Menopausal Symptom Effects
Key Recommendations
* In postmenopausal women with distressing vasomotor symptoms, initial treatment with isoflavones is reasonable.
* The starting isoflavone dose should be 50 mg/day or higher, and therapy should be given for at least 12 weeks.
* Studies of women who do not benefit from soy isoflavones should be undertaken to monitor longer-term beneficial or possible adverse effects.
* If a woman responds to isoflavone supplementation, treatment can continue with monitoring for side effects; if a woman does not respond after 12 weeks, other treatment options should be discussed.
* A supplement containing natural S(-)-equol may be effective for some women who do not have the capacity to produce equol.
Vasomotor Symptoms
In the past decade, a major effort has been made to determine if and to what extent soy or soy isoflavones can control menopause-related vasomotor symptoms (ie, hot flashes). The original basis for that effort was the observation that only 10% to 20% of Asian women report hot flashes whereas 70% to 80% of North American women report experiencing them. The speculation was that the isoflavones present in the high soy diets of Asian women were providing some protection by binding to ERs and thus might be comparable to the well-known benefits of prescription HT.
Clinical Outcomes of Soy Foods and Soy Supplements
The studies summarized below were selected as good examples of more recent randomized controlled trials (RCTs) evaluating the efficacy of isoflavones in the treatment of postmenopausal vasomotor symptoms. The majority focused specifically on soy isoflavones, while a few evaluated red clover isoflavones. Finding alternatives to HT has become a priority for midlife women since the Women's Health Initiative reported adverse cardiovascular and cancer outcomes in the estrogen-progestin group. Despite the fact that several RCTs have now been conducted, most have had some notable limitations, including:
Lack of comparability of agents (eg, soy and red clover isoflavones)
Individual versus combination isoflavones (eg, genistein alone vs a combination of genistein, daidzein, and glycitein)
Use of glycosides versus aglycones
Variations in dose and duration of therapy
Relatively small sample sizes
Use of a variety of tools to evaluate symptoms
Lack of measurement of compliance
Lack of identification of women who could convert daidzein to equol
Lack of control for concurrent use of medications (especially antibiotics, which may alter intestinal bacteria, hence decrease equol production)
Lack of control for dietary sources of isoflavones (possibly accounting for the observed placebo effect)
Lack of identifying potential modifiers of soy's effectiveness (eg, menopausal status, ability to produce equol, previous breast cancer, race/ethnicity)
Differences in definitions of menopause for inclusion purposes (>6 mo of amenorrhea vs >12 mo of amenorrhea)
The following 14 studies were selected by the panel because they all included the following: dose of soy isoflavones, mean age of the study participants; prevalence of hot flashes at baseline and also the magnitude of improvement, treatment duration of at least 12 weeks, and patient population who had experienced natural (not induced) menopause.
Combined statistics of the 14 trials:
* Total number of women in the trials was 1,422 (761 in the isoflavone arms and 661 in the placebo arms).
* Dose of isoflavones ranged from 40 to 160 mg/day.
* Mean age was 53.
* Duration of trials ranged from 12 to 96 weeks.
* Majority of women were Caucasian and within 5 years of their final menstrual period.
* Daily prevalence of hot flashes at baseline ranged from 3 to 11 episodes.
Combined results of the 14 trials:
* A total of 11 showed significant improvement of vasomotor symptoms in the isoflavone arms compared to placebo, while three trials failed to show any benefit.
* The percentage of decrease in daily frequency of hot flashes ranged from 24% to 60%.
* The dose of 50 to 60 mg/day was sufficient for significant symptom improvement over placebo in many of the studies.
* Although some studies using higher doses of soy isoflavones also reported significant benefit, no linear dose-response relationship was observed.
* It appeared that women who benefitted from isoflavones experienced at least four episodes per day at baseline, which generally agrees with previously published data.
* Women experiencing more than the four daily hot flashes did not necessarily show greater improvement over placebo.
* Trial duration of 12 weeks was sufficient to see a benefit in the isoflavone group over placebo; trials of longer duration did not necessarily result in a greater improvement in symptoms.
Clinical Outcomes of Supplements High in Genistein
A 2006 review of papers that characterized the isoflavone composition of the supplements used concluded that isoflavone supplements containing predominately genistein reduced hot flashes. In the five studies (177 treated patients) that provided more than 15 mg/day of genistein (in aglycone equivalents), a significant reduction was observed in hot flash symptoms. Whereas, in six studies (201 treated patients) that provided less than 15 mg genistein/day, only one reported any decrease in vasomotor symptoms.
Genistein given alone has been reported to have beneficial effects on vasomotor symptoms. One study used pure genistein (54 mg/d) with significantly beneficial results in reducing symptom frequency. Another study used the same product and replicated the results with a larger sample size (genistein, n = 119; placebo, n = 117). The women in the treatment group were given two tablets per day containing 27 mg total isoflavone, 98% of which was reported to be genistein. In addition, the tablets contained 400 IU of vitamin D and 500 mg calcium carbonate. At 12 and 24 months, the number of episodes experienced by the women in the placebo group was about four per day and the number in the treated group was about two per day (with both groups having at baseline about four episodes a day).
More than 12 studies have been conducted in which the genistein content of the supplement is known. Further analysis is needed to confirm the 2006 conclusion that more than 15 mg genistein/day results in a significant reduction in hot flashes.
Does Equol Production Predict the Effectiveness of Soy Isoflavone Treatment?
There is increasing evidence that women whose gut bacteria have little or no capacity to convert daidzein to equol may continue to suffer from severe hot flashes despite soy isoflavone supplementation. A 6-month proof-of-concept trial studied the importance of intestinal equol generation on improvement in hot flashes. Healthy menopausal women (n = 96) were randomized to the isoflavone or placebo group. The isoflavone group was further divided into equol producers (n = 34) and nonproducers (n = 32) based on urinary equol levels after consuming 135 mg isoflavones/day for a week. In both the equol producers and nonproducers, women ingested 3 g soy germ extract powder twice a day for 6 months (equivalent to 135 mg/d). Equol producers showed significantly greater reduction in some categories of Kupperman menopausal symptom scores than the placebo group, while no such benefit was observed in nonproducers.
Because the majority of trials of soy isoflavones did not measure serum or urinary levels of equol, the status of the study participants as equol producers or nonproducers is not known. Furthermore, as discussed previously, many factors influence the conversion of equol from daidzein. Recently, some attention has been directed toward using a natural equol supplement to treat menopausal symptoms in which the majority of daidzein is converted to S(-)-equol. A few clinical trials have been completed with such a product.
Is Equol Treatment Alone Effective?
The first RCT using a natural equol supplement in which the daidzein had been converted to S(-)-equol to evaluate its efficacy in relieving menopausal symptoms was conducted with Japanese women. In that 12-week trial, 134 healthy Japanese women ages 40 to 59 were divided into three groups: 10 mg equol/day (n = 44), 10 mg equol three times a day (n = 46), and placebo (n = 44). The self-reported menopausal symptom and mood scores before and after 12 weeks of intervention were evaluated. No benefit was seen in equol producers; improvement was seen only in the 10 mg equol thrice daily group of equol nonproducers in menopausal symptom and mood scores (decrease in somatic symptoms, anxiety, depression, tension, vigor, and fatigue). To confirm these findings, another 12-week RCT parallel trial in Japanese equol nonproducing peri- and postmenopausal women was performed. During the placebo run-in phase, equol nonproducers who showed a greater than 50% reduction of symptoms were excluded from the trial. The remaining participants, who were randomized to 10 mg S(-)-equol/day (n = 66), experienced a significant reduction in the frequency and severity of hot flashes compared with the placebo group (n = 60). Women in the equol group also showed a greater reduction in the severity of neck and shoulder stiffness (frequently reported menopausal symptoms in Japan) compared to the placebo group.
Another trial, conducted in the United States, compared the efficacy of a supplement containing primarily S(-)-equol to a supplement that combined genistein, daidzein, and glycetin. A total of 102 postmenopausal women (ages 45-65) with moderate to severe hot flashes were randomized to the S(-)-equol supplement at doses of 10, 20, or 40 mg/day or the combination supplement with a total isoflavone dose of 50 mg/day for 8 weeks. Reduction in hot flash frequency was similar in the 10 mg S(-)-equol and combination isoflavone groups. Women in the 20- and 40-mg equol groups, however, showed greater reduction in symptoms than those receiving the combination supplement.
Vaginal Dryness
Only two studies have explored the potential benefits of isoflavones for the treatment of postmenopausal vaginal dryness. In one double-blind, crossover RCT, the isoflavone treatment consisted of 114 mg isoflavones/day for 3 months. The investigators concluded that the isoflavones had no effect on subjective perception of vaginal dryness or on objective findings in the vagina.
A year later, in a second crossover RCT, the peri- and postmenopausal women were given either a daily placebo or 25 g soy. The authors concluded that a soy-rich diet did not relieve urogenital symptoms, restore vaginal epithelium, or improve vaginal health.
Adverse Effects
The majority of RCTs have reported mild adverse events with isoflavone use, mainly centered on gastrointestinal tolerability or taste issues. Although the studies discussed above were designed to evaluate the efficacy of soy isoflavones, some evaluated-and found no increase in-endometrial thickness, vaginal cytology, or breast density associated with soy isoflavone intake. While these data are reassuring, most of the trials were short-term. Long-term studies adequately powered to conclusively evaluate safety issues of soy supplementation are needed. Note that safety has not been discerned for breast cancer survivors.
Conclusions
Soy-based isoflavones are modestly effective in controlling hot flashes, as demonstrated to date in predominantly Caucasian women in early postmenopause who have at least four hot flashes a day. The minimal dose at which significant benefit has been seen is 50 mg total isoflavones/day, which could be considered the starting dose. A trial of 12 weeks is generally sufficient to evaluate response to therapy. Supplements providing pure or higher proportions of genistein have shown particular benefit. Initial trials of supplements containing primarily natural S(-)-equol also look promising.
Further research is needed to evaluate efficacy of isoflavones in racially and ethnically diverse populations and in younger perimenopausal and older postmenopausal women who can continue to have symptoms 10 to 20 years postmenopause. The role of isoflavones in equol producers versus nonproducers also needs to be evaluated.