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Supplement: Dietary Supplement Use in Women: Current Status and Future Directions

Phytoestrogen Supplement Use by Women

Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108

² To whom correspondence should be addressed. E-mail: mkurzer{at}umn.edu.

	ABSTRACT

TOP ABSTRACT Menopausal symptoms Cardiovascular health Bone health Breast health Conclusions LITERATURE CITED

 
Phytoestrogens are weak estrogens found concentrated in soybeans. Americans consume phytoestrogens primarily in traditional soy foods, soymilk and isolated soy protein added during food processing or consumed as a beverage. Extracted phytoestrogens are also marketed in numerous forms as dietary supplements regulated under the Dietary Supplement Health and Education Act. Consumers of phytoestrogen supplements tend to be peri- and postmenopausal women looking for an alternative to hormone therapy. Although there are no approved health claims for phytoestrogens at this time, numerous claims are being made regarding benefits to heart, bone, breast and general menopausal health. The data supporting these claims are generally not strong. The strongest data show that phytoestrogens reduce the number and intensity of hot flashes, although the reduction is a modest 10–20%. The studies showing cholesterol lowering have used soy protein rather than phytoestrogen extracts. The soy protein appears to be required for this effect, although phytoestrogen extracts may have other beneficial effects on the cardiovascular system. The data on bone metabolism are suggestive of possible benefits whereas the effects on the breast are the most poorly understood. Although most animal studies have shown cancer-preventive effects, a few recent studies suggest that soy phytoestrogens may stimulate breast cancer cell growth under certain circumstances. Before recommendations regarding phytoestrogen supplements can be safely made, we must have more information on the effects of the extracts on bone, heart and breast health. Until safety with respect to breast cancer is established, phytoestrogen supplements should not be recommended, particularly for women at high risk of breast cancer.

KEY WORDS: • isoflavone • red clover • women • hot flash • heart disease • breast cancer • osteoporosis

Phytoestrogens are estrogen-like compounds found in a wide variety of plants. Studies performed in vitro and using animal models report that these substances bind the estrogen receptor and exert hormonal and antihormonal effects (1). There has been tremendous interest in the possibility that dietary phytoestrogens may be an alternative to postmenopausal hormone therapy because of concerns about side effects and long-term health consequences that prevent many women from using hormone therapy for amelioration of the discomforts and increased disease risk associated with the menopausal transition.

Many postmenopausal women who have chosen not to take hormone therapy are currently using complementary and alternative therapies for menopause, and these include taking phytoestrogen supplements. Most of the supplements contain isoflavones derived from soybeans or red clover and some contain botanicals such as black cohosh. A web search in January 2001 suggested that there were 50–100 different phytoestrogen supplements available at that time, not including soy protein supplements and energy bars. Small supplement companies as well as large pharmaceutical companies market these products, in some cases in combination with popular vitamin-mineral supplements. The Nutrition Business Journal recently estimated the total market for mass-marketed menopause supplements to be over $100 million (2).

According to the Dietary Supplement Health and Education Act of 1998, dietary supplement marketers are not permitted to make health claims related to reduction of disease risk, but structure-function claims related to overall health are allowed. The main claims made for phytoestrogen supplements are reduction of menopausal symptoms, promotion of cardiovascular health, promotion of bone health and increased breast health. These are also the main reasons for phytoestrogen supplement use by peri- and postmenopausal women.

	Menopausal symptoms

TOP ABSTRACT Menopausal symptoms Cardiovascular health Bone health Breast health Conclusions LITERATURE CITED

 
The main motivation for phytoestrogen supplementation by peri- and postmenopausal women is reduction of the vasomotor symptoms of menopause. Anecdotal evidence suggests that many women believe that these supplements are helpful. In general, data support a benefit of phytoestrogens on hot flash frequency and severity, but only a small part of the benefit is due to phytoestrogens per se because in these studies the placebo group also reports a large benefit.

The notion that phytoestrogen consumption may decrease hot flashes is supported by a prospective study in postmenopausal Japanese women that reported an inverse association between hot flashes and soy food or isoflavone consumption (3). In this study, the hazard ratio for hot flashes was 0.42 in the highest tertile of isoflavone intake (51 mg/d) when compared with the lowest tertile (20 mg/d).

Almost all studies reported a 20–30% reduction of symptoms in the placebo group, but additional reductions of 10–20% were seen in intervention studies using soy foods (4), soy protein isolate (5,6) and soy extracts (7–9) providing 30–104 mg/d of isoflavones. Treatment groups have not always experienced a greater reduction than the placebo group. No benefits beyond the placebo were seen in two studies that each provided 80 mg isoflavones in soy protein isolate (10,11); one study of breast cancer patients consuming a soy beverage containing 90 mg isoflavones (12) or another study of breast cancer patients consuming soy extract containing 150 mg/d of isoflavones (13). No additional benefits were seen in two studies using red clover extract containing 30–120 mg isoflavones (14,15).

These data suggest that consumption of as little as 30 mg/d of soy isoflavones, intact with soy protein or as a semipurified extract, may reduce hot flashes by 30–50%. The greatest benefit of soy isoflavones may be realized when the supplement is taken in divided doses throughout the day by subjects with the most severe symptoms. It is important to remember that this total effect includes the placebo effect and the reduction due to the isoflavones per se is only 10–20%. Consumption of red clover isoflavones resulted in a comparable placebo effect but no further effect due to the isoflavones. The clinical relevance of the placebo effect and the small additional effect of soy phytoestrogens must be evaluated by each woman individually.

	Cardiovascular health

TOP ABSTRACT Menopausal symptoms Cardiovascular health Bone health Breast health Conclusions LITERATURE CITED

 
In 1999 the Food and Drug Administration approved a health claim for soy protein and cholesterol lowering, stating "Diets low in saturated fat and cholesterol that include 25 g of soy protein/d may reduce the risk of heart disease" (16). This health claim was approved after consideration of numerous studies, including the meta-analysis of 38 studies by Anderson et al. (17) that showed that an average intake of 47 g/d of soy protein results in a 9% decrease in total cholesterol, a 13% decrease in LDL cholesterol and a trend toward increased HDL cholesterol. More recent intervention studies are consistent with these findings (5,18–21).

To determine whether isoflavones are responsible for the lipid-lowering effects of soy, a few studies have compared the effects of isoflavone-rich soy protein isolate with soy protein isolate that has had most of the isoflavones removed by alcohol washing. These studies have consistently shown that the isoflavone-rich isolate exerts these effects whereas the isoflavone-poor isolate does not, suggesting that isoflavones are required (22–25). At the same time, studies using semipurified isoflavone extracts have not reported these effects on blood lipids, whether the isoflavones were derived from soy (8,26–30) or red clover (31,32).

Thus, soy isoflavones lower LDL cholesterol and probably increase HDL cholesterol, but this requires that they be consumed intact in soy protein. The effect is greatest in hypercholesterolemic women, although small but significant changes were reported in normocholesterolemic and moderately hypercholesterolemic women (23,24). Isoflavone extracts do not lower plasma cholesterol but may exert other benefits on the cardiovascular system, such as improved arterial compliance, which has been shown with both soy (26) and red clover (32) supplements.

	Bone health

TOP ABSTRACT Menopausal symptoms Cardiovascular health Bone health Breast health Conclusions LITERATURE CITED

 
The data supporting claims that isoflavone consumption improves bone health are not as strong as data on lipid lowering and reduction of menopausal symptoms. Animal studies suggest that dietary isoflavones may exert benefits on bone mineral density (BMD) (33–35) and bone turnover (33,34) but there have been very few human studies in this area.

A recent cross-sectional study of postmenopausal Japanese women reported significantly increased BMD in the highest two quartiles of isoflavone intake (>65 mg/d and 50–65 mg/d) when compared with the lowest quartile (35 mg/d) (36). This observation was confirmed in studies of postmenopausal (37) and premenopausal (38) women in Hong Kong, although in one study of premenopausal women (37) no association between isoflavone intake and BMD was found. A recent study performed in the United States reported no association between isoflavone intake and BMD in Chinese women although a positive association was seen for Japanese premenopausal but not perimenopausal women (39).

Only two human intervention studies have evaluated isoflavone effects on bone and used appropriate control groups. One study reported that postmenopausal women consuming 90 mg/d of isoflavones in soy protein isolate for 6 mo showed a small but statistically significant increase in lumbar spine BMD whereas women consuming casein or 56 mg/d of isoflavones in soy protein isolate did not show an increase (40). Another study of perimenopausal women reported that although women consuming whey protein showed a loss of bone over 6 mo, consumption of 80 mg/d of isoflavones in soy protein isolate had a positive effect on lumbar BMD and bone mineral content (41). These two clinical trials suggest that over the short term, soy isoflavones may attenuate lumbar spine bone loss in peri- and postmenopausal women despite reports that markers of bone turnover are not altered by isoflavone intake (42). Further studies are needed to establish whether these effects are sustained over 2–3 y and whether isoflavone extracts prevent postmenopausal bone loss.

	Breast health

TOP ABSTRACT Menopausal symptoms Cardiovascular health Bone health Breast health Conclusions LITERATURE CITED

 
The epidemiological data supporting an inverse association between phytoestrogens and breast cancer are weak at best. A number of case-control studies reported inverse associations between soy food intake and breast cancer risk in Asian populations (43–48), but this has not been observed in other case-control studies (49–51) or one large prospective study performed in Japan (52). Using urinary phytoestrogen excretion as a marker of intake and exposure, three case-control studies reported inverse associations between urinary phytoestrogens and breast cancer risk in Australia (53,54) and China (55); one prospective cohort study, performed in the Netherlands, reported no association (56). These epidemiological studies do not provide strong support for the hypothesis that phytoestrogen consumption protects against breast cancer risk.

Animal studies provide inconsistent but somewhat more compelling evidence of the cancer preventive effects of soy or phytoestrogen consumption. In an extensive review of the literature, Messina and Loprinzi (57) concluded recently that animals consuming soy in place of other protein generally develop 25–50% fewer tumors than control animals, although not all studies show protective effects. Similarly, studies using purified isoflavones generally show cancer preventive effects (58,59), although one study shows increased tumorigenesis (60).

The time of life of exposure to phytoestrogens may actually determine whether the effects on carcinogenesis are beneficial. The greatest cancer preventive effects occur in animals exposed during breast development (61,62), likely as a result of enhanced mammary gland development with growth of fewer terminal end buds, the mammary structure most vulnerable to carcinogenesis. Consistent with this observation are data from an epidemiological study performed in China in which a retrospective evaluation of early food intake shows that adolescent soy food intake is inversely associated with adult breast cancer risk, with an odds ratio of 0.5 at the highest quintile of intake (48). Results are significant for both pre- and postmenopausal women.

Studies of the effects of phytoestrogens on established tumors have raised some concerns that may be relevant to women at high risk of breast cancer. Although some studies have shown inhibitory effects of phytoestrogens (63), others have reported increased carcinogenesis in rodents (64–67). Of particular concern is a recent report that dietary genistein negates the inhibitory effect of tamoxifen in the athymic nude mouse model (68). Also of concern are two human studies performed in women consuming soy protein isolate that suggest weak estrogenic effects on the breast (69,70).

It thus appears that soy phytoestrogens may be cancer preventive, particularly when taken early in life. Effects in adulthood are less clear, and it is possible that phytoestrogens actually stimulate growth of established breast cancer cells.

	Conclusions

TOP ABSTRACT Menopausal symptoms Cardiovascular health Bone health Breast health Conclusions LITERATURE CITED

 
Isoflavones do appear to exert some benefits for menopausal health. Consumption of as little as 30 mg soy isoflavones, in soy protein or as an extract, reduces vasomotor menopausal symptoms by 30–50% including the placebo effect or 10–20% after subtracting the placebo effect. Soy protein and isoflavones work together to lower LDL cholesterol and increase HDL cholesterol. Purified isoflavones do not do this although they may exert other cardiovascular benefits. Benefits to bone health are less certain, although some data suggest that they may prevent bone loss over the short term. Effects on breast cancer risk are complex. Isoflavones are likely cancer preventive when consumed early in life, but a few animal studies showing stimulation of breast cancer cell growth raise sufficient concerns that phytoestrogen supplements should not be recommended for women at high risk of breast cancer.

Numerous unanswered questions remain concerning the effects of phytoestrogen supplements for women. Further studies should be performed to clarify the effects of soy protein versus isoflavone extracts; effects of red clover extracts; the most effective types and forms of phytoestrogens; optimal doses; the significance of individual variation in phytoestrogen metabolism; long-term effects, particularly on bone; benefits and adverse effects of consumption over the life cycle; interactions between phytoestrogens and tamoxifen; and safety, particularly with respect to breast cancer risk.

	FOOTNOTES

 
¹ From the National Institutes of Health (NIH) conference "Dietary Supplement Use in Women: Current Status and Future Directions" held on January 28–29, 2002, in Bethesda, MD. The conference was sponsored by the National Institute of Child Health and Human Development and the Office of Dietary Supplements, NIH, U.S. Department of Health and Human Services (DHHS) and was cosponsored by the Centers for Disease Control and Prevention, Food and Drug Administration Office of Women’s Health, NIH Office of Research on Women’s Health, National Institute of Diabetes and Digestive and Kidney Diseases Division of Nutrition Research Coordination, DHHS; National Center for Complementary Medicine, U.S. Department of Agriculture Agricultural Research Service; International Life Sciences Institute North America; March of Dimes; and Whitehall Robbins Healthcare. Conference proceedings were published in a supplement to The Journal of Nutrition. Guest editors for this workshop were Mary Frances Picciano, Office of Dietary Supplements, NIH, DHHS; Daniel J. Raiten, Office of Prevention Research and International Programs, National Institute of Child Health and Human Development, NIH, DHHS; and Paul M. Coates, Office of Dietary Supplements, NIH, DHHS.

	LITERATURE CITED

TOP ABSTRACT Menopausal symptoms Cardiovascular health Bone health Breast health Conclusions LITERATURE CITED

 

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