Soy and Hot Flashes
Soy and Hot Flashes
By Felise B. Milan, MD, Associate Professor of Clinical Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY. Dr. Milan reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Hot Flashes: The Scope of the Problem
Hot flashes are the most prevalent symptom associated with menopause and have been attributed with often causing significant sleep disturbances.1 Frequent awakenings at night can lead to chronic fatigue, irritability, mood disorders, and changes in memory or attention span.1-3 Although vasomotor symptoms can be treated effectively with estrogen replacement therapy, many women seek alternative therapeutic options due to the multiple risks associated with estrogen replacement therapy.4
The majority of women who experience hot flashes report them on average two years before the total cessation of menses.1 In one prospective study, 31% of women experienced some hot flashes before noting any irregularity in their menstrual cycle.5 The incidence of hot flashes reaches its highest incidence during the first two years post menopause.6 Although most women experience hot flashes for six months to two years, some can have them for 10 years or more.1,7 The frequency of hot flashes varies widely among affected women (monthly to hourly)8 and with regard to race and ethnicity. Women in Western countries have approximately an 80% incidence of hot flashes; Asian women living in China9 have an incidence of only 20% and Asian women living in Hong Kong10 have an incidence of 10%. The lower incidence of vasomotor symptoms in Asian women has been widely reported.11-13 It has been hypothesized that the differences may be attributed to soy-rich diets.9,14,15
Phytoestrogens
Phytoestrogens are a group of naturally occurring plant-derived nonsteroidal compounds that bind to estrogen receptors. There are three main classes of phytoestrogens: isoflavones, coumestans, and lignans. Although there is some overlap, isoflavones are found in legumes and beans, with the highest concentrations in soybeans. Lignans are found mostly in flaxseed with some found in other cereals, fruits, and vegetables. Coumestans are found in clover and sprouts (alfalfa and soybean sprouts). Isoflavones have the most potent estrogenic activity and therefore have received the most attention by the medical community.16
Active Ingredients and Mechanism of Action
Isoflavones have emerged as the most interesting class of phytoestrogens, as they have the most potent estrogenic activity and an extensive range of biological actions. Isoflavones have a common diphenolic structure that resembles the structure of the potent synthetic estrogen diethylstilbesterol,17 physiologic estrogen 17b-estradiol, and synthetic anti-estrogen tamoxifen.18 The major isoflavones—genistein, glycetein, and daidzein—occur in plants as inactive glycosides. They also are derived from precursors biochanin A and formononetin. The estrogenically active lignans—enterodiol and enterolactone—are derived from the compounds secoisolariciresinol and matairesinol found in plants.
In humans, lignans and isoflavones must undergo complex enzymatic metabolic conversions in the gastrointestinal tract to become compounds with estrogenic activity.16 For example, in some individuals, daidzein, is converted to equol, a potent isoflavone metabolite.19 Clover sprouts also contain the isoflavone formonetin, which is metabolized in the gastrointestinal tract to daidzein.19 The extent of those metabolic reactions can vary among individuals, with 5%-70% of the precursors becoming metabolized into active compounds.17 The variability is affected by gut microflora, diet, and concomitant intake of medications especially antibiotics.19 Absorption of isoflavones is decreased by both H2 blockers and proton-pump inhibitors.17 A carbohydrate-rich diet results in more extensive biotransformation of isoflavones by increasing intestinal fermentation.20
Phytoestrogens have demonstrated numerous biochemical properties. The level and direction of their estrogenicity depends on the target tissue, the receptor status of the tissue, and the level of endogenous estrogen. Phytoestrogens, including isoflavones, are essentially weak estrogens. They bind selectively and with high affinity to ER beta receptors.21 In premenopausal women who have high circulating levels of endogenous estrogen, phytoestrogens have an anti-estrogenic effect when they bind to estrogen receptors. In postmenopausal women, phytoestrogens bind to otherwise empty receptors and have an estrogenic effect.20 Isoflavones also stimulate sex hormone-binding globulin synthesis in the liver like estrogen.20 Isoflavones also have been found to inhibit tyrosine kinase, which may account for their nonestrogenic effects on bone.22 Other proposed mechanisms of action of isoflavones include: antioxidant effects on lipoproteins and DNA, effects on glucose transport, cell proliferation, and cell differentiation.18
Food Sources of Phytoestrogens
To best understand the phytoestrogen interventions being used in the literature, as well to advise patients with regard to diet, it is useful to discuss the food sources of soy, soy protein, and isoflavones. Soybeans and food products made from soybeans have the highest concentration of isoflavones but there is enormous variation depending on where the soybean is grown and how it is prepared. Isoflavones are more bioavailable from fermented soy products (i.e., tempeh) than other soy products or other fruits and vegetables.23 Lentils, peanuts, chickpeas, alfalfa, and barley all have isoflavones but at a concentration of 0.01%-0.1% of that found in soybeans.
Clinical Evidence
The literature on the clinical effects of a soy-enriched diet and isoflavone supplements is large and growing. Double-blind, randomized, controlled trials have evaluated the effect of soy on menopausal symptoms, cardiovascular disease and lipids, and breast cancer. The literature sometimes can be difficult to interpret as there are different terms to refer to different soy products. The term soy refers to use of the whole soybean, whereas soy protein refers to protein extracted from the soybean. Soy products and soy protein contain isoflavones in varying amounts. There are also isoflavone extracts that contain just individual compound(s), most commonly genistein and/or daidzein. Standardized isoflavone extracts derived from red clover, which is also a source of the phytoestrogen group coumestans, are being evaluated. Not all studies specify exactly the kind and quantity of isoflavones used in the intervention and almost every study has used a different soy product.
Efficacy of Soy and Isoflavones for Hot Flashes
Conventional estrogen replacement therapy has been shown to decrease hot flashes by about 70%.20 It has been clearly documented that in trials studying hot flashes, placebo alone reduces hot flashes by 15%-50%.20 This renders uncontrolled studies on treatment for hot flashes fairly useless and makes it a challenge for investigators to find a significant effect over placebo. Several placebo-controlled trials have evaluated the effectiveness of soy supplementation with foods or extracts for treating menopausal symptoms (see Table 1). Most studies have used some outcome measure to assess effect on vasomotor symptoms and some also have looked at serum hormone or isoflavone levels. A few have included either transvaginal ultrasound or endometrial biopsy to look for estrogenic effects on the endometrium. The studies have been fairly small, often underpowered, and have ranged in length from six weeks to two years.
The data regarding the benefit of soy for hot flashes are mixed. In a recent meta-analysis, Nelson et al searched all English-language published randomized controlled trials of nonhormonal therapies for treating hot flashes in menopausal women.24 The authors identified 17 trials of isoflavone extracts. Six trials of red clover isoflavones were included in a meta-analysis, which did not show a significant reduction in hot flashes. Six trials of soy isoflavones were used in a series of meta-analyses by length of study. A small but statistically significant decrease in number of daily hot flashes was seen for trials lasting four to six weeks, 12-16 weeks, or six months.
Another recent meta-analysis of five trials of red clover and 12 trials of soy isoflavones used regression analysis to examine the relationship between the number of baseline flashes, reduction in flashes compared with control, and isoflavone dose.25 The authors found that red clover and soy isoflavone supplementation both were associated with reductions in hot flashes. Effect sizes were greater for soy (-0.34, P < 0.0001) than for red clover (-0.16, P = 0.04), but both were statistically significant. There was a positive dose-response relationship. The reduction in flashes was greater for women experiencing more than four flashes a day at baseline.
A comprehensive systematic review analyzed data on three types of studies (soy foods, soy extracts, and extracts from red clover).26 The authors reviewed 10 published studies involving 995 participants and one abstract involving 99 participants evaluating the efficacy of soy foods, beverages, or powders for the treatment of hot flashes. Five of these trials27-31 provided enough information to allow calculations of effect sizes. Two of the studies showed a small31 and moderate29 effect favoring soy, while the other three were negative.27,28,30 They also reviewed seven trials involving 674 participants and two abstracts involving 180 additional participants, each evaluating a different soy extract product with isoflavone dosage varying between 50-150 mg. Results were mixed. Only two of these studies had the information necessary to calculate effect sizes. One had a moderate effect favoring soy32 and the other was negative.33 They reviewed separately three trials that studied the use of isoflavones in women with hot flashes who previously had breast cancer. Two of the trials included women on Tamoxifen28,34 while one excluded them.35 None of the three trials showed any benefit of soy over placebo for decreasing hot flashes. In contrast to the studies of products from soy, the studies on isoflavones all used the same proprietary product (Promensil) and one used an additional proprietary product made by the same company (Rimostil). Only one of the five studies reviewed showed a significant reduction in hot flashes with Promensil.36
There has been much speculation as to the reasons for the varied findings in the literature on isoflavones and hot flashes. The very high response rate among control groups in studies on hot flashes (10%-75%) presents a significant challenge to researchers in this area. The meta-analysis by Howes et al found that the respone to isoflavone therapy was significantly and inversely associated with the response to placebo.25 This suggests that the somewhat modest effect of isoflavones may be most apparent when the placebo effect is limited. Another possible confounder is that few studies have controlled the patients' dietary intake during the trials. Excluding patients who consume a diet high in soy and providing clear instructions on what food to avoid during the study might help decrease the influence of this variable. A very important finding that may shed some light on the problem is the discovery of equol. Equol, a metabolite of the isoflavone daidzen, binds to both alpha- and beta-estrogen receptors more strongly than its precursor.37 Equol has been identified as a metabolite in only 30% of women.38 Only these "equol producers" have the intestinal bacteria necessary to produce this metabolite, which then can be identified in both urine and serum. This difference in the ability to metabolize an important isoflavone may account for at least some of the variability on the findings in this literature. Future studies are likely to control for this variable.
Safety of Isoflavones
Many of the studies evaluating the use of isoflavones on vasomotor symptoms in postmenopausal women also have assessed the effect on the endometrium using either transvaginal ultrasound or endometrial biopsy. None39-41 have found an effect even after four42 or six31 months of treatment. Although more long-term human data are needed to feel confident that postmenopausal women are not at risk of an estrogenic effect on the endometrium,43 the evidence to date appears fairly promising.
Data from animal models looking at isoflavones effect on the breast has produced very mixed results. Most of the work has been done with genistein. In some animal models, genistein has been shown to be protective against the development of breast cancer in animals exposed to large quantities of carcinogens and in other models genistein has been shown to have a stimulatory effect on breast cancer.18 Epidemiological data and several case-control studies have shown high levels of soy intake to be protective against the development of breast cancer in humans44-46 although the effect seems to be stronger for premenopausal women than postmenopausal women. In summary, no firm conclusions can be made about the effect of isoflavones and soy on the risk of breast cancer.
Conclusion
The literature on soy food and isoflavone supplements from soy and red clover is inconclusive. Future studies need to be done which answer the important questions of which type of isoflavone works best and on which type of patient. It remains unclear whether all women are able to metabolize isoflavones sufficiently to gain the benefits of their estrogenic activity. Studies should be done comparing different sources and doses of isoflavones, taking into account women's different hormonal status, weight, symptom severity, and ability to metabolize isoflavones.
The North American Menopause Society (NAMS) published a position statement in January 2004 on the treatment of menopause-associated vasomotor symptoms. NAMS concluded that efficacy of soy foods and isoflavone supplements for hot flashes has been mixed but could be considered in women for whom lifestyle changes have not provided adequate relief. They recommend soy foods over isoflavone supplements as a safer alternative, but cite the overall lack of serious side effects associated with these therapies. They do advise caution in women for whom "estrogenicity" is of concern, especially women with a history or at high risk for breast cancer. These recommendations are prudent and consistent with the current literature.
Recommendation
Soy protein from food (25 g/d) or isoflavone supplements (maximum of 100 mg/d) can be considered in perimenopausal and menopausal women with bothersome hot flashes who have not experienced relief with lifestyle changes. Women with a history of breast cancer may want to choose soy foods, as a safe dose of isoflavone supplements has not yet been determined for this population.
References
1. Fitzpatrick LA, Santen RJ. Hot flashes: The old and the new, what is really true? Mayo Clinic Proc 2002;77:1155-1158.
2. Landau C, Milan FB. Prevalent psychological disorders during the menopause. Female Patient 1995;20:28-32.
3. Landau C, Milan FB. Assessment and treatment of depression during the menopause: A preliminary report. Menopause 1996;4:201-207.
4. Ma J, et al. U.S. women desire greater professional guidance on hormone and alternative therapies for menopause symptom management. Menopause 2006;13:506-516.
5. Freeman EW, et al. Hot flashes in the late reproductive years: Risk factors for African American and Caucasian women. J Womens Health Gend Based Med 2001;10:67-76.
6. North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: Position statement of The North American Menopause Society. Menopause 2004;11:11-33.
7. Kronenberg F. Hot flashes. In Lobo RA, ed. Treatment of the Postmenopausal Woman. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:157-177.
8. Freedman RR, et al. Core body temperature and circadian rhythm of hot flashes in menopausal women. J Clin Endocrinol Metab 1995;80:2354-2358.
9. Milan F, Montgomery K. The use of complementary and alternative therapies in older women. In Cherniak P, Cherniak N, eds. Alternative Medicine for the Elderly. Berlin, NY: Springer-Verlag; 2003:365-397.
10. Ho SC, et al. Menopausal symptoms and symptom clustering in Chinese women. Maturitas 1999;33:219-227.
11. Boulet MJ, et al. Climacteric and menopause in seven south-east Asian countries. Maturitas 1994;19:157-176.
12. Lock M. Ambiguities of aging: Japanese experience and perceptions of menopause. Cult Med Psychiatry 1986;10:23-46.
13. Tang GW. The climacteric of Chinese factory workers. Maturitas 1994;19:177-182.
14. Adlercruetz H, et al. Dietary phyto-estrogens and the menopause in Japan. Lancet 1992;339:1233.
15. Gold EB, et al. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am J Epidemiol 2000;152:463-473.
16. Murkies AL, et al. Clinical review 97: Phytoestrogens. J Clin Endocrinol Metab 1998;83:297-303.
17. Tham DM, et al. Clinical review 97: Potential health benefits of dietary phytoestrogens: A review of the clinical, epidemiological and mechanistic evidence. J Clin Endocrinol Metab 1998;83:2223-2235.
18. The role of isoflavones in menopausal health: Consensus opinion of The North American Menopause Society. Menopause 2000;7:215-229.
19. Nisly N. Phytoestrogens for the prevention and treatment of osteoporosis. Alt Med Alert 1999;2:138-142.
20. Vincent A, Fitzpatrick LA. Soy isoflavones: Are they useful in menopause? Mayo Clin Proc 2000;75:1174-1184.
21. Schreiber MD, et al. Dietary inclusion of whole soy foods results in significant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal postmenopausal women. Menopause 2001;8:384-392.
22. Kim H, et al. Mechanisms of action of the soy isoflavone genistein: Emerging role for its effect via transforming growth factor beta signaling pathways. Am J Clin Nutr 1998;68(6 Suppl):1418S-1425S.
23. Hutchins AM, et al. Vegetables, fruits and legumes: Effect on urinary isofavonoid phytoestrogen and lignan excretion. J Am Diet Assoc 1995;95:769-774.
24. Nelson HD, et al. Nonhormonal therapies for menopausal hot flashes: Systematic review and meta-analysis. JAMA 2006;295:2057-2071.
25. Howes LG, et al. Isoflavone therapy for menopausal flushes: A systematic review and meta-analysis. Maturitas 2006 May 2; [Epub ahead of print].
26. Krebs EE, et al. Phytoestrogens for treatment of menopausal symptoms: A systematic review. Obstet Gynecol 2004;104:824-836.
27. Burke GL, et al. Soy protein and isoflavone effects on vasomotor symptoms in peri- and postmenopausal women: The Soy Estroten Alternative Study. Menopause 2003;10:147-153.
28. Van Patten CL, et al. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: A randomized controlled clinical trial. J Clin Oncol 2002;20:1449-1455.
29. Knight DC, et al. Effects on menopausal symptoms and acceptability of isoflavone containing soy powder dietary supplementation. Climacteric 2001;4:13-18.
30. Washburn S, et al. Effect of soy protein supplementation on serum lipoproteins, blood pressure and menopausal symptoms in perimenopausal women. Menopause 1999;6:7-13.
31. Murkies AL, et al. Dietary flour supplementation decreases post-menopausal hot flushes: Effect of soy and wheat. Maturitas 1995;21:189-195.
32. Faure ED, et al. Effects of a standardized soy extract on hot flushes: A multicenter, double-blind, randomized, placebo-controlled study. Menopause 2002;9:329-334.
33. Penotti M, et al. Effects of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril 2003;79:1112-1117.
34. Quella SK, et al. Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors. J Clin Oncol 2000;18:1068-1074.
35. Nikander E, et al. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients Obstet Gynecol 2003;101:1213-1220.
36. Jeri AR. The use of an isoflavone supplement to relieve hot flashes. Female Patient 2002;27:35-37.
37. Setchell KD, et al. The clinical importance of the metoablite equol—A clue to the effectiveness of soy and its isoflavones. J Nutr 2002;132:3577-3584.
38. Setchell KD, et al. Bioavailability, disposition, and dose-response effects of soy isoflavones when consumed by healthy women at physiologically typical dietary intakes. J Nutr 2003;133:1027-1035.
39. Scambia G, et al. Clinical effects of a standardized soy extract in postmenopausal women: A pilot study. Menopause 2000;7:105-111.
40. Upmalis DH, et al. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: A multicenter, double-blind, randomized, placebo-controlled study. Menopause 2000;7:236-242.
41. Baber RJ, et al. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric 1999;2:85-92.
42. Han KK, et al. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol 2002;99:389-394.
43. Low Dog T. Menopause: A review of botanical dietary supplements. Am J Med 2005;118(12 Suppl 2):98-108.
44. Murkies A, et al. Phytoestrogens and breast cancer in postmenopausal women: A case control study. Menopause 2000;7:289-296.
45. Ingram D, et al. Case-control study of phyto-oestrogens and breast cancer. Lancet 1997;350:990-994.
46. Wu AH, et al. Soy intake and risk of breast cancer in Asians and Asian Americans. Am J Clin Nutr 1998;68(6 suppl):1437S-1443S.
47. Albertazzi P, et al. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998;91:6-11.
48. St. Germain A, et al. Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause 2001;8:17-26.
Milan FB. Soy and hot flashes. Altern Ther Women's Health 2006;8(10):73-78.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.