Beth Israel Deconess Medical Center Study Harvard Medical School, Boston, MA

Introduction:

• Hot Flashes occur in approximately 75% of menopausal women in western countries and are the main reason women entering menopause seek treatment.
• Although hormone therapy (HT) is the most effective treatment for the relief of hot flashes to date, evidence suggests that long-term use of HT may increase the risk of developing certain medical disorders such as coronary heart disease, stroke, pulmonary embolism, and breast cancer with estrogen + progestogen therapy. Thus safe and effective alternatives are needed.
• Recently interest has arisen in isoflavones as a potential therapy for menopausal hot flashes. Isoflavones are one of several classes of phytoestrogens, compounds that exert both estrogenic and antiestrogenic properties.  Daidzein and genistein are isoflavones that are found in rich supply in soybeans and soy products.
• In this study we used an isoflavone-rich supplement made from soy germ. The supplement is rich in daidzein, a precursor to equol, which also has estrogenic properties.
• In our nonrandomized, open-label pilot study, we found that 40 to 60 mg of daidzein-rich isoflavone aglycones (DRIs) improved the hot flash composite score (hot flash frequency X hot flash severity) by 54% at 8 weeks. In the present study we conducted a randomized, double0blind, placebo-controlled study to evaluate the changes in menopausal symptoms in response to DRI intake of 40 or 60 mg/day for 12 weeks.

• Two hundred thrity-five women were recruited from referring physicians in the Beth Israel Deaconess Medical Center adn from newspaper advertisements. Of those, 191 women met inclusion criteria and were randomized.
  
• The institutional Review Board of the Beth Israel Deaconess Medical Center approved the study protocol, and all participants gave written informed consent.
  
• The study took place over 13 weeks in an ambulatory care setting. at the initial visit a detailed medical history and a menstral and menopausal history were completed.
  
• The women were not given any supplements during the 1-week run-in period. At the second visit women returned their run-in week hot flash diaries, and those who fulfilled the entry criteria were included.
  
• Blood was obtained for baseline fasting. In addition, several hormone levels were measured. All hormone levels were measured by enzyme-linked immunosorbant assays.
  
• Extraction and analysis of isoflavones as aglycones from serum samples after enzymatic hydrolysis of conjugates followed a previously applied high-performance liquid chromotography protocol with modifications.
  
• A second menopause quality of life questionnaire was also completed at the second visit. All women were then randomized to placebo or 40 mg or 60 mg of a DRI every morning. This DRI (AglyMax, Nichimo Co, Ltd, Shinagawa, Tokyo, Japan) is a concentrated isoflavone product prepared from soyben germ fermentation with Koji fungus (Aspergliius awamori), producing beta-glycoside effiency, followed by ethanol and water extraction and purification using a propriatary extraction procedure. The product is rich in daidzein (70% daidzein, 10% genistein, and 20% glycitein).
  
• Women returned to the clinic after 4, 8 and 12 weeks on the supplement. At each visit women completed the Menopause-Specific Quality of Life survey, hot flash diaries were reviewed, and vital signs and adverse events were monitored. Blood samples were drawn for a lipdid panal and hormone levelsat every clinic visit and at 12 weeks for isoflavone levels and routine chemistry.
  

• A total of 147 women completed 12 weeks of supplementation. The main reason for withdrawl from the study was that the women were either unable to comply with the study protocol or were lost to follow-up (n=30). A total of 142 women had analyable data. of those who completed the study, 119 were postmenopausal and 28 women were perimenopausal. However, there were no differences in terms of body mass index, number of years after menopause, pervious use of HT or baseline hot flash activity between women who completed or did not complete the study.
  
• Our results showed that 12-week supplementation with a DRI signifigantly reduced hot flash frequency. Hot Flash frequency decreased by 43% in the 40-mg DRI group and by 41% in the 60-mg DRI group at 8 weeks, compared with 32% in the placebo group. At 12 weeks 40 and 60 mg of DRI produced 52% and 51%, respectively, reductions in hot flash frequency, compared with 39% in the placebo group.
  
• When comparing the two treatment groups together as one group (DRI supplement) against placebo, there were signifigant reductions in mean dailty hot flash frequency by 43% at 8 weeks and 52% at 12 weeks.
  
• Menopausal quality of life as measured by the Menopause Qualuity of Life summary score showed that women reported signifigant decreases of menopausal symptoms from baseline in all three groups, but there were no statistically signifigant differences between groups.
  
• All women reported no major side effects.
  
• During the 12 weeks of supplement use, women had no statically signifigant changes in their blood pressure, body weight, or lipid, glucose, leptin, or insulin levels as compared with the control group. The DRI supplement did not produce any signifigant changes in endgenous sex hormonen levels compared with the placebo. there were also no changes in serum thyroid-stimulating hormone, thyroxine, free triiodthyronine, total thyroxine, total triiodthyronine, or thyroglobobin level with supplements.
  
• Serum isoflavones at the begining of the study were similarily low among the three treatment groups. At the end of the study, serum daidzein, glycetein, and equol, but not genistein, signifigantly increased in the 40- and 60-mg DRI groups compared with the control group.
  

• This study observed that in postmenopausal women, with hot flashes, dietary supplementation with 40 to 60 mg of DRI per day signifigantly decreased hot flash frequency.
  
• Hot flash frequency was reduced by 43% to 52% at 8 to 12 weeks with the supplement, compared with 32% to 39% change in the placeo group.
  
• The degree of improvement with the DRI supplement is similar to that of the selective serotonin reuptake/serotonin and norepinephrine reuptak inihibtor treatment family (50-60%) but without the negative side effects.
• We also saw a similar improvement in menopausal quality of life in the two treatment groups; however, the sample size was insufficient to detect a statistically signifigant difference in this secondary outcome.
  
• Functionally, isofalvones can exert both estrogenic and antiestrogenic effects depending on their concentration, target tisue, receptor status of the tissue, and the level of endogenous estrogen. the structure of the isoflavones molecule resembles that of many estrogenic and weak antiestrogenic effects.
  
• Isoflavones are biotransformed extensively in the intestine by the action of bacterial enzymes. The extent of intestinal bacterial metabolism influences the bioavailabilty of isoflavones and therefore their potential for physiologic effects, although the degree of influence varies among individuals.
  
• When (soybeans) are consumed they undergo metabolic conversion in the intestine whereby a sugar molecule is removed from each, and conversion to metabolically active aglycones occurs.
  Both intact and metabolized isoflavones freely circulate in the blood and are excreted in the urine within 24 hours.
  
• Previous randomized controlled clinical trials of isoflavones supplementation in women with no history of breast cancer that lasted more than 6 weeks have shown either no improvement or a slight reduction in hot flashes in women who consumed soy isoflavones compared with control women. However, two other previous randomized, controlled studies using daidzein-rich isoflavone extracted from soy germ were conducted in Brazil and in Japan, and both studies showed signifigant improvement in hot flashes compared with placebo.
  
• The effort to determine the effects of isoflavones is complicated by the variety of different soy foods and an absence of standardized nomenclature. For instance, the chemical methods used to isolate isoflavones (eg, ethanol extraction) may alter their physiologic effects. In addition,  striking compositional differences are found between types of soy foods commonly used in Southeast Asia and those in Western countries. In the United States soy has been used mostly for the production of vegetable oils, whereas in Southeast Asia many of the soy foods used are fermented; the microorganisms used in their preperation are capable of hydrolyzing the inactive isoflavone aglycones. These differences may important with regard to metabolism and bioavailability. There is also considerable interindividual variation in gut bacterial metabolism of isoflavones, which transforms the glycoside isoflavones.
  
• In our study it is possible that the fermentation process, along with the higher concentration of daidzein relative to other isoflavone supplements, accounted for the efficacy of the supplement. Previous studies have also shown that the aglycone form may lead to faster and greater absorption of isoflavones than their glycoside counterpart.
  
• There were some limitations to this study. the washout period for the supplement or medication treatment of hot flashes of 6 weeks may not have been enough. A high dropout rate may have also led to underestimation of the efficacy and side effects of the supplement. Last, the inclusion of both perimenopausal and postmenopausal women in the study might have affected our results because hot flashes tend to improve over time even without treatment.
  

• In conclusion, this study suggests that DRI supplements may be an effective alternative treatment for menopausal hot flashes. the supplements do not haveany effect on the endogenous sex hormones, throid hormones, or lipid levels.