簡易檢索 / 詳目顯示

研究生: 黃秋薇
Chiu-Wei Huang
論文名稱: Isoflavones對賀爾蒙補充治療之停經婦女血脂與脂蛋白及尿液雌激素代謝物的影響
The effect of supplementation with isoflavones on plasma lipids, lipoproteins and urinary estrogen metabolites in postmenopausalwomen with hormone replacement therapy
指導教授: 吳文惠
Wu, Wen-Huey
學位類別: 碩士
Master
系所名稱: 人類發展與家庭學系
Department of Human Development and Family Studies
論文出版年: 2000
畢業學年度: 88
語文別: 中文
中文關鍵詞: isoflavones、賀爾蒙補充治療、三酸甘油酯、膽固醇、LDL氧化性、2OHE1、16αOHE1
英文關鍵詞: isoflavone, HRT(Hormone replacement therapy), 2OHE1,16αOHE1, LDL oxidation .
論文種類: 學術論文
相關次數: 點閱:229下載:9
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報
  • 本研究目的主要探討isoflavones的攝取對於有接受賀爾蒙補充治療之停經後婦女血脂、尿液中雌激素代謝物2-hydroxyestrone (2OHE1)、16α-hydroxyestrone(16αOHE1)濃度及其比值2OHE1 /16αOHE1(乳癌生化指標)與抗氧化性的影響,以期了解isoflavones在保護心血管疾病與抗癌上的效果。
    自醫院募集停經一年以上、身體健康且無服用isoflavones相關產品之停經婦女35名,受試者需接受賀爾蒙治療至少3個月以上,且方式為每天服用premarin 0.625毫克及provera 5毫克。實驗設計為單盲比較試驗,實驗前先給予每天6克的麥芽糊精作為安慰劑共14天,之後改服用純化自黃豆胚軸的isoflavones製劑,每天6克(約可攝取到114毫克isoflavones)共28天。實驗前後各採集一次空腹血液及早晨起床後第一次尿液,分析血漿及各種脂蛋白中的三酸甘油酯、膽固醇含量、血漿中總抗氧化狀態、isoflavones濃度、LDL氧化遲滯期和TBARS產生量與尿液中isoprostane、2OHE1、16αOHE1等含量的測量。
    結果顯示服用isoflavones後血漿中daidzein濃度較基礎期明顯增加,然而血漿與各種脂蛋白中的膽固醇、三酸甘油酯並沒有顯著影響,但HDL-C濃度及LDL-C/ HDL-C比值則分別在服用isoflavones後顯著增加及減少。儘管血漿總抗氧化狀態與尿液中isoprostane濃度並無顯著差異但LDL體外氧化實驗則能夠延長氧化遲滯期並減少TBARS產生量。而尿液中雌激素代謝物分佈於服用isoflavones前後並無顯著差異。由本研究結果來看,isoflavones可上升HDL-C,進而下降LDL-C/ HDL-C比值,且能增加LDL體外氧化耐受性及下降TBARS產生量,對停經後婦女在心血管疾病的預防上或許是有助益的,但對尿液雌激素代謝物則無影響。

    Isoflavones are soy phytoestrogens that have been suggested to be cardioprotective and anticarcinogenic. The aims of this trial were to determine the effect of supplementation with isoflavones on plasma lipids, oxidisability of low density lipoprotein ex vivo and two major urinary estrogen metabolites ( as a biomarker for breast cancer risk ) in postmenopausal women with hormone replacement therapy. Thirty-five apparently healthy postmenopausal women having taken combined continuous hormone replacement therapy (premarin 0.625mg, provera 5mg) for at least 3 monthes participated in a single-blind trial. An initial 14-day placebo period of supplementation with maltodextrin was followed by 28 -day periods of supplementation with 114mg isoflavones per day . Venous blood and fist morning urine sample were collected initially and at the end of isoflavone supple-mentation. Supplementation resulted in a 5-fold increase in plasma daidzein concentration. No changes in the plasma concentrations of total cholesterol , triglyceride or total antioxidant status and the urinary excretion of isoprostane or the estrogen metabolites : 2-hydroxyestrone, 16α-hydroxyestrone were observed following supplementation. However an significant beneficial effect was noted for the concentration of HDL-C or LDL-C /HDL-C ratio and in the oxidisability of LDL.The results suggest that isoflavones ameliorate the cardiovascular risk in postmenopausal women, but no effect on urinary estrogen metabolism.

    中文摘要 Ⅰ 英文摘要 Ⅱ 第一章 前言 1 第二章 文獻探討 3 一、 Isoflavones的簡介 3 (一) Isoflavones的發現與化學結構 3 (二) Isoflavones的消化吸收與生物利用率 5 二、 Isoflavones的生理作用 10 (一) 賀爾蒙的影響 10 (二) 抗氧化作用 14 (三) 抑制血管增生 19 (四) 抑制腫瘤細胞增殖 20 三、 Isoflavones與停經婦女健康相關的研究 20 (一) 減緩停經症狀 21 (二) 預防骨質疏鬆症 22 (三) 預防乳癌 25 (四) 預防心血管疾病 28 第三章 材料與方法 33 一、 市售黃豆製品分析 33 二、 人體實驗對象 33 三、 實驗設計 35 四、 實驗器材 37 五、 實驗材料 38 六、 分析項目與方法 40 (一) 市售各種黃豆製品與實驗補充品 40 (二) 血液的收集 41 (三) 血漿的分離 42 (四) 尿液的收集 42 (五) 血漿總抗氧化狀態的測定 42 (六) 血漿中isoflavones的測定 43 (七) 脂蛋白的分離 44 (八) 膽固醇之測定 45 (九) 三酸甘油酯之測定 45 (十) 低密度脂蛋白的透析及其蛋白質濃度的測定46 (十一) 尿液creatinine測量 47 (十二) 尿液isoprostane含量測定 48 (十三) 尿液estrogen 代謝物2OHE1/16α2OHE1含量分析50 五、 實驗品質控制 53 六、 統計分析 54 七、 實驗限制 55 第四章 結果 56 一、 市售各種黃豆製品中異黃酮含量之分析 56 二、 市售黃酮製劑中異黃酮含量 56 三、 受試者募集 57 四、 受試者基本資料 57 五、 受試者問卷調查 58 六、 血中三酸甘油脂的變化 58 七、 血中膽固醇的變化 59 八、 血漿中抗氧化狀態及異黃酮濃度的改變 59 九、 TBARS產生及變化 59 十、 Conjugated diene 形成之 lag time及變化60 十一、 尿液中雌激素代謝分佈的情形 60 十二、 尿液中氧化物質Isoprostane濃度的變化 61 十三、 受試者服用異黃酮後血漿中HDL-C濃度變化量與daidzein濃度 變化量間的相關性 61 十四、 受試者服用異黃酮後血漿中LDL脂蛋白以銅離子催化氧化反應 時conjugated dienes形成之lag time 變化及TBARS變化量與 daidzein濃度變化量間的相關性 62 第五章 討論 79 一、 黃豆製品中異黃酮含量的分析 79 二、 血中異黃酮濃度的變化 80 三、 血中三酸甘油脂濃度的變化 81 四、 血漿中膽固醇的變化 81 五、 抗氧化性的改變 82 六、 尿液中雌激素代謝物分佈的變化 86 第六章 總結 88 參考文獻 90 附錄一 邀請停經婦女參加服用異黃酮之計畫 110 附錄二 問卷調查 113 附錄三 飲食調查問卷 115 附錄四 同意書 117 附錄五 收集尿液以及血液注意事項 118 附錄六 服用賀爾蒙及異黃酮紀錄表 119 表目錄 表一、 phytoestrogens與雌激素接受體親和 11 表二、 potential mechanisms for a beneficial effect of soy protein on decreasing cardiovascular diseaes risk 30 表三、 市售黃豆製品每100g產品中所含genistein及daidsein濃度 63 表四、 市售黃酮製劑中之Isoflavones含量 65 表五、 受試者基本料 66 表六、 受試者服用異黃酮前後血漿及各種脂蛋白中三酸甘油酯的濃度 67 表七、 受試者服用異黃酮前後血漿及各種脂蛋白中膽固醇含量 68 表八、 受試者服用異黃酮前後血漿中總抗氧化狀態與異黃酮濃度 69 表九、 受試者服用異黃酮前或後LDL以銅離子催化氧化反應時 conjugated dienes 形成之lag time與TBAR產生量及變化 70 表十、 不同批實驗測量受試者服用異黃酮前或後LDL以銅離子催化氧 化反應時TBARS產生量及變化 71 表十一、 受試者服用異黃酮前後尿液中賀爾蒙代謝物分佈與氧化物濃度 72 表十二、 受試者服用異黃酮前後血漿中高密度脂蛋白膽固醇含量、 Isoflavone含量及低密度脂蛋白與高密度脂蛋白比的變化 73 圖目錄 圖一、 genistein化學結構及在分解或代謝作用不同步驟的鍵結 4 圖二、 Isoflavones的代謝簡圖 6 圖三、 daidazin及genisiein被人類腸道細菌分解代謝途徑 7 圖四、 比較內生性(endogenous estrong)、植物性 (isoflavone,lignans)及合成雌激素(synthetic molecules)的化學結構 12 圖五、 Calibration curves of genistein,daidzen,butyrophenone 74 圖六、 受試者服用異黃酮前後血漿中異黃酮含量 75 圖七、 受試者服用異黃酮前後血漿及各種脂蛋白中膽固醇含量 76 圖八、 受試者服用異黃酮前後對低密度脂蛋白TBARS濃度的影響 77 圖九、 每位受試者服用異黃酮前後之LDL以銅離子催化氧化反應時 conjugated diene形成之lag time變化 78

    1、Persky V. and Horn C.V. Epidemiology of soy and cancer:
    perspectives and directions J.Nutr. 1995;125:709S-712S.
    2、Grundy S.M.and Abrams J.J.Comparison of actions of soy
    protein and casein on metabolism of plasma lipoprotein and
    cholesterol in humans. Am.J.Clin.Nutr.1983;38:245-252.
    3、AnthonyM.S,Clarkson T.B,Hughes C.L,Morgan T.M.and Burke G.L.
    Soybean isoflavone improve cardiovascular risk factors
    without affecting the reproductive system of peripubertal
    rhesus monkeys. J.Nutr.1996;126:43-50.
    4、Ruiz-Larrea M.B,Mohan A.R.,Paganga G.,Miller N.J.,Bolwell
    G.P.,Piceevans.Antioxidant activity of phytoestrogenic
    isoflavones. Free Radic.Res.1997;26:63-70.
    5、Carroll kk. Review of clinical studies on cholesterol-
    lowering response to soy protein. J Am Diet Assoc 1991;91:820
    6、Anderson J.J.,Ambrose W.W.Orally dosed genistein from soy
    and prevention of cancellous bone loss in two ovariectomized
    rat models.J.Nutr. 1995; 125(suppl): 799S(abstr).
    7、Stephen Barnes, T.Greg Peterson, and Lori Coward. Rationale
    for the use of genistein-containing soy Matrices in chemo-
    prevention trials for Breast and Prostate cancer. Journal of
    cellular Biochemistry, supplement.1995;22:181-187
    8、Messina M.,Persky V.,Setchell K.D.R.Barnes S.Soy intake and
    cancer risk :A review of the in vitro and invivo data.Nutr
    Cancer. 1994; 21: 113-131.
    9、Rich-Edwards et al:The primary prevention of coronary heart
    disease in women.N.Engl.J.Med.1995;29:1758-66.
    10、Xu X.,Duncan A.M, Merz B.E. and Kurzer M.S.Effect of soy
    isoflavones on estrogen and phytoestrogen metabolism in
    premenopausal women. Cancer Epid. Biomarkers & prevention.
    1998;1101-1108.
    11、Barrett.J. phytoestrogens: friends or foes? Environmental
    Health perspectives.1996;104:478-482.
    12、Setchell K.Phytoestrogens:the biochemistry,physiology,and
    implications for human health of soy isoflavones. Am.J.Clin.
    Nutr, 1998;68(suppl):1333S-46S.
    13、Yasuda T.,Kano Y.,Saito K.,Ohsawa K.Urinary and biliary
    metabolites of daidzin and daidzein in rats. Biol.Pharm.Bull.
    1994;17:1369-74.
    14、Sfakianos J.Coward L.Kirk M.,Barnes S.Intestinal uptake and
    biliary excretion of the isoflavone genistein in the rat.J
    Nutr.1997; 127: 1260-8.
    15、Kurser M.S.and Xu X. Dietary phytoestrogens.Annu. Rev.
    Nutr. 1997; 17:353-81
    16、Setchell K.D.R.,Adlercreutz H.Mammalian lignans and
    phytoestrogen.Recent studies on their formation,matabolism
    and biological role in health and disease.In role of the gut
    flora in toxicity and cancer.London:Academic.1988;315-45.
    17、Morton MS,Matos-Ferreira A, Abranches-Monteiro L, Correia
    R, Blacklock N, Chan PSF, Cheng C, Lloyd S, Chieh-Ping W &
    Griffiths K. Measurement and metabolism of isoflavonoids and
    lignans in human male. Cancer.Letters. 1997;114:145-151.
    18、Hutchins A.M., Lampe J.W. ,Martini M.C., Campbell D.R.,
    Slavin J.L.. Vegetables, fruits,and legumes:effect on
    Urinary isoflavonoid phytoestrogen and lignan excretion. J
    Am Diet Assoc. 1995;95:769-774
    19、Lu L.H., Anderson K.E., Grady J.J., Nagamani M. Effects of
    soya consumption for one month on steroid hormone in
    premenopausal women: implication for breast cancer risk
    reduction. Cancer Epidemiol Biomarkers Prev. 1996.;5:63-70
    20、Xu, X., Harris, K.S., Nang, H.J., Murphy, P.A.& Hendrich,
    S. Bioavailability of soybean isoflavones dependends upon
    gut microflora in women. J. Nutr. 1995;125:2307-2315.
    21、Lampe, J.W., Karr, S.C., Hutchins, A.M. & Slavin, J.L.
    Urinary equol excretion with soy challenge:influence of
    habitual diet. Proc. Soc. Exp. Med.1998;217:335-339
    22、Kelly G.E., Joannou G.E., Reeder A.Y., Nelson C. & Waring
    M.A.The variable metabolic response to dietary isoflavones
    in human. Proceedings of the Society for Experimental
    Biology and Medicine.1995;208:40-43.
    23、Tew B.Y., Xu X., Wang H.J., Murphy P.A. & Hendrich S. A
    diet high in wheat fiber decrease the bioavailability of
    soybean isoflavones in a single meal fed to women.
    J.Nutr.1996;126: 871-877.
    24、Martin M.E., Haourigui M., Pelissero C., Benassayag C., and
    Nunez E.A. Interactions between phytoestrogens and human sex
    steroid binding protein. Life Science.1996;58:429-436.
    25、Adlercreutz H., Goldin B.R., Gorbach S.L., Hockerstedt
    K.A.V., Watanabe S., Hase T.A. & Fotsis T. Soybean
    phytoestrogen intake and cancer risk. Journal of
    Nutrition.1995;125:757S-770S.
    26、Adlercreutz H.Lignans and isoflavones:epidemiology and
    possible role in prevention of cancer.In Natural Antioxidants
    and food quality in atherosclerosis and cancer
    prevention.London:Royal Society of Chemistry.1996;349-355.
    27、Kirkman L.M., Lampe J.W., Campbell D.R., Martini M.C. &
    Slavin J.L .Urinary lignan and Isoflavonoid excretion in men
    and women consuming vegetable and soy diets, Nutrition and
    Cancer.1995;24:1-12.
    28、Adlercreutz H. Markkanen H. & Watanabe S. Plasma
    concentrations of phytoestrogens in Japanese men.
    Lancet.1993; 342:1209-1210.
    29、Adlercreutz H. Mazur W. Phyto-oestrogens and western
    diseases. Ann Med. 1997;29:95-120.
    30、Knight D.C., Eden J.A.. A review of the clinical effects of
    phytoestrogens. Obstet Gynecol. 1996;87:897-904.
    31、Katzenellenbogen B.S.,Mhardwaj B.Fujimoto N. Antiestrogens:
    mechanisms and actions in target cells.J.Steroid Biochem Mol
    Biol.1995;53:387-393.
    32、Miksicek R.J.Interactions of naturally occurring
    nonsteroidal estrogens with expressed recombinant human
    estrogen receptor. J.Steroid.Biochem.Mol.Biol.1994;49:153-160.
    33、Santell R.C.,Cheng Y.C.,Nair M.G.,et al.Dietary genistein
    exerts estrogenic effects upon the uterus,mammary gland and
    the hypothalamic/pituitary axis in rats.J.Nutr.1997;127:263-
    269.
    34、Adlercreutz H.,Fotsis T.,Heikkinen R,et al.Excretion of the
    lignansenterolactone and enterodiol and of equol in omnivorous
    and vegetarian postmenopausal women and in women with brease
    cancer.Lancet.1982;2:1295-1299.
    35、Kuiper G.G.J.M.,Lemmen J.G.,Carlsson B.,Corton J.C.,Safe
    S.H.van der Saag P,van der Burg B.,Gustafsson J.A.Interation
    of estrogenic chemicals and phytoestrogens with estrogen
    receptor bata. Endocrinology.1998;139:4252-4263.
    36、Cassidy A.Potential tissue selectivity of dietary
    phytoestrogens and estrogens.Current Opinion in Lipidology.
    1999;10:47-52.
    37、Adlercreutz H, Hockerstedt K, Bannwart C, et al. Effect of
    dietary components,including lignans and phytoestrogens, on
    enterohepatic circulation and liver metabolism of estrogens
    and on sex hormone binding globulin (SHBG). J.steroid Biochem
    1987;27:1135-44
    38、Mousavi Y, Adlercreutz H, Genistein is an effective
    stimulator of sex hormone-binding globulin production in
    hepatocarcinoma human liver cancer cells and suppresses
    proliferation of these cells in culture. Steroids 1993;58:301-4
    39、Loukovaara M, Carson M, Palotie A, Adlercreutz H.
    Regulation of sex hormone-binding globulin production by
    isoflavones and patterns of isoflavonoids conjugation in HepG2
    cell cultures. Steroids 1995; 60: 656-61.
    40、Adiercreutz H, Bannwart C, Wahala K, et al. Inhibition of
    human aromatase by mammalian lignans and isoflavonoid
    phytoestrogens. J. Steroid Biochem.1993;44:147-53.
    41、Cassidy A, Bingham S, Setchell KD. Biological effects of
    soy protein rich in isoflavones on the menstrual cycle of
    premenopausal women. Am J clin Nutr.1994;60:333-40
    42、Cassidy A, Bingham S, Setchell KDR. Biological effects of
    isoflavones in young women:importance of the chemical
    omposition of soybean products. Br. J. Nutr 1995; 74: 587-601
    43、Goldin B.R., Adlercreutz H.,Gorbach S., Woods M.N., Dwyer
    J.T., Bohn E., Gershoff S.N.,The relationship between estrogen
    levels and diets of Caucasian and Oriental immigrant women. Am
    J Clin Nutr.986;44:945-953.
    44 、Adlercreutz H., Hamalainen E., Gorbach S., Goldin B.
    Dietary phytoestrogens and menopause in Japan. Lancet. 1992;
    339: 123.3
    45、Treolar AE,Boynton RE, Behn BG, Brown BW. Variation of the
    human menstrual cycle through reproductive life. Int J Fertil.
    1970; 12: 77 – 126.
    46、Henderson B.E., Ross R.K., Judd H.L., Frailo M.D, Pike M.C.
    Do regulatory ovulatory cycles increase breast cancer risk?
    Cancer. 1985; 56:1206-8
    47、kapiotis S., Hermann M., Held I., Seelos C., Ehringer H.,
    Gmeiner B.M.K. Genistein, the dietary-derived angiogenesis
    inhibitor, prevents LDL oxidation and protects endothelial
    cells from damage by atherogenic LDL. Arterioscler. Thromb.
    Vasc. Biol. 1997; 17: 2868-2874.
    48、Arora A., Nair M.G. and Strasburg G.M. Antioxidant
    activities of isoflavones and there biological metabilities in
    a liposomal system.Arc. Biochem Biophys1998;356:133-141
    49、JHA H.C., Recklinghausen G.V., and Zilliken F. Inhibition
    of in vitro microsomal lipid peroxidation by isoflavonoids.
    Biochem Pharmacology.1985;34:1367-1369.
    50、Wiseman H & O’Reilly J. Oestrogens as antioxidant
    cardioprotectants. Biochemical Society Transactions. 1997; 25:
    54-59.
    51、Wei H, Cai Q., and O.Rahn R. Inhibition of UV light and
    Fenton reaction-induced oxidative DNA damage by the soybean
    isoflavone genistein. Carcinogenesis.1996;17:73-77.
    52、Anderson J.W., Diwadkar V.A., and Bridges S.R. Selective
    effects of different antioxidants on oxidation of Lipoproteins
    from rats. P.S.E.B.M.1998;218:376-381
    53、Tsai P.J. and Huang P.C.Effects of isoflavones containing
    soy protein isolate compared with fish protein on serum lipids
    and susceptibility of low density lipoprotein and liver lipids
    to in vitro oxidation in hamsters.J.Nutr. Biochem.1999; 10:631-
    637.
    54、Wei H, Bowen R, Cai Q, Barnes S,Wang Y. Antioxidant and
    antipromotional effects of the soybean isoflavone genistein.
    Proc. Soc. Exp. Biol Med.1995;208(1):124-130.
    55、Lu S.C.,Wu W.H.,Lee C.A.,Chou H.F.,Lee H.R.,and Huang
    P.C.LDL of Taiwanese vegetarians are less oxidizable than
    those of omnivores. J.Nutr.2000;130:1591-1596.
    56、O’Reilly J, Dean TS, Bowey E, Rowland I, Sanders TAB &
    Wiseman H. The influence of dietary isoflavones on markers of
    lipid peroxidation in health male and female volunteers.
    Proceedings of the Nutrition Society .1998;57,123A.
    57、Tikkanen M J, Wahala K, Ojala S, Vihma V & Adlercreutz H.
    Effect of soybean phytoestrogen intake on low density
    lipoprotein resistance. Proceedings of National Academy of
    Sciences.1998;95:3106-3110.
    58、Samman S., Wall P.M.L., Chan G.S.M, Smith S.J., Petocz P.
    The effect of supplementation with isoflavones on plasma
    lipids and oxidisability of low density lipoprotein in
    premenopausal women. Atherosclerosis.1999;147:277-283
    59、Takahashi K.,Nammour T.M.Fukunaga M.Ebert J.,Morrow
    J.D.,Roberts L.J.Glomerular actions of a free radical-
    generated novel prostaglandin,8-epi prostaglandin F in the
    rat:evidence for interaction with thromboxane A receptors.
    J.Clin. Invest. 1992; 90: 136-141.
    60、Witztum J.L. and Berliner J.A.Oxidized phospholipids
    andisoprostanes in atherosclerosis. Curr.Opin. Lipidol. 1998;
    9:441.
    61、Patrono C.,and Fitzgerald G.A.Isoprostanes:Potential
    markers of oxidant stress in atherothrombotic
    disease.Arterioscler Thromb Vasc Biol.1997;17:2309-2315.
    62、Shwaery G.T., Vita J.A., Keaney J.F. Antioxidant protection
    of LDL by physiologic concentrations of estrogens is specific
    for 17-beta-estradiol. Atherosclerosis. 1998; 138: 255-262
    63、Hammerschmidt P.A. and Prat D.E. Phenolic antioxidant of
    dried soybeans J.Food. Sci.1978;43:556-559
    64、Wei H., Wei L., Frenkel K., Bowen R., and Barnes S.
    inhibition of tumor-promoter induced hydrogen peroxide
    formation by genistein in vitro and in vivo. Nutr
    Cancer.1993;20:1-12.
    65、Fotsis T, Pepper M, Adlercreutz H, Flerischmann G, Hass T,
    et al.Genistein,a dietary-derived inhibitor of in vitro
    angiogenesis.Proc. Natl.Acad. Sci.U.SA.1993;90:2690-94.
    66、Molteni A, Brizio-Molteni L, Persky V. In vitro hormonal
    effects of soybean isoflavones. J. Nutr.1995;125:751-56S
    67、Wang C F, Kurzer M S. Phytoestrogen concentration
    determines on DNA synthesis in human breast cancer cells. Nutr
    Cancer. 1997; 28: 236 -247.
    68、Zava D T, Duwe G. Estrogenic and antiproliferative property
    of genistein and other flavonoids in human breast cancers cell
    in Nutr Cancer.1997;27:31-40.
    69、Peterson T G, Barnes S. Genistein inhibits both estrogen
    and growth factor stimulated proliferation of human breast
    cancer cell. Growth Diff.1996;7:1345-1351.
    70、Akiyama T, Ishida J, Nakagawa S, et al. Genistein:a
    specific inhibitor of tyrosine-specific protein kinase. J Biol
    Chem.1987;262:5592-5
    71、Kim H, Peterson T G, Barnes S. Mechanisms of action of the
    soy isoflavone genistein : emerging role for its effects via
    transforming growth factor B signaling pathways. Am J Clin
    Nutr. 1998; 68 (suppl): 1418S-25S.
    72、Higashi K, Ogawara H. Daidzein inhibits insulin-or insulin-
    like growth factor-1-mediated signaling in cell cycle
    progression of Swiss 3T3 cells. Biochem Biophys
    Acta.1994;1220:29-35.
    73、Wilcox J N, Blumenthal B F. Thrombotic mechanism in
    atherosclerosis: potential impact of soy proteins. J
    Nutr.1995;125:631S-8S.
    74、Yamamoto S, Shimizu K, Oonishi I, et al. Genistein
    suppresses cellular injury following hepatic
    ischemia/reperfusion. Transplant Proc.1996;28:1111-5.
    75、Okura A, Arakawa H, Oka H, Yoshinari T, Monden Y. Effect of
    genistein on topoisomerase activity and on the growth of [Val
    12] Ha-ras-transformed NIH 3T3 cells. Biophys Res
    Commun.1988;157:183-9.
    76、Markovits J, Linassier C, Fosse P, et al. Inhibitory
    effects of the tyrosine kinase inhibitor genistein on
    mammalian DNA topoisomerase.Cancer Res.1989;49:5111-7.
    77、Setchell KDR, Borriello SP, Hulme P, Kirk DN, Axelson M.
    Nonsteroidal estrogens of dietary origin:possible roles in
    Hormone-dependent disease. Am. J. Clin Nutr.1984;40:569-78
    78、Lock M. Contested meanings of the menopause. Lancet. 1991;
    337: 1270-72
    79、Colditz G A, Stampfer M J, Willett W C, Hunter D J, Manson
    J E, et al. Type of postmenopausal hoemone use and risk of
    breast cancer : 12 year follow-up from the Nurses’ Health
    Study. Cancer Cause Control.1992;3(5):433-39.
    80、Murkies A L, Lombard C, Strauss B J G, Wilcox G, Burger H
    G, et al. Dietary flour supplementation decrease post-
    menopausal hot flushes : effect of soy and wheat.
    Maturitas.1995;21:189-95.
    81、Baird D D, Umbach D M, Lansdell L, et al. Dietary
    intervention study to assess estrogenicity of dietary soy
    among postmenopausal women. J Clin Endocrinol
    Metab.1995;80:1685-90.
    82、Wilcox G, Wahlqvist M L, Burger H G, Medley G. Oestrogenic
    effects of plant foods in postmenopausal women. Br Med
    J.1990;301:905-6
    83、Cassidy A, Faughnan M, Hughes R, et al. Hormonal effects
    of phytoestrogens in postmenopausal women and middle aged
    men. Am J Nutr.1998;68(suppl):1531S-3S
    84、Komm B S, Tepen C M, Benz D J, et al. Estrogen binding,
    receptor mRNA ,and biological response in osteoblast-like
    osteocarcinoma cell. Science.1988;241:81-4.
    85、Eriksen E F, Colvard D S,Berg N J, et al. Evidence of
    estrogen receptor in normal human osteoblast-like cells.
    Science. 1988; 241: 84-6.
    86、Setchell K.D.R. Phytoestrogens : the biochemistry,
    physiology, and implications for human health of soy
    isoflavones. Am J Clin Nutr.1998;68(suppl):1333S-46S
    87、Potter S M, Baum J A, Teng H, Stillman R J, Shay N F,
    Erdman J M Jr. soy protein and isoflavones : their effects on
    blood lipids and bone density in postmenopausal women. Am J
    Clin Nutr. 1998; 68 (suppl): 1375S-9S
    88、Melis G B, Paoletti A M, Cagnacci A, Bufalino L, Spinetti
    A, Gambacciani M, Fioretti P. Lock of any estrogenic effect of
    ipriflavone in postmenopausal women. J Endocrinol Invest.
    1992; 15: 755-61.
    89、Reginster J Y. Ipriflavone : Pharmacological proterties and
    usefulness in postmenopausal osteoporosis. Bone Miner.1993;
    23:223-32
    90、Benvenuti S, Tanini A, Frediani U, Bianchi S, Masi L,
    Casano R, Bufalino L, Serio M, Brandi M L. Effects of
    ipriflavone and its metabolities on a clonal osteoblastic
    cell line. J Bone Miner Res.1991;6:987-96.
    91、Cheng S L, Zhang S F, Nelson T L, Warlow P M, Civitelli R.
    Stimulation of human osteoblast differentiation and function
    by ipriflavone and its metabolities. Calcif Tissue
    Int.1994;55:356-62.
    92、Brandi M L. Flavonoids : biochemical effects and
    therapeutic applications. Bone Miner.1992;19(suppl):S3-64
    93、Tsuda M, Kitazaki T, Ito T, Fujita T. The effect of
    ipriflavone (TC-80) on bone resorption in tissue culture. J
    B0ne Miner Res. 1986; 1: 207-11.
    94、Agnusdei D, Adami S, Cervetti R, Crepaldi G, Di Munno O,
    Fantasia L, Isaia G C, Letizia G, Ortolani S, Passeri M, et
    al. Effects of ipriflavone on bone mass and calcium
    metabolism in postmenopausal osteoporosis. Bone &
    Mineral.1992;19(suppl):S43-S48.
    95、Nakamura S, Morimoto S, Takamoto S, Onishi T, Kukuo k, Koh
    E, Kitano S, Miyashita Y, Yasuda 0, Tamatani M, et al.
    Effect of ipriflavone on bone mineral density and calcium-
    related factors in elderly females. Calcified Tissue
    International. 1992; 51 (suppl): S30-S34.
    96、Gambacciani M., Ciaponi M., Cappagli B., Piaggesi L.,
    Genazzani A.R.. Effects of combined low dose of the
    isoflavone derivative ipriflavone and estrogen replacement on
    bone mineral density and metabolism in postmenopausal women.
    Maturitas.1997;28:75-81
    97、Ross P D, Norimatsu H, Davis J W, et al. A comparison of
    hip fracture incidence among native Japanese, Japanese
    Americans, and American Caucasians. Am J Epidemiol
    1991;133:801-9.
    98、Russel-Aulet M, Wang J, Thornton J C, Colt E W, Pierson R N
    Jr. Bone mineral density and mass in a cross-sectional study
    of white and Asian women. J Bone Miner Res.1993;8:575-82
    99、Ross P D, Fujiwara S, Huang C, et al. Vertebral fracture
    prevalence in women in Hiroshima compared to Caucasians or
    Japanese in the US. Int J Epidemiol.1995;24:1171-7.
    100、Kardinaal A.F.M., Morton M.S., Bruggemann-Rotgans I.E.M.,
    and Beresteijn Van E C H. Phyto-oestrogen excretion and rate
    of bone loss in postmenopausal women. European Journal of
    clinical Nutrition.1998;52:850-855.
    101、Parkin D.M.Cancers of the breast,endometrium,and
    ovary:geographic correlations. Eur.
    J.Cancer.Clin.Oncol.1989;25:1917-1925.
    102、Rose D.P.,Boyar A.P.,Wynder E.L.International comparisons
    of mortality rates for cancer of breast,ovary,prostate and
    colon,and per capita food consumption.Cancer.1986;58:2363-
    2371.
    103、Barnes S.,Peterson T.G.,Coward L.Rationale for the use of
    genistein containing soy matrices in chemoprevention trials
    for breast and prostate cancer.J.Cell.Biochem.1995;22:181-187.
    104、Fisher B.,Costantino J.P.,Wickerham D.L.,Redmond
    C.K.,Kavanh M.,Cronin W.M.,et al.Tamoxifen for the prevention
    of breast cancer :Report of the national surgical adjuvant
    breast and bowel project P-1 study.J.Natl cancer inst
    1998;90:1371-1388.
    105、Barnes S.,Grubbs C.,Setchell K.D.R.,Carlson J.Soybeans
    inhibit mammary tumors in models of breast cancer.in:pariza
    MW, Aeschbacher H-U,Felton J.S.,Sato S.,eds.Mutagens and
    carcinogens in the diet.New York :Wiley Liss.1990:239-53.
    106、Ingram D.,Sanders K.,Kolybaba M.,Lopez D.Case-control
    study of phytoestrogen and breast cancer.Lancet.1997;350:990-
    994.
    107、Lee H.P.,Gourley L.,Duffy S.W.,Esteve J.,Day N.E.Dietary
    effects on breast-cancer risk in Singapore. Lancet.1991; 337:
    1197-200.
    108、Hirose K.,Tajima K.,Hamajima N,et al.A large-scale,
    hospital based case-control study of risk factors of breast
    cancers according to menopausal status. Jpn.J. Cancer.Res.
    1995;86:146-54.
    109、Yuan J-M.,Wang Q-S,RossR.K.,Henderson B.E.,Yu M.C.Diet and
    breast cancer in Shanghai andTianjin, China. Br. J. Cancer.
    1995;71:1353-8
    110、Peterson G.,Barnes S..Einstein potently inhibits the
    growth of human primary breast epithelial cells:correlation
    with lack of genistein metabolism.Mol.Biol Cell.1994;5:384a
    111、Lamartiniere C.A.Moore J.B.,Brown N.M.,Thompson R.,Hardin
    M.J.,Barnes S.Einstein suppresses mammary cancer in rats.
    carcinogensis.1995;16:2833-40.
    112、Brown N.M.,Lamartiniere C.A.Xenoestrogens alter mammary
    gland differentiation and cell proliferation in the
    rat.Environ.Health Perspect.1995;103:708-13.
    113、Murrill W.B.,Brown N.M.Zhang J-X, et al.Prepubertal
    genistein exposure suppresses mammary cancer and enhances
    gland differentitation in rats.Carcinogenesis.1996;17:1451-7.
    114、Macaulay A.P.,Meilaha E.N.,Bradliw H.L.,Sepkovic
    D.W.,Buhari A.M.:Urinarymarkers of estrogen matabolism 2-16α-
    hydroxylation in premenopausal women. Steroids. 1996; 61: 461-
    7.
    115、Meilahn E.N.,Stavola B.D.,Allen D.S.,Fentiman I.,Bradlow
    H.L.,Sepkovic D.W.,and Kuller L.H.Do urinary oestrogen
    metabolites predict breast cancer?Guernsey Ⅲcohort follow-
    up.British Journal of cancer.1998;78(9):1250-1255.
    116、Kabat G.C.,Chang C.J.,Sparano J.A.,Sepkovic D.W.,Hu
    X.P.,Khalil A.,Rosenblatt R.,and Bradlow H.L.Cancer
    Epidemiology. Biomarkers & Prevention.1997;505-509
    117、Clarson T B, Anthony M S and Hughes C L Jr. Estrogenic
    soybean isoflavones and chronic disease : risks and benefits.
    Trends in Endocrinology and Metabolism.1995;6:11-16.
    118、Raines E.W.,and Ross R.Biology of atherosclerotic plaque
    formation:possible role of growth factors in lesion
    development and the potential impact of soy.J.Nutr. 1995;
    125: 624s-630s.
    119、Chae C.U.,Ridker P.M.,Manson J.E.Postmenopausal hormone
    replacement therapy and cardiovascular disease. Thromb
    Haemost. 1997;78:770-780.
    120、Nagata C.,Takatsuka N.,Kurisu Y.,and Shimizu H.Decreased
    serum total cholestrol concentration is associated with high
    intake of soy products in japaneses men and women. J.Nutr.
    1998; 128:209-213.
    121、Lchtenstein A.H.Soy protein ,isoflavone and cardiovascular
    disease risk.J.Nutr.1998;128:1589-1592.
    122、Hodgson J.M.,Puddey I.B.,Beilin L.J.,Mori T.A.,and Croft
    K.D.Supplementation with isoflavonoid phytoestrogens does not
    alter serum lipid concentrations:a randomized controlled
    trial in humans. J.Nutr.1998;128:728-732.
    123、Nestel P.J.,Yamashita T.,Sasahara T.,Pomeroy S.,Dart
    A.,Komesaroff P., Owen A.,and Abbey M.Soy isoflavone improve
    systemic arterial compliance but not plasma lipids in
    menopausal and perimenopausal women.Arterioscler Thromb.
    Vasc.Biol. 1997; 17:3392-3398.
    124、Nestel P.J,Pomeroy S.,Kay S.,Komesaroff P.,Behrsing
    J.,Cameron J.D.,and West L.Isoflavone from red clover improve
    systemic aterial compliance but not plasma lipids in
    menopausal women. J.Clin.Endocrinol.metab.1999;84:895-898.
    125、Potter S.M.,Baum J.A.,Teng H.,Stillman R.J.,and Erdman Jr
    J.W.Soy protein and isoflavones:their effects on blood lipids
    and bone density in postmenopausal women. Am.J. Clin. Nutr.
    1998; 68 (suppl): 1375s -9s.
    126、Nestel P.J.,Pomeroy S.,Kay S.Komesaroff P.,Behrsing
    J.,Cameron J.D.,and West L.Isoflavones from red clover
    improve systemic arterial compliance but not plasma lipids in
    menopausal women. J.Clin.Endocrinol. Metab. 1999; 84: 895-898.
    127、Wilcox J.N.and Blumenthal B.F.Thrombotic mechanisms in
    atherosclerosis:potential impact of soy proteins. J.Nutr.
    1995; 125: 631S-638S.
    128、Melinda J.et al.A soy protein isolate rich in genistein
    and daidzein and its effects on plasma isoflavone
    concentrarions , Platelet aggregation,blood lipids and fatty
    acid composition of plasma phospholipid in normal men
    J.Nutr. 1996; 126:2000-2006.
    129、Klein K.O..Isoflavones,soy based infant formulas,and
    relevance to endocrine function.Nutr.Rew.1998;56:193-204.
    130、Wang G.,Kuan S.S.,Francis O.J.,Ware G.M.,and Carman A.S.A
    simplified HPLC method for the determination of phytoestrogens
    in soybean and its processed products.J.Agric.Food Chem. 1990;
    38:185 -190
    131、Franke A.A.,Custer L.J.,Wang W.,and Shi C.Y.HPLC analysis
    of isoflavones and other phenolic agents from foods and from
    human fluids.P.S.E.B.M.1998;217:263-273.
    132、Friedwald W.T.Levy R.I.and Frecrickson D.S.:Estimation of
    the concentration of low density lipoprotein cholesterol in
    plasma, without use of the preparative ultracetrifugation.
    Clin.Chem. 1972; 18:499-502
    133、Markwell M.A.K.,Hass S.M.,Bieber L.L.and Tolbert N.E.:A
    modification of the lowary precedure to simplify protein
    determination in membrane and lipoprotein samples. Anal.
    Biochem. 1978;87:206-210.
    134、Zawadzki Z.,Milne R.W.,and Marcel Y.L..Cu2+-mediated
    oxidation of dialyzed plasma :Effect on low density
    lipoproteins and cholestrol ester transfer protein .J.Lipid
    Res.1978;32:243-250.
    135、Beuge J.A. and Aust S.D..Microsomal lipids peroxidation.
    Methods Enzymol.1978;52:302-310.
    136、Smith C.Mitchinson M.J.Aruoma O.I.and Halliwell
    B..Stimulation of lipid peroxidation and hydroxyl-radical
    generation by contents of human atherosclerotic
    lesions.Biochem.J.1992;286:901-905.
    137、Pasgualini J.R et al.Metabolism and biologic response of
    estrogen sulfates in hormone-dependent and hormone-independent
    mammary cancer cell lines.Ann.NY.Acad.Sci.
    138、Fishman J.et al:Radiometric analysis of biological
    oxidants in man:sex differences inestradiol metabolism. Proc.
    Natl. Acad. Sci. 1980;77:4957-60.
    139、Lemon H.M.:Antimammary Carcinogenic activity of 17-alpha-
    ethinyl estriol.Cancer.1987;60:2873-81.
    140、Macaulay A.P.,Meilaha E.N.,Bradliw H.L.,Sepkovic
    D.W.,Buhari A.M.:Urinarymarkers of estrogen metabolism 2-and
    16α-hydroxylation in premenopausal women. Steroids.
    1996;61:461-7.
    141、Suzukawa M.,Abbey M.,Howe PRC,Nestel P.J..Effects of fish
    oil fatty acids on low density lipoprotein size,
    oxidisability,and uptake by microphages. J.Lipid.Res. 1995;
    36:473-484.
    142、Mcdowell I.F.W.,Mceneny J.,and trimble E.R.A rapid method
    for measurement of the susceptibility to oxidation of low
    density lipoprotein.Ann.Clin.Biochem.1995;32:167-174.
    143、Princen H.M.G.,Duyvenvoorde W.V.Buytenhek R.,Laarse A. V.
    D., Poppel G.V.,Leuven J.A.G..Supplementation with low doses
    of vitamin E protects LDL from lipid peroxidation in men and
    women. Arteroscler Thromb Vasc Biol.1995;15:325-333.
    144、Michoricz J.J et al.Changes in levels of urinary estrogen
    metabolites after oral indole-3-carbinol treament in
    humans .J.Natl Cancer Inst .1997;89:718-23
    145、Kappas A et al.Nutrition-endrocrine interactions.induction
    of reciprocal changes in the △-4-5α-reduction of
    testosterone and the cytochrome p-450-dependent oxidation of
    estradiol by dietary macronutrieats in human.Proc Natl Acad
    Sci.1983;80:7646-9.
    146、Wang H.J.and Murphy.P A. Isoflavone cotent in commerical
    soybean foods.J.Agric.food chem.1994;42:1666-1673.
    147、Dwyer J.T.Goldin B.R. et al.Tofu and soy drinks contain
    phytoestrogens J.Am.Diet Assoc.1994;94:739-743.
    148、King R.Daidzein conjugates are more bioavailable than
    genistein conjugates in rats.Am. J.Clin.Nutr.1998;68:1496S-9S.
    149、Lobo R.A.:Effects of hormonal replacement on lipids and
    lipoproteins in postmenopausal women. J.Clin. Endocrinol.
    Metab. 1991;73:925-930.
    150、Anthony M.S.,Clarkson T.B.,Bullock B.C.,&Wagner J.D.Soy
    Protein versus soy phytoestrogens in prevention of diet
    induced coronary artery atherosclerosis of male cynomolgus
    monkeys. Arteriosler. Thromb.Vasc.Biol.1997;17:2524-2531.
    151、Anderson J.W.,Johnstone B.M.,and Cook-Newell M.S.Meta-
    analysis of soy protein intake on serum ipids. N.Engl. J.Med.
    1995;333:276-82.
    152、Meng Q.H.,Lewis P.,et al.Incorporation of esterified
    soybean isoflavones with antioxidant activity into low density
    lipoprotein.Biochimica et Biophysica Acta.1999;1438:369-376.
    153、Messina M.J..Legumes and soy beans:overview of their
    nutritional profiles and health effects.Am.J.Clin.Nutr.1999;70
    (suppl):439s-50s.
    154、Tham M.O., Christopher D.G.and naskell W.L. Potential
    Health Benefits of dietary phytoestrogens: A review of
    clinical Epidemiological, and Mechanistic Evidence. Journal of
    clinical Endocrinology and Metabolism. J Clin Endocriol
    Metab . 1998 ; 83:2223-2235.

    QR CODE