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Soybean isoflavones warrant greater consideration as a treatment for the alleviation of menopausal hot flashes “
...it is surprising that genistein-rich isoflavone supplements have not been embraced as a treatment for hot flashes to a greater extent than they have...
”
Keywords: genistein • hot flashes • isoflavones • menopausal symptoms • phytoestrogens • soy
Interest in the health effects of isoflavones accounts for much of the research attention soyfoods have received over the past 25 years. These diphenolic molecules have a relatively limited distribution in nature, such that among commonly consumed foods they are found in nutritionally relevant amounts only in soybeans and foods made from this legume [1] . As a result, isoflavone intake is high in populations where soyfoods are commonly consumed but very low otherwise. For example, among older Japanese adults intake ranges from approximately 30–50 mg/day [2] versus less than 3 mg/day among adults in the USA [3] . The three isoflavones genistein, daidzein and glycitein and their respective glycosides account for approximately 50, 40 and 10%, respectively, of the total isoflavone content of soybeans [4] . For 50 years, isoflavones have been known to possess estrogen-like activity [5] , but not until 1992 did Adlercreutz et al. [6] propose that by compensating for the decline in estrogen levels as women enter menopause, isoflavones contribute to the low prevalence of hot flashes among native Japanese women. In 1995, the first clinical trial evaluating this hypothesis was published [7] and Thomas B Clarkson, who was well known for his work with hormone therapy (HT), along with his colleagues, noted the enthusiasm over the potential for isoflavones to reduce the risk of chronic diseases, including breast and prostate cancers, cardiovascular disease and osteoporosis [8] . Soon thereafter, with the recognition that isoflavones preferentially bind [9] to the newly discovered
10.2217/WHE.14.38 © 2014 Future Medicine Ltd
second estrogen receptor, ER-β [10] , isoflavones began to be viewed not simply as phytoestrogens but as selective estrogen receptor modulators [11,12] . There was hope that isoflavones might serve as a viable alternative to HT, which began to fall out of favor with the publication of the disappointing results of the Women’s Health Initiative trial [13] . However, beginning in the 1990s, work in athymic ovariectomized mice raised concerns that isoflavones might increase the risk of breast cancer in high-risk women and worsen the prognosis of breast cancer patients [14] . At about the same time, the results of clinical studies in several different areas challenged the efficacy of isoflavones [15] . Needless to say, controversy began to surround isoflavones and views about their health effects became rather muddled. Since the hypothesis was first proposed, there has been rigorous investigation of, and debate about, the efficacy of isoflavones for alleviating hot flashes. Over the years, a number of professional societies and health organizations have taken conflicting positions on this topic. Early on, the North American Menopause Society [16] concluded there were data in support of the efficacy of isoflavones, a view that was later shared by the American College of Obstetricians and Gynecologists [17] and the Agency for Healthcare Research and Quality [18] , although all three groups also strongly emphasized the inconsistency of the evidence. However, in 2006, the American Heart Association concluded that “it seems unlikely that soy isoflavones have enough estrogenic activity to have an
Womens Health (2014) 10(6), 549–553
Mark Messina Department of Nutrition, School of Public Health, Loma Linda University, Loma Linda, CA 92354, USA Tel.: +1 360 379 9544 markjohnmessina@ gmail.com
part of
ISSN 1745-5057
549
Editorial Messina important impact on vasomotor symptoms of estrogen deficiency in perimenopausal women” [19] . Even though the American Heart Association was well outside their established area of expertise and their discussion of this issue consisted of only 160 words and included just seven references, their conclusion carried significant weight because of the reputation of this organization [19] . A year later, a Cochrane analysis concluded that “there is no evidence of effectiveness in the alleviation of menopausal symptoms with the use of phytoestrogen treatments,” despite finding that five of nine trials comparing soy extracts in capsule or tablet form with placebo reported significant differences in efficacy in favor of the former [20] . Not surprisingly, enthusiasm for isoflavones as a treatment for hot flashes waned considerably. Meta-analyses published over the past decade have produced mixed results [21] , and results that are both supportive [22,23] and unsupportive [20] of the efficacy of isoflavones for alleviating hot flashes. In all cases however, these analyses have suffered from a critical limitation, which is that they failed to subanalyze the results according to the isoflavone profile of the soy extract. This failure is critical, since the content of the extracts employed varied in the relative amounts of the three soybean isoflavones, each of which possesses different molecular and physiological properties [24,25] . It is well recognized that drugs belonging to the same chemical class behave differently. For example, the US FDA approval of Brisdelle™ (Noven, NY, USA), which contains 7.5 mg of paroxetine, a selective serotonin-reuptake inhibitor, for the treatment of moderate-to-severe vasomotor symptoms associated with menopause [26] does not extend to all selective serotonin-reuptake inhibitors since they do not possess identical properties. In 2006, Williamson-Hughes et al. [27] concluded on the basis of their review of the literature that soy extracts providing sufficient amounts of the isoflavone genistein were consistently efficacious, whereas those that were low in genistein were not. This finding is important since the two primary types of supplements that have been used in the clinical trials vary markedly in genistein content. One is derived from the cotyledon portion of the soybean, which represents approximately 90% of the whole soybean, and is high in genistein and daidzein but low in glycitein, whereas the other is derived from the hypocotyledon portion of the bean and is very low in genistein and high in daidzein and glycitein [24] . In 2012, Taku et al. [28] became the first group to statistically evaluate the hypothesis proposed by Williamson-Hughes et al. [27] . Their meta-analysis included 17 studies that intervened with isoflavone-containing soy
550
Womens Health (2014) 10(6)
extracts or supplements containing isoflavones found in soybeans. The meta-analysis of the data on hot flash frequency, which included 13 studies involving 1196 women, found isoflavones were consistently efficacious, reducing the number of hot flashes per day by 20.6% (95% CI: -28.38 to -12.86; p < 0.00001) more than the reduction in the placebo group. Similarly, in the nine trials involving 988 women that evaluated hot flash severity, isoflavones reduced symptoms by 26.2% (95% CI: -42.23 to -10.15; p = 0.001) more than the reduction in the placebo group. Subanalysis of the data revealed three interesting findings. First, baseline hot flash frequency did not impact efficacy. The percent reduction in hot flash frequency was similar regardless of whether women had two or 10 hot flashes per day at baseline. Second, hot flashes were reduced to a greater extent (p = 0.006 between groups) in studies greater than 12 weeks in duration (-34.29%; 95% CI: -49.07–19.50%) than in shorter term studies (-12.66%; 95% CI: -17.09 to -8.23%), indicating the effects of isoflavones are not transient. Third, and most important, supplements that provided higher amounts of the isoflavone genistein were considerably more efficacious than supplements low in genistein. This difference helps explain the inconsistent results noted in past reviews of the data. In studies that intervened with supplements providing greater than or equal to 18.8 mg genistein (the median for all studies), hot flash frequency was reduced by 29.13% (95% CI: -43.09 to -15.17) vs only 12.47% (95% CI: -17.34 to -7.60) for studies providing less than this amount (p = 0.03 for difference between groups). Indirect support for this finding comes from a second Cochrane analysis, which while again failing to subanalyze the results according to the isoflavone profile of the soy extracts, did note that all four trials that intervened with genistein showed statistically significant reductions in hot flash frequency relative to the placebo [29] . Given the results of the meta-analysis by Taku et al. [28] , it is surprising that genistein-rich isoflavone supplements have not been embraced as a treatment for hot flashes to a greater extent than they have, especially in light of the FDA’s approval of Brisdelle, although this decision was controversial. Brisdelle was approved on the basis of two trials that enrolled 1184 women [30] , a sample size strikingly similar to the number of women included in the meta-analysis by Taku et al. [28] . Furthermore, Brisdelle reduced symptoms by only one to two hot flashes per day in women who at enrollment had at least ten hot flashes per day [26] . Thus, the effect of isoflavones is equal to or greater than that of this selective serotonin-reuptake inhibitor.
future science group
Soybean isoflavones warrant greater consideration as a treatment for the alleviation of menopausal hot flashes
What then has limited the acceptance of isoflavones? There are three probable contributing factors. First, beginning with the American Heart Association’s pronouncement, there has been a nearly decadelong acceptance that isoflavones lack efficacy [19] . The robust results of the meta-analysis by Taku et al. [28] simply have not prompted professional societies to reevaluate their position on isoflavones. Consequently, consumers and health professionals are likely not aware of the new data.
“
...the overwhelming amount of evidence indicates that isoflavone supplements, provided they contain a sufficient amount of genistein, alleviate hot flashes to a clinically relevant extent and have an acceptable safety profile.
”
Second, many health professionals and clinicians have recommended that women avoid or greatly limit isoflavone exposure due to concerns over an increased breast cancer risk. This cautionary stance is slowing becoming less of an impediment as the scientific and medical communities begin to recognize that over the past 10 years, extensive clinical research shows isoflavone exposure does not adversely affect breast tissue as assessed by effects on markers of breast cancer risk [31,32] . In addition, epidemiologic data indicate that post-diagnosis isoflavone intake reduces breast tumor recurrence and breast cancer-specific mortality [33,34] . Not surprisingly, given these data, both the American Institute for Cancer Research [35] and the American Cancer Society have concluded that breast cancer patients can safely consume isoflavone-rich soyfoods [36] . To be fair, these groups do not endorse supplements because they fear overconsumption and because their reviews of the literature rely heavily on the results of epidemiologic studies wherein isoflavone intake occurs via the consumption of soyfoods. However, nearly all of the clinical trials evaluating breast cancer risk markers involve supplements. Third, and most importantly, the hot flash trials in the meta-analysis by Taku et al. [28] included References
a wide variety of soy extracts and each of the individual trials was relatively small, unlike the research of Brisdelle, which involved two large trials and the same preparation. Consequently, while collectively the data are impressive, no individual soy extract has been extensively studied. Finally, although expert views on the use of HT for the treatment of menopausal symptoms have become less restrictive and more individualized than was the case immediately following the publication of the Women’s Health Initiative trial [37] , many women still prefer using nonhormonal alternatives for alleviation of hot flashes [38] . Furthermore, even those women who initially opt for HT may eventually need an alternative since upon discontinuation of HT hot flashes often resume [39] . Obviously, there is a need for HT alternatives. In conclusion, the overwhelming amount of evidence indicates that isoflavone supplements, provided they contain a sufficient amount of genistein, alleviate hot flashes to a clinically relevant extent and have an acceptable safety profile. The amount of total isoflavones (expressed in aglycone equivalent weight) needed for relief is estimated to be approximately 40–50 mg/day, which is provided by approximately two servings of traditional soyfoods, an amount that is well within the range of the soy/isoflavone intake of older adults in Japan [2] . Therefore, health professionals and clinicians are justified in advising their clients and patients to try isoflavones for the relief of hot flashes. Financial & competing interests disclosure M Messina regularly consults for companies/organizations that manufacture and/or sell soyfoods and/or soy supplements. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
4
Murphy PA, Barua K, Hauck CC. Solvent extraction selection in the determination of isoflavones in soy foods. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 777, 129–138 (2002).
5
Folman Y, Pope GS. The interaction in the immature mouse of potent oestrogens with coumestrol, genistein and other utero-vaginotrophic compounds of low potency. J. Endocrinol. 34, 215–225 (1966).
6
Adlercreutz H, Hamalainen E, Gorbach S et al. Dietary phytooestrogens and the menopause in Japan. Lancet 339, 1233 (1992).
Papers of special interest have been highlighted as: •• of considerable interest 1
Franke AA, Custer LJ, Wang W et al. HPLC analysis of isoflavonoids and other phenolic agents from foods and from human fluids. Proc. Soc. Exp. Biol. Med. 217, 263–273 (1998).
2
Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr. Cancer 55, 1–12 (2006).
3
Bai W, Wang C, Ren C. Intakes of total and individual flavonoids by US adults. Int. J. Food Sci. Nutr. 65, 9–20 (2014).
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Editorial Messina 7
Murkies AL, Lombard C, Strauss BJ et al. Dietary flour supplementation decreases post-menopausal hot flushes: effect of soy and wheat. Maturitas 21, 189–195 (1995).
8
Clarkson TB, Anthony MS, Hughes CL. Estrogenic soybean isoflavones and chronic disease. Risks and benefits. Trends Endocrinol. Metab. 6, 11–16 (1995).
9
Kuiper GG, Lemmen JG, Carlsson B et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139, 4252–4263 (1998).
24
Weaver CM, Martin BR, Jackson GS et al. Antiresorptive effects of phytoestrogen supplements compared with estradiol or risedronate in postmenopausal women using (41)Ca methodology. J. Clin. Endocrinol. Metab. 94, 3798–3805 (2009).
25
Muthyala RS, Ju YH, Sheng S et al. Equol, a natural estrogenic metabolite from soy isoflavones: convenient preparation and resolution of R- and S-equols and their differing binding and biological activity through estrogen receptors alpha and beta. Bioorg. Med. Chem. 12, 1559–1567 (2004).
10
Kuiper GG, Enmark E, Pelto-Huikko M et al. Cloning of a novel receptor expressed in rat prostate and ovary. Proc. Natl Acad. Sci. USA 93, 5925–5930 (1996).
11
Setchell KD. Soy isoflavones – benefits and risks from nature’s selective estrogen receptor modulators (SERMs). J. Am. Coll. Nutr. 20, 354S–362S (2001).
26
12
Brzezinski A, Debi A. Phytoestrogens: the “natural” selective estrogen receptor modulators? Eur. J. Obstet. Gynecol. Reprod. Biol. 85, 47–51 (1999).
Orleans RJ, Li L, Kim MJ et al. FDA approval of paroxetine for menopausal hot flushes. N. Engl. J. Med. 370, 1777–1779 (2014).
27
13
Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. J. Am. Med. Assoc. 288, 321–333 (2002).
Williamson-Hughes PS, Flickinger BD, Messina MJ et al. Isoflavone supplements containing predominantly genistein reduce hot flash symptoms: a critical review of published studies. Menopause 13, 831–839 (2006).
28
Hsieh CY, Santell RC, Haslam SZ et al. Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res. 58, 3833–3838 (1998).
Taku K, Melby MK, Kronenberg F et al. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and metaanalysis of randomized controlled trials. Menopause 19, 776–790 (2012).
••
Comprehensive statistical analysis evaluating the effect of soy isoflavones on the alleviation of hot flashes. First meta-analysis to subanalyze results according to the isoflavone profile of the intervention agent.
14
15
Balk E, Chung M, Chew P et al. Effects of soy on health outcomes. Evid. Rep. Technol. Assess. (Summ.) 126, 1–8 (2005).
16
The role of isoflavones in menopausal health: consensus opinion of The North American Menopause Society. Menopause 7, 215–229 (2000).
29
Lethaby A, Marjoribanks J, Kronenberg F et al. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst. Rev. 12, CD001395 (2013).
17
American College of Obstetricians and Gynecologists. Use of botanicals for management of menopausal symptoms. ACOG Pract. Bull. 28, 1–11 (2001).
30
18
Balk E, Chung M, Chew P et al. Effects of soy on health outcomes. Evidence report/technology assessment No. 126 (prepared by Tufts-New England Medical Center Evidencebased Practice Center under Contract No. 290–202–0022.). AHRQ Publication No. 05-E024–2, July 2005, Agency for Healthcare Research and Quality, Rockville, MD, USA (2005).
Simon JA, Portman DJ, Kaunitz AM et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause 20, 1027–1035 (2013).
31
Fritz H, Seely D, Flower G et al. Soy, red clover, and isoflavones and breast cancer: a systematic review. PLoS ONE 8, e81968 (2013).
••
Sacks FM, Lichtenstein A, Van Horn L et al. Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulation 113, 1034–1044 (2006).
Comprehensive review of the animal, clinical and epidemiologic data relevant to the effect of soy on risk of developing breast cancer and on the impact of soy on the prognosis of breast cancer patients.
32
Lethaby A, Brown J, Marjoribanks J et al. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst. Rev. CD001395 (2007).
Messina M, Caan BJ, Abrams DI et al. It’s time for clinicians to reconsider their proscription against the use of soyfoods by breast cancer patients. Oncology 27, 430–437 (2013).
••
Comprehensive review of the clinical and epidemiologic data relevant to the effect of soy on the prognosis of breast cancer patients.
33
Nechuta SJ, Caan BJ, Chen WY et al. Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women. Am. J. Clin. Nutr. 96, 123–132 (2012).
••
Pooled analysis of three prospective studies involving nearly 10,000 breast cancer patients that evaluated the
19
20
21
552
systematic review and meta-analysis. Menopause 17, 660–666 (2010).
Nelson HD, Vesco KK, Haney E et al. Nonhormonal therapies for menopausal hot flashes: systematic review and metaanalysis. J. Am. Med. Assoc. 295, 2057–2071 (2006).
22
Howes LG, Howes JB, Knight DC. Isoflavone therapy for menopausal flushes: a systematic review and meta-analysis. Maturitas 55, 203–211 (2006).
23
Bolanos R, Del Castillo A, Francia J. Soy isoflavones versus placebo in the treatment of climacteric vasomotor symptoms:
Womens Health (2014) 10(6)
future science group
Soybean isoflavones warrant greater consideration as a treatment for the alleviation of menopausal hot flashes
effect of post-diagnosis soy intake on tumor recurrence and breast cancer mortality. 34
Chi F, Wu R, Zeng YC et al. Post-diagnosis soy food intake and breast cancer survival: a meta-analysis of cohort studies. Asian Pac. J. Cancer Prev. 14, 2407–2412 (2013).
••
Meta-analysis of five prospective studies involving approximately 11,000 breast cancer patients that evaluated the effect of post-diagnosis soy intake on tumor recurrence and breast cancer mortality.
35
American Institute for Cancer Research. Soy is safe for breast cancer survivors (2013). www.aicr.org/cancer-research-update
future science group
36
Rock CL, Doyle C, Demark-Wahnefried W et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J. Clin. 62, 242–274 (2012).
37
ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet. Gynecol. 123, 202–216 (2014).
38
Butt DA, Deng LY, Lewis JE et al. Minimal decrease in hot flashes desired by postmenopausal women in family practice. Menopause 14, 203–207 (2007).
39
Perrone G, Capri O, Galoppi P et al. Menopausal symptoms after the discontinuation of long-term hormone replacement therapy in women under 60: a 3-year follow-up. Gynecol. Obstet. Invest. 76, 38–43 (2013).
www.futuremedicine.com
Editorial
553
Soybean isoflavones warrant greater consideration as a treatment for the alleviation of menopausal hot flashes “
...it is surprising that genistein-rich isoflavone supplements have not been embraced as a treatment for hot flashes to a greater extent than they have...
”
Keywords: genistein • hot flashes • isoflavones • menopausal symptoms • phytoestrogens • soy
Interest in the health effects of isoflavones accounts for much of the research attention soyfoods have received over the past 25 years. These diphenolic molecules have a relatively limited distribution in nature, such that among commonly consumed foods they are found in nutritionally relevant amounts only in soybeans and foods made from this legume [1] . As a result, isoflavone intake is high in populations where soyfoods are commonly consumed but very low otherwise. For example, among older Japanese adults intake ranges from approximately 30–50 mg/day [2] versus less than 3 mg/day among adults in the USA [3] . The three isoflavones genistein, daidzein and glycitein and their respective glycosides account for approximately 50, 40 and 10%, respectively, of the total isoflavone content of soybeans [4] . For 50 years, isoflavones have been known to possess estrogen-like activity [5] , but not until 1992 did Adlercreutz et al. [6] propose that by compensating for the decline in estrogen levels as women enter menopause, isoflavones contribute to the low prevalence of hot flashes among native Japanese women. In 1995, the first clinical trial evaluating this hypothesis was published [7] and Thomas B Clarkson, who was well known for his work with hormone therapy (HT), along with his colleagues, noted the enthusiasm over the potential for isoflavones to reduce the risk of chronic diseases, including breast and prostate cancers, cardiovascular disease and osteoporosis [8] . Soon thereafter, with the recognition that isoflavones preferentially bind [9] to the newly discovered
10.2217/WHE.14.38 © 2014 Future Medicine Ltd
second estrogen receptor, ER-β [10] , isoflavones began to be viewed not simply as phytoestrogens but as selective estrogen receptor modulators [11,12] . There was hope that isoflavones might serve as a viable alternative to HT, which began to fall out of favor with the publication of the disappointing results of the Women’s Health Initiative trial [13] . However, beginning in the 1990s, work in athymic ovariectomized mice raised concerns that isoflavones might increase the risk of breast cancer in high-risk women and worsen the prognosis of breast cancer patients [14] . At about the same time, the results of clinical studies in several different areas challenged the efficacy of isoflavones [15] . Needless to say, controversy began to surround isoflavones and views about their health effects became rather muddled. Since the hypothesis was first proposed, there has been rigorous investigation of, and debate about, the efficacy of isoflavones for alleviating hot flashes. Over the years, a number of professional societies and health organizations have taken conflicting positions on this topic. Early on, the North American Menopause Society [16] concluded there were data in support of the efficacy of isoflavones, a view that was later shared by the American College of Obstetricians and Gynecologists [17] and the Agency for Healthcare Research and Quality [18] , although all three groups also strongly emphasized the inconsistency of the evidence. However, in 2006, the American Heart Association concluded that “it seems unlikely that soy isoflavones have enough estrogenic activity to have an
Womens Health (2014) 10(6), 549–553
Mark Messina Department of Nutrition, School of Public Health, Loma Linda University, Loma Linda, CA 92354, USA Tel.: +1 360 379 9544 markjohnmessina@ gmail.com
part of
ISSN 1745-5057
549
Editorial Messina important impact on vasomotor symptoms of estrogen deficiency in perimenopausal women” [19] . Even though the American Heart Association was well outside their established area of expertise and their discussion of this issue consisted of only 160 words and included just seven references, their conclusion carried significant weight because of the reputation of this organization [19] . A year later, a Cochrane analysis concluded that “there is no evidence of effectiveness in the alleviation of menopausal symptoms with the use of phytoestrogen treatments,” despite finding that five of nine trials comparing soy extracts in capsule or tablet form with placebo reported significant differences in efficacy in favor of the former [20] . Not surprisingly, enthusiasm for isoflavones as a treatment for hot flashes waned considerably. Meta-analyses published over the past decade have produced mixed results [21] , and results that are both supportive [22,23] and unsupportive [20] of the efficacy of isoflavones for alleviating hot flashes. In all cases however, these analyses have suffered from a critical limitation, which is that they failed to subanalyze the results according to the isoflavone profile of the soy extract. This failure is critical, since the content of the extracts employed varied in the relative amounts of the three soybean isoflavones, each of which possesses different molecular and physiological properties [24,25] . It is well recognized that drugs belonging to the same chemical class behave differently. For example, the US FDA approval of Brisdelle™ (Noven, NY, USA), which contains 7.5 mg of paroxetine, a selective serotonin-reuptake inhibitor, for the treatment of moderate-to-severe vasomotor symptoms associated with menopause [26] does not extend to all selective serotonin-reuptake inhibitors since they do not possess identical properties. In 2006, Williamson-Hughes et al. [27] concluded on the basis of their review of the literature that soy extracts providing sufficient amounts of the isoflavone genistein were consistently efficacious, whereas those that were low in genistein were not. This finding is important since the two primary types of supplements that have been used in the clinical trials vary markedly in genistein content. One is derived from the cotyledon portion of the soybean, which represents approximately 90% of the whole soybean, and is high in genistein and daidzein but low in glycitein, whereas the other is derived from the hypocotyledon portion of the bean and is very low in genistein and high in daidzein and glycitein [24] . In 2012, Taku et al. [28] became the first group to statistically evaluate the hypothesis proposed by Williamson-Hughes et al. [27] . Their meta-analysis included 17 studies that intervened with isoflavone-containing soy
550
Womens Health (2014) 10(6)
extracts or supplements containing isoflavones found in soybeans. The meta-analysis of the data on hot flash frequency, which included 13 studies involving 1196 women, found isoflavones were consistently efficacious, reducing the number of hot flashes per day by 20.6% (95% CI: -28.38 to -12.86; p < 0.00001) more than the reduction in the placebo group. Similarly, in the nine trials involving 988 women that evaluated hot flash severity, isoflavones reduced symptoms by 26.2% (95% CI: -42.23 to -10.15; p = 0.001) more than the reduction in the placebo group. Subanalysis of the data revealed three interesting findings. First, baseline hot flash frequency did not impact efficacy. The percent reduction in hot flash frequency was similar regardless of whether women had two or 10 hot flashes per day at baseline. Second, hot flashes were reduced to a greater extent (p = 0.006 between groups) in studies greater than 12 weeks in duration (-34.29%; 95% CI: -49.07–19.50%) than in shorter term studies (-12.66%; 95% CI: -17.09 to -8.23%), indicating the effects of isoflavones are not transient. Third, and most important, supplements that provided higher amounts of the isoflavone genistein were considerably more efficacious than supplements low in genistein. This difference helps explain the inconsistent results noted in past reviews of the data. In studies that intervened with supplements providing greater than or equal to 18.8 mg genistein (the median for all studies), hot flash frequency was reduced by 29.13% (95% CI: -43.09 to -15.17) vs only 12.47% (95% CI: -17.34 to -7.60) for studies providing less than this amount (p = 0.03 for difference between groups). Indirect support for this finding comes from a second Cochrane analysis, which while again failing to subanalyze the results according to the isoflavone profile of the soy extracts, did note that all four trials that intervened with genistein showed statistically significant reductions in hot flash frequency relative to the placebo [29] . Given the results of the meta-analysis by Taku et al. [28] , it is surprising that genistein-rich isoflavone supplements have not been embraced as a treatment for hot flashes to a greater extent than they have, especially in light of the FDA’s approval of Brisdelle, although this decision was controversial. Brisdelle was approved on the basis of two trials that enrolled 1184 women [30] , a sample size strikingly similar to the number of women included in the meta-analysis by Taku et al. [28] . Furthermore, Brisdelle reduced symptoms by only one to two hot flashes per day in women who at enrollment had at least ten hot flashes per day [26] . Thus, the effect of isoflavones is equal to or greater than that of this selective serotonin-reuptake inhibitor.
future science group
Soybean isoflavones warrant greater consideration as a treatment for the alleviation of menopausal hot flashes
What then has limited the acceptance of isoflavones? There are three probable contributing factors. First, beginning with the American Heart Association’s pronouncement, there has been a nearly decadelong acceptance that isoflavones lack efficacy [19] . The robust results of the meta-analysis by Taku et al. [28] simply have not prompted professional societies to reevaluate their position on isoflavones. Consequently, consumers and health professionals are likely not aware of the new data.
“
...the overwhelming amount of evidence indicates that isoflavone supplements, provided they contain a sufficient amount of genistein, alleviate hot flashes to a clinically relevant extent and have an acceptable safety profile.
”
Second, many health professionals and clinicians have recommended that women avoid or greatly limit isoflavone exposure due to concerns over an increased breast cancer risk. This cautionary stance is slowing becoming less of an impediment as the scientific and medical communities begin to recognize that over the past 10 years, extensive clinical research shows isoflavone exposure does not adversely affect breast tissue as assessed by effects on markers of breast cancer risk [31,32] . In addition, epidemiologic data indicate that post-diagnosis isoflavone intake reduces breast tumor recurrence and breast cancer-specific mortality [33,34] . Not surprisingly, given these data, both the American Institute for Cancer Research [35] and the American Cancer Society have concluded that breast cancer patients can safely consume isoflavone-rich soyfoods [36] . To be fair, these groups do not endorse supplements because they fear overconsumption and because their reviews of the literature rely heavily on the results of epidemiologic studies wherein isoflavone intake occurs via the consumption of soyfoods. However, nearly all of the clinical trials evaluating breast cancer risk markers involve supplements. Third, and most importantly, the hot flash trials in the meta-analysis by Taku et al. [28] included References
a wide variety of soy extracts and each of the individual trials was relatively small, unlike the research of Brisdelle, which involved two large trials and the same preparation. Consequently, while collectively the data are impressive, no individual soy extract has been extensively studied. Finally, although expert views on the use of HT for the treatment of menopausal symptoms have become less restrictive and more individualized than was the case immediately following the publication of the Women’s Health Initiative trial [37] , many women still prefer using nonhormonal alternatives for alleviation of hot flashes [38] . Furthermore, even those women who initially opt for HT may eventually need an alternative since upon discontinuation of HT hot flashes often resume [39] . Obviously, there is a need for HT alternatives. In conclusion, the overwhelming amount of evidence indicates that isoflavone supplements, provided they contain a sufficient amount of genistein, alleviate hot flashes to a clinically relevant extent and have an acceptable safety profile. The amount of total isoflavones (expressed in aglycone equivalent weight) needed for relief is estimated to be approximately 40–50 mg/day, which is provided by approximately two servings of traditional soyfoods, an amount that is well within the range of the soy/isoflavone intake of older adults in Japan [2] . Therefore, health professionals and clinicians are justified in advising their clients and patients to try isoflavones for the relief of hot flashes. Financial & competing interests disclosure M Messina regularly consults for companies/organizations that manufacture and/or sell soyfoods and/or soy supplements. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
4
Murphy PA, Barua K, Hauck CC. Solvent extraction selection in the determination of isoflavones in soy foods. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 777, 129–138 (2002).
5
Folman Y, Pope GS. The interaction in the immature mouse of potent oestrogens with coumestrol, genistein and other utero-vaginotrophic compounds of low potency. J. Endocrinol. 34, 215–225 (1966).
6
Adlercreutz H, Hamalainen E, Gorbach S et al. Dietary phytooestrogens and the menopause in Japan. Lancet 339, 1233 (1992).
Papers of special interest have been highlighted as: •• of considerable interest 1
Franke AA, Custer LJ, Wang W et al. HPLC analysis of isoflavonoids and other phenolic agents from foods and from human fluids. Proc. Soc. Exp. Biol. Med. 217, 263–273 (1998).
2
Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr. Cancer 55, 1–12 (2006).
3
Bai W, Wang C, Ren C. Intakes of total and individual flavonoids by US adults. Int. J. Food Sci. Nutr. 65, 9–20 (2014).
future science group
Editorial
www.futuremedicine.com
551
Editorial Messina 7
Murkies AL, Lombard C, Strauss BJ et al. Dietary flour supplementation decreases post-menopausal hot flushes: effect of soy and wheat. Maturitas 21, 189–195 (1995).
8
Clarkson TB, Anthony MS, Hughes CL. Estrogenic soybean isoflavones and chronic disease. Risks and benefits. Trends Endocrinol. Metab. 6, 11–16 (1995).
9
Kuiper GG, Lemmen JG, Carlsson B et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139, 4252–4263 (1998).
24
Weaver CM, Martin BR, Jackson GS et al. Antiresorptive effects of phytoestrogen supplements compared with estradiol or risedronate in postmenopausal women using (41)Ca methodology. J. Clin. Endocrinol. Metab. 94, 3798–3805 (2009).
25
Muthyala RS, Ju YH, Sheng S et al. Equol, a natural estrogenic metabolite from soy isoflavones: convenient preparation and resolution of R- and S-equols and their differing binding and biological activity through estrogen receptors alpha and beta. Bioorg. Med. Chem. 12, 1559–1567 (2004).
10
Kuiper GG, Enmark E, Pelto-Huikko M et al. Cloning of a novel receptor expressed in rat prostate and ovary. Proc. Natl Acad. Sci. USA 93, 5925–5930 (1996).
11
Setchell KD. Soy isoflavones – benefits and risks from nature’s selective estrogen receptor modulators (SERMs). J. Am. Coll. Nutr. 20, 354S–362S (2001).
26
12
Brzezinski A, Debi A. Phytoestrogens: the “natural” selective estrogen receptor modulators? Eur. J. Obstet. Gynecol. Reprod. Biol. 85, 47–51 (1999).
Orleans RJ, Li L, Kim MJ et al. FDA approval of paroxetine for menopausal hot flushes. N. Engl. J. Med. 370, 1777–1779 (2014).
27
13
Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. J. Am. Med. Assoc. 288, 321–333 (2002).
Williamson-Hughes PS, Flickinger BD, Messina MJ et al. Isoflavone supplements containing predominantly genistein reduce hot flash symptoms: a critical review of published studies. Menopause 13, 831–839 (2006).
28
Hsieh CY, Santell RC, Haslam SZ et al. Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res. 58, 3833–3838 (1998).
Taku K, Melby MK, Kronenberg F et al. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and metaanalysis of randomized controlled trials. Menopause 19, 776–790 (2012).
••
Comprehensive statistical analysis evaluating the effect of soy isoflavones on the alleviation of hot flashes. First meta-analysis to subanalyze results according to the isoflavone profile of the intervention agent.
14
15
Balk E, Chung M, Chew P et al. Effects of soy on health outcomes. Evid. Rep. Technol. Assess. (Summ.) 126, 1–8 (2005).
16
The role of isoflavones in menopausal health: consensus opinion of The North American Menopause Society. Menopause 7, 215–229 (2000).
29
Lethaby A, Marjoribanks J, Kronenberg F et al. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst. Rev. 12, CD001395 (2013).
17
American College of Obstetricians and Gynecologists. Use of botanicals for management of menopausal symptoms. ACOG Pract. Bull. 28, 1–11 (2001).
30
18
Balk E, Chung M, Chew P et al. Effects of soy on health outcomes. Evidence report/technology assessment No. 126 (prepared by Tufts-New England Medical Center Evidencebased Practice Center under Contract No. 290–202–0022.). AHRQ Publication No. 05-E024–2, July 2005, Agency for Healthcare Research and Quality, Rockville, MD, USA (2005).
Simon JA, Portman DJ, Kaunitz AM et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause 20, 1027–1035 (2013).
31
Fritz H, Seely D, Flower G et al. Soy, red clover, and isoflavones and breast cancer: a systematic review. PLoS ONE 8, e81968 (2013).
••
Sacks FM, Lichtenstein A, Van Horn L et al. Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulation 113, 1034–1044 (2006).
Comprehensive review of the animal, clinical and epidemiologic data relevant to the effect of soy on risk of developing breast cancer and on the impact of soy on the prognosis of breast cancer patients.
32
Lethaby A, Brown J, Marjoribanks J et al. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst. Rev. CD001395 (2007).
Messina M, Caan BJ, Abrams DI et al. It’s time for clinicians to reconsider their proscription against the use of soyfoods by breast cancer patients. Oncology 27, 430–437 (2013).
••
Comprehensive review of the clinical and epidemiologic data relevant to the effect of soy on the prognosis of breast cancer patients.
33
Nechuta SJ, Caan BJ, Chen WY et al. Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women. Am. J. Clin. Nutr. 96, 123–132 (2012).
••
Pooled analysis of three prospective studies involving nearly 10,000 breast cancer patients that evaluated the
19
20
21
552
systematic review and meta-analysis. Menopause 17, 660–666 (2010).
Nelson HD, Vesco KK, Haney E et al. Nonhormonal therapies for menopausal hot flashes: systematic review and metaanalysis. J. Am. Med. Assoc. 295, 2057–2071 (2006).
22
Howes LG, Howes JB, Knight DC. Isoflavone therapy for menopausal flushes: a systematic review and meta-analysis. Maturitas 55, 203–211 (2006).
23
Bolanos R, Del Castillo A, Francia J. Soy isoflavones versus placebo in the treatment of climacteric vasomotor symptoms:
Womens Health (2014) 10(6)
future science group
Soybean isoflavones warrant greater consideration as a treatment for the alleviation of menopausal hot flashes
effect of post-diagnosis soy intake on tumor recurrence and breast cancer mortality. 34
Chi F, Wu R, Zeng YC et al. Post-diagnosis soy food intake and breast cancer survival: a meta-analysis of cohort studies. Asian Pac. J. Cancer Prev. 14, 2407–2412 (2013).
••
Meta-analysis of five prospective studies involving approximately 11,000 breast cancer patients that evaluated the effect of post-diagnosis soy intake on tumor recurrence and breast cancer mortality.
35
American Institute for Cancer Research. Soy is safe for breast cancer survivors (2013). www.aicr.org/cancer-research-update
future science group
36
Rock CL, Doyle C, Demark-Wahnefried W et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J. Clin. 62, 242–274 (2012).
37
ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet. Gynecol. 123, 202–216 (2014).
38
Butt DA, Deng LY, Lewis JE et al. Minimal decrease in hot flashes desired by postmenopausal women in family practice. Menopause 14, 203–207 (2007).
39
Perrone G, Capri O, Galoppi P et al. Menopausal symptoms after the discontinuation of long-term hormone replacement therapy in women under 60: a 3-year follow-up. Gynecol. Obstet. Invest. 76, 38–43 (2013).
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