Menopause: The Journal of The North American Menopause Society Vol. 22, No. 5, pp. 480/482 DOI: 10.1097/gme.0000000000000469 * 2015 by The North American Menopause Society
EDITORIAL Equalizing equol for hot flash relief? Still more questions than answers It is presently unclear what factors determine S-(j)equol production, but understanding why equol production varies among individuals is important, because of the increasing evidence supporting the hypothesis that the ability to produce equol contributes to the overall efficacy of a soy foodYbased diet.1
G
iven safety concerns with estrogen use in older postmenopausal women, there has been an explosion of interest in soy supplements and food additives for the treatment of hot flashes. In October 2010, The North American Menopause Society (NAMS) held the Wulf H. Utian Translational Science Symposium on Soy and Soy Isoflavones to clarify basic and clinical research findings on the risks and benefits of soy products for perimenopausal and postmenopausal women. A consensus statement on the state of evidencebased science on the effects of isoflavones on menopausal symptoms, breast and endometrial cancer, atherosclerosis, bone loss, and cognition was developed by leading experts in botanicals.2 With respect to relief of vasomotor symptoms (VMS), the evidence, when scrutinized by strict criteria, suggested only modest effects, with panelists noting numerous flaws in the designs and methods that plagued the body of work, making it difficult to determine true efficacy. Nonetheless, the report suggested that women should consider isoflavone supplementation as VMS treatment when estrogen therapy was not an option because its safety profile was acceptable. However, it also recommended that more clinical studies be performed to unravel multiple mediators and moderators that could potentially account for the wide variation in VMS responses. Of special interest was the need to compare outcomes among women based on their ability (or rather the ability of their gut bacteria) to convert daidzein, a key isoflavone, into its more potent metabolite, equol. Because equol is believed to have estrogen receptor-A agonist activity, it has been proposed to act as an endogenous selective estrogen receptor moderator with estrogenlike actions on the brain to dampen hot flashes.1 Such a hypothesis could go a long way toward explaining the low rates of VMS in Asian populations, where soy consumption is prevalent and the numbers of equol producers are twofold to threefold higher than in US white non-Hispanic groups. (In an earlier commentary,3 I discussed the merits of possible cultural explanations for differences in symptom reporting between Asian and US research volunteers). To account for later reports that emerged after the NAMS report, including one positive systematic review,4 a panel of experts from the prestigious Cochrane Collaboration updated
480
the results of an expanded set of trials published through late 2013. They, too, however, determined that there was no conclusive evidence that soy-based supplements reduced the frequency or intensity of VMS in premenopausal or postmenopausal women.5 Again, concerns with continuing problems with small sample sizes, high placebo responses, and poor study designs were cited. Moreover, most included studies did not examine equol status, although it was seen as a promising predictor in need of better scrutiny. Indeed, greater improvement in hot flashes, when stratified by equol-producing status, was reported in two small industry-sponsored trials using supplements of the biologically active S-isomer, S-equol.6,7 What was lacking was a large study capable of examining differences in VMS relief associated with soy diet used by a US population. However, given the low prevalence of soy consumption and an even lower prevalence of US women capable of producing equol, this was no small feat. In this issue of Menopause, Newton et al8 reported on results from a population-based, cross-sectional, observational study that improves upon the rigor of earlier approaches to better address whether equol producer status can help explain the wide variation in responses to soy supplements when used as a self-management therapy for hot flashes. Taking advantage of a large pool of approximately 19,000 middle-aged female enrollees of Group Health of Seattle (recruitment source), they characterized a highly screened set of 365 eligible perimenopausal or postmenopausal women for VMS, soy intake, and equol production using mailed survey questionnaires and electronic medical and pharmacy records. To qualify, participants must have consumed at least three servings of soy per week and reported no recent history of estrogen use or antibiotic therapy. To establish equol status, the investigators used 3-day diet diaries and 24-hour excretion of urinary isoflavone as measured by gas chromatographyYmass spectrometry, with accepted methods for defining adequate equol concentrations. To account for any bias in self-reported diaries, they assessed both hot flashes and night sweats by hot flash monitors to capture events in real time. The investigators predicted that, even with this Bsnapshot approach,[ equol producers would differ from nonequol producers by demonstrating a positive relationship between VMS frequency and daidzein intake, whereas no such association would be seen in the nonproducer group. The Lifetime Exposures And Vasomotor Symptoms (LEAVeS) study revealed several intriguing though disappointing findings. Although the primary hypothesis was supported, the strength of the association between VMS rates and daidzein intake was modest, as acknowledged by the investigators: equol producers with the highest levels of daidzein intake (six times the levels
Menopause, Vol. 22, No. 5, 2015
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
EDITORIAL
of the lowest group) Bwere 76% less likely to have above the mean number of VMS[ compared with those with low intake (significance trend, P = 0.06). As predicted, in equol nonproducers, there were no links between daidzein intake and VMS number. In the predominantly white sample (17% of women were Asian), 35% of participants were determined to be equol producersVa rate similar to those of other US studies when less discriminating assessments were used. As a whole, the women were slightly overweight and within 3 years of menopauseVa time when VMS are relatively common. Nearly 30% of participants self-identified as current smokers, a surprising statistic given the volunteers_ recruitment source, age (approximately 53 y), and socioeconomic status. Despite the presence of these VMS risk factors (higher body mass index, menopause stage, and smoker status), the average number of VMS for the sample as a whole was low at about 4.5 VMS/day, whether measured by self-report or real-time recordings. Indeed, the typical woman in this study would not have been eligible for a Food and Drug Administration efficacy trial, which requires an average of at least 8 VMS/day. Despite the positive though modest support for the primary hypothesis, no other differences in VMS characteristics emerged between equol producers and nonproducers. Not only were the levels of VMS bother and severity nearly identical across the study groups, they were also very low, with the mean score for Bsubjective bothersomeness[ rated below 0.85 (on a scale of 1-3, where 1 = not at all bothered). In both groups, those with severe or highly bothersome symptoms made up less than one in five participants. One might have predicted that clear differences in VMS rates and scores for severity and bother would have been apparent between groups, with more symptomatic women in the nonproducer group. Moreover, as the investigators speculated, women with the highest VMS may have been those consuming the highest amounts of soy foods, thus reducing estimates of their true symptom profile. However, in this regard, there were no differences in dietary intake of soy, urinary daidzein, or other gastrointestinal systemYrelated conditions between groups, making such a possibility improbable. The investigators also speculated that had the overall soy intake been higher, they might have seen a different result. (I am assuming they meant a greater diminishment in VMS numbers in equol producers with high daidzein intake.) Alternatively, one could argue that with such a low VMS frequency and minimal bother in this particular group of women, it would be difficult to demonstrate much more of a difference in VMS features between groups beyond what was observed. As concluded by the NAMS review of clinical trial data, a low to moderate VMS frequency may be most amenable to soy therapies in that women experiencing more than four daily hot flashes did not necessarily show greater improvement over placebo when they were treated with isoflavone supplements. Other possible influences on the reported findings not discussed in the report come to mind. Given that some 40% of women were classified as perimenopausal based on self-reports,
with approximately 30% reporting never having had hot flashes, it is unclear how estrogen status influenced the levels of VMS frequency and severity. The investigators mentioned that folliclestimulating hormone concentrations were not determined because the cost of blood collection was prohibitive; however, the Study of Women_s Health Across the Nation used urinary follicle-stimulating hormone as a biomarker and demonstrated a robust positive correlation with VMS.9 The authors were silent on how current smoking status may have confounded the data. Besides smoking_s well-known effects on VMS, it is unclear how the gut microbiome differs in smokers, not to mention the underlying metabolic conversion of daidzein into equol. It would be interesting to know whether the smokers were the ones most likely to have consumed the lowest (or highest) soy intake because of differences in lifestyles and health perceptions. If indeed equol production actually serves as a Bstand-in[ surrogate for other lifestyle/dietary factors that underlie the mystery of soy benefits, it would be important to tease this out. Although data are conflicting, some studies have suggested that equol excretion varies by duration of soy food exposure,1 micronutrients in the diet,10 type of antibiotic used,11 and smoking.12 So how should one interpret these findings? The authors concluded that only among equol producers can higher soy consumption diminish VMS, although in a modest way. For most US women who are not equol producers (for reasons not yet fully understood) and who experience more frequent and bothersome hot flash symptoms than those observed here, these results, although disheartening, should persuade them not to rely on soy foods for much help with hot flash symptoms. Moreover, as pointed out by the authors, without a commercialized test for equol status, even those women who could potentially enjoy some benefits from soy consumption cannot readily do so. Whether equalizing equol by ingesting exogenous supplements can help women relieve bothersome hot flashes remains a mystery until more definitive studies are in hand. Financial disclosure/conflicts of interest: None reported. Nancy King Reame, MSN, PhD, FAAN Columbia University, New York, New York REFERENCES 1. Setchell KD, Clerici C. Equol: pharmacokinetics and biological actions. J Nutr 2010;140:1363S-1368S. 2. The North American Menopause Society. The role of soy isoflavones in menopausal health: report of The North American Menopause Society/ Wulf H. Utian Translational Science Symposium in Chicago, IL (October 2010). Menopause 2011;18:732-753. 3. Reame NK. Learning more about the Japanese hot flash. Menopause 2009;16:846-847. 4. Taku K, Melby MK, Kronenberg F, Kurzer MS, Messina M. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause 2012;19:776-790. 5. Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst Rev 2013:12:CD001395. Menopause, Vol. 22, No. 5, 2015
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
481
EDITORIAL 6. Aso T, Uchiyama S, Matsumura Y, et al. A natural S-equol supplement alleviates hot flushes and other menopausal symptoms in equol nonproducing postmenopausal Japanese women. J Womens Health 2012;21:92-100. 7. Jenks BH, Iwashita S, Nakagawa Y, et al. A pilot study on the effects of S-equol compared to soy isoflavones on menopausal hot flash frequency. J Womens Health 2012;21:674-682. 8. Newton KM, Reed SD, Uchiyama S, et al. A cross-sectional study of equol producer status and self-reported vasomotor symptoms. Menopause 2015;22:489-495. 9. Gold EB, Lasley B, Crawford SL, McConnell D, Joffe H, Greendale GA. Relation of daily urinary hormone patterns to vasomotor symptoms in a
482
Menopause, Vol. 22, No. 5, 2015
racially/ethnically diverse sample of midlife women: Study of Women_s Health Across the Nation. Reprod Sci 2007;14:786-797. 10. Setchell KD, Brown NM, Summer S, et al. Dietary factors influence production of the soy isoflavone metabolite S-(j) equol in healthy adults. J Nutr 2013;143:1950-1958. 11. Franke AA, Lai JF, Pagano I, Morimoto Y, Maskarinec G. Equol production changes over time in pre-menopausal women. Br J Nutr 2012;107: 1201-1206. 12. Nagata C, Ueno T, Uchiyama S, et al. Dietary and lifestyle correlates of urinary excretion status of equol in Japanese women. Nutr Cancer 2008;60:49-54.
* 2015 The North American Menopause Society
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
EDITORIAL Equalizing equol for hot flash relief? Still more questions than answers It is presently unclear what factors determine S-(j)equol production, but understanding why equol production varies among individuals is important, because of the increasing evidence supporting the hypothesis that the ability to produce equol contributes to the overall efficacy of a soy foodYbased diet.1
G
iven safety concerns with estrogen use in older postmenopausal women, there has been an explosion of interest in soy supplements and food additives for the treatment of hot flashes. In October 2010, The North American Menopause Society (NAMS) held the Wulf H. Utian Translational Science Symposium on Soy and Soy Isoflavones to clarify basic and clinical research findings on the risks and benefits of soy products for perimenopausal and postmenopausal women. A consensus statement on the state of evidencebased science on the effects of isoflavones on menopausal symptoms, breast and endometrial cancer, atherosclerosis, bone loss, and cognition was developed by leading experts in botanicals.2 With respect to relief of vasomotor symptoms (VMS), the evidence, when scrutinized by strict criteria, suggested only modest effects, with panelists noting numerous flaws in the designs and methods that plagued the body of work, making it difficult to determine true efficacy. Nonetheless, the report suggested that women should consider isoflavone supplementation as VMS treatment when estrogen therapy was not an option because its safety profile was acceptable. However, it also recommended that more clinical studies be performed to unravel multiple mediators and moderators that could potentially account for the wide variation in VMS responses. Of special interest was the need to compare outcomes among women based on their ability (or rather the ability of their gut bacteria) to convert daidzein, a key isoflavone, into its more potent metabolite, equol. Because equol is believed to have estrogen receptor-A agonist activity, it has been proposed to act as an endogenous selective estrogen receptor moderator with estrogenlike actions on the brain to dampen hot flashes.1 Such a hypothesis could go a long way toward explaining the low rates of VMS in Asian populations, where soy consumption is prevalent and the numbers of equol producers are twofold to threefold higher than in US white non-Hispanic groups. (In an earlier commentary,3 I discussed the merits of possible cultural explanations for differences in symptom reporting between Asian and US research volunteers). To account for later reports that emerged after the NAMS report, including one positive systematic review,4 a panel of experts from the prestigious Cochrane Collaboration updated
480
the results of an expanded set of trials published through late 2013. They, too, however, determined that there was no conclusive evidence that soy-based supplements reduced the frequency or intensity of VMS in premenopausal or postmenopausal women.5 Again, concerns with continuing problems with small sample sizes, high placebo responses, and poor study designs were cited. Moreover, most included studies did not examine equol status, although it was seen as a promising predictor in need of better scrutiny. Indeed, greater improvement in hot flashes, when stratified by equol-producing status, was reported in two small industry-sponsored trials using supplements of the biologically active S-isomer, S-equol.6,7 What was lacking was a large study capable of examining differences in VMS relief associated with soy diet used by a US population. However, given the low prevalence of soy consumption and an even lower prevalence of US women capable of producing equol, this was no small feat. In this issue of Menopause, Newton et al8 reported on results from a population-based, cross-sectional, observational study that improves upon the rigor of earlier approaches to better address whether equol producer status can help explain the wide variation in responses to soy supplements when used as a self-management therapy for hot flashes. Taking advantage of a large pool of approximately 19,000 middle-aged female enrollees of Group Health of Seattle (recruitment source), they characterized a highly screened set of 365 eligible perimenopausal or postmenopausal women for VMS, soy intake, and equol production using mailed survey questionnaires and electronic medical and pharmacy records. To qualify, participants must have consumed at least three servings of soy per week and reported no recent history of estrogen use or antibiotic therapy. To establish equol status, the investigators used 3-day diet diaries and 24-hour excretion of urinary isoflavone as measured by gas chromatographyYmass spectrometry, with accepted methods for defining adequate equol concentrations. To account for any bias in self-reported diaries, they assessed both hot flashes and night sweats by hot flash monitors to capture events in real time. The investigators predicted that, even with this Bsnapshot approach,[ equol producers would differ from nonequol producers by demonstrating a positive relationship between VMS frequency and daidzein intake, whereas no such association would be seen in the nonproducer group. The Lifetime Exposures And Vasomotor Symptoms (LEAVeS) study revealed several intriguing though disappointing findings. Although the primary hypothesis was supported, the strength of the association between VMS rates and daidzein intake was modest, as acknowledged by the investigators: equol producers with the highest levels of daidzein intake (six times the levels
Menopause, Vol. 22, No. 5, 2015
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
EDITORIAL
of the lowest group) Bwere 76% less likely to have above the mean number of VMS[ compared with those with low intake (significance trend, P = 0.06). As predicted, in equol nonproducers, there were no links between daidzein intake and VMS number. In the predominantly white sample (17% of women were Asian), 35% of participants were determined to be equol producersVa rate similar to those of other US studies when less discriminating assessments were used. As a whole, the women were slightly overweight and within 3 years of menopauseVa time when VMS are relatively common. Nearly 30% of participants self-identified as current smokers, a surprising statistic given the volunteers_ recruitment source, age (approximately 53 y), and socioeconomic status. Despite the presence of these VMS risk factors (higher body mass index, menopause stage, and smoker status), the average number of VMS for the sample as a whole was low at about 4.5 VMS/day, whether measured by self-report or real-time recordings. Indeed, the typical woman in this study would not have been eligible for a Food and Drug Administration efficacy trial, which requires an average of at least 8 VMS/day. Despite the positive though modest support for the primary hypothesis, no other differences in VMS characteristics emerged between equol producers and nonproducers. Not only were the levels of VMS bother and severity nearly identical across the study groups, they were also very low, with the mean score for Bsubjective bothersomeness[ rated below 0.85 (on a scale of 1-3, where 1 = not at all bothered). In both groups, those with severe or highly bothersome symptoms made up less than one in five participants. One might have predicted that clear differences in VMS rates and scores for severity and bother would have been apparent between groups, with more symptomatic women in the nonproducer group. Moreover, as the investigators speculated, women with the highest VMS may have been those consuming the highest amounts of soy foods, thus reducing estimates of their true symptom profile. However, in this regard, there were no differences in dietary intake of soy, urinary daidzein, or other gastrointestinal systemYrelated conditions between groups, making such a possibility improbable. The investigators also speculated that had the overall soy intake been higher, they might have seen a different result. (I am assuming they meant a greater diminishment in VMS numbers in equol producers with high daidzein intake.) Alternatively, one could argue that with such a low VMS frequency and minimal bother in this particular group of women, it would be difficult to demonstrate much more of a difference in VMS features between groups beyond what was observed. As concluded by the NAMS review of clinical trial data, a low to moderate VMS frequency may be most amenable to soy therapies in that women experiencing more than four daily hot flashes did not necessarily show greater improvement over placebo when they were treated with isoflavone supplements. Other possible influences on the reported findings not discussed in the report come to mind. Given that some 40% of women were classified as perimenopausal based on self-reports,
with approximately 30% reporting never having had hot flashes, it is unclear how estrogen status influenced the levels of VMS frequency and severity. The investigators mentioned that folliclestimulating hormone concentrations were not determined because the cost of blood collection was prohibitive; however, the Study of Women_s Health Across the Nation used urinary follicle-stimulating hormone as a biomarker and demonstrated a robust positive correlation with VMS.9 The authors were silent on how current smoking status may have confounded the data. Besides smoking_s well-known effects on VMS, it is unclear how the gut microbiome differs in smokers, not to mention the underlying metabolic conversion of daidzein into equol. It would be interesting to know whether the smokers were the ones most likely to have consumed the lowest (or highest) soy intake because of differences in lifestyles and health perceptions. If indeed equol production actually serves as a Bstand-in[ surrogate for other lifestyle/dietary factors that underlie the mystery of soy benefits, it would be important to tease this out. Although data are conflicting, some studies have suggested that equol excretion varies by duration of soy food exposure,1 micronutrients in the diet,10 type of antibiotic used,11 and smoking.12 So how should one interpret these findings? The authors concluded that only among equol producers can higher soy consumption diminish VMS, although in a modest way. For most US women who are not equol producers (for reasons not yet fully understood) and who experience more frequent and bothersome hot flash symptoms than those observed here, these results, although disheartening, should persuade them not to rely on soy foods for much help with hot flash symptoms. Moreover, as pointed out by the authors, without a commercialized test for equol status, even those women who could potentially enjoy some benefits from soy consumption cannot readily do so. Whether equalizing equol by ingesting exogenous supplements can help women relieve bothersome hot flashes remains a mystery until more definitive studies are in hand. Financial disclosure/conflicts of interest: None reported. Nancy King Reame, MSN, PhD, FAAN Columbia University, New York, New York REFERENCES 1. Setchell KD, Clerici C. Equol: pharmacokinetics and biological actions. J Nutr 2010;140:1363S-1368S. 2. The North American Menopause Society. The role of soy isoflavones in menopausal health: report of The North American Menopause Society/ Wulf H. Utian Translational Science Symposium in Chicago, IL (October 2010). Menopause 2011;18:732-753. 3. Reame NK. Learning more about the Japanese hot flash. Menopause 2009;16:846-847. 4. Taku K, Melby MK, Kronenberg F, Kurzer MS, Messina M. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: systematic review and meta-analysis of randomized controlled trials. Menopause 2012;19:776-790. 5. Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst Rev 2013:12:CD001395. Menopause, Vol. 22, No. 5, 2015
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
481
EDITORIAL 6. Aso T, Uchiyama S, Matsumura Y, et al. A natural S-equol supplement alleviates hot flushes and other menopausal symptoms in equol nonproducing postmenopausal Japanese women. J Womens Health 2012;21:92-100. 7. Jenks BH, Iwashita S, Nakagawa Y, et al. A pilot study on the effects of S-equol compared to soy isoflavones on menopausal hot flash frequency. J Womens Health 2012;21:674-682. 8. Newton KM, Reed SD, Uchiyama S, et al. A cross-sectional study of equol producer status and self-reported vasomotor symptoms. Menopause 2015;22:489-495. 9. Gold EB, Lasley B, Crawford SL, McConnell D, Joffe H, Greendale GA. Relation of daily urinary hormone patterns to vasomotor symptoms in a
482
Menopause, Vol. 22, No. 5, 2015
racially/ethnically diverse sample of midlife women: Study of Women_s Health Across the Nation. Reprod Sci 2007;14:786-797. 10. Setchell KD, Brown NM, Summer S, et al. Dietary factors influence production of the soy isoflavone metabolite S-(j) equol in healthy adults. J Nutr 2013;143:1950-1958. 11. Franke AA, Lai JF, Pagano I, Morimoto Y, Maskarinec G. Equol production changes over time in pre-menopausal women. Br J Nutr 2012;107: 1201-1206. 12. Nagata C, Ueno T, Uchiyama S, et al. Dietary and lifestyle correlates of urinary excretion status of equol in Japanese women. Nutr Cancer 2008;60:49-54.
* 2015 The North American Menopause Society
Copyright © 2015 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
