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Soy isoflavones: hope or hype?
Maturitas 44 Suppl. 1 (2003) S21 /S29 www.elsevier.com/locate/maturitas
Soy isoflavones: hope or hype? Lorraine A. Fitzpatrick * Department of Internal Medicine and Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA Received 20 May 2002
Abstract Approximately 50% of Americans use dietary supplements on a regular basis spending an estimated $20 billion on supplements in the year 2000. Soy contains genistein and daidzein, two phytoestrogens, which work through the estrogen receptor and cause alterations in serum lipids, bone metabolism, and possibly cognition. In this article, we review the issues regarding the interpretation with studies using soy-based isoflavones, discuss their mechanism of action, and review the literature on the effect of these bio-active compounds on lipid metabolism, osteoblasts and osteoclasts, bone markers, bone mineral density, and cognition. # 2003 Published by Elsevier Science Ireland Ltd. Keywords: Isoflavones; Phytoestrogens; Bone and bones; Bone mineral density; Osteoblast; Lipids; Cognition
1. Introduction Dietary supplements have reached a multibillion dollar business, with an estimated $20 billion dollars being spent on supplements in the year 2000. The National Consumer’s League, which was originally founded in 1899 to root out ‘‘snake oil’’ or medically unsound remedies, performed a survey in 1999 regarding the use of dietary supplements. The consumer group included over 1000 adults and found that four out of five middle-aged women take herbal remedies and dietary supplements, prescription drugs, or both to treat health conditions that are associated * Corresponding author. Tel.: /1-507-255-6663; fax: /1507-255-4828.
with aging. The confidence and the safety of botanical and dietary supplements were 66% compared with an 85% confidence level in prescription drugs. Approximately 34% of patients believed that the FDA regulated supplements in a manner similar to the prescription drug use. The Dietary Supplement Health and Education Act defines dietary supplements as a product other than tobacco that contains a vitamin, mineral, amino acid, herb or other botanical or a dietary substance produced to supplement the diet by increasing the total dietary intake or a concentrate, metabolite, constituent, extract or combination of any ingredient described above. In addition, the compound must be intended for ingestion in the form of a capsule, powder, soft gel or gelcap and not representative of a conventional food or the
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sole item of the meal or diet. Dietary supplements are widely available through health food stores, pharmacies, grocery stores and by the internet or mail. It is estimated that 40 /55% of Americans use supplements on a regular basis. This can be broken down to about 69% who use vitamins or minerals as supplements and 24% who use herbal supplements. People take dietary supplements for multiple reasons. Often they are used with the hope that they will feel better about a medical condition. Some people take them for prevention, particularly as prevention against the effects of aging. Others believe that specific supplements will build strength and muscle or improve recovery when they are already ill. Doctors might suggest an individual to take supplements for health concerns. And last, but certainly not least, patients are motivated to take dietary supplements to live longer or to lose weight. The Dietary Supplement Health and Education Act of 1994 reclassified herbal remedies as dietary supplements which are in a category separate from food or drugs. These remedies do not carry an FDA approval but can be marketed at suggested doses. There cannot be a direct claim about cure or prevention of a disease but information providing supported physiologic effects can be included. This act created a new regulatory environment for dietary supplements, as the FDA cannot require pre-market testing of either efficacy or safety. The burden of proof to prove products were unsafe once they were on the market now falls on the FDA. Label claims are regulated in that they must not be false or misleading. The purpose of this review is to discuss the effects of soy-containing phytoestrogens on serum lipids and parameters of bone metabolism. The effects of soy phytoestrogens on hot flushes, uterus or vaginal epithelium have been extensively reviewed elsewhere [1]. Papers in this review were selected on the basis of being either large epidemiology studies or primary, randomized placebocontrolled clinical trials. No attempt has been made to rate the quality of these trials; however, summary of the published information has been provided.
2. Bioactive components of soy One of the most difficult issues in the evaluation of studies regarding soy protein is understanding the differences between phytoestrogens and soy protein (Table 1). Isolated soy protein that contains phytoestrogens (genistein and daidzein are in the greatest abundance) is considered ‘‘intact’’ soy protein. The reason for this is that often soy protein is washed with alcohol and extracted, and the alcohol extract is the portion that contains phytoestrogens and saponins. The alcohol extract can be dried-down and encapsulated, and sold in a capsule or tablet as isolated phytoestrogens. Bioavailability may vary greatly among the preparations.
3. Mechanism of action of genistein, an active isoflavone Genistein is the isoflavone of greatest interest in soy protein. Genistein has structural similarity to 17b-estradiol but binds to the estrogen receptor with lesser affinity than estrogen itself. Although genistein binds the ERb receptor with greater affinity than ERa, genistein initiates greater gene transcription of ERa compared with ERb. The estrogen receptor is not the only receptor that is affected by genistein. Genistein can also alter expression of the progesterone receptor, the androgen receptor, and the oxytocin receptor. Intracellularly, genistein can effect many different cellular mechanisms. Genistein has been shown to inhibit tyrosine kinases. There may be an effect on the cell cycle since genistein inhibits DNA topoisomerases I and II. Genistein may act as an antioxidant since it increases the activity of antioxidant enzymes. There are several reports that suggest that genistein can alter the metabolism of estrogen itself. For example, genistein inhibits the enzymes: aromatase and 5a-reductase. There is also evidence for inhibition of 17b-hydroxysteroid dehydrogenase by genistein. There are many contradictory reports about interactions with binding proteins such that some reports suggest that genistein increases sex hormone-binding globulin
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Table 1 Phytoestrogen content of selected soy-based foods
Nutlettes cereal Beef (not) soy granules Roasted soy nuts Tempeh Low-fat tofu Regular tofu Take Care High Protein beverage powder Regular soy milk Low-fat soy milk Roasted soy butter
Serving
Isoflavones (mg)
Calories
Fat (g)
1/2 cup 1/4 dry cup 1/4 cup 1/2 cup 1/2 cup 1/2 cup 2 scoops 1 cup 1 cup 1 tbsp
122 62 60 35 35 35 35 30 20 17
140 70 195 165 45 /75 105 /120 100 /130 130 /150 90 /120 170
1.5 1 9.5 6 1.5 /2.5 5.5 /6.5 1 /1.5 4 2 11
Adapted from ‘‘Menopause Naturally’’, Prevention, August 1996, p. 67.
(SHBG), while others suggest that there may be an inhibition of SHBG.
4. The effect of soy protein on serum lipids The isolation of certain soy components may result in different outcomes on varying target tissues. For example, isolated soy isoflavones have not been shown to reduce cholesterol [2]. This is in contrast to the Food and Drug Administration of the United States statement in October of 1999 that intact soy protein, in association with a diet low in saturated fat may reduce coronary artery disease by lowering serum cholesterol levels [3]. The effect of intact soy protein on lipid levels has been established in many studies [1]. This ‘‘stamp of approval’’ by the FDA is similar to the one that has previously been given to other food products such as oatmeal which also lowers total cholesterol levels. Studies show that 25 g of dietary soy protein daily is required to have a significant LDL or total cholesterol lowering effect. In one study, the average amount of decrease in total cholesterol was 9.3%, with LDL cholesterol falling 12.9%. In addition, the triglycerides were reduced by 10.5%. There was a modest increase in HDL cholesterol (2.4%) although most studies do not confirm this finding. Other studies describe a lesser or no effect on lowering of LDL cholesterol [4]. Although these are positive dietary trends for
the use of intact soy protein, this still cannot be considered a substitute for pharmacological therapy for people with severe combined hypercholesterolemia. Several studies have documented the positive effects of soy protein and soy phytoestrogens on plasma lipid levels in primates and in postmenopausal women [5,6]. Clarkson et al. [7] evaluated the effects of soy phytoestrogens on postmenopausal monkeys, with the objective of determining the role of the isolated phytoestrogen to lower plasma cholesterol levels. The control diet contained isolated alcohol-washed soy protein. The two treatment groups were provided either conjugated equine estrogens (dose equivalent to 0.625 mg per day) or soy protein isolate containing isoflavones (129 mg per day). After 3 years of treatment, both the isolated phytoestrogen group and the CEE-treated group had significantly lower total cholesterol levels. The CEE-treated croup had higher serum triglyercide levels, and the soy isoflavone-treated group had higher HDL-cholesterol levels. No differences in Lp(a) were noted among the groups. In the assessment of atherosclerotic plaques, there was a major treatment effect noted in both the CEE- and isoflavonetreated groups. In the control group, 63% had significant progression of atherosclerotic plaque compared with only 39% of the isoflavonetreated group and 35% of the CEE-treated group (Fig. 1).
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6. Soy and osteoclasts
Fig. 1. Effects of a diet containing isolated soy isoflavones, conjugated equine estrogen, or alcohol-extracted soy protein on atherosclerosis progression in cynomolgus monkeys. Data represent the mean of the ratio of plaque size at baseline and after 3 years of treatment. Reproduced from Ref. [7].
Regarding bone resorption, there have been studies on isolated osteoclasts that suggested genistein might have a direct effect. In the presence of genistein, there was marked increase in osteoclast intracellular calcium concentrations [9]. In another study using rat osteoclasts, genistein decreased phosphorylation [10]. There was also evidence that osteoclast recruitment was inhibited. Thus, there appears to be an increase in osteoblast proliferation, differentiation and collagen synthesis while in osteoclasts, there is inhibition of recruitment and function.
5. Effects of soy on osteoblasts
7. Soy and animal studies: effects on bone mineral density and strength
Ethanol-extracted soy protein has interesting effects on osteoblast-like cells in culture (Fig. 2). For example, compared with control, the isolated isoflavones increased osteoblast-like cell proliferation and this effect is attenuated by the addition of tamoxifen, an antiestrogen. Soy isoflavones compared with control or soy plus tamoxifen also markedly increase collagen synthesis. A marker of osteoblast differentiation, alkaline phosphatase activity, is increased in the presence of isoflavones [8]. Thus, soy isoflavones can enhance osteoblastlike cell proliferation, differentiation, and synthesis of collagen.
In an ovariectomized rat model, subcutaneous genistein was administered and resulted in an increased number of osteoblasts and an increased bone formation rate per tissue volume. The most noted effect was on cancellous bone. There was no effect noted on bone resorption as measured by osteoclast number in bone or urine markers such as deoxypyridinoline cross-links. Intact soy protein containing isoflavones had a more profound effect on bone than subcutaneous genistein alone. Biphasic effects were noted with subcutaneous genistein suggested a narrow therapeutic window for this compound. The mechanism of action is
Fig. 2. The effect of soy on osteoblasts. These three figures demonstrate the effect of ethanol-extracted soy protein on MC3T3-E1 cells, an osteoblast-like cell. Ethanol-extracted soy stimulated cell proliferation, collagen synthesis, and alkaline phosphatase activity. All three parameters were inhibited by the use of tamoxifen, a selective estrogen receptor modulator. Reproduced from Ref. [8].
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still speculative; however, there was an inhibition in TNFa production postoophorectomy suggesting that genistein is a TNFa inhibitor [11]. Other studies have measured bone mineral density (BMD) in oophorectomized rats. One study that used coumestrol as a phytoestrogen suggested that there was less bone loss at the femur, whole spine, and whole body in rats treated with coumestrol compared with control (P B/ 0.05). However, coumestrol was not as strong as estrogen in altering BMD when administered to the animals [12]. Using isolated isoflavones in a dose /response model, at the highest dose used (80 mg) there appeared to be an increase in diaphyseal and metaphyseal BMD compared with controltreated animals. In other studies in rats, BMD and bone strength were assessed (Figs. 3 and 4). Differences in BMD were found in ovariectomized rats that were treated with either daidzein or genistein. These effects were intermediate between the ovariectomized animals without treatment and those treated with estrone [13]. In assessing bone strength, this study showed that there was a marked increase in breaking force, equal to that of estrone, in ovariectomized rats treated with daidzein or genistein. The ovariectomized group had a marked decrease in breaking force. To evaluate the histomorphometric changes that occur in ovariectomized animals that were given genistein, Ishimi et
Fig. 3. The effect of isoflavones on BMD in rats. This study evaluated the effects of oral genistein, daidzein, or estrone on oophorectomized Sprague /Dawley rats. BMD was improved with isoflavones. Reproduced from Ref. [13].
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Fig. 4. The effect of isoflavones on breaking force in rats. This study evaluated the effects of oral genistein, daidzein, or estrone on oophorectomized Sprague /Dawley rats. Breaking force were improved with isoflavones. Reproduced from Ref. [13].
al. [14] evaluated the bone structure. Bone volume was restored to the level in sham-operated animals in genistein-treated ovariectomized animals. Trabecular thickness and trabecular spacing were also restored to that of sham-operated controls in the presence of genistein.
8. Human studies: differences in clinical trial results There are many human trials evaluating the effect of phytoestrogens on menopausal symptoms, cardiovascular markers, and bone. These vary greatly, partially because some studies are epidemiology based and may have different results compared with prospective, randomized trials. Some studies use dietary methods of recall versus keeping an active food diary. Another issue is the estrogen status of the subjects. This issue is important, as marked differences have been noted in premenopausal versus postmenopausal subjects. The age of postmenopausal subjects may provide disparate data, as bone turnover is usually more rapid in the perimenopausal and immediate postmenopausal period as compared with the older population. As mentioned above, the type of soy product (isolated isoflavones versus intact soy protein) may also influence the results. For certain studies, such as those with bone, study duration is critical as bone marker differences may be seen
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early, while bone density will take a great deal longer to detect significant effects.
9. Dietary soy isoflavones and BMD: epidemiology and diet-based studies One of the best epidemiology studies that has been recently completed is the Study of Women’s Health Across the Nation (SWAN). This was a community-based study in the United States that involved multiple centers and followed a longitudinal cohort of women aged 42 /52 years throughout the menopause. The inclusion criteria for the SWAN study were that women must have menses within the past 3 months and were not using any hormone replacement therapy. There were marked differences in ethnic composition (African-American, n /497; Caucasian, n /1003; Chinese, n /200; Japanese; n /227). At baseline, an analysis of the dietary intake of genistein was performed. The Block Food Frequency Questionnaire was utilized to assess continued genistein use. Measurements of BMD of the spine, femoral neck and total hip were completed [15]. Not surprisingly, the intake of genistein was too low to analyze among the African-American and Caucasian women, as this is not part of the usual diet in these ethnic groups. The median values, respectively, were 4 and 14 mg. For the Japanese and Chinese cohort, BMD was compared with genistein intake using an analysis of variance. Results were adjusted for age, current smoking, physical activity, dietary calcium, dietary alcohol, dietary protein, height, weight, and menopausal status. The study divided spine BMD by tertile of genistein intake. Interestingly, the mean values of genistein intake were higher for Japanese women compared with Chinese women. There was a substantial, positive, dose /response between BMD and genistein intake for the premenopausal Japanese women. There was no relationship of the BMD and genistein intake for Chinese women or for postmenopausal Japanese women. The results of this study suggested some very interesting phenomena about genistein use. There may be a threshold dose necessary for genistein to affect bone. Since the Japanese women had a much
higher intake of genistein, this may be one explanation for the differences between the Japanese and Chinese women. There may be ethnic differences in estrogen receptors within bone, such that Japanese women were able to respond to estrogen-like properties of genistein. This is purely theoretical, but it is certainly a provocative hypothesis. Finally, the Japanese diet may contain sources of genistein that are more readily absorbed such as the fermented soy products. Perhaps these products are metabolized more efficiently. These are also unknown hypotheses, and should be the center of future studies. Lastly, since this study depended on Food Frequency Questionnaire, there may be differences in the use of isolated isoflavones versus intact soy protein in the interpretation of this study.
10. The effect of soy isoflavones on bone markers In one randomized, crossover study, Wangen et al. evaluated the effects of soy protein isolates on pre- and postmenopausal women. The mean age of the premenopausal women was 26 years while the postmenopausal women averaged 57 years of age. Each group was randomized to three soy protein isolates. The control group was provided a mean of 8 mg of soy protein (0.13 mg/kg per day). The low-isoflavone group (low-iso) were given an average of 65 mg (1.00 mg/kg per day) and the high-isoflavone group were provided 130 mg (2.01 mg/kg per day) [16]. In the premenopausal women, measurements of bone markers were made throughout the menstrual cycle. Interestingly, only the deoxypyridinoline cross-links and IGFBP3 were different in the early follicular phase in the premenopausal women. There was an increase in deoxypyridinoline cross-links in the low- and high-iso groups compared with control. In contrast, there was a decrease in IGFBP3 in the high-iso group (P B/0.05). There were no changes in osteocalcin or IGF-I in premenopausal women in the early follicular phase. In periovulatory premenopausal women, only changes in IGF-I were noted with no changes in the osteocalcin, deoxypyridinoline cross-links or IGFBP3 among the three groups. In postmenopausal women, there
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were significant changes in bone formation markers (osteocalcin, bone alkaline phosphatase, IGF1) and no changes in bone resorption markers (deoxypyridinoline cross-links or C-telopeptide) among the control, low- and high-isoflavone groups. This study design emphasizes the differences of isoflavones in estrogen-replete women versus estrogen-deplete women. Even phases of the menstrual cycle may have profound effects on the estrogen-like activity of phytoestrogens.
11. Isoflavones and BMD Few studies have evaluated the gold standard for bone accretion, BMD, in response to administration of isoflavones. One short-term study indicated that compared with casein, isoflavoneenriched soy protein had a positive effect on BMD. Potter et al. showed that 90 mg per day over a 6-month period had an increase in vertebral BMD compared with casein controls. A group of women ingesting only 56 mg per day had no significant effects [5]. However, this was a shortterm study with few subjects. Additional research and longer-term studies are missing to prove the effect of soy isoflavones on BMD and fracture. One of the controls that has been proposed for soy protein is substituting another type of protein and comparing isoflavone-rich soy with isoflavone-poor soy. In a double-blind, randomized clinical trial, Alekel et al. [17] evaluated the effects of dietary soy proteins on perimenopausal women (Fig. 4). For 24 weeks, the women were randomized to an isoflavone-rich soy protein (80.4 mg per day, n /24), isoflavone-poor soy (n /24), or whey protein (n /21). This protein powder was baked into a jumbo muffin. Endpoints included BMD by DEXA, measurement of N -telopeptide and bone alkaline phosphatase. Compliance was assessed by measurement of the urinary excretion of isoflavones. The median age of women in this study was 50.6 years. Of note, women were told to substitute the muffin for an entire meal as it contained 600 mg of calcium and 500 calories. Bone alkaline phosphatase negatively correlated to the percentage change in BMD and bone mineral content. Overall, the percentage change in lumbar
Fig. 5. Dietary isoflavones and DEXA BMD measurement in postmenopausal women. The mean (/S.E.M.) percentage change in lumbar spine BMD from baseline to post-treatment in perimenopausal women: ( /) isoflavone-rich soy; (^) isoflavone-poor soy; (m) whey protein (control). Reproduced from Ref. [17].
spine BMD did not differ between the intact soy protein and the soy protein minus isoflavones groups. The control group BMD lost BMD and BMC at the lumbar spine ( /1.28 and /1.73%, respectively; Fig. 5). Regression analysis indicated that the soy protein isoflavone intact group had a positive effect on BMD (5.6%, P /0.023). Using analysis of covariance, the effect was owing to the isoflavone component.
12. Soy isoflavones and cognition Very little data exists regarding the use of soy isoflavones and cognitive effects in human. Animal studies have been published showing that brainderived neurotrophic factors are altered in the presence of estradiol and soy isoflavones in rats. For example, when compared with casein, soy isoflavones and 17b-estradiol increased brain-derived neurotrophic factor and choline acetyltransferase [18,19]. In addition, maze performance was improved in ovariectomized rats in a dose-dependent way with soy phytoestrogens and performance appeared very similar to the dose /response seen with oral micronized estradiol [20]. Thus, in retired breeder rats, both estradiol and soy isoflavones improved mRNA levels of brain-derived neurotrophic factor and choline acetyltransferase. Dose-dependent improvements in maze perfor-
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mance were seen with both estradiol and phytoestrogens in the ovariectomized rat model. In human, data are sparse regarding estrogen agonist or antagonist effects on the brain in the presence of isoflavones. The Honolulu /Asia Aging Study showed that there was an association between high-tofu consumption in men and lowcognition scores in mid-life. However, in JapaneseAmerican women living in Washington, estrogen users consuming tofu at least three times per week were less likely to have cognitive impairment.
13. Safety issues with phytoestrogens One of the major issues is the question regarding the safety of phytoestrogens. In human, there has been an increase length of the menstrual cycle with high dietary intake of isoflavones and a decline in a preovulatory LH and FSH. Although this has not been shown to have clinical relevance regarding fertility in human to date, there are abundant evidence in animals that phytoestrogens may alter reproductive status. For example, infertility was noted in captive cheetahs that were fed a high phytoestrogen diet. In ewes, there was compromise of follicular development with a shortened luteal phase resulting in decreased fertility. California quail had reduced breeding owing to a diet rich in phytoestrogens. And in cattle, cystic ovaries, irregular estrus and anestrus had been shown dependent on phytoestrogen content of their diet. Still, it is difficult to assess whether there are true harmful events that occur in human. Another unresolved issue is the effect of isoflavones on breast tissue. There have been studies that indicate that there may be promotion or inhibition of breast cancer by the isoflavones. There may be dose-dependent effects, not to mention the potential differences dependent on the estrogen milieu. Other potential problems may be owing to phytoestrogen metabolism or alterations in estrogens on the sex steroid pathway. Whether there is an inverse relationship between soy intake and testosterone concentrations owing to inhibition of 17b-hydroxy reductase has not been well established. There has been a proposal that male
infertility could also occur owing to high phytoestrogen intake. One study recently showed that in men, high levels of tofu were associated with low cognition scores. This study again may be difficult to interpret owing to the fact that it is based on epidemiology. There has also been long-term questions regarding whether soymilk for infants may cause long-term developmental problems.
14. Clinical recommendations It is difficult to give definitive answers for the practicing clinician to determine the best advice to give postmenopausal women. Many postmenopausal women perceive prescription estrogens of ‘‘unnatural’’ in spite of the fact that many prescription estrogens are derived from plants or other natural sources. Regarding phytoestrogens, there are potential problems for fertility issues in premenopausal issues, but there has been no evidence to date that this is truly an issue. In postmenopausal women, there have been reported cases of vaginal bleeding with high amounts of different types of phytoestrogens such that overuse should be avoided. Moderation is probably the best recommendation for the postmenopausal female.
15. Herbal myths One of the issues to remember is that a natural product does not necessarily mean that a product is safe [21]. Although some herbs have been used for thousands of years, they may have no effect or they may actually cause harm. When the herb is a plant that does not necessarily translate to it being the same compound as when it is put into a capsule or tablet. Some herbal preparations are adulterated with pharmaceutical products. Unsuspected addition of conventional drugs to herbal preparations has resulted in serious side effects [22]. Last of all, all brands of herbal preparations are not the same. Many herbal remedies are not manufactured under good agricultural practice and good manufacturing practice to provide a consistent and reliable product.
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References [1] Albertazzi P, Purdie DW. The nature of utility of the phytoestrogens: a review of the evidence. Maturitas 2002;42:173 /85. [2] Dewell A, Hollenbeck CB, Bruce B. The effects of soyderived phytoestrogens on serum lipids and lipoproteins in moderately hypercholesterolemic postmenopausal women. J Clin Endocrinol Metab 2002;87:118 /21. [3] Food and Drug Administration. Food labeling: health claims, soy protein and coronary artery disease, Fed. Regist. 1999;64:57699 /733. [4] Vigna GB, Pansini F, Bonaccorsi G, Albertazzi P, Donega P, Zanotti L, De Aloysio D, Mollica G, Fellin R. Plasma lipoproteins in soy-treated postmenopausal women: a double-blind, placebo-controlled trial. Nutr Metab Cardiovasc Dis 2000;10:315 /22. [5] Potter SM, Baum JA, Teng H, Stillman RJ, Shay NF, Erdman JW, Jr.. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr Suppl 1998;68:1375S /9S. [6] Washburn S, Burke GL, Morgan T, Anthony MS. Effect of soy protein supplementation on serum lipoproteins, blood pressure and menopausal symptoms in perimenopausal women. Menopause 1999;6:7 /13. [7] Clarkson TB, Anthony MS, Morgan TM. Inhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens. J Clin Endocrinol Metab 2001;86:41 /7. [8] Choi EM, Suh KS, Kim YS, Choue RW, Koo SJ. Soybean ethanol extract increases the function of osteoblastic MC3T3-E1 cells. Phytochemistry 2001;56:733 /9. [9] Kajiya J, Okabe K, Okamoto F, Tsuzuki T, Soeda H. Protein tyrosine kinase inhibitors increase cytosolic calcium and inhibit actin organization as resorbing activity in rat osteoclasts. J Cell Physiol 2000;183:83 /90. [10] Gao YH, Yamaguchi M. Suppressive effect of genistein on rat bone osteoclasts: involvement of protein kinase inhibition and protein tyrosine phosphatase activation. Int J Mol Med 2000;5:261 /7. [11] Fanti P, Monier-Faugere MC, Geng Z, Schmidt J, Morris PE, Cohen D, Malluche HH. The phytoestrogen genistein reduces bone loss in short-term ovariectomized rats. Osteoporos Int 1998;8:274 /81. [12] Draper CR, Edel MJ, Dick IM, Randall AG, Martin GB, Prince RL. Phytoestrogens reduce bone loss and bone
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
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resorption in oophorectomized rats. J Nutr 1997;127:1795 /9. Uesugi T, Toda T, Tsuji K, Ishida H. Comparative study on reduction of bone loss and lipid metabolism abnormality in ovariectomized rats by soy isoflavones, daidzein, genistein, and glycitin. Biol Pharm Bull 2001;24:368 /72. Ishimi Y, Miyaura C, Ohmura M, Onoe Y, Sato T, Uchiyama Y, Ito M, Wang X, Suda T, Ikegami S. Selective effects of genistein, a soybean isoflavone, on B-lymphopoiesis and bone loss caused by estrogen deficiency. Endocrinology 1999;140:1893 /900. Greendale GA, Fitzgerald G, Huang M-H, Sternfeld B, Gold E, Seeman T, Sherman S, Sowers M. Dietary soy isoflavones and bone mineral density: results from the Study of Women’s Health Across the Nation. Am J Epidemiol 2002;155:746 /54. Wangen KE, Duncan AM, Merz-Demlow BE, Xu X, Marcus R, Phipps WR, Kurzer MS. Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women. J Clin Endocrinol Metab 2000;85:3043 /8. Alekel DL, St Germain A, Peterson CT, Hanson KB, Stewart JW, Toda T. Isoflavone-rich soy protein isolate attenuates bone loss in the lumbar spine of perimenopausal women. Am J Clin Nutr 2000;72:844 /52. Pan Y, Anthony M, Clarkson TB. Effect of estradiol and soy phytoestrogens on choline acetyltransferase and nerve growth factor mRNAs in the frontal cortex and hippocampus of female rats. Proc Soc Exp Biol Med 1999;221:118 /25. Pan Y, Anthony M, Clarkson TB. Evidence for upregulation of brain-derived neurotrophic factor mRNA by soy phytoestrogens in the frontal cortex of retired breeder female rats. Neurosci Lett 1999;261:17 /20. Pan Y, Anthony M, Watson S, Clarkson TB. Soy phytoestrogens improve radial arm maze performance in ovariectomized retired breeder rats and do not attenuate benefits of 17beta-estradiol treatment. Menopause 2000;7:230 /5. Ernst E. The risk-benefit profile of commonly used herbal therapies: ginkgo, St. John’s wort, ginseng, echinacea, saw palmetto, and kava. Ann Intern Med 2002;136:42 /53. Ernst E. Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. J Intern Med 2002;252:107 /13.
Soy isoflavones: hope or hype? Lorraine A. Fitzpatrick * Department of Internal Medicine and Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA Received 20 May 2002
Abstract Approximately 50% of Americans use dietary supplements on a regular basis spending an estimated $20 billion on supplements in the year 2000. Soy contains genistein and daidzein, two phytoestrogens, which work through the estrogen receptor and cause alterations in serum lipids, bone metabolism, and possibly cognition. In this article, we review the issues regarding the interpretation with studies using soy-based isoflavones, discuss their mechanism of action, and review the literature on the effect of these bio-active compounds on lipid metabolism, osteoblasts and osteoclasts, bone markers, bone mineral density, and cognition. # 2003 Published by Elsevier Science Ireland Ltd. Keywords: Isoflavones; Phytoestrogens; Bone and bones; Bone mineral density; Osteoblast; Lipids; Cognition
1. Introduction Dietary supplements have reached a multibillion dollar business, with an estimated $20 billion dollars being spent on supplements in the year 2000. The National Consumer’s League, which was originally founded in 1899 to root out ‘‘snake oil’’ or medically unsound remedies, performed a survey in 1999 regarding the use of dietary supplements. The consumer group included over 1000 adults and found that four out of five middle-aged women take herbal remedies and dietary supplements, prescription drugs, or both to treat health conditions that are associated * Corresponding author. Tel.: /1-507-255-6663; fax: /1507-255-4828.
with aging. The confidence and the safety of botanical and dietary supplements were 66% compared with an 85% confidence level in prescription drugs. Approximately 34% of patients believed that the FDA regulated supplements in a manner similar to the prescription drug use. The Dietary Supplement Health and Education Act defines dietary supplements as a product other than tobacco that contains a vitamin, mineral, amino acid, herb or other botanical or a dietary substance produced to supplement the diet by increasing the total dietary intake or a concentrate, metabolite, constituent, extract or combination of any ingredient described above. In addition, the compound must be intended for ingestion in the form of a capsule, powder, soft gel or gelcap and not representative of a conventional food or the
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sole item of the meal or diet. Dietary supplements are widely available through health food stores, pharmacies, grocery stores and by the internet or mail. It is estimated that 40 /55% of Americans use supplements on a regular basis. This can be broken down to about 69% who use vitamins or minerals as supplements and 24% who use herbal supplements. People take dietary supplements for multiple reasons. Often they are used with the hope that they will feel better about a medical condition. Some people take them for prevention, particularly as prevention against the effects of aging. Others believe that specific supplements will build strength and muscle or improve recovery when they are already ill. Doctors might suggest an individual to take supplements for health concerns. And last, but certainly not least, patients are motivated to take dietary supplements to live longer or to lose weight. The Dietary Supplement Health and Education Act of 1994 reclassified herbal remedies as dietary supplements which are in a category separate from food or drugs. These remedies do not carry an FDA approval but can be marketed at suggested doses. There cannot be a direct claim about cure or prevention of a disease but information providing supported physiologic effects can be included. This act created a new regulatory environment for dietary supplements, as the FDA cannot require pre-market testing of either efficacy or safety. The burden of proof to prove products were unsafe once they were on the market now falls on the FDA. Label claims are regulated in that they must not be false or misleading. The purpose of this review is to discuss the effects of soy-containing phytoestrogens on serum lipids and parameters of bone metabolism. The effects of soy phytoestrogens on hot flushes, uterus or vaginal epithelium have been extensively reviewed elsewhere [1]. Papers in this review were selected on the basis of being either large epidemiology studies or primary, randomized placebocontrolled clinical trials. No attempt has been made to rate the quality of these trials; however, summary of the published information has been provided.
2. Bioactive components of soy One of the most difficult issues in the evaluation of studies regarding soy protein is understanding the differences between phytoestrogens and soy protein (Table 1). Isolated soy protein that contains phytoestrogens (genistein and daidzein are in the greatest abundance) is considered ‘‘intact’’ soy protein. The reason for this is that often soy protein is washed with alcohol and extracted, and the alcohol extract is the portion that contains phytoestrogens and saponins. The alcohol extract can be dried-down and encapsulated, and sold in a capsule or tablet as isolated phytoestrogens. Bioavailability may vary greatly among the preparations.
3. Mechanism of action of genistein, an active isoflavone Genistein is the isoflavone of greatest interest in soy protein. Genistein has structural similarity to 17b-estradiol but binds to the estrogen receptor with lesser affinity than estrogen itself. Although genistein binds the ERb receptor with greater affinity than ERa, genistein initiates greater gene transcription of ERa compared with ERb. The estrogen receptor is not the only receptor that is affected by genistein. Genistein can also alter expression of the progesterone receptor, the androgen receptor, and the oxytocin receptor. Intracellularly, genistein can effect many different cellular mechanisms. Genistein has been shown to inhibit tyrosine kinases. There may be an effect on the cell cycle since genistein inhibits DNA topoisomerases I and II. Genistein may act as an antioxidant since it increases the activity of antioxidant enzymes. There are several reports that suggest that genistein can alter the metabolism of estrogen itself. For example, genistein inhibits the enzymes: aromatase and 5a-reductase. There is also evidence for inhibition of 17b-hydroxysteroid dehydrogenase by genistein. There are many contradictory reports about interactions with binding proteins such that some reports suggest that genistein increases sex hormone-binding globulin
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Table 1 Phytoestrogen content of selected soy-based foods
Nutlettes cereal Beef (not) soy granules Roasted soy nuts Tempeh Low-fat tofu Regular tofu Take Care High Protein beverage powder Regular soy milk Low-fat soy milk Roasted soy butter
Serving
Isoflavones (mg)
Calories
Fat (g)
1/2 cup 1/4 dry cup 1/4 cup 1/2 cup 1/2 cup 1/2 cup 2 scoops 1 cup 1 cup 1 tbsp
122 62 60 35 35 35 35 30 20 17
140 70 195 165 45 /75 105 /120 100 /130 130 /150 90 /120 170
1.5 1 9.5 6 1.5 /2.5 5.5 /6.5 1 /1.5 4 2 11
Adapted from ‘‘Menopause Naturally’’, Prevention, August 1996, p. 67.
(SHBG), while others suggest that there may be an inhibition of SHBG.
4. The effect of soy protein on serum lipids The isolation of certain soy components may result in different outcomes on varying target tissues. For example, isolated soy isoflavones have not been shown to reduce cholesterol [2]. This is in contrast to the Food and Drug Administration of the United States statement in October of 1999 that intact soy protein, in association with a diet low in saturated fat may reduce coronary artery disease by lowering serum cholesterol levels [3]. The effect of intact soy protein on lipid levels has been established in many studies [1]. This ‘‘stamp of approval’’ by the FDA is similar to the one that has previously been given to other food products such as oatmeal which also lowers total cholesterol levels. Studies show that 25 g of dietary soy protein daily is required to have a significant LDL or total cholesterol lowering effect. In one study, the average amount of decrease in total cholesterol was 9.3%, with LDL cholesterol falling 12.9%. In addition, the triglycerides were reduced by 10.5%. There was a modest increase in HDL cholesterol (2.4%) although most studies do not confirm this finding. Other studies describe a lesser or no effect on lowering of LDL cholesterol [4]. Although these are positive dietary trends for
the use of intact soy protein, this still cannot be considered a substitute for pharmacological therapy for people with severe combined hypercholesterolemia. Several studies have documented the positive effects of soy protein and soy phytoestrogens on plasma lipid levels in primates and in postmenopausal women [5,6]. Clarkson et al. [7] evaluated the effects of soy phytoestrogens on postmenopausal monkeys, with the objective of determining the role of the isolated phytoestrogen to lower plasma cholesterol levels. The control diet contained isolated alcohol-washed soy protein. The two treatment groups were provided either conjugated equine estrogens (dose equivalent to 0.625 mg per day) or soy protein isolate containing isoflavones (129 mg per day). After 3 years of treatment, both the isolated phytoestrogen group and the CEE-treated group had significantly lower total cholesterol levels. The CEE-treated croup had higher serum triglyercide levels, and the soy isoflavone-treated group had higher HDL-cholesterol levels. No differences in Lp(a) were noted among the groups. In the assessment of atherosclerotic plaques, there was a major treatment effect noted in both the CEE- and isoflavonetreated groups. In the control group, 63% had significant progression of atherosclerotic plaque compared with only 39% of the isoflavonetreated group and 35% of the CEE-treated group (Fig. 1).
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6. Soy and osteoclasts
Fig. 1. Effects of a diet containing isolated soy isoflavones, conjugated equine estrogen, or alcohol-extracted soy protein on atherosclerosis progression in cynomolgus monkeys. Data represent the mean of the ratio of plaque size at baseline and after 3 years of treatment. Reproduced from Ref. [7].
Regarding bone resorption, there have been studies on isolated osteoclasts that suggested genistein might have a direct effect. In the presence of genistein, there was marked increase in osteoclast intracellular calcium concentrations [9]. In another study using rat osteoclasts, genistein decreased phosphorylation [10]. There was also evidence that osteoclast recruitment was inhibited. Thus, there appears to be an increase in osteoblast proliferation, differentiation and collagen synthesis while in osteoclasts, there is inhibition of recruitment and function.
5. Effects of soy on osteoblasts
7. Soy and animal studies: effects on bone mineral density and strength
Ethanol-extracted soy protein has interesting effects on osteoblast-like cells in culture (Fig. 2). For example, compared with control, the isolated isoflavones increased osteoblast-like cell proliferation and this effect is attenuated by the addition of tamoxifen, an antiestrogen. Soy isoflavones compared with control or soy plus tamoxifen also markedly increase collagen synthesis. A marker of osteoblast differentiation, alkaline phosphatase activity, is increased in the presence of isoflavones [8]. Thus, soy isoflavones can enhance osteoblastlike cell proliferation, differentiation, and synthesis of collagen.
In an ovariectomized rat model, subcutaneous genistein was administered and resulted in an increased number of osteoblasts and an increased bone formation rate per tissue volume. The most noted effect was on cancellous bone. There was no effect noted on bone resorption as measured by osteoclast number in bone or urine markers such as deoxypyridinoline cross-links. Intact soy protein containing isoflavones had a more profound effect on bone than subcutaneous genistein alone. Biphasic effects were noted with subcutaneous genistein suggested a narrow therapeutic window for this compound. The mechanism of action is
Fig. 2. The effect of soy on osteoblasts. These three figures demonstrate the effect of ethanol-extracted soy protein on MC3T3-E1 cells, an osteoblast-like cell. Ethanol-extracted soy stimulated cell proliferation, collagen synthesis, and alkaline phosphatase activity. All three parameters were inhibited by the use of tamoxifen, a selective estrogen receptor modulator. Reproduced from Ref. [8].
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still speculative; however, there was an inhibition in TNFa production postoophorectomy suggesting that genistein is a TNFa inhibitor [11]. Other studies have measured bone mineral density (BMD) in oophorectomized rats. One study that used coumestrol as a phytoestrogen suggested that there was less bone loss at the femur, whole spine, and whole body in rats treated with coumestrol compared with control (P B/ 0.05). However, coumestrol was not as strong as estrogen in altering BMD when administered to the animals [12]. Using isolated isoflavones in a dose /response model, at the highest dose used (80 mg) there appeared to be an increase in diaphyseal and metaphyseal BMD compared with controltreated animals. In other studies in rats, BMD and bone strength were assessed (Figs. 3 and 4). Differences in BMD were found in ovariectomized rats that were treated with either daidzein or genistein. These effects were intermediate between the ovariectomized animals without treatment and those treated with estrone [13]. In assessing bone strength, this study showed that there was a marked increase in breaking force, equal to that of estrone, in ovariectomized rats treated with daidzein or genistein. The ovariectomized group had a marked decrease in breaking force. To evaluate the histomorphometric changes that occur in ovariectomized animals that were given genistein, Ishimi et
Fig. 3. The effect of isoflavones on BMD in rats. This study evaluated the effects of oral genistein, daidzein, or estrone on oophorectomized Sprague /Dawley rats. BMD was improved with isoflavones. Reproduced from Ref. [13].
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Fig. 4. The effect of isoflavones on breaking force in rats. This study evaluated the effects of oral genistein, daidzein, or estrone on oophorectomized Sprague /Dawley rats. Breaking force were improved with isoflavones. Reproduced from Ref. [13].
al. [14] evaluated the bone structure. Bone volume was restored to the level in sham-operated animals in genistein-treated ovariectomized animals. Trabecular thickness and trabecular spacing were also restored to that of sham-operated controls in the presence of genistein.
8. Human studies: differences in clinical trial results There are many human trials evaluating the effect of phytoestrogens on menopausal symptoms, cardiovascular markers, and bone. These vary greatly, partially because some studies are epidemiology based and may have different results compared with prospective, randomized trials. Some studies use dietary methods of recall versus keeping an active food diary. Another issue is the estrogen status of the subjects. This issue is important, as marked differences have been noted in premenopausal versus postmenopausal subjects. The age of postmenopausal subjects may provide disparate data, as bone turnover is usually more rapid in the perimenopausal and immediate postmenopausal period as compared with the older population. As mentioned above, the type of soy product (isolated isoflavones versus intact soy protein) may also influence the results. For certain studies, such as those with bone, study duration is critical as bone marker differences may be seen
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early, while bone density will take a great deal longer to detect significant effects.
9. Dietary soy isoflavones and BMD: epidemiology and diet-based studies One of the best epidemiology studies that has been recently completed is the Study of Women’s Health Across the Nation (SWAN). This was a community-based study in the United States that involved multiple centers and followed a longitudinal cohort of women aged 42 /52 years throughout the menopause. The inclusion criteria for the SWAN study were that women must have menses within the past 3 months and were not using any hormone replacement therapy. There were marked differences in ethnic composition (African-American, n /497; Caucasian, n /1003; Chinese, n /200; Japanese; n /227). At baseline, an analysis of the dietary intake of genistein was performed. The Block Food Frequency Questionnaire was utilized to assess continued genistein use. Measurements of BMD of the spine, femoral neck and total hip were completed [15]. Not surprisingly, the intake of genistein was too low to analyze among the African-American and Caucasian women, as this is not part of the usual diet in these ethnic groups. The median values, respectively, were 4 and 14 mg. For the Japanese and Chinese cohort, BMD was compared with genistein intake using an analysis of variance. Results were adjusted for age, current smoking, physical activity, dietary calcium, dietary alcohol, dietary protein, height, weight, and menopausal status. The study divided spine BMD by tertile of genistein intake. Interestingly, the mean values of genistein intake were higher for Japanese women compared with Chinese women. There was a substantial, positive, dose /response between BMD and genistein intake for the premenopausal Japanese women. There was no relationship of the BMD and genistein intake for Chinese women or for postmenopausal Japanese women. The results of this study suggested some very interesting phenomena about genistein use. There may be a threshold dose necessary for genistein to affect bone. Since the Japanese women had a much
higher intake of genistein, this may be one explanation for the differences between the Japanese and Chinese women. There may be ethnic differences in estrogen receptors within bone, such that Japanese women were able to respond to estrogen-like properties of genistein. This is purely theoretical, but it is certainly a provocative hypothesis. Finally, the Japanese diet may contain sources of genistein that are more readily absorbed such as the fermented soy products. Perhaps these products are metabolized more efficiently. These are also unknown hypotheses, and should be the center of future studies. Lastly, since this study depended on Food Frequency Questionnaire, there may be differences in the use of isolated isoflavones versus intact soy protein in the interpretation of this study.
10. The effect of soy isoflavones on bone markers In one randomized, crossover study, Wangen et al. evaluated the effects of soy protein isolates on pre- and postmenopausal women. The mean age of the premenopausal women was 26 years while the postmenopausal women averaged 57 years of age. Each group was randomized to three soy protein isolates. The control group was provided a mean of 8 mg of soy protein (0.13 mg/kg per day). The low-isoflavone group (low-iso) were given an average of 65 mg (1.00 mg/kg per day) and the high-isoflavone group were provided 130 mg (2.01 mg/kg per day) [16]. In the premenopausal women, measurements of bone markers were made throughout the menstrual cycle. Interestingly, only the deoxypyridinoline cross-links and IGFBP3 were different in the early follicular phase in the premenopausal women. There was an increase in deoxypyridinoline cross-links in the low- and high-iso groups compared with control. In contrast, there was a decrease in IGFBP3 in the high-iso group (P B/0.05). There were no changes in osteocalcin or IGF-I in premenopausal women in the early follicular phase. In periovulatory premenopausal women, only changes in IGF-I were noted with no changes in the osteocalcin, deoxypyridinoline cross-links or IGFBP3 among the three groups. In postmenopausal women, there
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were significant changes in bone formation markers (osteocalcin, bone alkaline phosphatase, IGF1) and no changes in bone resorption markers (deoxypyridinoline cross-links or C-telopeptide) among the control, low- and high-isoflavone groups. This study design emphasizes the differences of isoflavones in estrogen-replete women versus estrogen-deplete women. Even phases of the menstrual cycle may have profound effects on the estrogen-like activity of phytoestrogens.
11. Isoflavones and BMD Few studies have evaluated the gold standard for bone accretion, BMD, in response to administration of isoflavones. One short-term study indicated that compared with casein, isoflavoneenriched soy protein had a positive effect on BMD. Potter et al. showed that 90 mg per day over a 6-month period had an increase in vertebral BMD compared with casein controls. A group of women ingesting only 56 mg per day had no significant effects [5]. However, this was a shortterm study with few subjects. Additional research and longer-term studies are missing to prove the effect of soy isoflavones on BMD and fracture. One of the controls that has been proposed for soy protein is substituting another type of protein and comparing isoflavone-rich soy with isoflavone-poor soy. In a double-blind, randomized clinical trial, Alekel et al. [17] evaluated the effects of dietary soy proteins on perimenopausal women (Fig. 4). For 24 weeks, the women were randomized to an isoflavone-rich soy protein (80.4 mg per day, n /24), isoflavone-poor soy (n /24), or whey protein (n /21). This protein powder was baked into a jumbo muffin. Endpoints included BMD by DEXA, measurement of N -telopeptide and bone alkaline phosphatase. Compliance was assessed by measurement of the urinary excretion of isoflavones. The median age of women in this study was 50.6 years. Of note, women were told to substitute the muffin for an entire meal as it contained 600 mg of calcium and 500 calories. Bone alkaline phosphatase negatively correlated to the percentage change in BMD and bone mineral content. Overall, the percentage change in lumbar
Fig. 5. Dietary isoflavones and DEXA BMD measurement in postmenopausal women. The mean (/S.E.M.) percentage change in lumbar spine BMD from baseline to post-treatment in perimenopausal women: ( /) isoflavone-rich soy; (^) isoflavone-poor soy; (m) whey protein (control). Reproduced from Ref. [17].
spine BMD did not differ between the intact soy protein and the soy protein minus isoflavones groups. The control group BMD lost BMD and BMC at the lumbar spine ( /1.28 and /1.73%, respectively; Fig. 5). Regression analysis indicated that the soy protein isoflavone intact group had a positive effect on BMD (5.6%, P /0.023). Using analysis of covariance, the effect was owing to the isoflavone component.
12. Soy isoflavones and cognition Very little data exists regarding the use of soy isoflavones and cognitive effects in human. Animal studies have been published showing that brainderived neurotrophic factors are altered in the presence of estradiol and soy isoflavones in rats. For example, when compared with casein, soy isoflavones and 17b-estradiol increased brain-derived neurotrophic factor and choline acetyltransferase [18,19]. In addition, maze performance was improved in ovariectomized rats in a dose-dependent way with soy phytoestrogens and performance appeared very similar to the dose /response seen with oral micronized estradiol [20]. Thus, in retired breeder rats, both estradiol and soy isoflavones improved mRNA levels of brain-derived neurotrophic factor and choline acetyltransferase. Dose-dependent improvements in maze perfor-
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mance were seen with both estradiol and phytoestrogens in the ovariectomized rat model. In human, data are sparse regarding estrogen agonist or antagonist effects on the brain in the presence of isoflavones. The Honolulu /Asia Aging Study showed that there was an association between high-tofu consumption in men and lowcognition scores in mid-life. However, in JapaneseAmerican women living in Washington, estrogen users consuming tofu at least three times per week were less likely to have cognitive impairment.
13. Safety issues with phytoestrogens One of the major issues is the question regarding the safety of phytoestrogens. In human, there has been an increase length of the menstrual cycle with high dietary intake of isoflavones and a decline in a preovulatory LH and FSH. Although this has not been shown to have clinical relevance regarding fertility in human to date, there are abundant evidence in animals that phytoestrogens may alter reproductive status. For example, infertility was noted in captive cheetahs that were fed a high phytoestrogen diet. In ewes, there was compromise of follicular development with a shortened luteal phase resulting in decreased fertility. California quail had reduced breeding owing to a diet rich in phytoestrogens. And in cattle, cystic ovaries, irregular estrus and anestrus had been shown dependent on phytoestrogen content of their diet. Still, it is difficult to assess whether there are true harmful events that occur in human. Another unresolved issue is the effect of isoflavones on breast tissue. There have been studies that indicate that there may be promotion or inhibition of breast cancer by the isoflavones. There may be dose-dependent effects, not to mention the potential differences dependent on the estrogen milieu. Other potential problems may be owing to phytoestrogen metabolism or alterations in estrogens on the sex steroid pathway. Whether there is an inverse relationship between soy intake and testosterone concentrations owing to inhibition of 17b-hydroxy reductase has not been well established. There has been a proposal that male
infertility could also occur owing to high phytoestrogen intake. One study recently showed that in men, high levels of tofu were associated with low cognition scores. This study again may be difficult to interpret owing to the fact that it is based on epidemiology. There has also been long-term questions regarding whether soymilk for infants may cause long-term developmental problems.
14. Clinical recommendations It is difficult to give definitive answers for the practicing clinician to determine the best advice to give postmenopausal women. Many postmenopausal women perceive prescription estrogens of ‘‘unnatural’’ in spite of the fact that many prescription estrogens are derived from plants or other natural sources. Regarding phytoestrogens, there are potential problems for fertility issues in premenopausal issues, but there has been no evidence to date that this is truly an issue. In postmenopausal women, there have been reported cases of vaginal bleeding with high amounts of different types of phytoestrogens such that overuse should be avoided. Moderation is probably the best recommendation for the postmenopausal female.
15. Herbal myths One of the issues to remember is that a natural product does not necessarily mean that a product is safe [21]. Although some herbs have been used for thousands of years, they may have no effect or they may actually cause harm. When the herb is a plant that does not necessarily translate to it being the same compound as when it is put into a capsule or tablet. Some herbal preparations are adulterated with pharmaceutical products. Unsuspected addition of conventional drugs to herbal preparations has resulted in serious side effects [22]. Last of all, all brands of herbal preparations are not the same. Many herbal remedies are not manufactured under good agricultural practice and good manufacturing practice to provide a consistent and reliable product.
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References [1] Albertazzi P, Purdie DW. The nature of utility of the phytoestrogens: a review of the evidence. Maturitas 2002;42:173 /85. [2] Dewell A, Hollenbeck CB, Bruce B. The effects of soyderived phytoestrogens on serum lipids and lipoproteins in moderately hypercholesterolemic postmenopausal women. J Clin Endocrinol Metab 2002;87:118 /21. [3] Food and Drug Administration. Food labeling: health claims, soy protein and coronary artery disease, Fed. Regist. 1999;64:57699 /733. [4] Vigna GB, Pansini F, Bonaccorsi G, Albertazzi P, Donega P, Zanotti L, De Aloysio D, Mollica G, Fellin R. Plasma lipoproteins in soy-treated postmenopausal women: a double-blind, placebo-controlled trial. Nutr Metab Cardiovasc Dis 2000;10:315 /22. [5] Potter SM, Baum JA, Teng H, Stillman RJ, Shay NF, Erdman JW, Jr.. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr Suppl 1998;68:1375S /9S. [6] Washburn S, Burke GL, Morgan T, Anthony MS. Effect of soy protein supplementation on serum lipoproteins, blood pressure and menopausal symptoms in perimenopausal women. Menopause 1999;6:7 /13. [7] Clarkson TB, Anthony MS, Morgan TM. Inhibition of postmenopausal atherosclerosis progression: a comparison of the effects of conjugated equine estrogens and soy phytoestrogens. J Clin Endocrinol Metab 2001;86:41 /7. [8] Choi EM, Suh KS, Kim YS, Choue RW, Koo SJ. Soybean ethanol extract increases the function of osteoblastic MC3T3-E1 cells. Phytochemistry 2001;56:733 /9. [9] Kajiya J, Okabe K, Okamoto F, Tsuzuki T, Soeda H. Protein tyrosine kinase inhibitors increase cytosolic calcium and inhibit actin organization as resorbing activity in rat osteoclasts. J Cell Physiol 2000;183:83 /90. [10] Gao YH, Yamaguchi M. Suppressive effect of genistein on rat bone osteoclasts: involvement of protein kinase inhibition and protein tyrosine phosphatase activation. Int J Mol Med 2000;5:261 /7. [11] Fanti P, Monier-Faugere MC, Geng Z, Schmidt J, Morris PE, Cohen D, Malluche HH. The phytoestrogen genistein reduces bone loss in short-term ovariectomized rats. Osteoporos Int 1998;8:274 /81. [12] Draper CR, Edel MJ, Dick IM, Randall AG, Martin GB, Prince RL. Phytoestrogens reduce bone loss and bone
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
S29
resorption in oophorectomized rats. J Nutr 1997;127:1795 /9. Uesugi T, Toda T, Tsuji K, Ishida H. Comparative study on reduction of bone loss and lipid metabolism abnormality in ovariectomized rats by soy isoflavones, daidzein, genistein, and glycitin. Biol Pharm Bull 2001;24:368 /72. Ishimi Y, Miyaura C, Ohmura M, Onoe Y, Sato T, Uchiyama Y, Ito M, Wang X, Suda T, Ikegami S. Selective effects of genistein, a soybean isoflavone, on B-lymphopoiesis and bone loss caused by estrogen deficiency. Endocrinology 1999;140:1893 /900. Greendale GA, Fitzgerald G, Huang M-H, Sternfeld B, Gold E, Seeman T, Sherman S, Sowers M. Dietary soy isoflavones and bone mineral density: results from the Study of Women’s Health Across the Nation. Am J Epidemiol 2002;155:746 /54. Wangen KE, Duncan AM, Merz-Demlow BE, Xu X, Marcus R, Phipps WR, Kurzer MS. Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women. J Clin Endocrinol Metab 2000;85:3043 /8. Alekel DL, St Germain A, Peterson CT, Hanson KB, Stewart JW, Toda T. Isoflavone-rich soy protein isolate attenuates bone loss in the lumbar spine of perimenopausal women. Am J Clin Nutr 2000;72:844 /52. Pan Y, Anthony M, Clarkson TB. Effect of estradiol and soy phytoestrogens on choline acetyltransferase and nerve growth factor mRNAs in the frontal cortex and hippocampus of female rats. Proc Soc Exp Biol Med 1999;221:118 /25. Pan Y, Anthony M, Clarkson TB. Evidence for upregulation of brain-derived neurotrophic factor mRNA by soy phytoestrogens in the frontal cortex of retired breeder female rats. Neurosci Lett 1999;261:17 /20. Pan Y, Anthony M, Watson S, Clarkson TB. Soy phytoestrogens improve radial arm maze performance in ovariectomized retired breeder rats and do not attenuate benefits of 17beta-estradiol treatment. Menopause 2000;7:230 /5. Ernst E. The risk-benefit profile of commonly used herbal therapies: ginkgo, St. John’s wort, ginseng, echinacea, saw palmetto, and kava. Ann Intern Med 2002;136:42 /53. Ernst E. Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. J Intern Med 2002;252:107 /13.