着床和机理第章

第章着床和着床机胞生长形成胎盘。胚胎着床的部位一般在体前、后壁。胚和内膜必须同步发言并相互配合；④孕妇体内必须有足够数量的孕酮。首先后6～7天早期囊胚的透明带，胚胎被引导到内膜，附着于特定的部位，同时内膜在孕激素的作用下分化到可接受胚胎种植的状态。它包括内膜形态上的一系列常复杂的过程，它涉及、内膜以及胚胎。在周期中分泌激素的变化刺激内膜的组织形态发生了相应的变化首先在增生期，（一）胚胎的着从胚胎内着床前的准备始首先膜在孕直接或接作用部D3T细胞由4%10%56+K育至在着床期主要细胞分泌一些细因子和长因（G-β、LI，促进了对胚胎的别。另外在内的着床容受期形过程中，胎也起了要作用。发育良好的胚胎使内膜进一步做好接受胚泡植入的准备，调节内膜生物活性物质的产生并控制着引导胚胎粘附于内膜，完成着床的附着过程（appositionphase。该过程中的免疫变化主要包括，１．抗粘附分子降解抗粘附分子是内膜上皮细胞顶端糖-蛋白结合物，是胚胎着床过程中的第一MUC-1的研究最深入。部。MUC1相关配基为选择素。人的内膜中的MUC1逐步增加，到分泌晚期合成下降。在雌激素替代治疗中它缺乏周期性变化，MUC1的表达。细胞角蛋白染色进一步证实，着床部位胚对内膜上皮细胞分泌MUC1的能力进行非常精细的调节。图图X-1.激素和囊胚 内膜上皮细胞分泌MUC1的能力进行的精细调2．趋化因子趋化因子是细胞因子超中的一员，多数为小分子多肽（70~80个氨基酸对定的白细胞有定向趋化作用它们参与分娩和胚胎着床以及一些病理状态如早产、内膜异位症、OHSS和HIV。一般根据起始的2~4个连续丝氨酸残基的位置将趋化因子分为两类，αCXC趋化因子（IL-8）βCC趋化因子（MCP-1，RANTES对单核细胞、巨噬细胞、T细胞、嗜碱性粒细胞、肥大细胞和NK细胞有定向趋化和激活作用。RANTEST细胞的一种细胞趋化因子，主要由正常内膜和异位种植的内膜的实质细胞产生。还能调节活化T细胞的合成和分泌功能。它不TT细胞的吸引，进一步加速趋化作用。CarlosSimon等人就胚胎对趋化因子的调节进行研究发现，IL-8、MCP-1及其相应的受体表达于腺Blot方法进行检测时，在内膜中仅检测到RANTES-mRNA，而在体外与囊胚共培养的EECs中未RANTES-mRNAIL-8MCP-1mRNA，流式细胞检测方法也证实了该中EECs合成IL-8和MCP-1。以上表明囊胚参与了囊胚附着期间内膜趋化因子作用的调节和（二）phase，（pinopodes，降解，内膜上皮粘附分子介导囊胚和内膜的结合以及细胞因子、生长因子、leptin等生物活性物质１．胞饮突（pinopodes）pinopode的形成通过扫描电镜研究发现，着床期间内膜上皮细胞表突仅在胚胎着床的粘附期出现，而且只表达在内膜腔上皮顶端。如，在后D6（接受性）妇女B受体表达下调有关。目前MUC-1在着床期间的变化已在附着期详细介绍。３．粘附分子介导囊胚与内膜的粘附孵化胚胎对内膜上皮的粘附依赖与粘附分子的表达。这些分子包括免疫球蛋白超和选择素有人认为Trophin、Bystin和Tastin形成的细胞粘附分子复合物可能介导了粘囊胚和内膜的初被整合素等其他粘附分子取代，使囊胚与内膜形成更牢固的粘附关系。期（相当于着床窗时期）仅表达于内膜的腺上皮。αvβ3整合素的出现于着床窗时期，它在着如合并和内异症时，过多的表达补体可能导致粘附失败。（三）侵入期（invasion，在侵入期内膜基质蛋白酶的变化，导致细胞外间质降解，并保持局部的止血和蜕膜中新生血管的形成而内膜上皮细胞的凋亡使胚泡能内膜上皮屏障植入内膜着床后蜕膜胎盘形成，，LIFEGFMMP-9２．EECs凋亡的调节细胞凋亡参与了多种的生殖过程，如的功能、内膜生理变化、着细胞，内膜基质细胞很少波及。Fas(CD95)和Fas-L(CD95L)在整个周期共表达于人内膜腺体的内膜上皮细胞凋亡是侵蚀上皮细胞关键步骤。Galan等人研究了附着期和粘附期单个囊胚对培养的人内EEC凋亡数（35.2%）EEC（48.8%，P<0.05（39.2%EEC中出现了大量的凋亡产生。这种胚胎的诱导作用可能是囊胚外胚层和EECs的直接作用。Fas/Fas-L系统是囊胚穿过上皮细胞屏障的重要机制，后的生长明显下降(40%versus82.8%)。（四）后第7天,滋养细胞分泌蛋白酶类物质,内膜上皮局部溶解破坏，滋养细胞上皮，第8～9天，合体滋养层深人内膜中，继续侵蚀。消化和破坏基质，形成众多滋养腔隙，其间充满母血第11～12天整个囊腔埋植于基质中植迅速被内膜上皮包盖着床过程完成。VEGFPLGFPAFHGF以及上皮细胞上表达的c-mettyrosinekinase受体，参与细胞滋养细胞的分化、生长，可能还参与对侵蚀深度其他参与调节滋养细胞生长的还有，IL-1、干细胞因子、CSF-1、IGF、Th细胞因子。IL-1CSF-1IGFBP-1Th-1IFN-γTNF限制滋养细胞的生长。hCG和孕酮的合成。素作用下，内膜HOXA-9，HOXA-10和HOXA-11调节内膜实质细胞的生长。HOXA-11还能促进LIF表达。HOXA-10和LIF影响内孕酮受体的表达，促进蜕膜化。IL-11也可能参与了蜕膜化，经IL-11受体的小鼠存在蜕膜化不完全的表现。泡的一段短暂时期，即所谓的“着床窗”或“种植窗。内膜的着床窗是短暂，同时在各个周期出现时是有空间性的。它代表了内膜上皮细胞的接受性。此时内膜的上皮细胞（EE）和滋养外胚，（TE）进行了直接的接触内膜出现许多的细胞和生物化学的改变作为标记。这些改变是受到，①表达于内膜上皮细胞②它应该是甾体激素依赖性的，尤其是孕激素依赖性的，具有周期性变化④knock-out动物模型表现为着床人们对胚胎着床的认识是随着科学研究的不断发展而不断深入的。knock-out小鼠模型建立技术，发现了许多在着床中起重要作用的生物活性物质。体外囊胚-单层内膜上皮细胞培养体系目前已知的着床窗标记物包括如下分子：①细胞因子：包括IL-1-18，CSF，IFN，TNF，和趋化因1．胞饮突（pinopodes）胞饮突是着床窗在细胞水平上的标志。胞饮突是孕激素依赖的，仅出现于囊胚粘附期，也见于分泌中期的内膜。大剂量的雌激素抑制胞饮突的形成，同时也抑制了着床过程。它的形成维持不到48小时，出现的鼎盛时期是第19~21天（以28天周期为例，多在20天。正常周期：D19~21，多在D20（D13为LH峰时间D18~8（D4：D20~22，（ECM合素受甾体激素调节，如α1和α4是孕酮驱动的，在孕酮开始产生，孕酮受体达到最大峰值时出现，β1在孕酮达到峰值，孕酮受体最少时产生。对不同整合素敲除的小鼠进行研究发现，β1敲除小鼠的胚胎能够发育到囊胚，但不能着床，α4、α5、α6、αv、β3敲除的小鼠没有着床相关现象。类除了注意组织学表现的变化外，还兼顾了整合素αvβ3的表达情况。新的内膜缺陷分类如下：型组织学表现为内膜分泌变化延迟，同时缺乏αvβ3型无组织学表现，但接受性标记αvβ3缺乏，多见于轻微内异症患者、积水、不明原因不孕、PCOS患者。３．Trophin、Bystin、Tastin复合体Trophinin是一种型的细胞膜内在蛋白，属于细胞膜粘trophinin、bystin、tastinEECs的粘附。而小鼠实验中，trophinin蛋白在其内膜的表达仅限于胚胎着床窗时期，trophinin位点突变的胚胎大多于假想的着床窗时期。成人正常组织细胞中trophinin、bystin、tastin仅表达于单核巨噬细胞、参与着床的分泌期内6~8周的胎盘绒毛细胞４．L-选择素（L-selectin）L-选择素是一种糖基结合蛋白，它通过特殊的寡糖结构，作用于白细的连接，从而移行到局部组织。D.OlgaL-选择素是胚胎着床的初始步骤。法在分泌期的内膜和内膜上皮细胞中也检测到瘦素及其受体的表达。ob/ob突变的小鼠分泌缺乏活性的瘦素蛋白片段，表现为肥胖和不孕，这些小鼠的生殖功能能６．白血病抑制因子（LeukemiaInhibitoryFactor，LIF）白血病抑制因子是一种由180个氨基酸组成的糖蛋白，单拷贝，高度保守，通过LIF-R和gp130（glycoprotein130）作用于靶细胞，参与LIF敲除小鼠囊胚不着床但其囊胚移植到正常小鼠后种植成功在其腹腔内注射LIF也R，LIF能促进胚胎发育和囊胚孵化。原因不明不孕妇女通过检测发现冲洗液中LIF表达下降，部７．同源框（homeobox，Hox）Hox是一类控制胚胎发育和细胞分化的调节，其同或种植不久被吸收——内膜血管通透性和蜕膜化严重损伤。Hoxa11缺陷小鼠存在生殖功能缺陷，Hoxa10突变小鼠LIF及其受体表达正常，而LIF是Hoxa10的上游调节Hoxa10突变小鼠COX-2表达显著下降，提示Hoxa10是其上游调节，而Hoxa11突变小鼠以上说明LIF–HOX-COX-2之间存在相控８．集落刺激因子-1（ColonyStimulatingFactor-1，CSF-1）CSF-1由巨噬细胞分泌，调节巨噬细胞增殖分化，受雌孕激素调节，由内膜上皮细胞、成纤维细胞以及上皮细胞分泌。CSF－l存在两种形式，可溶性的CSF-1和内膜上皮细胞成膜结合形式。可溶性的CSF-1在两力低下，子代偏小，有研究表明可能与其周期延长有关。患者中CSF-1水平低于正常妇女。甚至有作者认为外周血低CSF-1可能与复发性有关。９．白细胞介素-1（Interleukin-1，IL-1）IL-1是由多种细胞产生的一种多肽，有两种亚型：IL-1α和IL-1ß。其受体属于免疫球蛋白超，可能是胎母交流中第一个被活化的因子，并引起一系列的IL-1是胚胎着床过程的主要影响因素。IL-1knock-out小鼠模型不孕，可能直接影响了内膜，给予IL-1ra能囊胚粘附——正常内膜形态的转化，还能下调内膜整合素α4，αv、ß3的表达。受IL-1ra处理的小鼠胚胎在正常中发育正常，但不能着床。，内膜中发挥功能中期明显升高。IL-1R主要表达于蜕膜和胎盘。种植前胚胎表达IL-1ß、IL-1ra、IL-1RtImRNA。，IL-1PGE2ß3和LIF表达增IL-1ß。肝素结合性表皮生长因子（heparin-bindingepidermalgrowthfactor，HB-EGF）HB-EGF是表皮生长因子（EGF）超成员之一，为分子量约22kD的单链蛋白质，通过细胞表面的EGF受体较强的亲和性而得名。HB-EGFproHB-EGF）为其前体的形式存在于细胞HB-EGF在小鼠胚泡着床前和着床部位的内膜，以及猪胚泡种植前的内膜腺上皮细胞均有高表达。HB-EGF在人内膜周期中各期均有表达，受体内雌、孕激素的调节，呈明显的周期性变化。人内膜腔上皮和腺上皮细胞HB-EGF蛋白表达在植入期出现峰值表达，在来潮前显高，然后在分泌早期下降;还是在分泌中期升高未有定论。育。HB-EGF在体内、体外直接引起小鼠基质细胞多倍性和蜕膜化，与早期胎盘的形成有关。（LIF整合素β-3表达调控的容受性。环氧化酶(cyclooxygenase,COX)环氧化酶又称素合成酶，是素COX-1COX-2有COX-2在内质网（endosmireticular,ER）和核膜均有表达，说明PGｓ通过两种不同的受体系统EP1~4PGs的受体；另外一种是核受体途径，主要通过核醛X受体（retinoidXreceptor,RXR）中的一员形成二聚体来发挥作用。2-细胞期、4~8细胞期、桑椹胚等不同发COX2-COX-2mRNA和蛋白主要在滋养外胚层表达，提示COX-2可能促进胚泡的分化和着床，达到母胎之间同步发育的目的，COX-2PGI2PPAR的活化发在野生型小鼠怀孕d5时，检测着床点和着床点间的PGs水平，发现PGI2最高，PGE2其次，并且PGI2在着床点的水平明显高于着床点旁。小鼠在妊娠d1~4上午中PPAR表达很低，但d4晚上（22:00～23:00）PPARd5表达于胚胎周围，d6~8COX-2PGI2的表达具有与着床一致的时空性。，在敲除的动物模型中，COX-1缺陷小鼠表现为分娩延迟，但是有能力；而COX-2基因缺陷小鼠却有诸如率降低，着床、蜕膜化等生殖缺陷。并且该缺陷引起的生殖并非垂体促激素、激素或靶对激素的反应性降低，而是由于靶COX-2的缺陷直接导致的。这些证实，COX-2是着床过程中重要的参加者。，对着床失败的COX-2剔除小鼠将少量胚泡移植到P4方法诱导的COX-2剔除假孕小鼠，COX-2基COX-2增加着床点血管通透性，促进血管生成，是它在此外，COX-2还能促进着床过程中内膜细胞的蜕膜化。对假孕野生型小鼠角注射或不注射油有表达；同时PGI2激动剂cPGI（carbaprostacyclin）能恢复COX-2剔除小鼠内注射油剂引起COX-1COX-2mRNA和蛋白的表达。生物过程，另一方面对不孕症、习惯性、妊高征的发病机理研究、诊断和治疗将提供重要的线索。随着技术的飞速发展可以采用先进的技术大规模的筛查着床相关并进行功能的研究，（主编．现代辅助技术．：人民军医姜群英，，．雌、孕激素调控人内膜间质细胞HB-EGF的表达．中华，，姜群英．类肝素结合性表皮生长因子在人内膜植入窗期的表达和意义．生殖，，9：334-Alexander,J.P.,J.R.Samples&T.S.Acott.GrowthfactorandcytokinemodulationoftrabecularmeshworkmatrixmetalloproteinaseandTIMPexpression.Curr.EyeRes.1998;17:276-285AnetteLindahard,UrsulaBentin-Ley,VibekeRavn,etal.Biochemicalevaluationofendometrialfunctionatthetimeofimntation.Fertil.Steril.2002;78:221-233AokiR,FukudaMN.Recentmolecularapproachestoelucidatethemechanismofembryoimntation:trophinin,bystin,andtastinasmoleculesinvolvedintheinitialattaentofblastocyststotheuterusinhumans.Semin.Reprod.Med.AranchaGalan,RaquelHerrer,JoseRemohi,etal.Embryonicregulationofendometrialepithelialapoptosisduringhumanimntation.Hum.Reprod.2000;15(suppl):74-80Arici,A.,J.R.Head,P.C.MacDonald&M.L.Casey.Regulationofinterleukin-8geneexpressioninhumanendometrialcellsinculture.Mol.Cell.Endocrinol.1993;94:195-204Arici,A.,P.C.McDonald&M.L.Casey.Regulationofmonocytechemotacticprotein-1geneexpressioninhumanendometrialcellsincultures.Mol.Cell.Endocrinol.1995;107:189-197.Baggiolini,M.&A.Dahinden.CCChemokinesinallergic tion.Immunol.Today1994;15:127-BanyBM&KennedyTG.Roleofinterleukin1intheregulationofcyclooxygenasegeneexpressioninratendometriastromalcells.J.Reprod.Fertil.1999;115:125-131.BanyBM&KennedyTG.Regulationofcyclooxygenasegeneexpressioninratendometrialstromalcells:theroleofepidermalgrowthfactor.Dev.Genet.1997;21:109-115.BensonGV,LimH,PariaBC,etal.MechanismsoffemaleingertilityinHoxa-10mutantmice:UterinehomeosisversuslossofmaternalHoxa-10expression.Development.1995;122:2687-2696BhatnagarP,PapaioannouVE,BiggersJD.CSF-1andmousepreimntationdevelopmentinvitro.Development.1995;Bischof,P.,A.Meisser&A.Compana.Mechanismsofendometrialcontroloftrophoblastinvasion.J.Reprod.Fertil.2000;55(Suppl):65-71Campbell,S.,H.R.Swann,M.W.Seif,etal.Celladhesionmoleculesontheoocyteandpreimntationhumanembryo.Hum.Reprod.1992;1:1571-CarlosSimon,FranciscoDominguez,JoseRemohi,etal.EmbryoEffectsinHumanImntation:EmbryonicRegulationofEndometrialMoleculesinHumanImntation.AnnalsoftheNewYorkAcademyofSciences.2001;943:1-16Chardonnes,D.,P.Cameo,M.L.Aubert,etal.Modulationofhumancytotrophoblasticleptinsecretionbyinterleukin-1ßand17ß-estradiol,anditseffectonhumanchorionicgonadotropinsecretion.Mol.Hum.Reprod.1999;5:1077-1082Charnock-jonesDS,SharkeyAM,FenwickP,etal.LeukaemiainhibitoryfactormRNAconcentrationpeaksinhumanendometriumatthetimeofimntationandtheblastocystcontainsmRNAforthereceptoratthistime.J.Reprod.Fertil.1994;101:421-426Chegini,N.Oviductal-derivedgrowthfactorsandcytokines.Implicationinpreimntation.Semin.Reprod.1996;14:219-Chehab,F.,M.Lom&R.Lu.Correctionofthesterilitydefectinhomozygousobesefemalemicebytreatmentwiththehumanbinantleptin.NatureGenet.1996;12:318-320Clarke,I.J.&B.A.Henry.Leptinandreproduction.Rev.Reprod.1999;4:48-CohenPE,ZhuL,PollardJW.Absenceofcolonystimulatingfactor-1inosteopetrotic(csfmop/csfmop)micedisruptsestrouscyclesandovulation.Biol.Reprod.1997;56:110-118CreusM,OrdiJ,FabreguesFetal.alphavbeta3integrinexpressionandpinopodformationinnormalandout-of-phaseendometriaoffertileandinfertilewomen.Hum.Reprod.2002;17(9):2279-86Critchley,H.O.D.,R.W.Kelly&J.Kooy.Perivascularlocalizationofinterleukin-8inhumanendometrium:apreliminaryreport.Hum.Reprod.1994,8:1406-1409.Critchley,H.O.D.,R.W.Kelly,R.G.Lea,et steriodregulationofleukocytetrafficinhumandecidua.Hum.1996;11:2257-CullinanEB,AbbondanzoSJ,AndersonPS,etal.Leukemianinhibitoryfactorbyhumanendometriumsuggestsapotentialautocrine/paracrinefunctioninregulatingembryoimntation.Proc.Nal.Acad.Sci.USA.1996;93:3115-3120DaftaryGS,TaylorHS.Molecularmarkersofimntation:clinicalimplications.Curr.Opin.Obstet.Gynecol.2001;13:269-Damsky,C.H.,M.I.Fitzgerald&S.J.Fisher.Distributionpatternsofextracellarmatrixcomponentsandadhesionreceptorsareintricaymodulatedduringfirsttrimestercytotrophoblastdifferentiationalongtheinvasivepathway,invivo.J.Clin.Invest.1992;89:210-222.DaniC,ChambersI,JohnstoneS,etal.ParacrineinductionofstemcellrenewalbyLIF-deficientcells.Dev.Biol.1998;DasSK,WangXN,PariaBC,etal.Heparin-bindingEGFlikegrowthfactorgeneisinducedinthemouseuterustemporallybytheblastocystsolelyatthesiteofitsapposition:apossibleligandforinctionwithblastocystEGF-receptorinimntation.Development,1994；120:1071-DelPozo,M.A.,C.Cabañas,M.C.Montoya,etal.ICAMsredistributedbychemokinestocellularuropodsasamechanismforrecruitmentofT-lymphocytes.J.Cell.Biol.1997;137:1-16DingNZ,MaXH,DiaoHL,etal.Differentialexpressionofperoxisomeproliferator-activatedreceptordeltaatimntationsitesandindecidualcellsofratuterus.Reproduction.2003;125:817-25.DiRenzoJ,SoderstromM,KurokawaR,etal.Peroxisomeproliferator-activatedreceptorsandretinoicacidreceptorsdifferentiallycontroltheinctionsofretinoidXreceptorheterodimerswithligands,coactivators,andcorepressors.Mol.Cell.Biol.1997;17:2166-76.ErrolR.Norwitz,DannyJ.Schust,andSusanJ.Fisher.ImntationandtheSurvivalofEarlyPregnancy.N.Engl.J.2001;345:1400-Fassler,R.&M.Meyer.Consequencesoflackofß1integringeneexpressioninmice.GenesDev.1995;9:1876-37．F.Dominguez,P.Caballero-Campo,A.Pellicer&C.Simon.HormonalendembryonicregulationofchemokinesIL-8,MCP-1,RANTESandtheirreceptorsCXCRI,CCR2BandCCR5inhumanendometrium.2000,J.Soc.Gynecol.Invest.(Suppl.)7(1):213.FrederickSchatz,G.Krikun,R.Runic,etal.Implicationsofdecidualization-associatedproteaseexpressioninimntationandmenstruation.Semin.Reprod.Med.1999;17:3-11FukudaMN,NozawaS.Trophinin,tastin,andbystin:acomplexmediatinguniqueattaentbetweentrophoblasticandendometrialepithelialcellsattheirrespectiveapicalcellmembranes.Semin.Reprod.Endocrinol.1999;17:229-234FukudaMN,SatoT,NakayamaJ,etal.Trophininandtastin,anovelcelladhesionmoleculecomplexwithpotentialinvolvementinembryoimntation.Genens.Dev.1995;9:1199-1210Garcia-Velasco,J.A.&A.Arici.Interleukin-8expressioninendothelialstromalcellsisregulatedbyintegrin-dependentcelladhesion.Mol.Hum.Reprod.1999;5:1135-1140GenbacevOD,PrakobpholA,FoulkRA,etal.TrophoblastL-selectin-mediatedadhesionatthematernal-fetalScience2003;299(5605):405-GeorgeNikas.Pinopodesasmarkersofendometrialreceptivityinclinicalpractice.Hum.Reprod.1999;14:99-GierseJK,McDonaldJJ,HauserSD,etal.Asingleaminoaciddifferencebetweencyclooxygenase-1(COX-1)and-2(COX-2)reversestheselectivityofCOX-2specificinhibitors.J.Boil.Chem.1996;271:15810-4.Gimond,C.,C.Baun,R.VanderNeut,etal.Cre-loxP-mediatedinactivationofthealpha6Aintegrinsplicevariantinvivo:evidenceforaspecificfunctionalroleofalpha6Ainlymphocytemigrationbutnotinheartdevelopment.J.CellBiol.1998;143:253-266Gonzalez,R.,P.Caballero,M.Jasper,etal.Leptinandleptinreceptorareexpressedinthehumanendometriumandendometrialleptinsecretionisregulatedbythehumanblastocyst.J.Clin.Endocrinol.Metab.2000;85:4883-4888.Hey,N.A.&J.D.Aplin.Syalil-LewisxandSyalil-LewisaareassociatedwithMUC1inhumanendometrium.Glycoconj.1996;13:769-Hey,N.A.,R.A.Graham,M.W.Seif&J.D.Aplin.ThepolymorphicepithelialmucinMUC1isregulatedwith expressionintheimntationphase.J.Clin.Endocrinol.Metab.1994;78:337-342.Hey,N.A.,T.C.Li,P.L.Devine,etal.MUC1insecretoryphaseendometrium:expressioninpreciselydatedbiopsiesandflushingsfromnormalandrecurrentmiscarriagepatients.Hum.Reprod.1995;10:2655-2662.Hodivala-Dilke,K.M.,K.P.McHugh,D.A.Tsakiris,etal.1999.Beta3-integrin-deficientmiceareamodelforGlanzmannthrombastheniashowingcentaldefectsandreducedsurvival.J.Clin.Invest.103:229-238.Hoffman,L.H.,G.E.Olson,D.D.Carson,etal.ProgesteroneandimntingblastocystregulateMUC1expressioninrabbituterineepithelium.Endocrinology.1998;139:266-271.andendometriosistissuesandcells.J.Clin.Endocrinol.1997;82:1621-1628Houseknecht,K.L.,C.A.Baile,R.L.Matteri&M.E.Spurlock.1998.Thebiologyofleptin:areview.J.Anim.Sci.76:1405-Hsieh-LiHM,WitterDP,WeinsteinM,etal.Hoxa-11structure,extensiveantisensetranscription,andfunctioninmalandfemalefertility.Development.1995;121:1373-1385Hum.Reprod.1998;4:1157-Hynes,R.O.Integrins:versatility,modulation,andsignallingincelladhesion.Cell.1992;69:11-IlleraMJ,LorenzoPL,GuiYTetal.ARoleforalpha(v)beta(3)IntegrinDuringImntationintheRabbitModel.Reprod.2003;68(3):766-Ingamells,S.,I.G.Campbell,F.W.Anthony,etal.Endometrialprogesteronereceptorexpressionduringthehumanmenstrualcycle.J.Reprod.Fertil.1996;106:33-3859．J.J.Kim,R.C.Jaffe,A.T.Fazleabas.Blastocystinvasionandthestromalresponseinprimates.Hum.Reprod.1999;14(suppl.):Jones,R.L.,R.W.Kelly&H.O.D.Critchley.Chemokinesandcyclooxygenase-2expressioninhumanendometriumcoincideswithleukocyteaccumulation.Hum.Reprod.1997;12:1300-1306JOSEPHA.HILL.Maternal-EmbryonicCross-Talk.AnnalsoftheNewYorkAcademyofSciences.2001;943:17-25.62．KarpovichN,ChobotovaK,CarverJ,etal.Expressionandfunctionofinterleukin-11anditsreceptoralphainthehumanendometrium.MolHumReprod,2003;9:75-Kauma,S.W.&D.W.Matt.Coculturecellsthatexpressleukemiainhibitingfactorenhancemouseblastocystdevelopmentinvitro.J.Assist.Reprod.Genet.1995;12:153-156.KimGY,BesnerGE,SteffenCL,etal.Purificationofheparin-bindingepidermalgrowthfactor-likegrowthfactorfrompiguterineluminalflushings,anditsproductionbyendometrialtissues.Biol.Reprod.1995;52:561-71.King,A.,L.Gardner&Y.W.Loke.Evaluationofoestrogenandprogesteronereceptotrsexpressioninuterinemucosallymphocytes.Hum.Reprod.1996;11:1079-1082KorgunET,DohrG,DesoyeGetal.Expressionofinsulin,insulin-likegrowthfactorIandglucocorticoidreceptorinratuterusandembryoduringdecidualization,imntationandorganogenesis.Reproduction.2003;125(1):75-84KqumaSW,AukermanSL,EiermanD,etal.Colony-stimulatingfactor-1andc-fmsexpressioninhumanecdometrialtissuesandcentaduringthemenstrualcycleandearlypregnancy.J.Clin.Endocrinol.Metab.1991;73:746-751KruesselJS,HuangHY,WenY,etal.Differentpatternofinterleukin-1beta-(IL-1beta),interleukin-1receptorantagonist-(IL-1ra)andinterleukin-1receptortypeI-(IL-1RtI)mRNA-expressioninsinglepreimntationmouseembryosatvariousdevelopmentalstages.J.Reprod.Immunol.1997;34:103-120KrusselJ,SimonC,RubioMC,etal.Expressionofinterleukin-1systemmRNAinsingleblastomeresfromhumanpreimntationembyos.Hum.Reprod.1998;13:2206-2211LairdSM,TuckermanEM,DaltonCF,etal.Theproductionofleukaemiainhibitoryfactorbyhumanendometrum:presenceinuterineflushingsandproductionbycellsinculture.Hum.Reprod.1997;12:569-574LeachRE,KhalifaR,RamirezND,etal.Multiplerolesforheparin-bindingepidermalgrowthfactor-likegrowthfactoraresuggestedbyitscell-specificexpressionduringthehumanendometrialcycleandearlycentation.J.Clin.Endocrinol.Metab.1999;84:3355-63.LeachRE,KilburnB,WangJ,etal.Heparin-bindingEGF-likegrowthfactorregulateshumanextravillouscytotrophoblastdevelopmentduringconversiontotheinvasivephenotype.DevBiol,2004;266:223-37.J.Clin.Endocrinol.Metab.1994;79:643-LesseyBA,GuiY,ApparaoKB,etal.Regulatedexpressionofheparin-bindingEGF-likegrowthfactor(HB-EGF)inthehumanendometrium:apotentialparacrineroleduringimntation.MolReprodDev,2002;62:446-55.Lessey,B.A.,I.Yeh,A.J.Casbaum,etal.Endometrialprogesteronereceptorsandmarkersofuterinereceptivityinthewindowofimntation.Fertil.Steril.1996;65:477-483Lessey,B.A.,A.J.Castlebaum,S.J.Sawinetal.Integrinsasmarkersofuterinereceptivityinwomenwithprimaryunexinedinfertility.Fertil.Steril.1995;63:535-542.LimH,GuptaRA,MaWG,etal.Cyclo-oxygenase-2-derivedprostacyclinmediatesembryoimntationinthemouseLimH,PariaBC,DasSK,etal.Multiplefemalereproductivefailuresincyclooxygenase2-deficientmice.Cell.1997;Loke,Y.W.&A.King.Immunologicalaspectsofhumanimntation.J.Reprod.Fertil.2000;55（Suppl.）:88-90.80．Lopata,A.Blastocyst-endometrialinction:anappraisalofsomeoldandnewideas.Mol.Hum.Reprod.1996;7:519-525MaL,BensonGV,LimH,etal.AbdominalB(AbdB)Hoxagenes:Regulationinadultuterusbyestrogenandprogesteroneandrepressioninmüllerianductbythesyntheticestrogendiethylstilbestrol(DES).Dev.Biol.1998;197:141-154Ma,L.,M.Yao&R.I.Maas.Geneticcontrolofuterinereceptivityduringimntation.Sem.Reprod.Endocrinol.1999;17:MarionsL&DanielssonKG.Expressionofcyclooxygenaseinhumanendometriumduringtheimntationperiod.Hum.Reprod.1999;5:961-MatsumotoH,MaWG,DaikokuT,etal.Cyclooxygenase-2differentiallydirectsuterineangiogenesisduringimntationinmice.J.Biol.Chem.2000;277:29260-7.Meseguer,M.,A.Pellicer&C.Simón.MUC1andendometrialreceptivity.Mol.Hum.Reprod.1998;4:1089-1098.86．Meseguer,M.,J.Aplin,P.Caballero-Campo,etal.HumanendometrialMucinMUC1isup-regulatedbyprogesteroneanddown-regulatedinvitrobythehumanblastocyst.Biol.Reprod.2001;64(2):590-Meseguer,M.,P.Gaitan,A.Mercader,etal.HormonalregulationinvivoofMUC1inmockcyclesfrompatientsundergoingoocytedonation.Hum.Reprod.1998;13:121-122.Meyer,W.R.,A.J.Casbaum,S.Somkutietal.Hydrosalesadverselyaffectmarkersofendometrialreceptivity.Reprod.1997;12:1393-Mounzih,K.,R.Lu&F.F.Chehab.Leptintreatmentrescuesthesterilityofgeneticallyobeseob/obmales.1997;138:1190-NaglichJG,MetherallJE,RussellDW,etal.Expressioncloningofadiphtheriatoxinreceptor:identitywithaheparin-bindingEGF-likegrowthfactorprecursor.Cell,1992,69:1051-61.NardoLG,SabatiniL,RaiRetal.Pinopodeexpressionduringhumanimntation.EurJObstetGynecolReprodNawaz,S.,M.P.Lynch,P.Galand&L.E.Gerschenson.Hormonalregulationofcelldeathinrabbituterineepithelium.Am.J.Pathol.1987;127:51-59Paria,B.C.&S.K.Dey.Preimntationembryodevelopmentinvitro:cooperativeinctionsamongembryosandtheroleofgrowthfactors.Proc.Natl.Acad.Sci.USA.1990;87:4756-4760.Parr,E.L.,H.N.Tung&M.B.Parr.Apoptosisasthemodeofuterineepithelialcelldeathduringembryoimntationinmiceandrats.Biol.Reprod.1987;36:211-225PollardJW,HuntJS,Wiktor-JedrzejczakW,etal.Apregnancydefectintheosteopetrotic(op/op)mousedemonstratestherequeirementforCSF-1infemalefertility.Dev.Biol.1991;148:273-283RaabG&KlagsbrunM.Heparin-bindingEGF-likegrowthfactor.BiochimBiophysActa,1997；1333:179-RalphP,Sampson-JohannesA.Macrophagegrowthandstimulatingfactor,M-CSF.Prog.Clin.Biol.Res.1990;338:43-6398．Rango,U.,I.Classen-Linke,C.A.Krusche&H.Beier.Thereceptiveendometriumischaracterizedbyapoptosisintheglands.Hum.Reprod.1998;13:3177-Ruoslahti,E.RGDandotherrecognitionsequencesforintegrins.Annu.Rev.Cell.Dev.Biol.1996;12:697-Saito,S.,T.Kasahara,S.Sakakura,etal.1994.Detectionandlocalizationofinterleukin-8mRNAandproteininhumancentaanddecidualtissues.J.Reprod.Immuol.27:161-172.Senaris,R.,T.Garcia-Caballero,X.Casabiell,etal.Synthesisofleptininhumancenta.Endocrinology.1997;138:4501-SethGuller,LindaLaChapelle.TheroleofcentalFasligandinmaintainingimmuneprivilegeatmaternal-fetalinterfaces.Semin.Reprod.Med.1999;17:39-44SimonC,FrancesA,PiquetteGN,etal.Embryonicimntationinmiceisblockedbyinterleukin-1receptorEndocrinology.1994;134:521-SimonC,GimenoMJ,MercaderA,etal.Embryonicregulationofinegrinsbeta3,alpha4,andalpha1inhumanendometrialepithelialcellsinvitro.J.Clin.Endocrinol.Metab.1997;82:2607-2619Simón,C.,P.Caballero-Campo,J.A.García-Velascoetal.Potentialimplicationsofchemokinesinreproductivefunction:anattractiveidea.J.Reprod.Immunol.1998;38:169-193SimonC,PiquetteGN,FrancesA,etal.Localizationofnterleukin-1typeIreceptorandinterleukin-1betainhumanendometriumthroughoutthemenstrualcycle.3;77:549-555SimonC,ValbuenaD,KrusselJ,etal.Interleukin-1receptorantagonistpreventsembryonicimntationbyadirecteffectontheendometrialepithelium.Fertil.Steril.1998;70:896-906SongH,LimH,DasSK,etal.DysregulationofEGFfamilyofgrowthfactorsandCOX-2intheuterusduringthepreattaentandattaentreactionsoftheblastocystwiththeluminalepitheliumcorrelateswithimntationfailureinLIF-deficientmice.MolEndocrinol.2000;14:1147-61Stavreus-EversA,NikasG,SahlinLetal.Formationofpinopodesinhumanendometriumisassociatedwiththeconcentrationsofprogesteroneandprogesteronereceptors.Fertil.Steril.2001;76(4):782-91StephenK.Smith.Angiogenesisiandimntation.Hum.Repord.2000;15(suppl.):59-Stephens,L.E.,A.E.Sutherland,I.V.Klimanskaya,etal.Deletionofß1integrinsinmiceresultsininnercellmassfailureandperi-imntationlethality.GenesDev.1995;9:1883-1895StewartCL,AbbondanzoSL&CullinanEB.Regulationbymaternallyderivedcytokinesofpre-imntationdevelopmentanduterinereceptiveness.ContraceptFertil,1995；23:555-61.StewartCL,KasparP,BrunetJ,etal.Blastocystimntationdependsonmaternalexpressionofleukaemiainhibitoryfactor.Nature.1992:359:76-79SuzukiNA,ZaraJA,FukudaMN,etal.Acytosmicprotein,bystin,inctswithtrophinin,tastin,andcytokeratinandmaybeinvolvedintrophinin-mediatedcelladhesionbetweentrophoblastandendometrialepithelialcells.Porc.Natl.Acad.Sci.USA.1998;95:5027-5032TabibzadehS,KaffkaKL,SatyaswaroopPG,etal.Interleukin-1(IL-1)regulationofhumanendometrialfunction:presengceofIL-1receptorcorrelateswithIL-1-stimulatedprostaglandinE2production.J.Clin.Endocrinol.Metab.1990;70:1000-1006TakacsP,KaumaS.Theexpressionofinterleukin-1alpha,interleukin-1beta,andinterleukin-1receptortypeImRNAduringpreimntationmousedevelopment.J.Reprod.Immunol.1996