative effect of
phytoestrogens.
Clinical evidence from uncontrolled trials is consistent
with a protective effect of phytoestrogens against the devel-
opment of breast cancer. For example, a meta-analysis of
14 case-control and 7 cohort studies found a pooled risk re-
duction of 25% (Relative Risk [RR] 0.75; 95% Confidence
Interval [CI] 0.59 to 0.95) for past soyfood, tofu, miso, or iso-
flavone intake (46). A recent nested case-control study within
a Dutch prospective cohort found high plasma levels of gen-
istein to be associated with a 32% reduced odds of developing
breast cancer (47). In contrast to this evidence, three prospec-
tive trials evaluated this issue (1, 48, 49). All of these pro-
spective trials showed no statistically significant reduction
in breast cancer incidence. There has been no prospective,
randomized study evaluating phytoestrogens as a primary
preventive therapy of breast cancer. It is of note that a protec-
tive effect of isoflavones could not be reproduced in Euro-
pean or U.S. studies such as the San Francisco Bay study
(50). Some researchers have claimed that the effect of a phy-
toestrogen diet depends—at least in part—on the individual
age of the woman when starting the diet. Asian women are
exposed to phytoestrogens starting with early childhood,
but the typical Western initiation of a phytoestrogen-rich
diet or phytoestrogen supplementation in perimenopause or
postmenopause may be too late to exert a protective effect
on the breast. Phytoestrogens may induce differentiation of
breast epithelium during early childhood and puberty, thus
making the breast epithelium less sensitive to noxious agents
such as chemical carcinogens. Breast epithelia may no longer
be sensitive to phytoestrogens after pregnancy. This model of
a lifetime-dependent effect of protective agents has been
demonstrated by Russo and Russo (51).
Putting these data into a clinical perspective, women plan-
ning to use phytoestrogens can be advised that phytoestro-
gens can be used safely on a long-term basis. There are no
data indicating that prolonged use of a phytoestrogen-rich
diet induces malignant growth of hormone-dependent tissue.
On the other hand, none of the compounds investigated so far
has been proven to protect against breast cancer. There are no
data with respect to other malignancies, but there is no indica-
tion that phytoestrogens increase the risk of malignant disease.
PHYTOESTROGENS AND THE SKELETAL SYSTEM
Isoflavones have been demonstrated to increase the synthe-
sis of vitamin D in a number of nonrenal cell types (52).
Due to this mechanism, isoflavones are thought to contrib-
ute to bone mineral density. A prospective, randomized

1246 Tempfer et al. Literature review Vol. 87, No. 6, June 2007
 TABLE 3
Clinical outcomes of trials and symptom score results.
HF/day at HF/day at
Study (reference) baseline (mean SD study end Decrease HF/day
and intervention or median range) (mean SD) (P value) Symptom score
Albertazzi et al., 1998 (5)
Soy 11.4 (10.7–12.7) 6.4 (–) –5.0 None reported
Placebo 10.9 (10.2–11.8) 7.5 (–) –3.4
P< .01
Faure et al., 2002 (6)
Soy 10.1 (6.4) 3.9 (0.7) –6.4 None reported
Placebo 9.4 (3.4) 7.0 (1.2) –2.2
P¼ .01
Han et al., 2002 (7)
Soy — — — Kupperman index
Placebo — — –19.7 (soy) vs
þ1.3 (placebo)
— P< .01
Jeri, 2002 (8)
Red clover 7.0 (0.5) 3.6 (0.3) –3.4 None reported
Placebo 5.7 (0.4) 5.1 (0.3) –0.6
P¼ .001
Upmalis et al., 2000 (9)
Soy 8.8 (6.2) — Mean % HF/d None reported
Placebo 9.4 (6.0) — –20 (placebo)
vs –28 (soy)
P< .05
Note: HF, hot flashes; SD, standard deviation.
Tempfer. Literature review. Fertil Steril 2007.

study of 66 women found that 88 mg of isoflavones per day
have a protective effect on the skeletal system, increasing
the bone mineral density in the lumbar spine (53). On the
other hand, a large study of 202 postmenopausal women
found no benefit after 12 months of daily 99-mg isoflavone
supplementation (52 mg of genistein, 41 mg of daidzein,
and 6 mg of glycitein) (54). This double-blind, randomized
trial does not support the hypothesis that the use of a soy
protein supplement containing isoflavones improves cogni-
tive function, bone mineral density, or plasma lipids in
healthy postmenopausal women when started at the age of
60 years or later. Based on these data, isoflavones cannot
be clinically recommended as a valuable intervention to
increase bone health. No data are available to assess the
efficacy of isoflavones as a means to treat women with
osteoporosis and should thus not be recommended as the
sole treatment in this indication. No RCTs are available,
documenting the efficacy of phytoestrogens regarding the
prevention of osteoporosis or bone fracture.
PHYTOESTROGENS AND THE CARDIOVASCULAR SYSTEM
Endothelium-derived nitric oxide (NO) is a potent vasodila-
tor and mediates the effects of antihypertensive drugs such
as nitroglycerin. Isoflavones have been shown to stimulate
the activity of the endothelial NO synthase (NOS3), thus
inducing vasodilation via NO (55). Isoflavones also have
antithrombotic and antiatherogenic effects. For example,
genistein and daidzein decrease monocyte chemoattractant
protein-1 and collagen-induced platelet aggregation in a
dose-dependent manner (56). In addition, 54 mg/day of gen-
istein are sufficient to significantly decrease fasting glucose,
fasting insulin, and insulin resistance (57). Clinical studies
have assessed the effect of isoflavones on surrogate end
points of cardiovascular health. A meta-analysis of 38 con-
trolled human studies of soy consumption provides evi-
dence for its positive effect on lipid profiles, including
reduction in levels of low-density lipoproteins (LDL) and
triglycerides and increases in high-density lipoprotein
(HDL) (58). In a population-based study of 301 postmeno-
pausal women, however, intake of between 0.2 mg and 11.4
mg of isoflavones did not alter systolic or diastolic blood
pressure, or the prevalence of hypertension (59). In accor-
dance, a 12-month, double-blind, randomized trial com-
pared the effects of soy protein containing 99 mg of
isoflavones/day (aglycone weights) with those of milk
protein (placebo) and found no effect on blood pressure and

Fertility and Sterility 1247

endothelial function in 202 postmenopausal women aged
60 to 75 years (60).
No RCTs regarding clinical end points of cardiovascular
health (i.e., myocardial infarction, angina pectoris) are avail-
able to date. Therefore, phytoestrogens cannot be recommen-
ded as a primary preventive intervention to reduce the risk of
cardiovascular disease. Women using phytoestrogens may be
advised, however, that phytoestrogens used for the treatment
of the climacteric syndrome have additional benefits on the
cardiovascular system by reducing established risk factors
of atherosclerosis such as hyperlipidemia and hypertension.
Whether this translates into a clinical benefit regarding the re-
duction of clinical end points such as myocardial infraction is
unknown.
PHYTOESTROGENS AND SKIN HEALTH
Isoflavones may have a protective effect on skin health. It has
been hypothesized that skin elasticity is improved by in-
creased local blood flow. In addition, the carcinogenic effect
of exogenous noxious agents such as ionizing radiation and
chemical compounds may be alleviated by the antioxidant
and anti-inflammatory properties of phytoestrogens (61).
Also, red clover protects from inflammation and immune
suppression induced by ultraviolet radiation (62). No data
with respect to clinical end points of skin health have been
published.
STANDARDIZATION OF PHYTOESTROGENS
Because phytoestrogens are listed as food supplements,
quality standards regarding manufacturing and isoflavone
content are important. Phytoestrogen compounds used to
treat women with climacteric syndrome should contain 40
to 100 mg of isoflavones consisting of variable combina-
tions of different aglycans (i.e., genistein, daidzein, glyci-
tein, formononetin, and biochanin A). A daily dose of
40–100 mg of isoflavones is toxicologically safe and is
consistent with the dietary content of isoflavones in Asian
countries (63). Interactions between an isoflavone supple-
mentation in this dosage and other pharmaceutic interven-
tions are not known.
Acknowledgments: The authors thank M. Metka, B. Kleine-Gunk, A. Jungba-
uer, L. Krenn, G. Freude, F. Fischl, D. Foth, and W. Clementi for their
contributions to the design of this paper.
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