Vademecum

NOTE: In the US, nutraceuticals are marketed under the Dietary Supplement and Health Education Act of 1994 (DSHEA). Consequently, scientific data supporting claimed benefit(s) are not always available for nutraceuticals as they are for traditional pharmaceuticals since nutraceuticals are not regulated as drugs. Consumers should also note that rigid quality control standards are not required for nutraceuticals and substantial variability can occur in both the potency and the purity of these products. Monographs on nutraceuticals are included in CP when reliable clinical data are available. The information presented below is condensed from the best clinical data we could find. Description: Soy isoflavones are phenolic phytoestrogens extracted from the soybean, Glycine max, a member of the legume family. The soy isoflavones are present in the plant as glycosides; once ingested, they yield the active isoflavonoids daidzein, genistein, and glycetin. Foods such as tofu, tempeh, miso, textured vegetable protein, soy milk and soy cheese are rich in soy isoflavones; soy sauce is not a significant source. Genistein and daidzein are also found in lesser amounts in natural foods such as chickpeas, lentils, and beans, as well as herbs (see Red clover monograph). Epidemiologically, high consumption of soy is associated with low rates of cardiovascular disease, hormone-dependent cancers, and menopausal symptoms.[3035] In October 1999, the FDA authorized health claims for reduced risk of heart disease on foods containing at least 6.25 g/serving of soy protein, if the food also meets low fat, low saturated fat, and low cholesterol requirements. Whole soy-foods (e.g., tofu), may also qualify if they contain no added fat (i.e., other than soybean-derived fat). Soy isoflavone supplements are claimed to reduce hot flashes during menopause, maintain bone density, maintain prostate health, and to promote cardiovascular health. However, these health claims need to be sufficiently evaluated scientifically. Mechanism of Action: The pharmacology of soy isoflavones is complex; both hormonal and nonhormonal actions contribute to their activity on various tissues. Clinical data in humans are primarily from trials of total soy protein versus study of the isolated, extracted isoflavones. Comparisons of studies are difficult due to the variability in the source materials administered and the dosage of the soy isoflavones. Thus, some of the clinical pharmacologic effects of soy-based foods may be different from those that occur with the isolated and concentrated soy isoflavones found in dietary supplements. �Effects on the menstrual cycle and menopausal symptoms: The soy isoflavones have a diphenolic structure similar to that of the potent synthetic and natural estrogens. All isoflavones are competitive ligands of in vitro estrogen receptor assays and appear to function as selective estrogen receptor modifiers (SERMs).[3035] However, the estrogenic potencies of the soy isoflavones genistein and daidzein are much weaker (roughly <= 1/50 of the potency) than that of native estradiol. The daidzein metabolite equol has higher estrogenic potency than either genistein or daidzein. Soy isoflavones appear to have greater affinity for the beta-estradiol receptor than the alpha-estradiol receptor; beta-estradiol receptors are concentrated in the heart, vasculature, bone, and bladder, but their role in physiology compared to alpha-estradiol receptors is not yet determined. The relative selectivity of the soy isoflavones for the beta-estradiol receptor may explain some of the pharmacologic differences of soy relative to natural estrogens. Epidemiologically, menopausal female populations regularly consuming soy isoflavones exhibit a lower incidence of hot flashes than Western societies with low dietary intakes.[3036] In healthy, premenopausal women, the soy isoflavones do not appear to have significant effects on the different phases of the menstrual cycle or on serum hormones in doses up to 128 mg/day PO.[3037] The effects on plasma hormones, compared to the known effects of estrogens, appear modest.[3038] Significant estrogen-like effects on endometrial or vaginal tissues do not occur, even at isoflavone doses of 2 mg/kg/day PO.[3039] Trials of various soy isoflavones in menopausal women have been equivocal. One trial of soy protein isolate failed to report significant reductions in the frequency of vasomotor symptoms; however, symptom severity was decreased in some women.[3040] In another study, soy protein powder reduced the average number of hot flashes by 15% over placebo, but other menopausal symptoms, as assessed by the Kupperman index, were unaltered.[3041] �Effects on bone density: Limited animal and human data suggest that phytoestrogens may be beneficial for maintaining bone density.[3042] Epidemiologically, female populations consuming soy isoflavones regularly in the diet exhibit a lower incidence of bone density loss and fractures with age than Western societies with low dietary intakes.[3036] The beta-estrogen receptors are found in the bone and genistein binds to this receptor, which may result in estrogen-like actions similar to the selective estrogen receptor modulators (SERMs). Much of the data concerning the positive effects of isoflavones on bone density comes from study of ipriflavone, an isoflavone derivative used medicinally at doses much higher than those usually achieved with dietary intake of soy. Authorities caution against extrapolating results of ipriflavone studies to the actions of the natural soy isoflavones.[3035] In one trial of soy protein isolate (containing isoflavones), small, but clinically insignificant, increases in bone formation and decreases in bone resorption occurred in postmenopausal women after 3 months of treatment.[3043] Evidence of fracture risk reduction is not available. �Effects on the cardiovascular system: Most studies have reported a reduction in both total and LDL cholesterol following the addition of soy protein to a low fat, low cholesterol diet; however, the effects of the isolated soy isoflavones on serum lipids have not been consistent in clinical trials.[3044] Populations consuming >= 25 g/day of intact soy protein, as part of a diet low in saturated fat and cholesterol, typically have a lower incidence of CHD than societies with lower intakes.[3044] The mechanisms of cholesterol reduction are unclear; soy isoflavones probably modulate the metabolism of cholesterol and other lipids to some degree. The soy isoflavones appear to have estrogenic, antioxidant, and anti-atherosclerotic actions (e.g., effects on platelet activation and intimal lesion development) in vitro that may contribute to the role of the soy-foods in cardioprotection.[3035] [3036] Clinical trial data suggest that there is synergy among the active components of the soybean to achieve maximum cardiovascular health benefits; ingestion of soy isoflavones alone may not be as effective.[3044] �Chemoprevention: Epidemiologically, populations that consume roughly 50 mg/day of soy isoflavones exhibit a lower incidence of breast and prostate cancer than Western societies with low dietary intakes. The pharmacologic actions of the isoflavones lend credence to their chemoprotective potential. Soy isoflavones appear to alter the plasma concentration, production, metabolism and excretion of testosterone and estrogens; they also appear to alter the impact of hormones and other factors on target tissues. The mechanisms involve hormonal and non-hormonal actions.[3036] The soy isoflavones increase the hepatic production of sex-hormone binding globulin (SHBG), which decreases the bioavailability (and the biological effects) of testosterone (males) and estrogens (females).[3036] In females, the isoflavones may exhibit modest anti-estrogenic or pro-estrogenic effects depending on the baseline estrogen environment, but exact actions have yet to be determined, and study results are not consistent.[3036] In vitro, both genistein and daidzein inhibit 5alpha-reductase isoenzyme II, resulting in decreased conversion of testosterone to the potent androgen 5-alpha-dihydrotestosterone (DHT) and a subsequent reduction in testosterone-dependent tissue proliferation.[3036] The action is similar to that of finasteride, but is thought to be less potent. The proliferation of mammary and prostatic tumors in vitro has been significantly reduced by genistein, suggesting activity on intracellular enzymes, protein synthesis, or growth factors and a resultant antimetastatic effect. In vitro, genistein inhibits the growth of certain cancer cell lines via apoptosis (programmed cell death) and inhibits angiogenesis.[3036] Genistein also has an inhibitory effect on cytoplasmic tyrosine kinases and topoisomerase I and II; the end result may be the disruption of cancer-initiating processes.[3036] The actions of the isoflavones on female breast tissue proliferation are unresolved and require further scientific study; some actions of the soy isoflavones on breast tissue may be independent of the estrogen receptor. There is some concern that genistein, under certain clinical conditions in vivo, would unfavorably influence the risk of breast cancer.[3036] The effects of soy isoflavones may be beneficial to prostate tissues, but in vitro results require clinical confirmation in vivo. �Effects on thyroid regulation: Soy isoflavones may have antithyroid-like actions on thyroid metabolism. The soybean has been implicated in diet-induced goiter in several trials, mostly in populations where nutritional deficiencies, like iodine deficiency, coexist and there is high ingestion of soy-based formula in infancy and a largely vegetarian diet. The soy isoflavones genistein and daidzein appear to block thyroid hormone production by interfering with thyroid peroxidase catalyzed iodination of thyroglobulin.[3045] Pharmacokinetics: Soy isoflavones are administered orally. After ingestion, the soy isoflavones undergo enzymatic conversion by glucosidases produced by the bowel microflora; the process yields the active heterocyclic isoflavonoids (primarily genistein and daidzein, but also the minor isoflavonoid glycetin). The isoflavones are absorbed from the intestine as either glucuronides or aglycones (i.e., unconjugated forms), and undergo significant first-pass metabolism in the liver. Most isoflavones circulate in human blood in the glucuronide form. The aglycones are primarily (>= 50%) bound to serum albumin.[3046] The peak plasma levels of the soy isoflavones occur roughly 4�8 hours after oral ingestion. The disposition of the soy isoflavones in humans is still poorly understood. The metabolism of the soy isoflavones is highly variable from individual to individual, and may represent variable metabolic capacities or pathways.[3047] Genistein undergoes some enterohepatic circulation. Metabolites of daidzein include equol and O-desmethylangolensin (O-Dma). The serum half-lives of genistein and daidzein are roughly 9�12 hours; urinary recovery of a single ingested dose is typically complete within 24�48 hours. The half-lives of the equol and O-Dma are substantially longer than those of the parent compound. The kidneys and liver eliminate the soy isoflavones primarily as glucuronides and sulfates.[3046] Some researchers have correlated the amount of soy consumption to the level of urinary isoflavonoid excretion, but given the great individual variability in metabolism, comparisons may be difficult. Metabolites are found primarily in the urine, but some genistein may be lost in the feces with enterohepatic cycling. �Special populations: The soy isoflavones (e.g., genistein and daidzein) may accumulate in severe renal impairment (i.e., CrCl <= 30 ml/min). After ingestion, isoflavone blood concentrations remain elevated for several days due to the lack of renal excretion. The elimination half-life of the isoflavones in those with end-stage renal disease is roughly 10-times longer than in those patients with normal renal function, but individual variability can occur. Soy isoflavones are not removed by hemodialysis; this is not unexpected given the high molecular weight (> 330 daltons) of circulating isoflavone conjugates and the high percentage of aglycones that are bound to serum albumin.[3048] At this time, no data are available to describe the clearance of soy isoflavones in those patients with hepatic disease.

Indications...Dosage For the reduction of hot flashes�: NOTE: Soy isoflavone supplements have not been evaluated by the FDA and are not intended to diagnose, treat, cure, or prevent any disease. �for reducing hot flashes� associated with menopausal symptoms�: Oral dosage (general dose recommendations for hot-flashes�): Adult females: 34�76 mg/day PO of soy isoflavones, or intact soy protein 20�60 g/day PO has been used. In one study there was a modest reduction in the severity, but not the number, of daily hot flashes.[3040] In another trial, soy protein powder (with 76 mg/day of soy isoflavones) reduced the frequency of daily hot flashes by 15% over placebo, but other symptoms (per Kupperman index) were unaltered.[3041] Oral dosage (Healthy Woman� Soy Menopause): Adults: 1 tablet (55 mg of soy isoflavones) PO once per day with food. Oral dosage (Natrol� for Women� Soy Isoflavones): Adults: Take 1�4 capsules/day (each capsule contains 10 mg soy isoflavones) in divided doses with meals (manufacturer recommendation). �for the treatment of hot flashes� in breast cancer survivors: Oral dosage (general dose recommendations): Adult females: 50 mg/day PO of soy isoflavones failed to reduce hot flash frequency or intensity in one study.[3049] NOTE: The safety of soy isoflavones in those with breast cancer is still uncertain. For for peri- or postmenopausal osteoporosis prophylaxis�: NOTE: Soy isoflavone supplements have not been evaluated by the FDA and are not intended to diagnose, treat, cure, or prevent any disease. Oral dosage (general dose recommendations for bone health): Adult females: Clinical data are limited. Soy protein isolate (containing 90 mg/day soy isoflavones) PO resulted in increased bone mineral density of the lumbar spine at 6 months in one study.[3042] Oral dosage (Healthy Woman� Soy Menopause): Adults: 1 tablet (55 mg of soy isoflavones) PO once per day with food. Oral dosage (Natrol� for Women� Soy Isoflavones): Adults: Take 1�4 capsules/day (each capsule contains 10 mg soy isoflavones) in divided doses with meals. Oral dosage (Caltrate� 600 plus Soy): Adults: 1 tablet (600 mg calcium, 200 IU vitamin D, and 25 mg soy isoflavones) PO twice daily with food. Oral dosage (One-A-Day� Bone Health): Adults: 1�2 tablets (each tablet contains 500 mg calcium, 100 IU vitamin D, and 28 mg soy extract) PO once daily with food. For nutritional supplementation� to promote cardiovascular health, or as an adjunct to a low-fat, low-cholesterol diet for the treatment of hypercholesterolemia�: NOTE: Soy isoflavone supplements have not been evaluated by the FDA and are not intended to diagnose, treat, cure, or prevent any disease. Oral dosage (general dose recommendations): Adults: The AHA has announced that >= 25 g/day PO of intact soy protein, as part of a diet low in saturated fat and cholesterol, may reduce LDL cholesterol by 4�8% and decrease the risk of CHD.[3044] Data suggest that soy isoflavone supplements are less effective at lowering cholesterol than soy protein isolates.[3044] In one study 55 mg/day PO of a soy isoflavones supplement failed to reduce serum lipids.[3050] Children: Dietary supplements are not recommended. Maximum Dosage Limits: �Adults: Maximum dosage information is not available. �Elderly: Maximum dosage information is not available. �Adolescents: Safety and efficacy have not been established. �Children: Safety and efficacy have not been established. Patients with hepatic impairment: It is not known if dosage adjustment is needed in hepatic impairment. Patients with renal impairment: CrCl > 30 ml/min: No dosage adjustment needed. CrCl <= 30 ml/min: Soy isoflavones may accumulate; specific guidelines for dosage adjustments are not available. Intermittent hemodialysis: Soy isoflavones may accumulate; hemodialysis does not remove the soy isoflavones from the blood. �non-FDA-approved indication

NOTE: Potency for nutraceutical products can vary substantially from manufacturer to manufacturer. The use of standardized product from a reliable manufacturer is recommended. Oral Administration �Administered orally, usually with food.

Contraindications Extracted soy isoflavones have not been evaluated by the Food and Drug Administration. Supplement products containing soy isoflavones are not intended to diagnose, treat, cure, or prevent any disease. Consumers should also be informed that rigid quality control standards are not required for nutraceuticals and substantial variability can occur in both the potency and the purity of these products. Soy isoflavones are contraindicated for use in patients who exhibit allergies to soybeans, soy protein, or soya lecithin hypersensitivity. Caution should be used in those with peanut oil hypersensitivity or hypersensitivity to other members of the legume-family. Dietary recommendations for soy intake are based on adult data; no specific recommendations are available for the pediatric population. Extracted soy isoflavone supplements are not recommended for use in children or infants, due to the concentration of the isoflavones in these products. Children or infants with soy protein-related asthma or atopy (not common in adults) should not be given soy isoflavones. Perimenopausal and menopausal females are encouraged to consult their health care professionals regarding the approach to menopause that is best for them individually. Due to a lack of long-term study of the effects of isolated soy isoflavones, self-treatment should not exceed 3�6 months without the supervision of a health care professional. Females taking hormonal regimens (e.g., estrogens or hormonal contraception) should consult their health care professional prior to use of soy isoflavones. Patients with hormone-responsive breast cancer are encouraged to consult their health care professionals before the use of soy isoflavones. No controlled, scientific studies have determined the clinical effects of soy isoflavones or phytoestrogens on breast cancer or the proliferation of human breast tissue. The effect of genistein on breast tissue, in particular, is a topic of scientific debate that can only be resolved by further research. While the phytoestrogenic effects of soy isoflavones on the menstrual cycle in premenopausal females appear to be of minimal concern, soy isoflavone supplements are best avoided by women who are receiving infertility treatments until further study is performed. Soy isoflavones, when concentrated in therapeutic supplements, have the potential for hormone-like actions and are not recommended for use during pregnancy. In animal studies, the high-level consumption of the soy isoflavone genistein has resulted in decreased birth weights, decreased anogenital distances at birth, and delayed onset of puberty. There is no experience with concentrated soy isoflavones in human pregnancy. However, soy-based foods are generally recognized as safe for consumption. Until more information on the soy isoflavones is available, therapeutic products containing soy isoflavones are not recommended for use during breast-feeding, due to the concentration of the isoflavones in these products. Soy isoflavones are transferred to human milk. Ingestion of soy-based foods usually results in less passage of soy isoflavones than would normally be found in soy-based infant formulas, and thus soy-foods are generally recognized as safe for consumption during lactation. Soy isoflavones may accumulate in severe renal impairment (CrCl < 30 ml/min) or renal failure. After ingestion, soy isoflavone blood concentrations remain very high for several days due to the lack of renal excretion. Soy isoflavones are not removed by dialysis. Until the routes of elimination of soy isoflavones are well known, these phytoestrogens should be used cautiously by patients with hepatic disease. The soy isoflavones are conjugated by the liver to glucuronides and sulfates. It is not clear if soy isoflavones can improve benign prostatic hypertrophy (BPH) or reduce the risk of prostate cancer; more research is needed. BPH is not a self-limiting condition and should not be self-diagnosed; self-treatment could delay the detection of a serious urinary tract problem. Epidemiologically, consumption of roughly 50 mg/day PO of soy isoflavones is associated with a low incidence of prostate cancer. Males are encouraged to consult their health care professionals regarding the approach to treatment that is best for them individually prior to consuming soy isoflavones supplements. Preliminary data suggest that men with prostate CA can include soy protein in the diet safely (i.e., low PSA levels at 6-months post prostatectomy); however, final conclusions will not be available for several years.[3051] In one study of patients with diagnosed prostate cancer, soy isoflavones did not reduce serum PSA or other biomarkers of the disease.[3052] Patients with thyroid disease, under selected circumstances, should consume soy isoflavones with caution. Soy isoflavones, in the presence of iodine deficiency, appear to block thyroid hormone production by interfering with thyroid peroxidase catalyzed iodination of thyroglobulin.[3045]

Interactions No drug interactions with the isolated soy isoflavones have been reported. However, it is possible that soy isoflavones may affect drug absorption and biliary excretion via interference with drug transporters such as intestinal P-glycoprotein, and may also inhibit oxidative and conjugative metabolism of some drugs. Antibiotics (e.g., clindamycin, macrolides, neomycin, tetracyclines) may interfere with the metabolism of the soy isoflavones. Bacteria in the intestine produce enzymes which hydrolyze the soy isoflavones to the active isoflavonoids genistein and daidzein. Some antibiotics significantly reduce the GI flora and could essentially prevent the formation of the active components of the soy isoflavones. Theoretically, the soy isoflavones may compete with drugs that have estrogenic activity or which selectively modulate estrogen receptors. Soy isoflavones should be used with caution in patients taking estrogens or combination hormonal oral contraceptives. Theoretically, the soy isoflavones may compete with drugs that selectively modulate estrogen receptors. Soy isoflavones should be used with caution in patients taking SERMS (e.g., clomiphene, raloxifene, tamoxifen, or toremifene). Theoretically, because the soy isoflavones appear to inhibit type II 5-alpha-reductase, the soy isoflavones may counteract the activity of the androgens or may have additive effects with finasteride. Until more data are available, caution is warranted when coadministering soy isoflavones with thyroid hormones in selected circumstances. Soy isoflavones may reduce thyroid hormone production by interfering with thyroid peroxidase catalyzed iodination of thyroglobulin. TSH secretion may increase. Red clover, Trifolium pratense is an herb belonging to the legume family; red clover contains phytoestrogenic isoflavones. The isoflavones from red clover would be additive with the soy isoflavones. A daily maximum recommended intake of genistein or daidzein has not been established.

Adverse Reactions Adverse reactions of the isolated, extracted soy isoflavones are unclear at this time. Manufacturers have not reported adverse reactions or intolerances; side effects have not been reported to the FDA special nutritional adverse event monitoring system. Evidently, no changes in uterine bleeding patterns or endometrial thickness have been observed (manufacturer data). However, more study is needed to assess the effects of the soy isoflavones on both female and male urogenital tissues. As with any plant derived product, allergic reactions [e.g., asthma-like dyspnea or anaphylactoid reactions, rash (unspecified), pruritus, or urticaria] to soy are potentially possible. Such reactions have been reported with the use of soy protein isolates and other soy protein supplements. It is unclear if extracted soy isoflavones would also cause allergic reactions; however, such side effects appear to be possible. In those who ingest isolated soy protein powders as their source of soy isoflavones, GI side effects are fairly common. Roughly 25% will discontinue use of such soy-powders due to constipation, bloated or "gassy" feelings (flatulence), dyspepsia, or nausea/vomiting. Non-IgE mediated allergic reactions, such as disturbances of the GI tract (e.g., diarrhea), may occur in response to ingestion of soy products. In sheep, the isoflavones genistein and daidzein, which are also found in red clover as well as soybeans, may result in "clover disease". The consumption of large amounts of red clover leads to reproductive disturbances (e.g., infertility) thought to be related to the conversion of the isoflavones to equol by the ovine intestinal flora. The problem appears to be specific for the ovine population. No adverse effects on fertility have been observed in humans. The soybean has been implicated in diet-induced goiter in several trials, mostly in populations where nutritional deficiencies, like iodine deficiency coexist. The soy isoflavones genistein and daidzein appear to block thyroid hormone production by interfering with thyroid peroxidase catalyzed iodination of thyroglobulin; the action may cause goiter in susceptible patients.[3045]

Soy Isoflavones CloverSoy�, Healthy Woman� Soy Menopause, Natrol� for Women� Soy Isoflavones, Nature Made� Soy 50 | Caltrate� 600 plus Soy | Naturade Total Soy Calcium 1000 Meal Supplement | One-A-Day� Bone Strength

3035. Tham DM et al. Potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrin Metab 1998;83:2223�35.

3036. Aldercreutz H, Mazur W. Phyto-estrogens and western diseases. Annals of Medicine 1997;29:95�120.

3037. Duncan AM, Merz BE, Xu X. et al. Soy isoflavones exert modest hormonal effects in premenopausal women. J Clin Endocrin Metab 1999;84:192�7.

3038. Ginsburg J, Prelevic GM. Lack of significant hormonal effects and controlled trials of phytoestrogens. Lancet 2000;355:1633�64.

3039. Duncan AM, Merz BE, Xu X. et al. Soy isoflavones exert modest hormonal effects in postmenopausal women. J Clin Endocrin Metab 1999;84:3479�484.

3040. Washburn S, Burke GL, Morgan T. et al. Effect of soy protein supplementation on serum lipoproteins, blood pressure and menopausal symptoms in perimenopausal women. Menopause 1999;6:7�13.

3041. Albertazzi P, Pansisni F, Bonaccorsi G, et al. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998;91:6�11.

3042. Potter SM, Baumm JA, Teng H, et al. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr 1998;68(suppl):1375S�9S.

3043. Wangen KE, Duncan AM, Merz-Demlow BE, et al. Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women. J Clin Endocrin Metab 2000; 85:3043�3048.

3044. Erdman JW and the AHA Nutrition committee. Soy protein and cardiovascular disease - a statement for healthcare professionals from the nutritional committee of the AHA. Circulation 2000;102:2555�9.

3045. Divi RL, Chang HC, Doerge Dr. Anti-thyroid isoflavones from soybean; isolation, characterization, and mechanisms of action. Biochem Pharmacol 1997;54:1087�96.

3046. Doerge DR, Chang HC, Churchwell MI, et al. Analysis of soy isoflavone conjugation in vitro and in human blood using liquid chromatography-mass spectrometry. Drug Metab Dispos 2000; 28:298�307.

3047. Kelly GE, Joannou GE, Reeder Ay et al. The variable metabolic response to dietary isoflavones in humans. Proc Soc Exp Biol Med 1995;208(1):40�3.

3048. Fanit P, Sawaya BP, Custer LJ et al. Serum levels and metabolic clearance of the isoflavones genistein and daidzein in hemodialysis patients. J Am Soc Nephrol 1999;10:864�71.

3050. Hodgson JM, Pudey IB, Belin LJ et al. Supplementation with soy isoflavinoid phytoestrogens does not alter serm lipid concentrations: a randomized controlled trial in humans. J Nutr 1998;128:728�32.

3049. Quella SK, Loprinzi 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�74.

3051. Yip I, Heber D, Aronson W, et al. Nutrition and prostate cancer. Urol Clin North Am 1999;26:403�11.

3052. Urban D, Irwin W, Kirk M, et al. The effect of isolated soy protein on plasma biomarkers in elderly men with elevated prostate specific antigen. J Urol 2001;165:294�300.