重組人生長(zhǎng)激素預(yù)處理對(duì)卵巢儲(chǔ)備功能減退和卵巢低反應(yīng)患者IVF-ET治療結(jié)局的研究

重組人生長(zhǎng)激素預(yù)處理對(duì)卵巢儲(chǔ)備功能減退和卵巢低反應(yīng)患者IVF-ET治療結(jié)局的研究摘要目的探討重組人生長(zhǎng)激素（GH）對(duì)卵巢儲(chǔ)備功能減退（DOR）和卵巢低反應(yīng)（POR）患者在體外受精-胚胎移植（IVF-ET）周期中治療結(jié)局的影響。方法回顧性分析2019年6月-2020年12月在淄博市婦幼保健院生殖醫(yī)學(xué)中心行IVF-ET治療的DOR、POR的不孕癥患者。DOR患者分為應(yīng)用GH治療組（40個(gè)周期）和未應(yīng)用GH的對(duì)照組（42個(gè)周期）；POR的患者應(yīng)用GH治療前后進(jìn)行自身對(duì)照研究（31個(gè)周期）。比較每組患者應(yīng)用GH治療后超促排卵相關(guān)參數(shù)、獲卵數(shù)、受精率、優(yōu)質(zhì)胚胎數(shù)、優(yōu)胚率、著床率及妊娠結(jié)局。結(jié)果：（1）DOR患者GH治療組Gn啟動(dòng)劑量、Gn總天數(shù)、Gn總量均明顯少于對(duì)照組，HCG日子宮內(nèi)膜厚度在GH治療組顯著厚于對(duì)照組（P<0.05）；DOR患者受精率在GH治療組顯著高于對(duì)照組（P<0.05）；無(wú)可利用胚胎率在GH治療組顯著低于對(duì)照組（P<0.05）。（2）POR患者的可利用胚胎數(shù)、優(yōu)質(zhì)胚胎數(shù)、優(yōu)質(zhì)胚胎率在GH治療后顯著高于GH治療前（P<0.05）；無(wú)可利用胚胎率與GH治療前比較顯著降低（P<0.05）。結(jié)論：DOR和POR患者應(yīng)用GH預(yù)處理可以改善IVF-ET的治療結(jié)局，減少周期取消率。關(guān)鍵詞生長(zhǎng)激素；卵巢低反應(yīng)；卵巢儲(chǔ)備功能減退；體外受精-胚胎移植；妊娠結(jié)局InvestigatetheeffectofrecombinanthumangrowthhormonepreconditioningontheIVF-EToutcomeofthepatientswithdiminishedovarianreserveandpoorovarianresponseAbstractObjective：Investigatetheeffectofrecombinanthumangrowthhormone(GH)ontheinvitrofertilization-embryotransfer(IVF-ET)outcomeofthepatientswithdiminishedovarianreserve(DOR)andpoorovarianresponse(POR).Methods：RetrospectiveanalysiswasperformedoninfertilepatientswithDOR,PORwhoreceivedIVF-ETtreatmentinReproductiveMedicineCenterofZiboMaternalandChildHealthHospitalfromJune2019toDecember2020.PatientswithDORweredividedintoGHtreatmentgroup(40cycles)andcontrolegroupwithoutGHtreatment(42cycles).PatientswithPORweretreatedwithGHandself-controlledstudiedwereconducted(31cycles).Theparametersrelatedtoovulationinduction,thenumberofoocytes,fertilizationrate,thenumberofembryowithhighquality,goodqualityembryorate,implantingrateandpregnancyoutcomeswerecomparedbetweeneachgroups.Results：(1)TheGnstartingdose,totalGndaysandtotalGndoseintheGHtreatmentgroupofDORpatientsweresignificantlylowerthanthoseinthecontrolgroup,andtheendometrialthicknessofHCGdaysintheGHtreatmentgroupwassignificantlythickerthanthatinthecontrolgroup(P<0.05).TherateofunusedembryosintheGHtreatmentgroupwassignificantlylowerthanthatinthecontrolgroup(P<0.05).(2)Thenumberofavailableembryos,thenumberofhigh-qualityembryosandtherateofhigh-qualityembryosinPORpatientsafterGHtreatmentweresignificantlyhigherthanthosebeforeGHtreatment(P<0.05).Conclusions：GHpreconditioninginpatientswithDORandPORcanimprovethetreatmentoutcomeofIVF-ETandreducecyclecancellationrate.Keywordsgrowthhormone(GH),poorovarianresponse(POR),diminishedovarianreserve(DOR),invitrofertilization-embryotransfer(IVF-ET),pregnancyoutcome項(xiàng)目基金：山東省醫(yī)藥衛(wèi)生發(fā)展計(jì)劃項(xiàng)目（2019WS301）；山東省醫(yī)藥衛(wèi)生發(fā)展計(jì)劃項(xiàng)目（2017WS5630）作者單位：淄博市婦幼保健院生殖醫(yī)學(xué)中心淄博山東255000通訊作者：路鴻艷，電子郵箱：honeyan_99@163.com近年來(lái)輔助生殖技術(shù)已廣泛應(yīng)用于不孕癥患者的臨床治療，但其臨床妊娠率及活產(chǎn)率仍未有明顯提高。隨著婚育年齡推遲、生活節(jié)奏加快、社會(huì)的競(jìng)爭(zhēng)壓力、心理壓力、食品安全、環(huán)境污染等不良因素的增加，加之二孩兒政策放開，有生育需求的卵巢儲(chǔ)備功能減退（diminishedovarianreserve,DOR）的患者明顯增多。由于卵巢儲(chǔ)備功能減退，體外受精-胚胎移植（invitrofertilization-embryotransfer,IVF-ET）治療過(guò)程中易出現(xiàn)卵巢反應(yīng)不良、胚胎質(zhì)量差、周期取消率高等問(wèn)題，影響IVF-ET的治療結(jié)局ADDINEN.CITEADDINEN.CITE.DATA[1]。對(duì)于年齡＞35歲的女性而言，卵巢對(duì)促性腺激素（Gn）的反應(yīng)性下降是影響妊娠率的重要環(huán)節(jié)。目前有報(bào)道顯示在輔助生殖促排卵過(guò)程中，大約有9％～24％的人發(fā)生卵巢低反應(yīng)（poorovarianresponse,POR）ADDINEN.CITE<EndNote><Cite><Author>Surrey</Author><Year>2000</Year><RecNum>623</RecNum><DisplayText>[2]</DisplayText><record><rec-number>623</rec-number><foreign-keys><keyapp="EN"db-id="w2ssrprdrwwdtrexsw9pvtf2r9vzeez9e9wv"timestamp="1615724768">623</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Surrey,E.S.</author><author>Schoolcraft,W.B.</author></authors></contributors><auth-address>ColoradoCenterforReproductiveMedicine,Englewood,Colorado,USA.</auth-address><titles><title>Evaluatingstrategiesforimprovingovarianresponseofthepoorresponderundergoingassistedreproductivetechniques</title><secondary-title>FertilSteril</secondary-title></titles><periodical><full-title>FertilSteril</full-title></periodical><pages>667-76</pages><volume>73</volume><number>4</number><edition>2000/03/25</edition><keywords><keyword>ClinicalProtocols</keyword><keyword>Dose-ResponseRelationship,Drug</keyword><keyword>EvaluationStudiesasTopic</keyword><keyword>Female</keyword><keyword>Gonadotropin-ReleasingHormone/*agonists</keyword><keyword>Gonadotropins/*therapeuticuse</keyword><keyword>GrowthHormone-ReleasingHormone/therapeuticuse</keyword><keyword>HumanGrowthHormone/therapeuticuse</keyword><keyword>Humans</keyword><keyword>Ovary/drugeffects/*physiology</keyword><keyword>OvulationInduction/*methods</keyword><keyword>PredictiveValueofTests</keyword><keyword>Pregnancy</keyword></keywords><dates><year>2000</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0015-0282(Print) 0015-0282(Linking)</isbn><accession-num>10731523</accession-num><urls><related-urls><url>/pubmed/10731523</url></related-urls></urls><electronic-resource-num>10.1016/s0015-0282(99)00630-5</electronic-resource-num></record></Cite></EndNote>[2]。POR是指在超促排卵過(guò)程中患者對(duì)外源性促性腺激素反應(yīng)低下，主要表現(xiàn)為獲卵數(shù)、可移植胚胎數(shù)少，臨床妊娠率低和周期取消率高，是不孕癥患者行輔助生殖助治療獲得成功妊娠的一大障礙ADDINEN.CITEADDINEN.CITE.DATA[3]。在臨床工作中如何使DOR和POR患者獲得更高的臨床妊娠率及活產(chǎn)率是生殖醫(yī)學(xué)工作者努力的目標(biāo)。Xu等ADDINEN.CITE<EndNote><Cite><Author>Xu</Author><Year>2019</Year><RecNum>1216</RecNum><DisplayText>[4]</DisplayText><record><rec-number>1216</rec-number><foreign-keys><keyapp="EN"db-id="w2ssrprdrwwdtrexsw9pvtf2r9vzeez9e9wv"timestamp="1615728923">1216</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Xu,Y.M.</author><author>Hao,G.M.</author><author>Gao,B.L.</author></authors></contributors><auth-address>DepartmentofReproductiveMedicine,TheSecondHospital,HebeiMedicalUniversity,Shijiazhuang,China. DepartmentofMedicalResearch,ShijiazhuangFirstHospital,HebeiMedicalUniversity,Shijiazhuang,China.</auth-address><titles><title>ApplicationofGrowthHormoneininvitroFertilization</title><secondary-title>FrontEndocrinol(Lausanne)</secondary-title></titles><periodical><full-title>FrontEndocrinol(Lausanne)</full-title></periodical><pages>502</pages><volume>10</volume><edition>2019/08/10</edition><keywords><keyword>effect</keyword><keyword>growthhormone</keyword><keyword>invitrofertilization</keyword><keyword>infertility</keyword><keyword>reproduction</keyword></keywords><dates><year>2019</year></dates><isbn>1664-2392(Print) 1664-2392(Linking)</isbn><accession-num>31396161</accession-num><urls><related-urls><url>/pubmed/31396161</url></related-urls></urls><custom2>PMC6663998</custom2><electronic-resource-num>10.3389/fendo.2019.00502</electronic-resource-num></record></Cite></EndNote>[4]查閱大量文獻(xiàn)總結(jié)了生長(zhǎng)激素（growthhormone,GH）在IVF-ET中的作用，認(rèn)為補(bǔ)充GH可能提高卵巢的反應(yīng)性、子宮內(nèi)膜的容受性、臨床妊娠率和活產(chǎn)率。本研究旨在探討重組人生長(zhǎng)激素（GH）的預(yù)處理對(duì)DOR和POR患者在IVF-ET周期中治療結(jié)局的影響，為減少周期取消率，增加可利用胚胎數(shù)和優(yōu)質(zhì)胚胎率，提高DOR和POR患者的臨床治療結(jié)局尋找治療方案。材料與方法1.1、資料收集回顧性分析2019年6月-2020年12月在淄博市婦幼保健院生殖醫(yī)學(xué)中心行IVF-ET治療的DOR、POR的不孕癥患者，DOR患者分為應(yīng)用GH治療組（40個(gè)周期）和未應(yīng)用GH治療的對(duì)照組（42個(gè)周期），均采用拮抗劑方案；POR患者為應(yīng)用GH治療前后的自身對(duì)照研究（31個(gè)周期）。1.2、納入與排除標(biāo)準(zhǔn)DOR是指卵巢內(nèi)卵母細(xì)胞的數(shù)量減少和（或）質(zhì)量下降，同時(shí)伴有抗苗勒管激素（AMH）水平降低、竇卵泡數(shù)（AFC）減少、卵泡刺激素（FSH）水平升高ADDINEN.CITE<EndNote><Cite><Year>2015</Year><RecNum>844</RecNum><DisplayText>[5]</DisplayText><record><rec-number>844</rec-number><foreign-keys><keyapp="EN"db-id="sppr5x25wzew9refefmvazdmvxwz50przdp0">844</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors></contributors><titles><title>Testingandinterpretingmeasuresofovarianreserve:acommitteeopinion</title><secondary-title>FertilSteril</secondary-title><alt-title>Fertilityandsterility</alt-title></titles><periodical><full-title>FertilSteril</full-title><abbr-1>Fertilityandsterility</abbr-1></periodical><alt-periodical><full-title>FertilSteril</full-title><abbr-1>Fertilityandsterility</abbr-1></alt-periodical><pages>e9-e17</pages><volume>103</volume><number>3</number><edition>2015/01/15</edition><keywords><keyword>Anti-MullerianHormone/blood</keyword><keyword>CellCount/standards/statistics&numericaldata</keyword><keyword>Clomiphene</keyword><keyword>DataInterpretation,Statistical</keyword><keyword>Estradiol/blood</keyword><keyword>ExpertTestimony</keyword><keyword>Female</keyword><keyword>FollicleStimulatingHormone/blood</keyword><keyword>Humans</keyword><keyword>Infertility,Female/blood/diagnosis</keyword><keyword>OvarianDiseases/blood/*diagnosis</keyword><keyword>OvarianFollicle/cytology</keyword><keyword>OvarianFunctionTests/standards/statistics&numericaldata</keyword><keyword>*OvarianReserve</keyword></keywords><dates><year>2015</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1556-5653(Electronic) 0015-0282(Linking)</isbn><accession-num>25585505</accession-num><work-type>PracticeGuideline</work-type><urls><related-urls><url>/pubmed/25585505</url></related-urls></urls><electronic-resource-num>10.1016/j.fertnstert.2014.12.093</electronic-resource-num><language>eng</language></record></Cite></EndNote>[5]。AMH<（0.5-1.1）μｇ/L，AFC<（5-7）枚。POR診斷標(biāo)準(zhǔn)滿足以下3條中的2條即可：①高齡（≥40歲）或存在卵巢反應(yīng)不良的其它危險(xiǎn)因素；②前次IVF周期卵巢低反應(yīng)，常規(guī)方案獲卵數(shù)≤3個(gè)；③卵巢儲(chǔ)備下降（AFC<5~7個(gè)或AMH<0.5~1.1μg/L）[3]。如果年齡＜40歲或卵巢儲(chǔ)備功能檢測(cè)正常，患者連續(xù)2個(gè)周期應(yīng)用最大化的卵巢刺激方案仍出現(xiàn)POR也可診斷ADDINEN.CITE<EndNote><Cite><Author>Ferraretti</Author><Year>2011</Year><RecNum>843</RecNum><DisplayText>[6]</DisplayText><record><rec-number>843</rec-number><foreign-keys><keyapp="EN"db-id="sppr5x25wzew9refefmvazdmvxwz50przdp0">843</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Ferraretti,A.P.</author><author>LaMarca,A.</author><author>Fauser,B.C.</author><author>Tarlatzis,B.</author><author>Nargund,G.</author><author>Gianaroli,L.</author></authors></contributors><auth-address>S.I.S.Me.RReproductiveMedicineUnit,ViaMazzini12,40138Bologna,Italy.annapia.ferraretti@sismer.it</auth-address><titles><title>ESHREconsensusonthedefinitionof'poorresponse'toovarianstimulationforinvitrofertilization:theBolognacriteria</title><secondary-title>HumReprod</secondary-title></titles><periodical><full-title>HumReprod</full-title></periodical><pages>1616-24</pages><volume>26</volume><number>7</number><edition>2011/04/21</edition><keywords><keyword>Europe</keyword><keyword>Female</keyword><keyword>*FertilizationinVitro</keyword><keyword>Humans</keyword><keyword>MaternalAge</keyword><keyword>Ovary/*drugeffects</keyword><keyword>*OvulationInduction</keyword><keyword>*ReproductiveMedicine</keyword><keyword>RiskFactors</keyword><keyword>Societies,Medical</keyword><keyword>*TerminologyasTopic</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1460-2350(Electronic) 0268-1161(Linking)</isbn><accession-num>21505041</accession-num><urls><related-urls><url>/pubmed/21505041</url></related-urls></urls><electronic-resource-num>10.1093/humrep/der092</electronic-resource-num><language>eng</language></record></Cite></EndNote>[6]。排除標(biāo)準(zhǔn)：A：盆腔結(jié)核、子宮內(nèi)膜異位癥、排卵障礙（多囊卵巢綜合征等）、腦垂體疾病及其它疾?。谞钕俟δ芸哼M(jìn)及減退、高泌乳素血癥、糖尿病、高血壓等）；B：近3個(gè)月內(nèi)服用類固醇類藥物；C：排除子宮畸形；D：夫婦雙方染色體異常以及復(fù)發(fā)性流產(chǎn)史者。1.3研究方法1.3.1IVF的方案拮抗劑方案：月經(jīng)第2天檢測(cè)女性基礎(chǔ)激素水平、陰道超聲監(jiān)測(cè)竇卵泡數(shù)目，給予促排卵藥物【重組人促卵泡激素（果納芬）、注射用尿促性素（麗申寶）和尿促性素（HMG）這三種促排卵藥物】，在Gn使用的第5～6天根據(jù)激素水平及卵泡生長(zhǎng)情況，添加促性腺激素釋放激素拮抗劑（注射用醋酸西曲瑞克）每天0.25mg，皮下注射，當(dāng)有2個(gè)主導(dǎo)卵泡平均徑線達(dá)到18mm或3個(gè)卵泡平均徑線達(dá)到17mm以上時(shí)，根據(jù)當(dāng)日血清E2水平，于當(dāng)晚8點(diǎn)肌肉注射HCG6000～8000U，34～36小時(shí)后行取卵術(shù)。微刺激方案：枸櫞酸氯米芬（CC）50-l00mg或來(lái)曲唑（LE）2.5-5.0mg，可加Gn（不超過(guò)150IU），或后期用低劑量（CC25mg）抑制LH峰，達(dá)必佳（GnRH-a）或HCG扳機(jī)。GH治療方案：促排卵前4-6周GH（rhGH，安科生物工程股份有限公司，合肥）6iu隔日一次皮下注射用至HCG日。對(duì)照組：未添加GH。1.4胚胎質(zhì)量評(píng)估取卵后根據(jù)原核評(píng)分標(biāo)準(zhǔn)在卵子受精后的18小時(shí)觀察原核和極體等評(píng)價(jià)受精情況，第2天和第3天觀察胚胎發(fā)育情況。D3胚胎形態(tài)學(xué)分級(jí)標(biāo)準(zhǔn)：I級(jí)：卵裂球大小一致，胞質(zhì)均勻，細(xì)胞碎片<10%；Ⅱ級(jí)：卵裂球大小一致，胞質(zhì)均勻，10%≤細(xì)胞碎片≤20%；Ⅲ級(jí)：卵裂球大小不一致，胞質(zhì)不均勻，細(xì)胞碎片≤20%。本性研究中可移植胚胎的標(biāo)準(zhǔn)為：D3細(xì)胞數(shù)4細(xì)胞以上，Ⅰ、Ⅱ、Ⅲ級(jí)胚胎。優(yōu)質(zhì)胚胎的標(biāo)準(zhǔn)為：D3細(xì)胞數(shù)為7-8，分級(jí)為Ⅰ級(jí)、Ⅱ級(jí)的胚胎。1.5觀察指標(biāo)所有患者的年齡、不孕年限、BMI、基礎(chǔ)E2、FSH、LH，AMH、Gn啟動(dòng)劑量、Gn總天數(shù)、Gn總量、HCG日大卵泡數(shù)、HCG日子宮內(nèi)膜厚度、HCG日E2、LH，獲卵數(shù)、受精率、可利用胚胎數(shù)、優(yōu)質(zhì)胚胎數(shù)以及妊娠結(jié)局等相關(guān)指標(biāo)。觀察指標(biāo)計(jì)算公式：受精率=雙原核（2PN）數(shù)/獲卵總數(shù)×100%；優(yōu)質(zhì)胚胎率=優(yōu)質(zhì)胚胎數(shù)/卵裂胚胎數(shù)×100%；鮮胚移植率=鮮胚移植周期數(shù)/總周期數(shù)×100%；無(wú)可利用胚胎率=無(wú)可利用胚胎周期數(shù)/總周期數(shù)×100%；著床率=孕囊總數(shù)/移植胚胎總數(shù)×100%；生化妊娠率=生化妊娠周期數(shù)/臨床妊娠周期數(shù)×100%；臨床妊娠率=臨床妊娠周期數(shù)/移植周期數(shù)×100%；早期流產(chǎn)率=孕12周內(nèi)流產(chǎn)周期數(shù)/臨床妊娠周期數(shù)×100%；1.6確診妊娠胚胎移植術(shù)后第14天檢測(cè)血HCG確定是否妊娠。HCG<10U/L提示未妊娠；HCG≥10U/L提示生化妊娠；生化妊娠是指血中可以檢測(cè)到HCG升高或尿妊娠試驗(yàn)陽(yáng)性，但超聲檢查看不到孕囊，隨后血HCG下降轉(zhuǎn)陰；臨床妊娠的診斷為生化妊娠后3周行腹部超聲檢查，發(fā)現(xiàn)孕囊、胚芽或原始心管搏動(dòng)者。早期流產(chǎn)是指在妊娠12周之前所發(fā)生的難免流產(chǎn)、不全流產(chǎn)、完全流產(chǎn)以及稽留流產(chǎn)。1.7統(tǒng)計(jì)學(xué)方法采用SPSS19.0軟件進(jìn)行統(tǒng)計(jì)分析。計(jì)量資料采用均數(shù)±標(biāo)準(zhǔn)差（X±S）來(lái)表示，參數(shù)若是符合正態(tài)分布需用t檢驗(yàn),若是呈非正態(tài)分布需用Mann-WhitneyU檢驗(yàn)。自身前后比較應(yīng)用配對(duì)t檢驗(yàn)。計(jì)數(shù)資料采用率（%）表示，應(yīng)用χ2檢驗(yàn)。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。2.結(jié)果2.1DOR患者應(yīng)用GH治療組和對(duì)照組一般情況、控制性卵巢刺激（COS）及治療結(jié)局的比較兩組患者一般情況如年齡、不孕年限、BMI、不孕類型、基礎(chǔ)E2、FSH、LH、AMH的比較均無(wú)顯著性差異（P>0.05）。兩組患者COS情況的比較顯示：GH治療組Gn啟動(dòng)劑量、Gn總天數(shù)、Gn總量均明顯少于對(duì)照組，HCG日子宮內(nèi)膜厚度在GH治療組顯著厚于對(duì)照組，差異有統(tǒng)計(jì)學(xué)意義（P<0.05）。兩組患者治療結(jié)局的比較顯示：受精方式比較無(wú)顯著性差異（P>0.05），數(shù)據(jù)具有可比性。受精率在GH治療組顯著高于對(duì)照組（P<0.05）。無(wú)可利用胚胎率在GH治療組顯著低于對(duì)照組，差異有統(tǒng)計(jì)學(xué)意義（P<0.05）。著床率和臨床妊娠率在GH治療組與對(duì)照組比較有增高的趨勢(shì)（P>0.05）。見表1。表1DOR患者應(yīng)用GH治療組和對(duì)照組一般情況、COS及治療結(jié)局的比較GH治療組對(duì)照組X2P周期數(shù)4042年齡（歲）35.28±4.1834.12±4.541.200.24不孕年限（年）3.42±2.583.25±2.100.340.73BMI（kg/cm2）21.93±3.0421.99± 3.060.100.92原發(fā)性不孕（%）30(12/40)47.62(20/42)繼發(fā)性不孕（%）70(28/40)52.38(22/42)2.670.10基礎(chǔ)E2（pg/ml）57.07±31.6057.28±30.320.030.98基礎(chǔ)FSH（mIU/ml）12.07±2.3611.56±1.451.190.24基礎(chǔ)LH（mIU/ml）4.18±2.264.45±1.680.610.54AMH（ng/ml）0.84±0.310.69±0.242.470.16Gn啟動(dòng)劑量（U）270.94±54.03360.71±104.094.87<0.001Gn總天數(shù)（天）10.20±1.8811.02±1.852.00.049Gn總量（U）3102.19±866.864148.21±1452.183.98<0.001HCG日大卵泡數(shù)（個(gè)）（≥14mm的卵泡數(shù)）7.23±3.935.93±3.631.550.125HCG日子宮內(nèi)膜厚度（mm）10.85±1.988.60±3.763.420.001HCG日E2（pg/ml）2143.97±1204.222168.75±1114.770.100.92HCG日LH（mIU/ml）3.18±2.753.49±3.480.440.66獲卵數(shù)（個(gè)）4.70±2.793.74±2.941.230.22受精方式IVF（%）75(30/40)83.33(35/42)ICSI（%）25(10/40)16.67(7/42)0.890.35受精率（%）84.93(186/219)70.14(155/221)13.81<0.001可利用胚胎數(shù)（個(gè)）2.35±1.562.02±1.850.860.39優(yōu)質(zhì)胚胎數(shù)（個(gè)）2.02±1.851.50±1.321.470.15優(yōu)質(zhì)胚胎率（%）37.27(60/161)30.53(40/131)1.450.23鮮胚移植率（%）55(22/40)40.48(17/42)1.730.19無(wú)可利用胚胎率（%）0(0/40)23.81(10/42)8.740.003著床率（%）24.32(9/37)16.67(4/24)0.510.48生化妊娠率（%）9.09(2/22)0(0/17)1.630.50臨床妊娠率（%）40.91(9/22)17.65(3/17)2.440.12早期流產(chǎn)率（%）11.11(1/9)0(0/3)0.360.992.2POR患者自身應(yīng)用GH治療前后一般情況、COS及治療結(jié)局的比較POR患者GH治療前后一般情況如年齡、基礎(chǔ)E2、FSH、LH、AMH的比較均無(wú)顯著性差異（P>0.05）。POR患者GH治療前后COS情況的比較：COS方案兩組比較無(wú)顯著性差異（P>0.05），數(shù)據(jù)具有可比性。Gn啟動(dòng)劑量、Gn總天數(shù)、Gn總量等比較均無(wú)顯著性差異（P>0.05）。HCG日大卵泡數(shù)、獲卵數(shù)與GH治療前比較有增多的趨勢(shì)（P>0.05）。兩組患者治療結(jié)局的比較顯示：可利用胚胎數(shù)、優(yōu)質(zhì)胚胎數(shù)、優(yōu)質(zhì)胚胎率在GH治療后顯著高于GH治療前，差異有統(tǒng)計(jì)學(xué)意義（P<0.05）。無(wú)可利用胚胎率與GH治療前比較顯著降低（P<0.05）。著床率和臨床妊娠率在GH治療后有增高的趨勢(shì)（P>0.05）。見表2。表2POR患者自身應(yīng)用GH治療前后一般情況、COS及治療結(jié)局的比較GH治療前GH治療后X2P周期數(shù)3131年齡（歲）34.74±4.0535.06±4.080.310.76不孕年限（年）2.78±2.263.11±2.570.5280.60BMI（kg/cm2）21.96±3.1821.96±3.170.0010.99原發(fā)性不孕（%）22.58(7/31)22.58(7/31)繼發(fā)性不孕（%）77.42(24/31)77.42(24/31)0.001.00基礎(chǔ)E2（pg/ml）52.22±29.0651.50±29.280.100.92基礎(chǔ)FSH（mIU/ml）8.06±3.058.67±3.690.710.48基礎(chǔ)LH（mIU/ml）4.50±2.494.19±1.690.580.56AMH（ng/ml）1.15±1.091.06±1.040.010.99COS方案拮抗劑方案64.52(20/31)54.84(17/31)微刺激方案12.90(4/31)16.13(5/31)0.6040.739黃體期促排卵方案22.58(7/31)29.03(9/31)Gn啟動(dòng)劑量（U）234.68±67.75266.13±69.391.810.08Gn總天數(shù)（天）9.58±2.579.84±2.110.430.67Gn總量（U）2566.93±1165.602972.18±1034.441.450.15HCG日大卵泡數(shù)（個(gè)）（≥14mm的卵泡數(shù)）7.03±6.747.55±4.760.350.73HCG日子宮內(nèi)膜厚度（mm）10.53±1.9410.40±2.470.250.81HCG日E2（pg/ml）2220.25±2107.532403.06±1607.000.380.70HCG日LH（mIU/ml）2.83±2.143.07±2.110.440.66獲卵數(shù)（個(gè)）4.65±2.955.90±3.551.520.14受精方式IVF（%）83.87(26/31)74.19(23/31)ICSI（%）16.13(5/31)25.81(8/31)0.880.35受精率（%）75(108/144)76.50(140/183)0.100.75可利用胚胎數(shù)（個(gè)）1.00±1.052.19±1.623.400.001優(yōu)質(zhì)胚胎數(shù)（個(gè)）0.29±0.591.45±1.394.290.004優(yōu)質(zhì)胚胎率（%）10.47(9/86)36.89(45/122)18.32<0.001鮮胚移植率（%）29.03(9/31)48.39(15/31)2.450.12無(wú)可利用胚胎率（%）38.71(12/31)3.23(1/31)11.780.001著床率（%）15.38(2/13)34.78(8/23)1.560.21生化妊娠率（%）11.11(1/9)6.67(1/15)0.140.99臨床妊娠率（%）22.22(2/9)40(6/15)0.200.66早期流產(chǎn)率（%）50(1/2)16.67(1/6)0.890.463.討論臨床上在COS過(guò)程中，總會(huì)有部分女性對(duì)外源性Gn的反應(yīng)不佳，尤其是對(duì)高齡女性而言，這些女性即POR患者，IVF成功率很低ADDINEN.CITEADDINEN.CITE.DATA[7]。生長(zhǎng)激素也是IVF-ET患者備孕期常用的輔助治療藥物，GH可刺激患者的卵泡生長(zhǎng)，促進(jìn)卵泡的排卵功能，并提高卵子質(zhì)量，從而提高患者胚胎著床率和臨床妊娠率ADDINEN.CITEADDINEN.CITE.DATA[8]。一些IVF中心在COS過(guò)程中聯(lián)合使用GH，以期能夠提高卵母細(xì)胞質(zhì)量和臨床妊娠率ADDINEN.CITEADDINEN.CITE.DATA[9,10]。Cui研究ADDINEN.CITEADDINEN.CITE.DATA[11]顯示人卵和顆粒細(xì)胞表面表達(dá)有GH受體，GH不僅能通過(guò)受體-配體相互作用的方式直接影響卵子和顆粒細(xì)胞的發(fā)生發(fā)展，還能通過(guò)刺激胰島素樣生長(zhǎng)因子-Ⅰ（IGF-Ⅰ）合成或促進(jìn)卵泡刺激素誘導(dǎo)的卵巢甾體激素生成來(lái)提高卵子質(zhì)量。3.1GH對(duì)DOR患者治療結(jié)局的影響2016年美國(guó)疾病控制與預(yù)防中心全國(guó)輔助生殖技術(shù)數(shù)據(jù)顯示，DOR女性占助孕人群的30%左右ADDINEN.CITEADDINEN.CITE.DATA[12]，并與IVF-ET中的POR、高周期取消率及不良妊娠結(jié)局相關(guān)ADDINEN.CITEADDINEN.CITE.DATA[13]。2018年有研究報(bào)告：促排卵中DOR的患者添加GH后雖然總的獲卵數(shù)沒(méi)有變化，但獲成熟卵率明顯增加，作者認(rèn)為相對(duì)于增加獲卵數(shù)而言，GH更能改善卵子質(zhì)量ADDINEN.CITEADDINEN.CITE.DATA[14]。Hull等研究報(bào)道，GH能增強(qiáng)顆粒細(xì)胞對(duì)促性腺激素的反應(yīng)性，促進(jìn)卵泡生長(zhǎng)發(fā)育及雌激素合成ADDINEN.CITE<EndNote><Cite><Author>Hull</Author><Year>2014</Year><RecNum>621</RecNum><DisplayText>[15]</DisplayText><record><rec-number>621</rec-number><foreign-keys><keyapp="EN"db-id="w2ssrprdrwwdtrexsw9pvtf2r9vzeez9e9wv"timestamp="1615722086">621</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Hull,K.L.</author><author>Harvey,S.</author></authors></contributors><auth-address>DepartmentofBiology,Bishop'sUniversity,Sherbrooke,QC,CanadaJ1M1Z7;CentredeRechercheCliniqueEtienne-LeBel,UniversitedeSherbrooke,Sherbrooke,QC,CanadaJ1H5N4. DepartmentofPhysiology,UniversityofAlberta,Edmonton,AB,CanadaT6G2R3.</auth-address><titles><title>Growthhormoneandreproduction:areviewofendocrineandautocrine/paracrineinteractions</title><secondary-title>IntJEndocrinol</secondary-title></titles><periodical><full-title>IntJEndocrinol</full-title></periodical><pages>234014</pages><volume>2014</volume><edition>2015/01/13</edition><dates><year>2014</year></dates><isbn>1687-8337(Print) 1687-8337(Linking)</isbn><accession-num>25580121</accession-num><urls><related-urls><url>/pubmed/25580121</url></related-urls></urls><custom2>PMC4279787</custom2><electronic-resource-num>10.1155/2014/234014</electronic-resource-num></record></Cite></EndNote>[15]，但其是否能夠改善DOR患者的IVF-ET臨床結(jié)局尚存爭(zhēng)議。GH能提高卵巢對(duì)促性腺激素的反應(yīng)性，促進(jìn)卵泡發(fā)育和成熟，改善卵子質(zhì)量ADDINEN.CITEADDINEN.CITE.DATA[16]，增加優(yōu)質(zhì)胚胎數(shù)ADDINEN.CITEADDINEN.CITE.DATA[17]，增加子宮內(nèi)膜腺體數(shù)量，改善子宮內(nèi)膜組織形態(tài)和功能，有助于提高IVF-ET臨床妊娠率ADDINEN.CITE<EndNote><Cite><Author>Drakopoulos</Author><Year>2016</Year><RecNum>287</RecNum><DisplayText>[18]</DisplayText><record><rec-number>287</rec-number><foreign-keys><keyapp="EN"db-id="w2ssrprdrwwdtrexsw9pvtf2r9vzeez9e9wv"timestamp="1615720351">287</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Drakopoulos,P.</author><author>Pluchino,N.</author><author>Bischof,P.</author><author>Cantero,P.</author><author>Meyer,P.</author><author>Chardonnens,D.</author></authors></contributors><titles><title>EffectofGrowthHormoneonEndometrialThicknessandFertilityOutcomeintheTreatmentofWomenwithPanhypopituitarism:ACaseReport</title><secondary-title>JReprodMed</secondary-title></titles><periodical><full-title>JReprodMed</full-title></periodical><pages>78-82</pages><volume>61</volume><number>1-2</number><edition>2016/03/22</edition><keywords><keyword>Adult</keyword><keyword>Endometrium/*drugeffects</keyword><keyword>Female</keyword><keyword>*GrowthHormone/pharmacology/therapeuticuse</keyword><keyword>Humans</keyword><keyword>Hypopituitarism/*drugtherapy</keyword><keyword>Pregnancy</keyword><keyword>PregnancyOutcome</keyword></keywords><dates><year>2016</year><pub-dates><date>Jan-Feb</date></pub-dates></dates><isbn>0024-7758(Print) 0024-7758(Linking)</isbn><accession-num>26995894</accession-num><urls><related-urls><url>/pubmed/26995894</url></related-urls></urls></record></Cite></EndNote>[18]。學(xué)者們發(fā)現(xiàn)GH可以調(diào)控卵巢激素，卵泡的生長(zhǎng)發(fā)育以及影響子宮內(nèi)膜的容受性等ADDINEN.CITEADDINEN.CITE.DATA[19]。本研究顯示DOR患者GH治療組Gn啟動(dòng)劑量、Gn總天數(shù)、Gn總量均明顯少于對(duì)照組，HCG日子宮內(nèi)膜厚度在GH治療組顯著厚于對(duì)照組（P<0.05），DOR患者用GH預(yù)處理后卵巢對(duì)Gn的反應(yīng)性增加，減少Gn劑量及天數(shù)，增加子宮內(nèi)膜厚度。曾有少部分研究ADDINEN.CITE<EndNote><Cite><Author>Drakopoulos</Author><Year>2016</Year><RecNum>287</RecNum><DisplayText>[18]</DisplayText><record><rec-number>287</rec-number><foreign-keys><keyapp="EN"db-id="w2ssrprdrwwdtrexsw9pvtf2r9vzeez9e9wv"timestamp="1615720351">287</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Drakopoulos,P.</author><author>Pluchino,N.</author><author>Bischof,P.</author><author>Cantero,P.</author><author>Meyer,P.</author><author>Chardonnens,D.</author></authors></contributors><titles><title>EffectofGrowthHormoneonEndometrialThicknessandFertilityOutcomeintheTreatmentofWomenwithPanhypopituitarism:ACaseReport</title><secondary-title>JReprodMed</secondary-title></titles><periodical><full-title>JReprodMed</full-title></periodical><pages>78-82</pages><volume>61</volume><number>1-2</number><edition>2016/03/22</edition><keywords><keyword>Adult</keyword><keyword>Endometrium/*drugeffects</keyword><keyword>Female</keyword><keyword>*GrowthHormone/pharmacology/therapeuticuse</keyword><keyword>Humans</keyword><keyword>Hypopituitarism/*drugtherapy</keyword><keyword>Pregnancy</keyword><keyword>PregnancyOutcome</keyword></keywords><dates><year>2016</year><pub-dates><date>Jan-Feb</date></pub-dates></dates><isbn>0024-7758(Print) 0024-7758(Linking)</isbn><accession-num>26995894</accession-num><urls><related-urls><url>/pubmed/26995894</url></related-urls></urls></record></Cite></EndNote>[18]顯示GH對(duì)子宮內(nèi)膜也有作用，GH不僅在誘導(dǎo)排卵和子宮內(nèi)膜厚度的發(fā)育上起重要作用，而且可以提高子宮內(nèi)膜的容受性。這與本研究結(jié)果相一致，DOR患者應(yīng)用GH預(yù)處理后子宮內(nèi)膜厚度顯著增加，有助于改善子宮內(nèi)膜容受性，提高臨床治療結(jié)局。本研究顯示：受精率在GH治療組顯著高于對(duì)照組；無(wú)可利用胚胎率在GH治療組顯著低于對(duì)照組（P<0.05）。著床率和臨床妊娠率在GH治療組與對(duì)照組比較有增高的趨勢(shì)（P>0.05）。GH預(yù)處理后DOR患者的受精率增加，周期取消率降低，提高臨床治療的結(jié)局。3.2GH對(duì)POR患者治療結(jié)局的影響目前POR尚無(wú)特效治療方式，其治療方式一般包括調(diào)整COS方案和在COS過(guò)程中添加輔助用藥，目前常用的添加藥物有生長(zhǎng)激素（GH）ADDINEN.CITE<EndNote><Cite><Author>Hart</Author><Year>2017</Year><RecNum>709</RecNum><DisplayText>[20]</DisplayText><record><rec-number>709</rec-number><foreign-keys><keyapp="EN"db-id="w2ssrprdrwwdtrexsw9pvtf2r9vzeez9e9wv"timestamp="1615725844">709</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Hart,R.J.</author><author>Rombauts,L.</author><author>Norman,R.J.</author></authors></contributors><auth-address>aSchoolofWomen'sandInfants'Health,UniversityofWesternAustralia,PerthbFertilitySpecialistsofWesternAustralia,BethesdaHospital,Claremont,WesternAustraliacWomen'sHealth,MonashHealthdDepartmentofObstetricsandGynaecology,MonashUniversity,Clayton,VictoriaeRobinsonInstitute,UniversityofAdelaide,FertilitySA,Adelaide,SouthAustralia,Australia.</auth-address><titles><title>GrowthhormoneinIVFcycles:anyhope?</title><secondary-title>CurrOpinObstetGynecol</secondary-title></titles><periodical><full-title>CurrOpinObstetGynecol</full-title></periodical><pages>119-125</pages><volume>29</volume><number>3</number><edition>2017/03/18</edition><keywords><keyword>CellCount</keyword><keyword>EmbryonicDevelopment</keyword><keyword>Female</keyword><keyword>FertilityAgents,Female/*therapeuticuse</keyword><keyword>*FertilizationinVitro</keyword><keyword>HumanGrowthHormone/*therapeuticuse</keyword><keyword>Humans</keyword><keyword>Infertility,Female/therapy</keyword><keyword>Oocytes</keyword><keyword>OvulationInduction</keyword><keyword>PolycysticOvarySyndrome/complications</keyword></keywords><dates><year>2017</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1473-656X(Electronic) 1040-872X(Linking)</isbn><accession-num>28306560</accession-num><urls><related-urls><url>/pubmed/28306560</url></related-urls></urls><electronic-resource-num>10.1097/GCO.0000000000000360</electronic-resource-num></record></Cite></EndNote>[20]、脫氫表雄酮（DHEA）和重組黃體生成素（r-LH）等。近年來(lái)關(guān)于GH應(yīng)用于IVF患者促排卵的報(bào)道很多，尤其在高齡及POR患者中應(yīng)用廣泛且效果明顯ADDINEN.CITEADDINEN.CITE.DATA[21]。Meta分析證實(shí)，POR患者的IVF促排卵過(guò)程中添加GH可提高臨床妊娠率和活產(chǎn)率，且不良事件無(wú)明顯增加ADDINEN.CITE<EndNote><Cite><Author>Hart</Author><Year>2017</Year><RecNum>709</RecNum><DisplayText>[20]</DisplayText><record><rec-number>709</rec-number><foreign-keys><keyapp="EN"db-id="w2ssrprdrwwdtrexsw9pvtf2r9vzeez9e9wv"timestamp="1615725844">709</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Hart,R.J.</author><author>Rombauts,L.</author><author>Norman,R.J.</author></authors></contributors><auth-address>aSchoolofWomen'sandInfants'Health,UniversityofWesternAustralia,PerthbFertilitySpecialistsofWesternAustralia,BethesdaHospital,Claremont,WesternAustraliacWomen'sHealth,MonashHealthdDepartmentofObstetricsandGynaecology,MonashUniversity,Clayton,VictoriaeRobinsonInstitute,UniversityofAdelaide,FertilitySA,Adelaide,SouthAustralia,Australia.</auth-address><titles><title>GrowthhormoneinIVFcycles:anyhope?</title><secondary-title>CurrOpinObstetGynecol</secondary-title></titles><periodical><full-title>CurrOpinObstetGynecol</full-title></periodical><pages>119-125</pages><volume>29</volume><number>3</number><edition>2017/03/18</edition><keywords><keyword>CellCount</keyword><keyword>EmbryonicDevelopment</keyword><keyword>Female</keyword><keyword>FertilityAgents,Female/*therapeuticuse</keyword><keyword>*FertilizationinVitro</keyword><keyword>HumanGrowthHormone/*therapeuticuse</keyword><keyword>Humans</keyword><keyword>Infertility,Female/therapy</keyword><keyword>Oocytes</keyword><keyword>OvulationInduction</keyword><keyword>PolycysticOvarySyndrome/complications</keyword></keywords><dates><year>2017</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1473-656X(Electronic) 1040-872X(Linking)</isbn><accession-num>28306560</accession-num><urls><related-urls><url>/pubmed/28306560</url></related-urls></urls><electronic-resource-num>10.1097/GCO.0000000000000360</electronic-resource-num></record></Cite></EndNote>[20]。GH能增加卵泡顆粒細(xì)胞上FSH、LH受體的數(shù)量，提高卵巢對(duì)Gn的敏感性，從而促進(jìn)早期卵泡的生長(zhǎng)發(fā)育和卵母細(xì)胞成熟，提高卵子質(zhì)量進(jìn)而改善胚胎質(zhì)量，提高妊娠率ADDINEN.CITEADDINEN.CITE.DATA[22]。本研究結(jié)果顯示POR患者HCG日大卵泡數(shù)、獲卵數(shù)與GH治療前比較有增多的趨勢(shì)（P>0.05）。Lattes等ADDINEN.CITEADDINEN.CITE.DATA[17]通過(guò)自身對(duì)照發(fā)現(xiàn)GH應(yīng)用后獲卵數(shù)和Gn量無(wú)差異，但臨床妊娠率明顯提高，這與本研究結(jié)果相一致。Safdarian等研究顯示ADDINEN.CITEADDINEN.CITE.DATA[23]，COS過(guò)程中應(yīng)用外源GH能明顯改善POR患者IVF-ET治療的實(shí)驗(yàn)室指標(biāo)和臨床結(jié)局，與接受GH的兩個(gè)實(shí)驗(yàn)組相比，安慰劑組中收集的卵母細(xì)胞，臨床妊娠率顯著較低，表明GH可能在優(yōu)勢(shì)卵泡的募集中起重要作用，并促進(jìn)細(xì)胞增殖，從而產(chǎn)生高質(zhì)量的胚胎，因此，使用GH可大幅提高POR患者的卵巢反應(yīng)。本研究顯示POR患者可利用胚胎數(shù)、優(yōu)質(zhì)胚胎數(shù)、優(yōu)質(zhì)胚胎率在GH治療后顯著高于GH治療前（P<0.05）。GH預(yù)處理后可以改善POR患者卵母細(xì)胞的質(zhì)量及胚胎的質(zhì)量，使優(yōu)胚數(shù)和優(yōu)胚率增加，改善臨床治療結(jié)局。曾有研究顯示補(bǔ)充GH可以提高卵巢反應(yīng)性，改善胚胎質(zhì)量，增加優(yōu)質(zhì)胚胎率及活產(chǎn)率ADDINEN.CITEADDINEN.CITE.DATA[24,25]，這與本研究結(jié)果相一致。然而Dunne等ADDINEN.CITEADDINEN.CITE.DATA[26]研究顯示GH應(yīng)用并不能改善POR患者的優(yōu)胚率和臨床妊娠率，用藥方法為微刺激方案前黃體期給予GH10U/d，持續(xù)14d?？紤]跟應(yīng)用的方案、GH的劑量、應(yīng)用方法不一致有關(guān)，尚需大樣本的研究。本研究顯示無(wú)可利用胚胎率與GH治療前比較顯著降低（P<0.05）。著床率和臨床妊娠率在GH治療后有增高的趨勢(shì)（P>0.05）。POR患者應(yīng)用GH預(yù)處理可以增加可利用胚胎數(shù)，減少周期取消率，改善臨床治療結(jié)局。綜上所述，本研究顯示DOR的患者應(yīng)用GH治療可以減少Gn的啟動(dòng)劑量、Gn總天數(shù)、Gn總量，增加HCG日子宮內(nèi)膜的厚度，提高體外受精的受精率，減少無(wú)可利用胚胎率。POR患者應(yīng)用GH治療可以提高可利用胚胎數(shù)、優(yōu)質(zhì)胚胎數(shù)、優(yōu)質(zhì)胚胎率，減少無(wú)可利用胚胎率。DOR和POR患者應(yīng)用GH治療后著床率和臨床妊娠率均有增高的趨勢(shì)。因此DOR和POR患者應(yīng)用GH治療可以改善體外受精-胚胎移植的治療結(jié)局，減少周期取消率。利益沖突所有患者均聲明不存在利益沖突參考文獻(xiàn)[ADDINEN.REFLIST1] Ob'edkovaK,KoganI,KrikheliI,etal.Growthhormoneco-treatmentinIVF/ICSIcyclesinpoorresponders[J].GynecolEndocrinol,2017,33:15-17.[2] SurreyES,andSchoolcraftWB.Evaluatingstrategiesforimprovingovarianresponseofthepoorresponderundergoingassistedreproductivetechniques[J].FertilSteril,2000,73:667-676.[3] EstevesSC,RoqueM,BedoschiGM,etal.DefiningLowPrognosisPatientsUndergo