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Soy Isoflavones: Are They Useful in Menopause?

      In October 1999, the US Food and Drug Administration authorized the use on food labels of health claims associated with soy protein and the reduced risk of coronary heart disease. Several studies have indicated that a total daily intake of 25 g of soy protein paired with a low-fat diet resulted in clinically important reductions of total cholesterol and low-density lipoprotein (LDL) cholesterol levels. Soybeans are a rich source of isoflavones, a class of phytoestrogens found predominantly in legumes and beans. Soy isoflavones are heterocyclic phenols with structural similarity to estradiol-17β 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. Studies of soy-based diets evaluating the relation between soy consumption and serum lipid concentrations revealed that soy consumption significantly decreased total cholesterol, LDL cholesterol, and triglyceride levels. However, the soy isoflavones do not increase high-density lipoprotein cholesterol or triglyceride levels. The effects of soy protein on other target tissues reflect estrogenlike agonist and antagonist effects. 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. Data available from human studies on the effect of isoflavones on osteoporosis are limited, and additional studies are needed to support a role in osteoporosis prevention. Thus far, there is no evidence for a stimulatory effect of isoflavones on the endometrium. A few studies reveal a minimal effect of soy on hot flashes, with soy reducing hot flashes 45% and placebo causing a 30% re duction compared with an approximate 70% reduction in hot flashes with estrogen replacement therapy. Evidence from laboratory studies reveals neither a positive nor a negative effect of soy isoflavones on cognition. To date, no adverse effects of short- or long-term use of soy proteins are known in humans. The only adverse effects known are those reported in animals (infertility in sheep and quails grazing on phytoestrogen-rich pastures). In conclusion, soy isoflavones are biologically active compounds. Current data are insufficient to draw definitive conclusions regarding the use of isoflavones as an alternative to estrogen for hormone replacement in postmenopausal women. Although epidemiological and basic laboratory studies allude to the possible protective effects of soy isoflavones at specific target tissues, randomized, placebo-controlled clinical trials are necessary to address these important issues.
      CHAT (choline acetyltransferase), DES (diethylstilbestrol), ER (estrogen receptor), ERT (estrogen replacement therapy), FSH (follicle-stimulating hormone), HDL (high-density lipoprotein), LDL (low-density lipoprotein), LH (luteinizing hormone), SERM (selective estrogen receptor modulator), SHBG (sex hormone-binding globulin), UVR (ultraviolet ray)
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        • Adlercreutz H
        • Mazur W
        Phyto-oestrogens and Western diseases.
        Ann Med. 1997; 29: 95-120
        • Maconur W
        Phytoestrogen tent in foods.
        Baillierea Clin Endo-crinol Metab. 1998; 12: 729-742
        • US Department of Agriculture
        Agricultural Research Service. 1999. [USDA Nutrietru Database for Standard Reference. Release 13. Nulrient Da1a Laboratory Home Page.
        (Accessed September 19. 2000.)
        • Yokotruka T
        Soy sauce biochemistry-.
        Adv Food Res. 1986; 30: 195-329
        • Leclercq G
        • Heuson JC
        Physiological and pharmacological effects of estrogens in breast cancer.
        Biochim Biophys Acta. 1979; 560: 427-455
        • Seiche]] KD
        Phytoeslrogens: the biochemistry, physiology, and implications for human health of soy isoflavones.
        Am J Clin Nutr. 1998; 68: 1333S-1346S
        • Axelson M
        • Sjovall J
        • Gustafsson BE
        • Setchell KD
        Soya-a dietary source of the non-steroidal oestrogen equol in man and animals.
        JEndocrinol. 1984; 102: 49-56
        • Joannou GE
        • Kelly GE
        • Reeder AY
        • Waring M
        • Nelson C
        A urinary profile study of dietary phytoeslrogens: the identification and mode of metabolism of new isollavono ids.
        Steroid Biochem Kid Bid. 1995; 54: 167-184
        • Kelly GE
        • Joannou GF
        • Reeder AY
        • Nelson C
        • Waring MA
        The variable metabolic response to dietary isoflavones in humans.
        Proc Soc Exp Biothted. 1995; 208: 40-43
        • Sctchell KD
        • Horriello SP
        • Nulme P
        • Kirk DN
        • Axelson M
        Nonsteroidal estrogens of dietary origin: possible roles in hormone-dependent disease.
        Am J Clin Nutr. 1984; 40: 569-578
        • Markiewiez L
        • Garey J
        • Adlercreutz H
        • Gurpide E
        In vitro bioas-says of non-steroidal phytoestrogens.
        Steroid Biochem Mol Biol. 1993; 45: 399-405
        • Miksicek RJ
        Kstrogenie flavonoids: structural requirements for biological activity.
        Proc Sac Exp Biol Med. 1995; 208: 44-50
        • Kuiper GG
        • Carlsson B
        • Grandien K
        • et al.
        Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors a and β.
        Endocrinology. 1997; 138: 863-870
        • Paech K
        • Webb P
        • Kuiper GB
        • et al.
        Differential ligand activation of estrogen reeeplors 1-ERα and l-ERβ at API sites.
        Science. 1997; 277: 1508-1510
        • Fitzpatrick LA
        Selective estrogen receptor modulators and phytoestrogens: new therapies for the postmenopausa woman.
        Mayo ClinProc. 1999; 74: 601-607
        • Ruiz-Hrrea MB
        • Mohan AR
        • Paganga G
        • Miller NJ
        • Bolwell GP
        • Rice-Evans CA
        Antioxidant actvity of phytoestrogenic isoflavones.
        Free Radic Res. 1997; 26: 63-70
        • Wei H
        • Bowen R
        • Cai Q
        • Barnes S
        • Wang Y
        Ancioxidant and antipromotional elfects of the soybean isoflavone genistein.
        Proc Soc Exp Biothied. 1995; 208: 124-130
        • Mäkelä S
        Chemoprevention of prostate cancer: role of plant estrogens in normal and estrogen-related growth of rodent prostate.
        Turn Yliopiston Jülkaisuja Ann Univ Turkiienis. 1995; 170: 1-1.38
        • Evans BA
        • Griffiths K
        • Morion MS
        Inhibition of 5 alpha-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids.
        J Endocrirol. 1995; 147: 295-302
        • Campbell DR
        • Kurzer MS
        Flavonoid inhibition of aroma1ase enzyme activity in human preadi pocytes.
        J Steroid Biochem M Biol. 1993; 46: 381-388
        • Akiyama T
        • Ishida J
        • Nakagawa S
        • et al.
        Genistein, a specific inhibitor of tyrosine-specilic protein kinases.
        J Biol Cham. 1987; 262: 5592-5595
        • Adlercreutz H
        • Hockerstedt K
        • Bannwart C
        • et al.
        Effect of dieiary components, including lignans and phytoeslrogens on entero-hepatic circulation and liver metabolism of estrogens and on sex hormone binding globulin (SHBG).
        J Steroid Biochem. 1987; 27: 1135-1144
        • Adlercreutz H
        • Hockerstedt K
        • Leannwart C
        • Hämälainen E
        • Fotsis T
        • Bloigu S
        Association between dieiary fiber, urinary excretion of lignans and isoflavonic phytoestrogens and plasma non-protein bound sex hormones in relation to breast cancer.
        in: Bresciani F King RTB Lippman ME Raynaud JP Hormones and Cancer S. Raven Press, New York, NY1988: 409-412 (Progress in Cancer Research and Therapy, vol 35.)
        • Fitzpatrick LA
        • Iitin SC
        • Bell MR
        The Women's Health Initiative: a heart-to-HRf conversation [editorial].
        Mayo Clin Proc. 2000; 75: 559-561
        • Meng QH
        • Iewis P
        • Wähälä K
        • Adlercreutz H
        • Tikkanen MJ
        Incorporation of esterified soybean isoflavones with antioxidant activity into low density lipoprotein.
        Biochim Biophys Acta. 1999; 1438: 369-376
        • Honore ICK
        • Williams JK
        • Anthony MS
        • Clarkson IB
        Soy isoflavoncs enhance coronary vascular reaelivily in atherosclerotic female macaques.
        Fertil Steril. 1997; 67: 148-154
        • Huff MW
        • Roberts DC
        • Carroll KK
        Long-term effects of semi-purified diets containing casein or soy protein isolate on atheroselerosis and plasma lipoproteins in rabbits.
        Atherosclerosis. 1982; 41: 327-336
        • Anthony MS
        • Clarkson TB
        • Bullock BC
        • Wagner JD
        Soy protein versus soy phytoestrogens in the prevention of diet-induced coronary artery atherosclerosis of male eynomolgus monkeys.
        Arlerio-sclerThromb Vase Biol. 1997; 17: 2524-2531
        • Anderson W
        • Johnstone BM
        • Cook-Newell ME
        Meta-analysis of the effects: of soy protein intake on serum lipids.
        N Engl J Med. 1995; 333: 276-282
        • Clarkson TH
        • Anthony MS
        Phytoestrogens and coronary heart disease.
        BaillteresClin Endocrinol Metab. 1998; 12: 589-604
        • Crouse III, JR
        • Terry Jr, G
        • Morgan TM
        • et al.
        Soy protein containing isoflavones reduces plasma concentrations of lipids and lipopro-teins [abstract].
        Circulation. 1998; 97 (Abstract 17.): 816
        • Potter SM
        • Baum JA
        • Teng H
        • Stillman RJ
        • Shay NF
        • Erdman Jr, JW
        Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women.
        Am J Clin Nutr. 1998; 68: 1375S-1379S
        • Nestel PJ
        • Yamashita T
        • Sosahara T
        • et al.
        Soy isoflavones improve systemic arterial compliance hut not plasma lipids in menopausal and perimenopausal women.
        Arterioscler Thromb Vasc Biol. 1997; 17: 3392-3398
        • Hodgson JM
        • Puddey IB
        • Beilin I, J
        • Mori TA
        • Croft KD
        Supplementation with isoflavonoid phytoestrogens does not alter serum lipid concentrations: a randomized controlled trial in humans.
        J Nutr. 1998; 128: 728-732
        • Clarkson TB
        Soy phytoestrogens: what will be their role in postmenopausal hormone replacement therapy? [editorial].
        Menopause. 2000; 7: 71-75
        • Wargreaves PG
        • Licking EF
        • Sargeant P
        • Sage SO
        • Barnes MJ
        • Farndale RW
        The tyrosine kinase inhibitors, genistein and methyl 2,5-dihydrolycinnamate, inhibit the release of (3H)arachidonate from human platelets stimulated by thrombin or collagen.
        Thromh Haemost. 1994; 72: 634-642
        • Nakashima S
        • Koike T
        • Nozawa Y
        Genistein, a protein tyrosine kinase inhibitor, inhibits thromboxane A2-mediated human platelet responses.
        Mol Pharmacol. 1991; 39: 475-480
        • Ozaki Y
        • Yatomi Y
        • Jinnai Y
        • Kume S
        Effects of genistein, a tyrosine kinasc inhibitor, on platelet functions: genistein attenuates thrombin-induced Ca2- mobilization in human platelets by affecting polyphosphoinositide turnover.
        Biochem Pharmacol. 1993; 46: 395-403
        • Schoene NW
        • Guidry CA
        Dietary soy isoflavones inhibit activation of rat platelets.
        J Nutr Biochem. 1999; 10: 421-426
        • Adlerereutz II
        • Mousavi Y
        • Ilöekerstedl K
        Diet and breast cancer.
        Ada Oncol. 1992; 31: 175-181
        • Dunn JE
        Cancer epidemiology in populations of 1he United States with emphasis on Hawaii and California and Japan.
        Cancer Res. 1975; 35: 3240-3245
        • Henderson MM
        Nutritional aspects of breast cancer.
        Cancer. 1995; 76: 2053-2058
        • Adlerereutz H
        Phytoestrogens: epidemiology and a possible role in cancer protection.
        Environ Health Perspect. 1995; 103: 103-112
        • Martin PM
        • Horwilz KW
        • Ryan DS
        • MeGuire WW
        Phytoestrogen interaction with estrogen receptors in human breasi cancer cells.
        Endocrinologl. 1978; 103: 1860-1867
        • Adlcereutz H
        • Fotsis H
        • Ieikkinen R
        • et al.
        Excretion of the lignans enlerolaclone and enlerodiol and of equol in omnivorous and vegetarian postmenopausal women and in women with breast cancer.
        Lancet. 1982; 2: 1295-1299
        • Adlerereulz H
        • Eotsis T
        • Bannwart C
        • et al.
        Determination of urinary lignans and phytoestrogen metabolites, potential antiestrogens and anticarcinogens. in urine of women on various habitual diets.
        J Steroid Biochem. 1986; 25b: 791-797
        • Barnes S
        • Grubbs C
        • Setchell KD
        • Carlson J
        Soybeans inhibit mammary tumors in models of breast cancer.
        Prog Clin Biol Res. 1990; 347: 239-253
        • Lee HP
        • Gourley L
        • Duffy SW
        • Esteve J
        • Le J
        • Day NE
        Dietary-effects on breast-cancer risk in Singapore.
        Lancet. 1991; 337: 1197-1200
        • Peterson G
        • Barnes S
        Genistein inhibition of the growth of human breast cancer cells: independence from eslrogen receptors and the multi-drug resistance gene.
        Biochem Biophys Res Commun. 1991; 179: 661-667
        • Troll W
        • Wiesner R
        • Shellabarger CJ
        • Holtzman S
        • Stone JP
        Soybean diet lowers breast tumor incidence in irradiated rats.
        carcino-genesis. 1980; 1: 469-472
        • Zava DT
        • Bien M
        • Duwe G
        Estrogenic activity of natural and synthetic estrogens in human breast cancer cells in culture.
        Environ Health Perspect. 1997; 105: 637-645
        • Wang TT
        • Salhyamoorthy N
        • Phang JM
        Molecular effects of genistein on estrogen receptor mediated pathways.
        Carcinogenesis. 1996; 17: 271-275
        • Knight DC
        • Eden JA
        A review of the clinical effects of phytoestrogens.
        Obstet Gynecol. 1996; 87: 897-904
        • Fotsis T
        • Pepper M
        • Adlerereutz H
        • et al.
        Genistein, a dietary-derived inhibitor of in vitro angiogenesis.
        Proc Natl Acad Sci U S A. 1993; 90: 2690-2694
        • Colditz GA
        • Ilankinson SH
        • Hunter DJ
        • et al.
        The use of estrogens and progestins and the risk of breast cancer in postmenopausal women.
        N Engl J Med. 1995; 332: 1589-1593
        • Collaborative Group on Hormonal Factors in Breast Cancer
        Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52.705 women with breast cancer and 108.411 women without breast cancer [published correction appears in Lancet. 1997:350:1484].
        Lancet. 1997; 350: 1047-1059
        • Schairer C
        • Lubin J
        • Troisi R
        • Sturgeon S
        • Brinton L
        • Hoover R
        Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk.
        JAMA. 2000; 283: 485-491
        • Bush TE
        • Whiteman MK
        Hormone replacement therapy and risk of breast cancer [editorial].
        JAMA. 1999; 281: 2140-2141
        • Nagata C
        • Kabuto M
        • Kurisu Y
        • Shimizu H
        Decreased serum estradiol concentration associated with high dietary intake of soy products in premenopausal Japanese women.
        Nutr Cancer. 1997; 29: 228-233
        • Cassidy A
        • Bingham S
        • Setchell KD
        Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women.
        Am J Clin Nutr. 1994; 60: 333-340
        • Lu LJ
        • Anderson KE
        • Grady JJ
        • Xagamani M
        Effects of soya consumption for one month on steroid hormones in premenopausal women: implications for breast cancer risk reduction.
        Cancer Epidemiol Biomarkers Prev. 1996; 5: 63-70
        • Hargreaves DF
        • Potten CS
        • Harding C
        • et al.
        Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast.
        J Clin Endocrinol Metab. 1999; 84: 4017-4024
        • Zheng W
        • Dai Q
        • Coster LJ
        • et al.
        Urinary excretion of isoflavonoids and the risk of breast cancer.
        Cancer Epidemiol Biomarkers Prev. 1999; 8: 35-40
        • Arjmandi BH
        • Alekel L
        • Hollis BW
        • et al.
        Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis.
        J Nutr. 1996; 126: 161-167
        • Blair HC
        • Jordan SE
        • Peterson TB
        • Barnes S
        Variable effects of tyrosine kinase inhibitors on avion osteoclastic activity and reduction of bone loss in ovariectomized rats Jcell.
        Biochem. 1996; 61: 629-637
        • Anderson JJ
        • Garner SC
        Phytoestrogens and bone.
        Batliieres Clin Endocrinol Metab. 1998; 12: 543-557
        • Tsutsumi N
        Effect of coumestrol on bone metabolism in organ culture.
        Biol Pharm Bull. 1995; 18: 1012-1015
      1. Bonaeeorsi Ci. Albertazzi P. Constantino D. Soy phytoestrogens and bone [abstract]. In: Program and Abstracts of the North American Menopause Society Meeting: September 2-5. 1997: Washington. DC: 44.

        • Atkinson C
        • Compston JE
        • Robins SP
        • Bingham SA
        The effects of isoflavone phytoestrogens on bone: preliminary results from a large randomized controlled trial [abstract].
        Endocr Soc Annu Meet Program Abstr. 2000; 12: 43
        • Shaywitz SE
        • Shaywitz BA
        • Pugh KR
        • et al.
        Effect of estrogen on brain activation patterns in postmenopausal women during working memory lasks.
        JAMA. 1999; 281: 1197-1202
        • Simpkins JW
        • Singh M
        • Bishop J
        The potential role for estrogen replacement therapy in the treatment of the cognitive decline and neurodegeneration associated with Alzheimer's disease.
        Neurobiol Aging. 1994; 15: S195-S197
        • Pan Y
        • Anthony M
        • Clarkson TB
        Effect of estradiol and soy phiytoestrogens on choline acetyltransferase and nerve growth factor mRNAs in the frontal cortex and hippocampus of female rats.
        Proc Soc Exp Biol Med. 1999; 221: 118-125
        • Murphy DD
        • Segal M
        Regulation of dendritic spine density in cultured rat hippocampal neurons by steroid hormones.
        J Xeurosci. 1996; 16: 4059-4068
        • Clarkson TB
        Can soy phiytoestrogens substitute for traditional hormone replacement therapy?.
        Menopausal Meet. 1997; 5: 1-4
        • Foth D
        • Cline JM
        Effects of mammalian and plant eslrogens on mammary glands and uteri of macaques.
        Am J Clin Nutr. 1998; 68: 1413S-1417S
        • Duncan AM
        • Underbill KE
        • Xu N
        • Iavalleur J
        • Phipps WR
        • Kurzer MS
        Modest hormonal effects of soy isoflavones in postmenopausal women [published correction appears in.]Clin J Endocrinol Metab. 2000;85:448].
        J Clin Endocrinol Metab. 1999; 84: 3479-3484
        • Mesiano S
        • Katz SL
        • Lee JB
        • Jaffe RB
        Phytoestrogens alter adrenocortical function: genislein and daidzein suppress glucocorticoid and stimulate androgen production by cultured adrenal cortical cells.
        J Clin Endocrinol Melah. 1999; 84 (2418): 2443
        • Duncan AM
        • Merz BE
        • Xu X
        • Nagel TC
        • Phipps WR
        • Kurzer MS
        Soy isollavones elert modest hormonal effects in premenopausal women.
        J Clin Endocrinol Metab. 1999; 84: 192-197
        • Brezinski A
        • Adlerzreutz H
        • Shaoul R
        • et al.
        Short-term effects of phytoestrogen-rich diet on postmenopausal women.
        Menopause. 1997; 4: 89-94
        • Whitten PL
        • Nallolin F
        Reproductive actions of phytoestrogens.
        Baillieres Clin Endocrinol metab. 1998; 12: 667-690
        • Baird DD
        • Umbach DM
        • Iansdell I
        • et al.
        Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women.
        J Clin Endocrinol Metab. 1995; 80: 1685-1690
        • Chung TK
        • Yip SK
        • Lqun P
        • Chang AM
        • Haines CJ
        A randomized. double-blind, placebo-controlled, crossover study on lhe effect of oral oestradiol on acute menopausai symptoms.
        Maturitas. 1996; 25: 115-123
        • Murkies AL
        • Lombard C
        • Strauss BJ
        • Wilcox G
        • Burger HG
        • Morton MS
        Dietary Hour supplementation decreases poslmeno-pausal hot Hushes: effect of soy and wheat.
        Maturitas. 1995; 21: 189-195
        • Albertazzi P
        • Pansini F
        • Bonaccorsi G
        • Zanotti L
        • Forini E
        • De Aloysio D
        The effect of dietary soy supplementation on hot flushes.
        Obstet Gynecot. 1998; 91: 6-11
        • Quella SK
        • Ioprinzi CL
        • Barton DL
        • et al.
        Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: a North Central Cancer Treatment Group Trial.
        J Clin Oncol. 2000; 18: 1068-1074
        • Cai Q
        • Wei H
        Effect of dietary genistein on antioxidant enzyme activities in SKNCARmice.
        Slur Cancer. 1996; 25: 1-7
        • Wei II
        Photoprotective action of isoflavone genistein: models, mechanisms, and relevance to clinical dermatology.
        J Am acad Dermatol. 1998; 39: 271-272
        • Köhler L
        • Meeuwisse G
        • Mortensson W
        W. Food intake and growth of infants between six and twenty-six weeks of age on breast milk cow's milk formula, or soy formuki.
        Acta Paediatr Scand. 1984; 73: 40-48
        • Moule GR
        • Braden AH
        • Lamond DR
        The significance of oestrogens in pasture plants in relation to animal production.
        Anim Breed Abstr. 1963; 32: 139-157
        • Setchell KD
        • Gosselin SJ
        • Welsh MB
        • et al.
        Dietary estrogens a probable cause of infertility and liver disease in captive cheetahs.
        Gastroenterology. 1987; 93: 225-233
        • I-eopold AS
        • Envin M
        • Oh J
        • Browning B
        Phytoestrogens: adverse effects on reproduction in California quail.
        Science. 1976; 191: 98-100