北医三院生殖医学中心讲义.ppt

Factors influencing IVF outcomesPeking University Third HospitalQiao JieFactors Affecting ConceptionProduction of healthy sperm Healthy eggs by the womanUnblocked fallopian tubesThe ability for the sperm to fertilize the eggThe ability for the embryo to implant in the uterusIVF success rateDespite the progress in IVF,people undertaking IVF often face a considerable risk of failure.-Pregnancy rate per transfer remained 30%-35%in 2006.-Delivery rate by OPU was 15%-30%in fresh cycle in 2005.Data from ESHREFactors affecting IVF resultsAgeAgeCauses of infertilityCauses of infertilityResponsiveness to ovulation inductionResponsiveness to ovulation inductionDifferent stimulation protocolsEmbryoEmbryo qualityqualitySperm qualitySperm qualityEmbryo transfer Embryo transfer technique techniqueLuteal phase supportLuteal phase support Factors affecting IVF resultsAgeAgeCauses of infertilityCauses of infertilityResponsiveness to ovulation inductionResponsiveness to ovulation inductionDifferent stimulation protocolsEmbryoEmbryo qualityqualitySperm qualitySperm qualityEmbryo transfer Embryo transfer technique techniqueLuteal phase supportLuteal phase support Endometriosis and IVF Lower pregnancy ratesLower pregnancy rates (Barnhart et al.,2002,P.Kuivasaari et al.2005,De Hondt A,et al,2005;Azem F De Hondt A,et al,2005;Azem F et al,1999et al,1999)Reduced fertilization rate (Bergendal et al.1998,Azem et al.,1999,Yamashita Y,et al,2002,Al-Fadhli R,et al,2006;Barnhart K,Yamashita Y,et al,2002,Al-Fadhli R,et al,2006;Barnhart K,et al,2002et al,2002 )Decreased implantation ratesDecreased implantation rates (Azem et al.,1999;Barnhartet al.,2002;Kuivasaari et al.,2005;Kumbak B Kumbak B et al,2008)et al,2008)A lower number of oocytes retrievedof oocytes retrieved (Bergendal et al.1998,Azem et al.,1999,Suzuki T,et al,2005;Kumbak B et al,2008;Barnhart Suzuki T,et al,2005;Kumbak B et al,2008;Barnhart K,et al,2002K,et al,2002;Nakahara K et al,1998Nakahara K et al,1998)A lower ovarian response to gonadotrophins (Azem et al,1999;Al-Azemi et al,2000;Aboulghar,2003;Barnhart et al,2002;Kuivasaari et al,2005;Al-Fadhli Al-Fadhli R,et al,2006;Kumbak B et al,2008R,et al,2006;Kumbak B et al,2008)Endometriosis and IVF Poor Poor embryo quality (Barnhartet al.,2002;Kuivasaari et al.,2005;Kumbak B et al,2008Kumbak B et al,2008)Higher rate of early pregnancy lossHigher rate of early pregnancy loss (Yanushpolsky EH et al,1998)(Yanushpolsky EH et al,1998)Reduced birth rate per cycleReduced birth rate per cycle (Azem F et al,1999)(Azem F et al,1999)Pregnancy rates for women with severe Pregnancy rates for women with severe endometriosis were significantly lower than for endometriosis were significantly lower than for women with mild diseasewomen with mild disease (Barnhart K,et al,2002)(Barnhart K,et al,2002)Endometriosis and IVF Lower VEGF gene expression in granulosa Lower VEGF gene expression in granulosa cells may adversely affect oocyte cells may adversely affect oocyte development and maturationdevelopment and maturation (Yamashita Y,et(Yamashita Y,et al,2002)al,2002)Altered folliculogenesisAltered folliculogenesis (Tummon IS,et(Tummon IS,et al,1988)al,1988)Embryo toxicityEmbryo toxicity (Damewood MD et al,1990;Simon C et(Damewood MD et al,1990;Simon C et al,1992)al,1992)Increased apoptosis in granulosa cellsIncreased apoptosis in granulosa cells (Nakahara K et(Nakahara K et al,1998)al,1998)Endometriosis and IVFDecreased expression of biomarkers of implantation-decreased expression of HOXA10HOXA10 (Wei Q et al,2009;Taylor HS et al,1999;Browne H et al,2006)-decreased expression of glycodelin A (Kao LC,2003;Wei Q et al,2009;Burney RO et al,2007)-decreased expression of osteopontin (Burney RO et al,2007;Wei Q et al,2009)-decreased expression of lysophosphatidic acid receptor 3 (Wei Q et al,2009)-decreased expression of integrindecreased expression of integrin (Lessey BA et al,1994;Khorram O et al,2002)Khorram O et al,2002)Alterations in endometrial apoptosisAlterations in endometrial apoptosis (Gebel HM et al,1998;Bergqvist A et al,1993)Hydrosalpinx and IVFReduced clinical pregnancy rate (Sims et al.1993;Vejtorp et al,1995;Katz et al,1996;Andersen et al,1994;Zeyneloglu HB et al,1998)Higher miscarriage rate (Sims et al.1993;Strandell et al,1994;Andersen et al,1994;Zeyneloglu HB et al,1998)Lower ongoing pregnancy rate (Sims et al,1993)Hydrosalpinx and IVFReduced implantation rate (Strandell et al,1994;Katz et al,1996;Andersen et al,1994;Freeman et al,1996;Zeyneloglu HB et al,1998)Fewer blastocysts developing (Freeman et al,1996)Improved pregnancy,implantation and delivery rates after salpingectomy for hydrosalpinges before IVF (Strandell A,et al 2001;Johnson NP.et al,2002;Fleming and Hull 1996;Murray DL,et al,1998;Johnson et al.,2004)Hydrosalpinx and IVFHydrosalpinx fluid may contain cytokines,prostaglandins or other inflammatory compounds.These compounds may have either direct embryo-toxicity or adversely affect the endometrium.(Meyer et al.,1997)Simple mechanical flushing of embryos from the uterine cavity.(Mansour RT,et al,1991)Hydrosalpinx and IVFEmbryotoxic effects -lower lower rate of of the embryos reaching the morula stage and the blastocyst stage (Schenk et al.1996;Sachdev R,Et al,1997;Koong MK,et al,1998)-higher fragmentation and degeneration rate of the embryos (Schenk et al.1996;Mukherjee T.et al,1996)-poor cavitation rates(Mukherjee T.et al.1996)-retardation of mouse embryo development (Beyler et al,1996;Mukherjee T.et al,1996)Hydrosalpinx and IVFReduce endometrial receptivity -lower levels of integrins V3 in the endometrium (Lessey et al.1994;Meyer W et al,1997)-diminished expression of HOXA10 in the endometrium (Daftary GS et al,2002;Daftary GS et al,2007)-reduced LIF level in the endometrium (Seli E et al,2005)-increase of integrin V3 expression after surgical correction of hydrosalpinx (Meyer W et al,1997)Hydrosalpinx and IVFChanges in endometrial pattern and endometrial blood flow -patients with hydrosalpinx had a significantly higher proportion of the non-multilayered endometrial pattern and significantly lower endometrial and subendometrial blood flowsNg EHY.et al,2006Intra-ovarian Factors in Polycystic Ovary Syndrome(PCOS):Impact on Oocyte Maturation and Embryo Developmental CompetencePCOS patients typical characterization In IVF Increased number of oocytesLower fertilization,cleavage ratesLower implantation ratesHigher miscarriage ratesPoor quality of oocytes and embryosHuman Reproduction Update,Vol.12,No.1 pp.1321,2006PCOS during folliculogenesis and follicle maturationabnormal endocrine/paracrine factors metabolic dysfunctionintrafollicular microenvironment alterations Impaired oocyte maturation and embryonic developmental competenceSeminar Reprod Med 2008;26:53-61 Transforming growth factors(TGF-)Anti-Mllerian hormone(AMH)Growth differentiation factor(GDF9)Inhibins ActivitinsBone morphological protein-15(BMP15)TGF-AMHserum AMH levels reduces throughout reproductive lifeSerum AMH levels stable throughout the menstrual cycleHuman Reproduction Update,Vol.16,No.2 pp.113130,2010Mean AMH serum levelssignificantly higher in PCOS patientsassociated with increased development of antral follicles and follicular arrest in PCOS patientslower in POF patientsTrends in Endocrinology and Metabolism Vol.19 No.9PCOS-IVFAMH PCOS patients:higher levels of follicular MIS follicular MIS level correlating with a greater number of immature oocytes retrievedFertil Steril.1997 May;67(5):962-5PCOS in IVF:Serum and FF AMH significantly higher PCOS in IVF:Serum and FF AMH significantly higher The AMH levels The AMH levels significantly lowersignificantly lower patients who began a patients who began a pregnancypregnancy (22.0 vs.50.5 pMol/L,P=0.018)a negative link between AMH and final oocyte maturationa negative link between AMH and final oocyte maturation，possibly because of impaired access of FSH to possibly because of impaired access of FSH to folliclesfolliclesFertil Steril.2010 Jun;94(1):198-204TGF-InhibinsInhibinsproduced by the dominant folliclestimulate theca cell androgen production for E2 synthesisIn IVF patients,higher FF inhibin A and B levels(measured on the day of oocyte retrieval)better oocyte maturity and fertilization rateshigher pregnancy ratesEurop J Obstet Gynecol Reprod Biol 2004;115:194199 PCOSInhibinsFF inhibin A and inhibin B concentrations are FF inhibin A and inhibin B concentrations are significantly reduced in PCOSsignificantly reduced in PCOS compared with those compared with those in size-matched follicles from normal women in size-matched follicles from normal women (J Clin Endocrinol Metab.2005 Oct;90(10):5582-7J Clin Endocrinol Metab.2005 Oct;90(10):5582-7）FF inhibin B levels are significantly correlated FF inhibin B levels are significantly correlated to embryo qualityto embryo quality(Hum Reprod.2002 Jul;17(7):1724-8)TGF-GDF 9GDF9,an oocyte-secreted factorpromotes granulosa cell proliferation and preantral follicle growthits deficiency impairs granulosa cell proliferation and causes follicular arrest at the primary follicle stageSemin Reprod Med.2008 January;26(1):5361PCOSGDF 9PCOS oocytes GDF9 mRNA levels reduced Impaired follicle growthLead to premature luteinization Decrease luteal generationMaybe altered granulosa cell-oocyte signalingJ Clin Endocrinol Metab 2002;87:1337-1344Insulin-like growth factorsmultifunctional polypeptides with insulin-like activitytwo receptor ligands(IGF-I and IGF-II)two surface-receptors(IGF1R and IGF2R)six high-affinity IGF binding proteins(IGFBP 1-6)PCOS IGF-I levels in immature follicles is decreased IGF-II and IGFBP-1 levels lower lower IGFBP-1 leading to follicular arrestExpert Rev Endocrinol Metab 2007;2(2):215-223 IGFserum and follicular serum and follicular fluidfluid IGF-I/IGFBP-1 higher IGF-I/IGFBP-1 higher in women who became in women who became pregnantpregnantThe ratio IGF-I/IGFBP-1 The ratio IGF-I/IGFBP-1 may reflect oocyte may reflect oocyte qualityqualityJ Assist Reprod Genet 2003;20:167-176 PCOSIGFuIGF-I plays a key role in oocyte maturation in PCOS patientsuAlterations in IGFBP-3 concentration during stimulation may be a critical mechanism in modulating IGF-I activityPCOS patients:Mean serum IGF-I and IGFBP-3 levels increased during stimulationuSerum IGF-I levels decreased uhigher mean number of immature oocytes retrieved (4.81.1 vs.2.40.4;P.02)uSerum IGFBP-3 levels increase ugreater pregnant(P.03)uongoing pregnancy(P.02)Fertil Steril 2007;88:13944Cytokine Familya large family of soluble polypeptide regulatorsinterleukins(IL135)Leukemia Inhibitory Factor(LIF)Tumor necrosis factor-alpha(TNF)Soluble Fas(sFas)Soluble Fas ligand(sFasL)regulating ovarian functionexerting an influence on proliferation,differentiation,follicular maturation,steroidogenesis and apoptosisBest Practice and Res Clinical Obste and Gynaecology.2004;18:755-771 PCOS undergoing IVF1)higher serum and FF interleukin-6 and TNF-1)higher serum and FF interleukin-6 and TNF-2)cytokine concentrations:FF 2)cytokine concentrations:FF serumserum3)FF TNF-concentrations were inversely 3)FF TNF-concentrations were inversely correlated to the estradiol levelscorrelated to the estradiol levels，indicative indicative poor quality oocytes and embryospoor quality oocytes and embryosObstet Gynecol 2003;101:1177 82 CKTNF Exposure of porcine oocytes to an elevated TNF-a ua reduction in their maturation from GV stage to MII stage uincreased the proportion of oocytes with abnormal uchromosome alignment and cytoskeleton structureuPCOS patients treated with pioglitazone during COSuFF TNF-a and IL-6 levels significantly lower uThe clinical pregnancy rate higherFert Steril 2009;92(suppl):s104-105 Fertil Steril 2010;93:9206CKLIFLIF enhances embryonic development and increases blastocyst formation,decreasing the rate of embryo degeneration FF concentrations of PCOS during IVFFF concentrations of PCOS during IVFThe LH/FSH ratio negatively correlated with LIF PCOS:Implatation rates lower FF LIF appears to function as an embryotrophic agent PCOSPCOSControl Control Donor Donor P PLIF(pg/ml)LIF(pg/ml)2652658168167497490.0010.001Hum Reprod.2001 Oct;16(10):2073-8 CKFas FasLsFas and sFasL,anti-and pro-apoptotic factors,respectivelyPCOS in IVFPCOS in IVFserum sFas serum sFas treated with treated with metforminmetformin serum sFasserum sFas FF sFasL FF sFasL r reduceeduce GC DNA GC DNA fragmentation fragmentation increasincrease e implantation and implantation and clinical clinical pregnancy ratespregnancy ratesHum Reprod.2005 Sep;20(9):2391-5 Homocysteine(Hcy)a homologue of the amino acid cysteine recycled into methionine or converted into cysteine in the presence of B-vitamins serum and FF homocysteine levels elevated are inversely associated with oocyte and embryo quality Hum Reprod 2006;21:17251733 PCOSHcy52 PCOS patients underwent GnRHagonist/r-FSH treatmenthigher FF Hcy group:Grade 3 oocyteGrade 12 embryo fertilization rateHum Reprod.2009 Sep;24(9):2293-302 multiple linear regression analyses：FF Hcy is an independent determinant of oocyte quality and embryo qualityHum Reprod.2009 Sep;24(9):2293-302 PCOS pregnance after IVF or ICSIFF Hcy levels negatively associated with FF E2FF Hcy levels negatively associated with FF E2The E2-enriched follicular fluid positively correlated The E2-enriched follicular fluid positively correlated with oocyte fertilization,cleavage and implantationwith oocyte fertilization,cleavage and implantationhigher follicular fluid Hcy levels may suppress E2 higher follicular fluid Hcy levels may suppress E2 production and interfere with the development of production and interfere with the development of dominant follicles,oocyte maturation and fertilization dominant follicles,oocyte maturation and fertilization in women with PCOS undergoing assisted reproductionin women with PCOS undergoing assisted reproductionHum Reprod.2009 Sep;24(9):2293-302 Leptin16kDa protein hormoneregulating energy intake,energy expenditure,and their balancehigh FF and serum leptin levels closely associated with decreased oocyte maturity,poor fertilization and embryo quality,and lower pregnancy ratesReproduction 2005;130:917921 PCOS undergoing ARTLeptinvariablevariableART successART successART failure ART failure smokerssmokersPCOSPCOSAgeAge34.134.135.035.034.734.731.531.5Serum oestradiol(pg/ml)Serum oestradiol(pg/ml)1456.31456.31639.61639.61344.21344.21781.01781.0Oocytes retrieved(n)Oocytes retrieved(n)11.111.110.510.511.811.816.816.8FF leptin(ng/ml)FF leptin(ng/ml)11.9411.9417.0017.0017.2317.2320.8720.87Serum leptin(ng/ml)Serum leptin(ng/ml)16.4616.4619.0319.0322.2422.2431.7931.79uART success group:low FF and serum leptinuPCOS group:higher FF and serum leptinuelevated leptin levels may block E2 production,disturbing follicular development and oocyte maturationHum Reprod.2000 Mar;15(3):539-44 VEGF and FGFVascular endothelial growth factor(VEGF)a homodimeric glycoprotein angiogenesis,follicular vascularization and intrafollicular oxygenationFibroblas