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Soy and Menopausal Health

Course Authors

Mark J. Messina, Ph.D.

Dr. Messina is Adjunct Associate Professor, Loma Linda University,Loma Linda, CA, and President, Nutrition Matters, Inc., Port Townsend, WA.

In the past three years, Dr. Messina has consulted for Archer Daniels Midland Company and the United Soybean Board.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 
Learning Objectives

Upon completion of this Cyberounds®, you should be able to:

  • List the physiologic effects of soybean isoflavones

  • Describe the likely impact of soy consumption on diseases affected by HRT in the HERS II and/or WHI

  • Discuss the association between soy and breast cancer risk.

 

Soy foods have played an important role in the diets of many Asian cultures for centuries. Within the last decade, soy foods and soybean constituents have attracted widespread research attention in the West for their purported health benefits. Media coverage of this research has led to an increased consumer awareness of soy and to skyrocketing sales of soy foods, which have more than tripled in the United States during the past decade. The entrance of mainstream food companies into the soy foods market has greatly increased consumers' access to soy foods; currently, about half of all soy products are now sold in large retail establishments rather than specialty stores.

Many of the newly developed "Westernized" soy products are marketed specifically to women, largely because of evidence suggesting that soy may be helpful for conditions and diseases associated with menopause. Soy is viewed as a possible alternative to conventional hormone replacement therapy (HRT) because it is a unique, natural dietary source of isoflavones, a chemical class of compounds with estrogen-like properties.

This perspective may gain even further acceptance as a result of the recently published findings from the Heart and Estrogen/Progestin Replacement Study (HERS) I/II,(1),(2) and the Women's Health Initiative (WHI).(3) The results of both studies have seriously weakened the case for the routine, long-term use of HRT, at least with respect to dose and type of hormones (0.625 mg/day conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) employed in these studies.

In HERS I/II, treatment failed to reduce the overall rate of coronary heart disease (CHD) events (the primary outcome of the study), and increased the rate of venous thromboembolism and biliary tract surgery. Similarly, in the WHI, overall health risks associated with treatment exceeded benefits, resulting in the suspension of the trial after 5.2 years instead of the planned 8.5 years. Given the current popularity of soy foods, it is important to consider whether findings from the HERS I/II and WHI have any implications, negatively or positively, for soy. This review addresses this question and provides soy intake guidelines for the generally healthy adult population.

What's So Special About Soy?

The soybean is a complex mixture of biologically active chemicals. The two components thought to be primarily responsible for the hypothesized health benefits of soy are the protein and isoflavones, with the latter largely accounting for interest in soy as an alternative to HRT. The quality of soy protein is similar to that of meat and milk protein(4) but soy protein appears to favorably affect renal function(5) and is less hypercalciuric than animal protein.(6)

Isoflavones are a subclass of a larger and more ubiquitous group of nutraceuticals called flavonoids. In comparison to most flavonoids, however, isoflavones have a very limited distribution in the plant kingdom. The soybean is the only nutritionally relevant, naturally occurring dietary source of isoflavones (although isoflavones are now widely available in supplement form and are being used as food fortificants).

The primary isoflavones in soybeans are genistein (4'5,7-trihydroxyisoflavone) and daidzein (4',7-dihydroxyisoflavone), and their respective ß-glycosides, genistin and daidzein. Typically, more genist(e)in exists in soybeans and soy foods than daidz(e)in.(7) There are also small amounts of a third isoflavone in soybeans, glycitein (7,4'-dihydroxy-6-methoxyisoflavone), and its glycoside, glycitin.

In the Spotlight: Isoflavones

More than 600 scientific papers are now published on isoflavones annually, compared with just 12 for the entire year of 1985. The US government is actively investigating the health effects of isoflavones. For example, the National Cancer Institute (NCI) has been investigating the anticancer effects of soy, especially isoflavones, since 1991.(8) In 1999, the US Department of Agriculture (USDA), in conjunction with Iowa State University, created an online database of the isoflavone content of foods, and in that same year, the National Institute of Aging (NIA) and the National Institute of Health (NIH) convened a three-day workshop on isoflavones.(9)

The chemical structure of isoflavones is similar to that of estrogen; therefore, it is not surprising that isoflavones bind to estrogen receptors and are for this reason considered to be phytoestrogens. Compared with 17b-estradiol, however, isoflavones have a relatively low binding affinity for estrogen receptor-alpha (ERa); their binding affinity for the recently discovered estrogen receptor-beta (ERß) is only slightly lower.(10) But even their lower binding affinity for ERa suggests that isoflavones hold the potential to exert physiologic effects in vivo, because serum isoflavone levels in people who eat soy foods reach the low micromolar range, which is approximately 1000-fold higher than endogenous estrogen levels.(11)

Of course, estrogen binding is only one factor that determines the effects of estrogen-receptor binding ligands in cells possessing estrogen receptors. The way in which the conformational change in the receptor that occurs in response to binding (which differs among ligands) affects the interaction between the receptor-ligand complex and coactivators and corepressors within cells ultimately determines the overall effect.(12)

Consequently, each ligand needs to be evaluated individually when researchers are attempting to determine probable physiologic effects. For this reason, it is more appropriate to refer to the estrogen-like properties of isoflavones rather than to their estrogenic properties, since isoflavones are different from estrogen. Furthermore, isoflavones are arguably more accurately classified as selective estrogen receptor modulators (SERMs), such as the breast cancer drug tamoxifen and the osteoporosis drug raloxifene, rather than as phytoestrogens.(13) Unlike estrogen, SERMs are tissue-selective and have estrogen-like effects in some tissues but either no effects or anti-estrogenic effects in other tissues.

The ideal SERM would seemingly have estrogen-like effects on the coronary vessels, skeletal system and brain but anti-estrogenic effects on the breast and endometrium.

Support for the SERM-like qualities of isoflavones include the observations that estrogen increases endometrial cell proliferation (thereby increasing endometrial cancer risk)(14) as well as serum triglyceride levels,(15) whereas isoflavone-rich soy protein(16),(17) and isolated isoflavones(18),(19) do not affect endometrial cell proliferation and either do not affect or slightly decrease serum triglyceride levels.(20),(21) The SERM-like qualities of isoflavones likely stem at least in part from their preferential binding to ERb and to their greater ability to trigger transcriptional activity when bound to ERß than to ERa.(22) However, isoflavones also have potentially important nonhormonal effects that likely contribute to their physiologic effects; therefore, even classifying isoflavones as SERMs is an incomplete characterization.(23)

Outcomes of HERS I/II and WHI: Likely Effects of Soy

Breast Cancer

The relative hazard ratio (HR)for invasive breast cancer was 1.26 and 1.27 in WHI(3) and HERS II, respectively, although the latter finding was not statistically significant. However, nearly all of the increased breast cancer risk in WHI occurred in the final years of the study, suggesting that the annual percentage increased risk for those years was as high as 8-9%. If this level of risk continued unabated, breast cancer risk would be two- to three-fold higher in lifetime HRT users. Several epidemiologic studies have noted increases of this magnitude, especially among women of normal weight.(24),(25) Similarly, subgroup analysis in the WHI noted increases of two-fold and higher in long-time users of HRT. Furthermore, for women overall, when excluding events occurring 6 months after discontinuing HRT, the relative HR ratio increased from 1.26 to 1.49.

Most evidence indicates that it is the combination of estrogen and progestin, and not estrogen alone, that increases breast cancer risk. In studies comparing estrogen alone to the combination of estrogen and progestin, the combination of hormones is associated with greater breast tissue density(26),(27) and increased breast(28) and mammary(29) cell proliferation. We do know that breast cell replication is four times greater during the second two weeks (luteal phase) of the menstrual cycle, when endogenous serum progesterone levels are high, than during the first two weeks (follicular phase), when progesterone levels are low.(30) In support of these observations are several epidemiologic studies, which have found that estrogen alone only slightly increases breast cancer risk, whereas the combination of hormones markedly increases risk. The most telling observation may prove to be that in contrast to the combination of hormones, the estrogen-only arm of the WHI was not discontinued and that, thus far, no increase in breast cancer risk has been reported.

Likely Effects of Soy

For more than ten years there has been considerable research interest in the anticancer effects of soy, especially in relation to breast cancer.(8) This research has been spawned partly because of the low breast cancer mortality rates in Asia(31) but also because weak estrogens, such as isoflavones, have been known for decades to exert anti-estrogenic effects under certain experimental conditions.(32) In fact, the first study demonstrating anti-estrogenic effects of genistein in rodents was published in 1966.(33) Isoflavones can exert anti-estrogenic effects in several ways [for review see Messina and Loprinzi(34)], although convincing data of these effects in humans are lacking. Overall, the evidence that soy intake by adults reduces breast cancer risk is equivocal but an exciting hypothesis, based on studies of Japanese immigrants(35) as well as on animal(36) and epidemiologic studies involving soy,(37) is that soy (isoflavone) consumption early in life markedly reduces adult breast cancer risk.

Despite the interest in the anticancer effects of soy, concern has been expressed that the estrogen-like properties of isoflavones might increase breast cancer risk in certain high-risk women. However, the aforementioned relationship between HRT, estrogen and breast cancer risk suggests that neither soy nor isoflavones are a concern because soy does not exert progestin activity.(38) Among other studies in support of this contention are two year-long intervention studies: in one studey, isoflavone supplements had no effect on breast tissue density in premenopausal women (Gertraud Maskarinec, Cancer Research Center of Hawaii, 2001, personal communication), whereas in the other, isoflavones decreased breast tissue density in women 56-65 years of age.(39) These effects are not only opposite to those of HRT, but suggest that soy either has no effect on or decreases breast cancer risk, because decreased breast tissue density is associated with decreased breast cancer risk.(40) [For a review of the effects of soy and isoflavones on breast cancer risk see Messina and Loprinzi(34)]. Overall, indications are that soy, unlike HRT, does not increase breast cancer risk.

Venous Thromboembolic Disease

In the WHI, the relative HRs for deep vein thrombosis and pulmonary embolism in the treatment groups were 2.13 and 2.07, respectively.(3) The relative HR for venous embolism declined from 2.66 in HERS I to 1.4 in HERS II.(2) The increased risks seen in these studies are likely the results of the estrogen component of HRT.(41) Estrogen is thought to increase risk of thrombosis by altering hepatic production or metabolism of coagulation factors; however, no clear mechanism has yet been identified.(42)

Likely Effects of Soy

Evidence suggests that, unlike estrogen, isoflavone-rich soy protein and isoflavones either reduce or have no effect on platelet aggregation. Gooderham et al.(43) found no effect on platelet aggregation in 20 male subjects who were randomly assigned to consume a soy protein isolate beverage powder (60 g/day) or a casein supplement for 28 days. Similarly, Dent et al.(21) found 40 g isolated soy protein to have no effect on several coagulation and fibrinolytic factors in postmenopausal women. And in a randomized crossover trial, Sanders et al(44) found no differences in plasma VII coagulant levels and plasminogen activator inhibitor I activities in healthy young men and women fed a high- or low-isoflavone isolated soy protein for 17 days each. In contrast, in vitro(45) and animal research suggests that soy and isoflavones may actually inhibit platelet aggregation.(46),(47) Overall, there is no evidence to suggest that like estrogen, isoflavones, or soy, would increase thrombosis.

Stroke

The relative HR for stroke in the treatment group of the WHI was 1.41; stroke risk was not increased in the HERS I/II. The mechanism by which HRT increases risk is unknown, although one observational study reported that estrogen plus progestin is associated with a slightly higher risk of stroke than is estrogen alone.(48)

Likely Effects of Soy

It is difficult to comment about the implications of the increased stroke risk in the WHI, since the mechanism by which risk is increased is unknown and little investigation of the relationship between soy and stroke risk has been conducted. However, one large prospective epidemiologic study of more than 18,000 Chinese men found that fatal stroke risk was unrelated to soy intake.(49) Animal research suggests that genistein may be of value in the prevention of cerebral stroke via hormonal and nonhormonal mechanisms but this is highly speculative.(50),(51)

Studies of monkeys(52) have reported potential beneficial effects of soy on stroke risk; for example, in diabetic adult monkeys who were fed an atherogenic diet containing different protein sources -- low-density lipoprotein (LDL) cholesterol permeability in the carotid bifurcation and internal carotid arteries was reduced in the soy protein-fed group compared with the casein-and-lactalbumin-fed group.(53) Given the preferential binding of isoflavones to ERß, of possible relevance is the finding that after endothelial denudation of rat carotid artery, the mRNA of ERa is constitutively expressed at a low level, whereas the expression of ERß increases more than 40-fold. Treatment of ovariectomized female rats with genistein provides similar dose-dependent vasculoprotective effects as does 17ß-estradiol in the rat carotid injury model but treatment with 17ß-estradiol and not genistein is accompanied with a dose-dependent uterotrophic effect.(54) Aside from the potential implications for stroke risk, these findings provide a good example of the SERM-like qualities of isoflavones.

The incidence of stroke in Asia, where soy foods are commonly consumed, is relatively high compared with the West but stroke rates in Asia have decreased dramatically over the past 30-50 years(55) as hypertension has become less prevalent.(56) The incidence of hemorrhagic stroke (the most common type of stroke in Asia) has declined markedly, especially as compared to ischemic stroke incidence.(57) A slight increase in serum cholesterol levels over the past several decades may also be a factor in the decline in intracerebral hemorrhage,(58) as might be the increased intake of animal protein.(59) Soy intake has remained fairly constant in Japan since about 1960,(60) suggesting that soy does not increase stroke risk; furthermore, some evidence suggests that soy protein may decrease blood pressure.(61)

Biliary Tract Surgery

In HERS II, the relative HR in the treatment group for biliary tract surgery was 1.48,(2) which was higher than noted in HERS I.(62) This effect probably results from estrogen because high-dose estrogen therapy has been shown to cause gallbladder disease in men.(63) Estrogen may increase gallbladder disease risk by altering the concentration of cholesterol in the bile.(64)

Likely Effects of Soy

Animal studies suggest that soy protein, in contrast to estrogen, may actually lower gallbladder risk by decreasing liver and biliary cholesterol concentrations.(65),(66),(67) However, in normocholesterolemic subjects fed textured vegetable (soy) protein for 6-7 weeks, there was no change in gallbladder bile molar percent cholesterol or saturation index.(68) Although Duane et al.(69) found legume consumption lowered LDL cholesterol by partially interrupting the enterohepatic circulation of bile acids and increased cholesterol saturation of bile by increasing hepatic secretion of cholesterol, soy was not a part of the intervention.

Coronary Heart Disease

The relative HR for CHD in the WHI was 1.29,(3) whereas there was no increased risk noted in HERS II.(1) The failure of HRT to reduce CHD events in both HERS I/II and WHI is somewhat puzzling given the effects of estrogen on coronary vessels noted in previous short-term intervention studies(70),(71) and the generally improved serum lipid profiles in HERS I/II and the WHI.(72) Serum levels of LDL cholesterol decreased by 11% and 13%, and levels of high-density lipoprotein (HDL) cholesterol increased by 10% and 7%, respectively, in the HERS and WHI. However, serum triglyceride levels, which may be an independent risk factor for CHD,(73) increased by 8% and 7% respectively in the HER(74) and WHI,(73) respectively.

Likely Effects of Soy

In 1999, the US Food and Drug Administration approved a health claim for the cholesterol-lowering effects of soy protein and set 25 g/day as the target intake goal for cholesterol reduction.(75) In 2000, the American Heart Association endorsed the use of soy foods for people with elevated cholesterol.(76) The hypocholesterolemic effects of soy protein are relatively modest, particularly so in people with only mildly elevated cholesterol, although there may be people who are particularly sensitive to the cholesterol-lowering effects of soy protein.(20)

Independent of cholesterol reduction, isoflavones may have direct coronary benefits as they have been shown to enhance systemic arterial compliance, an indicator of arterial flexibility.(77) Some evidence suggests that decreased arterial flexibility is associated with an increased risk of CHD.(78) Isoflavone-rich soy protein may have other benefits as well, such as decreasing blood pressure(61) and inhibiting LDL cholesterol oxidation(79) but the research surrounding these effects is more speculative.

Only limited epidemiologic investigation of the relationship between CHD risk and soy intake has been conducted but data from two Japanese epidemiologic studies support the cardioprotective effects of soy. One, which examined the relationship of selected foods to nonfatal acute myocardial infarction (AMI) and involved 632 cases with their first episode of AMI between the ages of 40 and 79 years compared with 1214 matched controls, found tofu consumption to be inversely related to risk of AMI in women but not in men.(80) The other study, an ecologic analysis of 47 prefectures in Japan, found that after controlling for covariates, a statistically significant inverse correlation between soy intake and CHD mortality rate was noted in women but not in men.(81) Although no intervention studies to date have actually examined the impact of soy consumption on coronary events, the available evidence suggests that soy and isoflavones warrant inclusion as part of an overall lifestyle aimed at reducing CHD risk.

Colorectal Cancer

In the WHI, the relative HR for colorectal cancer in the treatment group was 0.63(3) Several epidemiologic studies have also found that HRT users are less likely to develop colon cancer and that there are a variety of mechanisms by which estrogen may decrease colorectal cancer risk.(82),(83)

Likely Effects of Soy

Soy consumption is hypothesized to reduce certain forms of cancer and evidence suggests that isoflavones are the primary anticarcinogens in soy. However, most of the research in this area has been on breast and prostate cancer.(60) The evidence that soy reduces colon cancer risk is somewhat mixed, with the epidemiologic data being the least supportive.(84),(85) The most impressive study found that in subjects with a history of colon polyps or colon cancer who were fed 39 g soy protein/day for one year, there was a statistically significant decrease in colon cell proliferation and in the proliferation zone when compared with baseline values, whereas no changes occurred in the group fed a similar amount of casein.(84) These changes are indicative of a major reduction in colon cancer risk.

If soy does reduce risk it is not clear whether isoflavones are responsible for the protective effects [genistein has actually been found to increase colon tumorigenesis in animals(86)]. At this point, the evidence is too limited to draw conclusions about the impact of soy or isoflavones on colon cancer risk.

Fractures

In the WHI, the relative HR for fractures at all sites for those in the treatment group was 0.76 and was 0.66 for hip and vertebral fractures individually.(3) These findings are generally consistent with the literature on this subject.(87)

Likely Effects of Soy

Not surprisingly, because of the estrogen-like properties of isoflavones, there is much interest in their possible benefits on the skeletal system. Isolated isoflavones, as well as isoflavone-rich soy protein, inhibit bone loss in ovariectomized rats,(88) a model accepted by the US Food and Drug for studying osteoporosis.(89) Studies involving postmenopausal women are generally favorable, although a bit inconsistent and, thus far, effects have been noted primarily for the spine(90) However, most of these studies have been of short duration (<1 year) and have involved relatively few subjects. Furthermore, it should be noted that although there was considerable experimental support for the skeletal benefits of the synthetic isoflavone, ipriflavone, which has a chemical structure similar to that of soybean isoflavones, ipriflavone recently failed to favorably affect bone mineral density or fracture risk in a 3-year study involving approximately 500 women.(91)

In addition to the short-term clinical studies, there is a fairly impressive amount of epidemiologic data indicating that, among Asians, those women who consume above average amounts of soy or isoflavones have higher bone mineral density(92),(93),(94),(95) than women who consume less than this amount. However, not all studies are in agreement,(96),(97) though the data are mostly supportive for protection against spinal fractures.

Finally, in addition to the possible benefits of isoflavones, soy protein, when substituted for animal protein, may improve bone health by decreasing urinary calcium excretion. The metabolism of soy protein, primarily because it has fewer sulfur amino acids than animal protein, results in a reduced acid load, which, in turn, decreases bone dissolution and urinary calcium excretion. Evidence suggests that every gram of soy protein substituted for animal protein decreases urinary calcium excretion by 0.5-1.0 mg/day.(98) With all other things being equal, and because net calcium absorption is probably no more 10%, this type of substitution over the course of many years is likely to be clinically relevant.(99),(100)

Conclusions

Much less is known about the health effects of soy than of those of HRT. Thus far, no intervention studies have actually examined the impact of soy consumption on disease outcomes; only markers of disease risk have been considered. As demonstrated by the results of HERS I/II and WHI, long-term intervention studies that have disease outcomes as endpoints are necessary before we can draw definitive conclusions about the health effects of any biologically active agent. Therefore, extrapolating the results of these trials to soy should be done very cautiously, if at all.

The HRT used in HERS I/II and WHI consists not of a single estrogen but of a complex mixture of estrogens derived from the urine of pregnant mares, in combination with a synthetic progestin. Obviously, this chemical mix is very different from soy and isoflavones. Nevertheless, on the basis of the available data, there is little reason to think that soy consumption will increase any of the disease risks that were increased in HERS I/II and WHI. There is, however, at least preliminary data to suggest that soy may decrease colorectal cancer and fracture risk (as was the case in the WHI) but this is still speculative.

Therefore, if the results of HERS I/II or WHI have implications for soy, they are that soy may have some of the advantages, without the disadvantages, of HRT but that large, long-term intervention studies are needed before definitive conclusions can be drawn. Whether soy alone can serve as a safe and effective alternative to HRT remains to be determined. There is no doubt, however, that menopausal women should be encouraged to consume isoflavone-rich soy products, although the effect of soy or isoflavone supplements on the alleviation of hot flashes is less pronounced than that of estrogen.(101)

Soy Intake Recommendations

As noted previously, in issuing a health claim for soy protein, the US Food and Drug Administration set 25 g soy protein/day (no isoflavone recommendation was made) as the target intake goal for cholesterol reduction.(75) However, this level of intake should not be used as a reference for the generally healthy adult population. The health claim is primarily intended for people with hypercholesterolemia. Furthermore, by almost any measure, 25 g soy protein/day is quite high; it is about half the recommended daily allowance for adult women and is approximately 2½ times the average soy protein intake of Japanese adults.(102) A more appropriate intake recommendation is 15 g (with a range of 10-25 g) soy protein and 50 mg (aglycone weight) isoflavones (range of 30-100 mg/day).

Traditional soy foods have an isoflavone (mg) to protein (g) ratio of approximately 3.5:1; therefore, consuming 15 g soy protein will result in consuming approximately 50 mg isoflavones. These amounts of soy protein and isoflavones are provided by approximately two servings of traditional soy foods and are likely to be efficacious for those diseases for which soy is proven to be beneficial. In fact, this amount of soy protein may even exert hypocholesterolemic effects, as shown by recent studies that have failed to find dose-response relationships between soy protein and cholesterol reduction(103) and cross-sectional studies suggesting that fewer than 25 g/day is needed to lower cholesterol.(104) Furthermore, even traditional Western consumers can easily incorporate 15 g soy protein into their daily diets. And it is important to note that this recommendation is consistent with the general advice to eat a varied diet, and there is little reason to think that these intake levels will be associated with any adverse effects.

Finally, one perspective by which to view this recommendation is to consider that substituting 15 g soy protein for animal protein would cause the current US dietary animal to plant ratio to fall from 2:1 to 1:1, the ratio of the US diet during the early 1900s.And, yet, soy protein would still represent less than 20% of the typical protein intake of US adults.(105) Thus, soy could serve to bring more balance to the US diet and, at the very least, would function as one other source of high-quality protein but without the saturated fat and cholesterol typical of many of the most common sources of protein eaten by US residents.(4)
Footnotes

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