雌酮的危害.pptx

雌酮的危害雌酮的危害进一步代谢成致癌物：儿茶酚雌激素；进一步代谢为醌类自由基；与蛋白质和核酸结合导致细胞损伤和诱发癌症；自由基加速机体老化、损伤机体的三大抗凝系统导致血栓；代谢速率越快细胞损伤作用和致癌性越强，雌酮代谢速率比雌二醇快10倍（不同雌激素活性不同的主要原因是雌激素受体复合物占据细胞核的时间不同）。炎症致氧化应激炎症致氧化应激活性氧（活性氧（ROS)ROS)致炎致炎二者致血栓形成二者致血栓形成细菌及颗粒性异物：中性粒细胞、巨噬细胞等吞噬后可引起这些细胞发生呼吸爆发(respiratory burst)：细胞耗氧量迅速增加，NADPH氧化酶激活，大量和H2O2产生，以杀灭、清除细菌或异物。当呼吸爆发反应过强，活性氧簇产生过多，引起氧化应激。促进花生四烯酸代谢，增加炎症介质形成：环加氧酶和脂加氧酶是关键酶，具有限速作用。研究证明，活性氧簇和脂质过氧化物可激活这两种酶并维持其活性。ROS可抑制前列环素(PGI2)合成酶活性，同时促进血栓烷A 2(TXA 2)的合成，使PGI2 TXA 2比值下降，导致血小板聚集，血栓形成。细胞因子：TNF可刺激白细胞产生大量活性氧簇，IL1吸引、激活巨噬细胞引起呼吸爆发。自由基可作用于前趋化因子(可能是脂肪酸或其他脂类与血浆蛋白的结合物)使之转化为趋化因子，吸引中性粒细胞向炎症灶游走和聚积。ROS还通过使过氧化脂质增加，导致红细胞和血浆蛋白交联而使血黏度升高。免疫复合物和补体系统：在自身免疫性疾病，如红斑狼疮、肾小球肾炎、类风湿性关节炎等常有免疫复合物形成并沉积在血管壁、肾小球、关节、皮肤等处，补体系统被激活,产生多种趋化因子吸引白细胞聚积，吞噬免疫复合物，引起呼吸爆发,产生大量活性氧簇和导致氧化应激。自由基促进溶酶体的释放：非酶性成分阳离子蛋白和阴离子蛋白、组织蛋白酶和中性蛋白酶(胶原酶可使胶原组织变性，弹性蛋白酶可破坏弹性蛋白和弹性纤维），组织蛋白酶可分解纤维联接蛋白和蛋白多糖等。这些酶这些酶在血管炎、关节炎和肾小球肾炎等的在血管炎、关节炎和肾小球肾炎等的发病中起重要的致炎作用。发病中起重要的致炎作用。使抗凝血酶蛋白-抗凝血酶（AT）及组织因子途径抑制物（TFPI）肽链断裂、交联而影响其功能或酶活性的丧失体液抗凝。LDLLDL氧化氧化导致动脉粥样硬化为特点的慢性炎症ROS和OX-LDL自身和通过内皮损伤途径激活血小板和形成白色微栓。内皮细胞氧化使粘附分子增加粘附分子增加，促使白细胞粘附：缺血再灌注机制之一炎症和ROS都使TNF、IL-1、IL-6等炎症介质释放活化血小板。氧化应激氧化应激血栓形成的恶性循环血栓形成的恶性循环细胞损伤细胞损伤血栓形成血栓形成炎症炎症损伤内皮抗凝，损伤内皮抗凝，AT3抗凝，红细胞膜脂质过氧化和血浆抗凝，红细胞膜脂质过氧化和血浆蛋白交联增高血粘度，促使血小板聚集蛋白交联增高血粘度，促使血小板聚集舒瓦兹贝恩大夫：当妊娠雌酮第一次在市场上出现时，它仅仅用于短期内治疗潮热，但是后来它的用途被扩大了（我想补充一点，这是在没有任何研究结果的情况下），它们应用于荷尔蒙替代疗法中，长期治疗各种更年期症状。我认为在更年期后，任何一种荷尔蒙替代疗法都应该使人免于患心脏病，但妊娠雌酮就没有这样的作用。大多数内分泌医生用缓解症状的方法来治疗更年期。他们认为只要妇女不再出现潮热现象，就是使用了正确的治疗方法。但事实并非如此。（性感岁月）霍华德赫迪兹在南加利弗尼亚大学的研究证实了雌二醇既不是妊娠雌酮，也不是合成荷尔蒙，也不是药物，而是在人体的卵巢中发现的生理性雌激素（雌二醇），可以保护妇女不患心脏病。（性感岁月）经皮雌激素可能是有效的抗抑郁药：可以证明所有雌激素引起的严重副作用均限于口服结合雌激素联合疗法。与传统抗抑郁药相比，经皮吸收雌二醇见效相当迅速，用药2-4周内抑郁症状就可以得到明显改善。而且，在总共12周的研究期间，该药的抗抑郁功效在最后四周的“清洗期”里仍表现得非常显著。（中国处方药2003年4月第4期 让女人快乐起来）从1970年7月至1974年12月，某医疗中心诊断了94例子宫内膜腺癌。另选年龄相近和正常子宫的妇女188例(2倍于子宫内膜腺癌患者)作对照组。据报道，94例子宫内膜腺癌患者中，有57%的患者应用了结合性雌激素(主要是硫酸钠雌酮)，而对照组中仅有15%。应用雌激素组与对照组相比，子宫内膜腺癌发生率为7.6倍，比率从应用雌激素14.9年的5.6倍上升到应用雌激素7年以上为13.9倍。国际大规模临床验证HERS（美国20个中心2763例绝经期妇女参加），2000年将作为HERS-II期试验的结果发表在JAMA杂志上），口服雌酮（孕马尿中提取），引发心脑血管病急性发着率，未见可以阻止骨质疏松所引起的骨折，而且，不少受试对象尿失禁症状反而加重，静脉血栓栓塞性疾病发生增加大约3倍，增加胆道手术率。美国NIH组织的WHI大规模临床验证（27348例）：口服雌酮（孕马尿中提取）使乳腺浸润癌比预先设定的风险范围高出了26%；脑卒中、肺栓塞、子宫内膜癌、结肠/直肠癌、股骨颈骨折以及意外死亡其风险也都增加达15%。静脉血栓栓塞性疾病增加110%，脑卒中增加41，冠心病增加29%，乳腺癌增加26%以及胆道手术增加48%。试验被迫中止。WHI试验设计试验设计子宫切除术子宫切除术是是否否妊马雌酮（妊马雌酮（CEE）0.625 mg/d+甲羟孕酮甲羟孕酮（MPA）2.5 mg/d 安慰剂安慰剂妊马雌酮（妊马雌酮（CEE）0.625 mg/d安慰剂安慰剂来自国际妇科杂志报道：美国KN妇科疾病研究中心著名妇科专家DianeFMerritt博士通过多年临床研究，首次提出“雌毒学说”。该学说指出：女性雌激素代谢产生的垃圾雌毒，才是女人衰老、更年期提前以及子宫、卵巢、乳房疾患的根本原因。多年来致力于妇科领域研究的DianeFMerritt博士，2001年12月从刚刚摘除的子宫肌瘤活捡取样中发现，在瘤体中不规则分布着大量类雌激素代谢垃圾雌酮物质，这令DianeFMerritt博士很意外。随即他又对50名乳房肿块、卵巢囊肿、子宫肌瘤患者的切除物进行分析，结果惊人的一致，即都发现了这种物质。进一步实验证实：这种物质是激素代谢垃圾雌酮与大量沉积毒素的聚集体，在体内生成后不断“流窜”，刺激腺体、血液、骨骼、器官，导致细胞增生、肿大甚至产生细胞变异、癌变，这是目前发现的对女性身体伤害最大的沉积毒素。2004年12月DianeFMerritt博士正式将这种类雌酮命名为雌毒。他说：雌毒是女人特有的毒素。女性的近百种常见病症都与雌毒堆积有关。例如：色素沉着有黑、黄色斑块；月经不规律经血量大、颜色暗红黏稠、腥臭并伴黑色血块；白带清稀、味异、免疫力低；经前乳房胀痛，小腹坠胀，腰酸，经期腹痛，手脚冰凉、乏力失眠、烦躁、关节不适、骨质疏松、性冷淡等等。2007年4月19日，Lancet在线提前发表了“百万妇女研究”（MWS）的最新结果，研究表明，激素补充治疗（HRT）可增加妇女患卵巢癌的风险。1)服用类固醇Livial(tibolone，替勃龙)的停经期后妇女发展乳腺癌的风险比非用者高45%，而服用仅含雌激素的HRT(激素替代治疗)风险增加30%；2)服用雌激素-孕激素复方HRT的妇女乳腺癌风险明显升高2倍。最近的临床研究也证实口服雌酮（结合雌激素）刺激乳腺增生和原癌基因表达而经皮补充雌二醇不会如此Effects of percutaneous estradiol-oral progesterone versus oral conjugated equine estrogens-medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy women.（Fertil Steril.2011 Mar 1;95(3):1188-91.Epub 2010 Nov 10.）Post-treatment change in serum estrone predicts mammographic percent density changes in women who received combination estrogen and progestin in the Postmenopausal Estrogen/Progestin Interventions(PEPI)Trial.J Clin Oncol.2004 Jul 15;22(14):2842-8.Increases in serum estrone sulfate level are associated with increased mammographic density during menopausal hormone therapy.Cancer Epidemiol Biomarkers Prev.2008 Jul;17(7):1674-81.H.Leon Bradlow,M.D.and a group at Strang-Cornell Cancer Research Laboratory,New York City,as well as other prominent researchers have developed a body of evidence concerning 16-alpha-hydroxyestrone，one of metabolites of estrone，is bad estrogen with a endency to increase cellular growth and proliferation,and even cancerous transformation in estrogen-responsive tissues.还有人认为对于人体来说马妊娠雌酮是一种外来物质，因此人体会因摄入这种物质而持续地发炎(C反应蛋白和IL-6增高）。如果由于持续地摄入这种物质而使人持续发炎五到十五年，会增加你患心脏病和早老性痴呆的风险，并会影响器官的正常功能。乳腺癌在目前妇女恶性肿瘤上升到第一位，发病率45-50岁较高，绝经后发病率上升，可能与年老雌酮含量提高有关。（超声在诊断乳腺实性占位中的临床应用价值，兵团医学，2009,1（19）：24-25；外科学，第六版，人民卫生出版社2006,327)雌酮比例增加的原因：卵巢功能下降，雌二醇和孕酮下降，FSH、LH增高（芳香化酶活性增加）、肥胖、口服雌激素（因肝脏及胃肠道的首过效应而使雌酮增加）、口服避孕药，摄入外源性雌激素、氧化应激等。临床上更年期妇女随着好雌激素和坏雌激素比例改变，乳腺癌发病率大增。美国神经骨科博士，营养学学士，美国执业医师，美国抗衰老医学协会会员黄颖2009年在中国做有关荷尔蒙与疾病的讲学中直言雌酮为“坏”雌激素。Hormone therapy administration in postmenopausal women and risk of stroke.Womens Health(Lond Engl).2011 May;7(3):355-61.Renoux C,Suissa S.SourceCenter For Clinical Epidemiology,Jewish General Hospital-Lady Davis Research Institute,Montreal,Quebec,Canada.AbstractHRT,consisting of estrogens alone,or in combination with a progestogen,is widely used for the relief of symptoms in postmenopausal women.Early observational studies have suggested that HRT might be associated with a reduced risk of cardio-and cerebro-vascular events.These encouraging results prompted randomized controlled trials assessing the risks and benefits of HRT in primary and secondary prevention of arterial vascular events.However,these clinical trials and further observational studies did not confirm the protective effect of HRT;it is now established that HRT increases the risk of stroke.This increased risk is mainly related to an increased risk of ischemic stroke.Oral estrogen alone and combined with progestogen are associated with a similar increased risk,which may be dose dependent.Conversely,a low dose of transdermal estrogens with or without a progestogen does not seem to be associated with such an increased risk of stroke,whereas the impact of tibolone,a synthetic steroid,remains uncertain.In summary,there is now a large amount of evidence demonstrating that HRT is associated with increased risk of stroke,in particular,ischemic subtype.Serum concentrations of 17beta-estradiol and estrone after multiple-dose administration of percutaneous estradiol gel in symptomatic menopausal women.Ther Drug Monit.2001 Apr;23(2):134-8.Brennan JJ,Lu Z,Whitman M,Stafiniak P,van der Hoop RG.SourceClinical Operations,Solvay Pharmaceuticals,Inc.,Marietta,Georgia 30062,USA.In two multicenter phase III efficacy studies,blood samples were obtained to evaluate the serum concentrations of 17beta-estradiol(E2)and unconjugated estrone(E1)after administration of a percutaneous gel or transdermal patch containing estradiol.In postmenopausal women,normal laboratory E2 and E1 serum concentrations range from 10-30 pg/mL and 20-40 pg/mL,respectively.Study subjects were healthy postmenopausal women with moderate to severe hot flushes occurring at least seven times daily or 60 times per week.Study 1 was a randomized,double-blind,multicenter study of percutaneous E2 gel 1.25 or 2.5 g(0.75 and 1.5 mg E2,respectively)versus placebo gel.Study 2 was a double-blind(blinded to E2 gel dose),randomized,active-controlled,multicenter,12-week phase 3 study of E2 gel 0.625,1.25,or 2.5 g(0.375,0.75,or 1.5 mg E2,respectively)versus a transdermal E2 patch delivering 0.05 mg E2 per day.Serum E2 and E1 concentrations were evaluated at baseline and at week 12 for study 1 and at baseline and weeks 4,8,and 12 for study 2 using radioimmunoassay.Median serum concentrations of E2 after 1.25-and 2.5-g gel administration appeared to be dose-proportional throughout both studies.In study 1,the median serum concentrations of E2 at week 12 were 33.5 and 65.0 pg/mL for 1.25-and 2.5-g gel dose,respectively.The corresponding E1 values were 49.0 and 58.0 pg/mL.In study 2,both E2 and E1 concentrations were relatively stable at weeks 4,8,and 12.E2 values at week 12 for 0.625-,1.25-,and 2.5-g gel doses and E2 patch were 25.0,32.0,60.0,and 38.5 pg/mL,respectively.The corresponding E1 values were 39.0,41.0,62.5,and 40.0 pg/mL.Application of the 1.25-g gel dose and a transdermal patch delivering 50 microg per day of E2 resulted in comparable median E2 and E1 concentrations.However,the 0.625-g gel dose did not produce E2 levels in a range expected to be consistently therapeutic in most postmenopausal women.Increases in serum estrone sulfate level are associated with increased mammographic density during menopausal hormone therapy.Cancer Epidemiol Biomarkers Prev.2008 Jul;17(7):1674-81.Crandall CJ,Guan M,Laughlin GA,Ursin GA,Stanczyk FZ,Ingles SA,Barrett-Connor E,Greendale GA.SourceDavid Geffen School of Medicine,University of California at Los Angeles,Los Angeles,CA 90024,USA.AbstractBACKGROUND:Menopausal hormone therapy increases mammographic density.We determined whether increases in serum estrone sulfate(E(1)S)levels during menopausal hormone therapy predict increased mammographic density.METHODS:We measured percent mammographic density and serum E(1)S levels in 428 participants of the Postmenopausal Estrogen/Progestin Interventions study who were randomly assigned to daily conjugated equine estrogen(CEE)0.625 mg alone,CEE+daily medroxyprogesterone acetate(MPA)2.5 mg,CEE+cyclical MPA(10 mg days 1-12 per 28-day cycle),or CEE+cyclical micronized progesterone(10 mg days 1-12).Serum E(1)S levels were determined by RIA.Information about covariates was determined by annual questionnaire.Using linear regression,we determined the association between change in E(1)S level from baseline to 12 months and change in percent mammographic density(by semiquantitative interactive threshold method).RESULTS:After controlling for baseline mammographic density,age,body mass index,alcohol intake,parity,smoking,ethnicity,physical activity,and age at first pregnancy,mammographic density increased by 1.3%for every 1 ng/mL increase in E(1)S level(P 0.0001).The association between change in E(1)S level and change in mammographic density differed by treatment group(greater effect in CEE+cyclical MPA group versus CEE group;P=0.05).After controlling for treatment group,change in the ratio of E(1)S to E(1)was also positively associated with change in mammographic density.CONCLUSIONS:Increases in serum E(1)S levels during menopausal hormone therapy are associated with increases in mammographic density.The relative contribution of E(1)S and E(1)to stimulation of breast tissue awaits further elucidation.Post-treatment change in serum estrone predicts mammographic percent density changes in women who received combination estrogen and progestin in the Postmenopausal Estrogen/Progestin Interventions(PEPI)Trial.J Clin Oncol.2004 Jul 15;22(14):2842-8.Ursin G,Palla SL,Reboussin BA,Slone S,Wasilauskas C,Pike MC,Greendale GA.SourceDepartment of Preventive Medicine,Norris Comprehensive Cancer Center,Room 4407,USC Keck School of Medicine,1441 Eastlake Avenue,Los Angeles,CA 90089,USA.AbstractPURPOSE:Postmenopausal estrogen and progestin therapy(EPT)increases mammographic percent density and breast cancer risk substantially more than does estrogen therapy alone.We determined whether increases in serum estrone as a function of treatment predict increases in mammographic percent density.METHODS:We measured mammographic percent density and serum estrone levels in participants in the Postmenopausal Estrogen/Progestin Interventions Trial who were randomly assigned to receive conjugated equine estrogens(CEE)0.625 mg/d;CEE and medroxyprogesterone acetate(MPA)10 mg on days 1 to 12 per 28-day cycle;CEE and MPA 2.5 mg/d;or CEE and micronized progesterone(MP)200 mg on days 1 to 12 per 28-day cycle.We used linear regression to determine whether serum estrone changes predicted mammographic percent density changes from baseline to 1 year.RESULTS:Mammographic percent density increased with increasing change in estrone level in the EPT groups,but not in the CEE group.Combined,the mammographic percent density in the three EPT groups demonstrated an absolute increase of 2.95%per 100 pg/mL increase in serum estrone level(P=.0003).The absolute increases were 4.09%(P=.0018)in the CEE+MPA continuous group,2.79%(P=.0292)in the CEE+MPA cyclical group,and 1.40%(P=.36)in the CEE+MP group,but the differences among the EPT groups were not statistically significant.CONCLUSION:Greater increase in serum estrone level as a function of treatment is a significant predictor of increase in mammographic percent density in women randomly assigned to the combination of estrogen and progestin.从1970年7月至1974年12月,某医疗中心诊断了94例子宫内膜腺癌。另选年龄相近和正常子宫的妇女188例(2倍于子宫内膜腺癌患者)作对照组。据报道,94例子宫内膜腺癌患者中,有57%的患者应用了结合性雌激素(主要是硫酸钠雌酮),而对照组中仅有15%。应用雌激素组与对照组相比,子宫内膜腺癌发生率为7.6倍,比率从应用雌激素14.9年的5.6倍上升到应用雌激素7年以上为13.9倍。据全国肿瘤防治办公室与卫生部卫生信息中心统计，我国大中城市乳腺癌发病率呈不断上升趋势，1993 年至 1997 年，年发病率为 33.710 万人，但到 2005 年，上海、北京、天津等大中城市乳腺癌发病率上升到 43.810万人。北京肿瘤医院乳腺癌防治中心副主任医师解云涛博士介绍说，中国乳腺癌患者数量增长迅速的原因之一可能与人们高热量、高脂肪食物摄入过多，体内脂肪含量超标（雌酮增多）有很大关系。子宫内膜癌是最常见的妇科恶性肿瘤。发病率近年有上升倾向。根据国际癌瘤联合中心的汇编,世界各地的发病率差异很大。在美国的发病亦受种族因素的影响。子宫内膜癌可发生于任何年龄,但多见于5060岁。诊断时的平均年龄为57岁,75%发生在绝经后。有人认为雌激素与子宫内膜癌发病有关,但机理不清。病人的类脂醇生成、激素排泄及前趋病变正在广泛研究中。当体内男性素前身和雄甾烯二酮增加,或外源性性激素快速芳香化和转化为雌酮,均被认为是发展成子宫内膜腺癌的危象。谢谢各位的聆听