The efficacy of soy isoflavones on menopausal vasomotor

symptoms: A review

Lindsay Gullen

University of British Columbia

333 University Way

Kelowna, BC

V1V 1V7

April 1, 2014

Abstract

Due to the risks associated with steroidal hormone

replacement therapy, many menopausal women are seeking

natural alternatives to treat vasomotor symptoms (VMS).

Research focusing on the effectiveness of phytohormones has

had mixed results, although soy-derived isoflavones have

provided promising treatment. This review investigates the

biochemistry and mode of action of soy isoflavones,

evaluates current research on the efficacy of soy

isoflavones on VMS, and makes recommendations for future

work in the field.

Keywords

hormone replacement alternatives, isoflavones, menopause,

phytoestrogen efficacy, soy, vasomotor symptoms

2

Abbreviations

FDA, Food and Drug Administration; HRT, hormone replacement

therapy; SERM, selective estrogen receptor modulators; SHBG,

Sex Hormone Binding Globlin; SPARE, Soy Phytoestrogens As

Replacement Estrogen; VMS, vasomotor symptoms

Graphical abstract

Soy-derived isoflavones contain two hydroxyl groups in

approximately the same positions as estradiol. Consequently,

isoflavones exhibit weakened but similar properties as

estradiol, such as decrease in menopausal vasomotor

symptoms.

3

Highlights

Soy-derived isoflavones provide a promising alternative

to hormone replacement therapy (HRT)

Isoflavones weakly activate estrogen receptors

Isoflavone

Estrogen(17β-

4

Clinical trials have shown mixed results in decreasing

vasomotor symptoms in menopausal women through use of

soy isoflavones

Future research must be conducted to improve

consistency amongst results, and to approve product by

FDA

1.0 Introduction

Menopause, or the “change of life”, is experienced by

women between the ages of 46 to 50 and involves the

termination of menstruation. The ovaries gradually lose

their capability of responding to the hormones responsible

for stimulation of ripening egg cells, and no longer produce

the sex hormone estrogen. The deficit in estrogen may lead

to a number of physiological changes, including vasomotor

symptoms (VMS) (Rathus et al., 2012).

VMS include a sudden onset of feeling hot (hot

flashes), looking reddened (hot flushes), and night sweats.

These subjective experiences occur due to the vasodilation

of blood vessels in the face and upper body. It is suggested

5

that deficiency in estrogen disturbs the hypothalamus and

offsets a number of hormonal pathways responsible for

temperature regulation (Rathus et al., 2012).

VMS are experienced globally by 22% to 74% of

menopausal women (Villaseca, 2012). Although these symptoms

are not a severe threat to health, they can negatively

impact a woman’s quality of life (Bedell et al., 2014). Some

women partake in steroidal hormone replacement therapy (HRT)

to help alleviate menopausal symptoms. Although HRT has been

clinically shown to be the most effective treatment for VMS,

only 10% to 15% of menopausal women in Western countries

currently use it (Brzezinksi and Debi, 1999). Women became

reluctant to use HRT after a 2002 study conducted by the

Women’s Health Initiative terminated an 8-year study early

due to an increase in breast cancer incidence amongst women

treated with HRT. Consequently, the Canadian Cancer Society

strongly discourages use of HRT unless menopausal symptoms

are severe and women are unable to use alternative

treatments (Rathus et al., 2012).

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One area of growing research involves the use of

phytoestrogens as a non-steroidal substitute. Soybeans are

rich in isoflavones, which behave similarly to estradiol by

displaying weakened estrogenic effects (Albertazzi et al.,

1998; Bedell et al., 2014; Carmignani et al., 2010). The

objectives of this review are: (1) to investigate the

biochemistry and mode of action of soy isoflavones, (2) to

evaluate current research on the efficacy of soy isoflavones

on VMS and (3) to make recommendations for future work in

the field.

1.1 Biochemistry

Phytoestrogens, which are of plant origin, are non-

steroidal classes of compounds. When humans consume certain

plants, phytoestrogens can also be derived by the in vivo

metabolism of precursors (Brzezinksi and Debi, 1999).

Soybeans contain genistin, daidzin, and glycitin, which

belong to the phytoestrogen class of isoflavones. These

compounds consist of a heterocyclic structure and two

hydroxyl groups in approximately the same positions as

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estradiol. Consequently, isoflavones are capable of binding

and activating estrogen receptors (Fig 1) (Alamo et al.,

2010).

Upon ingestion of soy products, bacteria in the gut

convert genistin, daidzin, and glycitin into active,

aglycone forms (genistein, daidzein, and glycitein). Gut

flora activate isoflavones from their glycone to aglycone

structures by removal of the sugar molecule via beta-

glucosidase (Alamo et al., 2010; Vincent and Fitzpatrick,

2000). Daidzein undergoes further modification by intestinal

flora producing equol, which is ten times more potent than

its precursor (Bedell et al., 2014).

Absorbed isoflavones can vary between individuals. Only

30%-50% of the human population is capable of producing

equol (Uehara et al., 2008). Moreover, diet, illness and

antibiotic use can cause intestinal flora populations to

fluctuate, thus impacting equol production (Bedell et al.,

2014). For example, Setchell and Cassidy (1999) found that

higher levels of equol were found in those with a diet high

in carbohydrates. Variations in gut flora may potentially

8

pose a problem in the administered dose, enabling relevant

research investigation.

1.2 Mode of Action

All estrogens (including steroidal) are classified as

Selective Estrogen Receptor Modulators (SERMs) (Bedell et

al., 2014). Their effects are dependent on target tissues

and the concentration of circulating estrogen levels

(Carmignani et al., 2010). With high circulating

concentrations, isoflavones act as estrogen antagonists. In

menopausal women, where circulating estrogen is low,

isoflavones act as estrogen agonists (Vincent and

Fitzpatrick, 2000). For example, the soy-derived drug

Femarelle has agonistic activity in the brain and bone, thus

alleviating menopausal symptoms and increasing bone density.

However, the makers of Femarelle report antagonistic,

antiproliferative effects on breast and endometrial tissue

(Fig 2) (Yoles et al., 2004).

Although less potent than estradiol, isoflavones bind

to both alpha and beta estrogen receptors, with greater

9

affinity for the latter. Beta estrogen receptor stimulation

is responsible for antiproliferation in reproductive

tissues, whereas alpha estrogen receptor stimulation induces

breast and uterine growth and development (Villaseca, 2012).

Further complicating matters, isoflavones also have the

ability to bind to androgen

receptors, suppressing androgen receptor expression

(Hamilton-Reeves et al., 2007). Isoflavones also prompt the

synthesis of Sex Hormone Binding Globulin (SHBG), which

moderates circulating sex hormones (Villaseca, 2012). In

vitro studies have also shown inhibition of aromatase, an

enzyme involved in estrogen biosynthesis (Brzezinski and

Debi, 1999). It is critical to take these multiple stimuli

into consideration especially in the context of breast and

endometrial cancer.

2.0 Effects of soy-derived isoflavones on VMS

The research pertaining to the effects of soy-derived

isoflavones on VMS has been inconsistent (Table 1). Through

a randomized, double-blinded study, Murkies et al. (1995)

10

investigated the effects of a soy-rich diet in 58 women

between the ages of 30 to 70. Before the clinical trial,

women reported having experienced a frequency of 14 or more

hot flashes/week. In the first 2 weeks, the women recorded

the number of VMS experienced and their daily diet. Twenty-

eight women added 45g of soy flour to their daily diet for

12 weeks. The results were most prominent in weeks 6 to 12.

In comparison to those in the wheat-flour control group,

women who supplemented their diet with soy flour reported a

40% decrease in VMS frequency.

Albertazzi et al. (1998) had a larger sample of 104

postmenopausal women. Also in a double-blinded, randomized

study, 51 subjects aged 48 to 61 consumed 60g of soy protein

isolate on a daily basis (76mg isoflavones). In the control

group, 53 patients in an age range of 45 to 62 years were

assigned a 60g daily dose of casein placebo. After a 12-week

trial, the average number of VMS per 24 hours significantly

decreased in comparison to the control group, although the

difference was not very large. Mean VMS

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decreased by 26% by week 3, 33% in week 4, and 45% by the

end of the experiment. In the casein group, VMS decreased

only by 30% after 12 weeks. These results compare poorly

with an 83% VMS reduction with steroidal hormone replacement

therapy. Unfortunately, 25 patients were unable to complete

the study (11 in soy group; 14 in placebo group) due to

gastrointestinal side effects such as bloating and

constipation, significantly reducing the data set by more

than 20%.

In a more recent study by Carmignani et al. (2010), soy

supplementation was found to have equal effects as low-dose

steroidal hormone therapy. Sixty women ranging from 40 to 60

years of age were randomly assigned a soy supplement

containing 90mg of isoflavones (n=20), 1 mg estradiol

(n=20), or a placebo (n=20). After 16 weeks, users of the

hormone therapy experienced a 45.6% decrease in VMS

frequency. Subjects using the soy supplement reported a

similar 49.8% decrease in VMS occurrence. Results differed

from the placebo group, which experienced a 28% decrease in

VMS.

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Conversely, Brzezinski et al. (1997) did not report

any improvement in VMS between the placebo and

phytoestrogen-treatment group. One hundred forty five women

ranging from 43 to 65 years were randomly assigned to either

a treatment (n=78) or placebo (n=67). Women in the treatment

group consumed 25% of their caloric intake in phytoestrogen-

rich foods consisting of tofu, miso and soy beverage. After

12 weeks, SHBG serum levels significantly increased in women

in the treatment group (28%), and remained at baseline in

the placebo (7%). Moreover, subject phytoestrogen serum

levels (daidzein, equol, genistein) were significantly

increased in the phytoestrogen-rich diet (1086%, 1107%,

2089%), whereas women in the control group experienced no

change. VMS decreased in both the placebo (48%) and

phytoestrogen-treatment groups (50%). Although the treatment

group experienced slightly less VMS than the placebo, the

different was statistically insignificant.

The Soy Phytoestrogens As Replacement Estrogen (SPARE)

study in 2004 was funded by the National Institute of

Health. The study aimed to overcome past obstacles by

13

incorporating a larger sample size, longer clinical trial

and improved experimental design. Two hundred forty eight

women ages 45 to 60 who have progressed into menopause

within 5 years of enrollment were randomized into two

groups. Participants were assigned either daily 200mg soy

isoflavone (n=122) or a placebo (n=126) for 2 years. No

significant difference was found between the treatment and

control group after 2 years. Forty-eight percent of the

women in the soy isoflavone, and 32% in the placebo group

still reported having VMS (Chalupka, 2011; Levis et al.,

2010).

A study conducted by Quella et al. (2000) investigated

the effects of soy phytoestrogens on VMS in the survivors of

breast cancer. In a double-blinded, randomized trial,

patients with VMS were assigned to either a soy group (n=87)

or a placebo group (n=88). It should be noted that 68% of

patients were on the breast tissue antagonist drug,

tamoxifen, which may have influenced results. The groups

were instructed to take a tablet three times daily. The soy

group’s tablet was comprised of 50mg isoflavone (40%-45%

14

genistein, 40%-45% daidzein, and 10%-20% glycitein) totaling

to 150mg/day. After 4 weeks, the soy group was prescribed

the placebo and the placebo group was assigned the soy

tablet. In total, the experiment lasted 8 weeks. Out of all

the subjects, only 149 produced usable data by completing

the study. Results indicated no beneficial effects on VMS

with isoflavone supplementation.

A 2011 meta-analysis showed that 30 studies from 1999-

2011 displayed mixed results. According to Villaseca (2012),

most trials were of short duration and poor quality. Three

placebo-controlled studies indicated a significant decrease

in VMS frequency (61%, 74%, 50% reduction in the soy-

treatment compared to 21%, 43%, 38% reduction in the

placebo, respectively). Moreover, Villaseca (2012) reported

that more recent studies show greater VMS improvement

compared to older studies. A study where women took a high

dose of soy isoflavones (100mg/day) showed significant

improvement in VMS compared to placebo; however, a study

where women only took 40mg experienced VMS equivalent to

placebo. In defiance of relatively short experimental

15

durations, most studies have found that VMS alleviation is

most prominent within the first 12 weeks of treatment.

2.1 Critique of studies

In spite of conflicting results, there is evidence that

menopausal women may benefit from soy-derived isoflavones to

alleviate VMS. Inconsistent results may be attributed to:

participant dropout, failure to evaluate menopausal

progression, inconsistent administered dose, and variable

participant metabolism/adsorption of isoflavones.

2.1.0 Dropout rates

Many clinical trials faced challenges with high dropout

rates: 11 out of 58 participants in the Murkies et al.

(2008) study, 25 out of 104 in the Albertazzi et al. (1998)

study, 31 out of 145 in the Brzezinski et al. (1997) study,

and 26 out of 175 patients in the Quella et al. (2000) study

withdrew, often due to gastrointestinal side effects or lack

of participant compliance.

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2.1.1 Evaluation of menopausal progression

VMS frequency and intensity typically predominate

during the first 2 years of menopause; consequently, VMS

improvement can be expected over time without medical

intervention (Bedell et al., 2014). Many studies, including

SPARE (Chalupka, 2011; Levis et al., 2010), failed to take

this phenomenon into account by involving postmenopausal

women who have progressed into menopause for up for 5 years.

The remaining studies failed to evaluate the duration

between menopausal onset and experimentation. The cancer-

survivor study conducted by Quella et al. (2000) involved

participants from 19-50+ years of age, thus a mix of

patients who have and have not yet reached menopause. Quella

et al. (2000) also failed to distinguish menopausal VMS from

symptoms attributed to chemotherapy side effects (Table 1).

2.1.2 Inconsistent administered dose

Administered dose has been inconsistent throughout

studies, ranging from 76mg/day to 200mg/day. Other studies

failed to investigate isoflavone concentrations, for

17

example, in the cases of Murkies et al. (1995) and

Brzezinski et al. (1997). Interestingly, the larger

isoflavone doses of 200mg/day (Levis et al., 2004) and 150

mg/day (Quella et al., 2000) failed to significantly differ

from the control groups. Perhaps partial antagonistic

effects of the SERM isoflavones are responsible for this

finding; however, more research regarding optimal dose must

be conducted.

2.1.3 Participant metabolism and absorption

Variable outcomes may have also been attributed to each

participant’s metabolism and absorption. As aforementioned,

the bioavailability of isoflavones is dependent on gut

flora. The extent of this biotransformation differs between

individuals and can vary as a result of diet, illness and

antibiotic use (Bedell et al., 2014; Setchell and Cassidy,

1999). Some studies considered the effects of antibiotics on

gut flora and excluded these candidates (Murkies et al.,

1995; Levis et al., 2010). Only Brzezinski et al. (1997)

implemented a strict macronutrient composition consisting of

50-55% carbohydrates. Ironically, Murkies et al. (1995) used

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a wheat flour control group, which may have had equol-

synthesizing effects on gut flora.

2.2 Future work

Given that serious adverse side effects have seldom

been reported, isoflavones are a highly optimistic

alternative to HRT; however, it does not preclude from the

need to further our understanding. A comprehensive

literature search on the SERM properties of soy isoflavones

would provide a better knowledge of potential risks and

benefits in regards to breast cancer, bone health,

endometrial hyperplasia, and other menopausal symptoms. To

become approved by the FDA, more research pertaining to the

safety of soy isoflavones must be conducted.

Improved experimental design would ameliorate the

quality of the data, which may produce more consistent

results. By excluding participants who have progressed

through menopause for more than 2 years, researchers can

control for the suspected decline in VMS incidence. Optimal

isoflavone dose must also undergo further investigation to

19

balance antagonist/agonist effects. A tablet containing

isolated isoflavones may reduce the gastrointestinal

discomfort frequently reported with soy foods, which may

reduce participant dropout. Moreover, a diet with strict

macronutrient restrictions may be necessary to control for

increased biotransformation upon ingestion of carbohydrates.

Exclusion of individuals with recent illness and/or

antibiotic use may also improve results by considering the

roles of gut flora.

3.0 Concluding remarks

Soy isoflavones are an optimistic alternative to HRT

for menopausal women suffering from VMS. Isoflavones exhibit

weakened estrogenic effects on estrogen receptors depending

on the target tissue and concentration of circulating

estrogen levels.

Clinical trials of soy or isoflavone-supplemented diets have

investigated the relationship between soy intake and

alleviation of VMS. Inconsistent results were found amongst

the literature reviewed. Improved experimental design may

20

enhance consistency between future clinical trials and

reduce the common theme of high dropout rates in current

literature. Investigation of the biological mechanisms

involved with soy isoflavones would provide insight on the

safety of these supplements, and potential approval by the

FDA. Soy isoflavones in the treatment of VMS appear to be

promising, and deserve further research and consideration

for therapy.

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Fig 1. Structural analogy between isoflavones (daidzein, genistein, glycitein) and estradiol.

26

SERM

Estrogen receptor in bone & brain

Estrogen receptor in breast & uterus

Estrogen receptor not activated (antagonistic activity)

Estrogen receptor activated(agonistic activity)

No breast & uterine cell proliferation

Menopausal symptoms relief & bone cell proliferation

27