JOURNAL OF MEDICINAL FOOD J Med Food 10 (4) 2007, 571–580 © Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition DOI: 10.1089/jmf.2006.0620 Review Soy Isoflavones as Safe Functional Ingredients Won O. Song, 1 Ock Kyoung Chun, 1 Inkyeong Hwang, 2 Han Seung Shin, 3 Bong-Gwan Kim, 4 Kun Soo Kim, 5 Sang-Yun Lee, 5 Dayeon Shin, 6 and Sung G. Lee 7 1 Department of Food Science and Human Nutrition, Michigan State University; 7 East Lansing Ob-Gyne Associates, East Lansing, Michigan; 2 Department of Food and Nutrition, Seoul National University; 3 Dongguk University; 4 HF Foods Co. Ltd.; 5 Pulmuone Health and Living Co. Ltd.; and 6 Department of Food and Nutriton, Ewha Womans University, Seoul, Republic of Korea ABSTRACT In recent years, isoflavones have increased in popularity as an alternative to estrogen therapy, particularly af- ter the Women’s Health Initiative demonstrated an increased risk of breast cancer, stroke, and heart attacks in response to es- trogen and progesterone intervention. Isoflavones are heterocyclic phenols with structural similarity to estradiol-17beta and selective estrogen receptor modulators. Actions at the cellular level depend on the target tissue, receptor status of the tissue, and the level of endogenous estrogen. Clinical studies of soy-based diets evaluating the relation between soy consumption and serum lipid concentrations revealed that soy consumption significantly decreased total cholesterol, low-density lipopro- tein cholesterol, and triglyceride levels. Epidemiological studies suggest a protective effect of soy protein on breast tissue as evidenced by the lower rates of breast cancer in East Asian countries where soy is a predominant part of the diet. Soy prod- ucts also alleviate menopausal symptoms by reducing hot flashes. However, whether these biological effects of soy products originated from isoflavones is not clear. Furthermore, data available from human studies on the effect of isoflavones on os- teoporosis are limited, and additional studies are needed to support a role in osteoporosis prevention. To date, no adverse ef- fects of short- or long-term use of soy proteins are known in humans, and the only adverse effects known are those reported in animals. In conclusion, isoflavones are biologically active compounds, and current data are insufficient to draw definitive conclusions regarding the use of isoflavones as an alternative to estrogen for hormone replacement in postmenopausal women. Large, long-term intervention studies examining adverse effects and disease outcomes are needed before definitive conclu- sion can be drawn. KEY WORDS: • anti-estrogen • estrogen • health • isoflavone • safety • soybean 571 INTRODUCTION S OY BEANS AND SOY PRODUCTS have been extensively used as safe food items throughout the world, particularly in Asia. Isoflavones are one category of active compounds in soy foods. 1 Isoflavones function in the body similarly to es- trogen, and thus called phytoestrogens. 2 Phytoestrogenic isoflavones in soy products that have been studied the most are genistein, daidzein, and glycitein. 3–6 The phytoestro- genic function of isoflavones have made isoflavones a pop- ular alternative to estrogen therapy, particularly after the Women’s Health Initiative demonstrated an increased risk of breast cancer, stroke, and heart attacks in response to es- trogen and progesterone intervention. 7–9 The amount of isoflavones derived from usual intakes of soy and soy prod- ucts has been presumed to be safe historically. 10,11 By binding to the estrogen receptors in certain cells in the body, phytoestrogenic isoflavones produce weak estrogenic effects, especially when an inadequate amount of estrogen is present in the body. Alternatively, in the presence of an adequate amount of endogenous estrogens, phytoestrogen- tic isoflavones can reduce the efficacy of estrogens by block- ing estrogen receptors. As isoflavones play these double- edge functions in the body, that ameliorate health benefits of estrogens. 12 Phytoestrogens help prevent osteoporosis in the presence of subnormal endogenous estrogen, 13 as well as reducing the risk of breast and uterine cancers by pro- tecting against overexposure of endogenous estrogens by certain organs in the body. Many studies 14–17 have reported that soy consumption induced small but measurable changes in menstrual cycles and sexual hormones in young women, Manuscript received 30 November 2006. Revision accepted 5 March 2007. Address reprint requests to: Won O. Song, Ph.D., M.P.H., R.D., Department of Food Sci- ence and Human Nutrition, Room 131, GM Trout Building, Michigan State University, East Lansing, MI 48824, E-mail: song@msu.edu