北医三院生殖医学中心讲义（英文版） 王志燮教授.ppt

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1、Factors influencing IVF outcomes,Peking University Third HospitalQiao Jie,Factors Affecting Conception,Production 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 uterus,IVF success rate,Desp

2、ite 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 ESHRE,Factors affecting IVF results,AgeCauses of infertilityResponsiveness to ovulation indu

3、ctionDifferent stimulation protocolsEmbryo qualitySperm qualityEmbryo transfer techniqueLuteal phase support,Factors affecting IVF results,AgeCauses of infertilityResponsiveness to ovulation inductionDifferent stimulation protocolsEmbryo qualitySperm qualityEmbryo transfer techniqueLuteal phase supp

4、ort,Endometriosis and IVF,Lower pregnancy rates(Barnhart et al.,2002,P.Kuivasaari et al.2005,De Hondt A,et al,2005;Azem F et 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,et al,2002)Decreased implantation rates(Azem

5、et al.,1999;Barnhartet al.,2002;Kuivasaari et al.,2005;Kumbak B et al,2008)A lower number of oocytes retrieved(Bergendal et al.1998,Azem et al.,1999,Suzuki T,et al,2005;Kumbak B et al,2008;Barnhart K,et al,2002;Nakahara K et al,1998)A lower ovarian response to gonadotrophins(Azem et al,1999;Al-Azemi

6、 et al,2000;Aboulghar,2003;Barnhart et al,2002;Kuivasaari et al,2005;Al-Fadhli R,et al,2006;Kumbak B et al,2008),Endometriosis and IVF,Poor embryo quality(Barnhartet al.,2002;Kuivasaari et al.,2005;Kumbak B et al,2008)Higher rate of early pregnancy loss(Yanushpolsky EH et al,1998)Reduced birth rate

7、per cycle(Azem F et al,1999)Pregnancy rates for women with severe endometriosis were significantly lower than for women with mild disease(Barnhart K,et al,2002),Endometriosis and IVF,Lower VEGF gene expression in granulosa cells may adversely affect oocyte development and maturation(Yamashita Y,et a

8、l,2002)Altered folliculogenesis(Tummon IS,et al,1988)Embryo toxicity(Damewood MD et al,1990;Simon C et al,1992)Increased apoptosis in granulosa cells(Nakahara K et al,1998),Endometriosis and IVF,Decreased expression of biomarkers of implantation-decreased expression of HOXA10(Wei Q et al,2009;Taylor

9、 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 in

10、tegrin(Lessey BA et al,1994;Khorram O et al,2002)Alterations in endometrial apoptosis(Gebel HM et al,1998;Bergqvist A et al,1993),Hydrosalpinx and IVF,Reduced 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 ra

11、te(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 IVF,Reduced 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 dev

12、eloping(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 IVF,Hydrosalpinx fluid may contain cytokines,p

13、rostaglandins 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 IVF,Embryotoxic effects-lower rate of of

14、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 dev

15、elopment(Beyler et al,1996;Mukherjee T.et al,1996),Hydrosalpinx and IVF,Reduce 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 lev

16、el 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 IVF,Changes in endometrial pattern and endometrial blood flow-patients with hydrosalpinx had a significantly higher proportion of the non-multila

17、yered endometrial pattern and significantly lower endometrial and subendometrial blood flows,Ng EHY.et al,2006,Intra-ovarian Factors in Polycystic Ovary Syndrome(PCOS):Impact on Oocyte Maturation and Embryo Developmental Competence,PCOS patients typical characterization In IVF,Increased number of oo

18、cytesLower fertilization,cleavage ratesLower implantation ratesHigher miscarriage ratesPoor quality of oocytes and embryos,Human Reproduction Update,Vol.12,No.1 pp.1321,2006,PCOS,during folliculogenesis and follicle maturationabnormal endocrine/paracrine factors metabolic dysfunctionintrafollicular

19、microenvironment alterations Impaired oocyte maturation and embryonic developmental competence,Seminar 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-AMH,serum AMH lev

20、els reduces throughout reproductive life,Serum AMH levels stable throughout the menstrual cycle,Human Reproduction Update,Vol.16,No.2 pp.113130,2010,Mean AMH serum levels,significantly higher in PCOS patientsassociated with increased development of antral follicles and follicular arrest in PCOS pati

21、entslower in POF patients,Trends in Endocrinology and Metabolism Vol.19 No.9,PCOS-IVFAMH,PCOS patients:higher levels of follicular MIS follicular MIS level correlating with a greater number of immature oocytes retrieved,Fertil Steril.1997 May;67(5):962-5,PCOS in IVF:Serum and FF AMH significantly hi

22、gher The AMH levels significantly lower patients who began a pregnancy(22.0 vs.50.5 pMol/L,P=0.018)a negative link between AMH and final oocyte maturation，possibly because of impaired access of FSH to follicles,Fertil Steril.2010 Jun;94(1):198-204,TGF-Inhibins,Inhibinsproduced by the dominant follic

23、lestimulate 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 rates,Europ J Obstet Gynecol Reprod Biol 2004;115:194199,PCOSInhibins,FF inhibin A and in

24、hibin B concentrations are significantly reduced in PCOS compared with those in size-matched follicles from normal women(J Clin Endocrinol Metab.2005 Oct;90(10):5582-7）FF inhibin B levels are significantly correlated to embryo quality,(Hum Reprod.2002 Jul;17(7):1724-8),TGF-GDF 9,GDF9,an oocyte-secre

25、ted factorpromotes granulosa cell proliferation and preantral follicle growthits deficiency impairs granulosa cell proliferation and causes follicular arrest at the primary follicle stage,Semin Reprod Med.2008 January;26(1):5361,PCOSGDF 9,PCOS oocytes GDF9 mRNA levels reduced Impaired follicle growt

26、hLead to premature luteinization Decrease luteal generationMaybe altered granulosa cell-oocyte signaling,J Clin Endocrinol Metab 2002;87:1337-1344,Insulin-like growth factors,multifunctional polypeptides with insulin-like activitytwo receptor ligands(IGF-I and IGF-II)two surface-receptors(IGF1R and

27、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 arrest,Expert Rev Endocrinol Metab 2007;2(2):215-223,IGF,serum and follicular fluid IGF-I/IGFBP-1 higher in women who became

28、 pregnantThe ratio IGF-I/IGFBP-1 may reflect oocyte quality,J Assist Reprod Genet 2003;20:167-176,PCOSIGF,IGF-I plays a key role in oocyte maturation in PCOS patientsAlterations in IGFBP-3 concentration during stimulation may be a critical mechanism in modulating IGF-I activity,PCOS patients:Mean se

29、rum IGF-I and IGFBP-3 levels increased during stimulation,Serum IGF-I levels decreased higher mean number of immature oocytes retrieved(4.81.1 vs.2.40.4;P.02),Serum IGFBP-3 levels increase greater pregnant(P.03)ongoing pregnancy(P.02),Fertil Steril 2007;88:13944,Cytokine Family,a large family of sol

30、uble 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 apoptosis,Best Practice a

31、nd Res Clinical Obste and Gynaecology.2004;18:755-771,PCOS undergoing IVF,1)higher serum and FF interleukin-6 and TNF-2)cytokine concentrations:FF serum3)FF TNF-concentrations were inversely correlated to the estradiol levels，indicative poor quality oocytes and embryos,Obstet Gynecol 2003;101:1177 8

32、2,CKTNF,Exposure of porcine oocytes to an elevated TNF-a a reduction in their maturation from GV stage to MII stage increased the proportion of oocytes with abnormal chromosome alignment and cytoskeleton structure,PCOS patients treated with pioglitazone during COSFF TNF-a and IL-6 levels significant

33、ly lower The clinical pregnancy rate higher,Fert Steril 2009;92(suppl):s104-105,Fertil Steril 2010;93:9206,CKLIF,LIF enhances embryonic development and increases blastocyst formation,decreasing the rate of embryo degeneration FF concentrations of PCOS during IVF,The LH/FSH ratio negatively correlate

34、d with LIF PCOS:Implatation rates lower FF LIF appears to function as an embryotrophic agent,Hum Reprod.2001 Oct;16(10):2073-8,CKFas FasL,sFas and sFasL,anti-and pro-apoptotic factors,respectively,PCOS in IVFserum sFas treated with metformin serum sFas FF sFasL reduce GC DNA fragmentation increase i

35、mplantation and clinical pregnancy rates,Hum 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 embr

36、yo quality,Hum Reprod 2006;21:17251733,PCOSHcy,52 PCOS patients underwent GnRHagonist/r-FSH treatment,higher FF Hcy group:Grade 3 oocyteGrade 12 embryo fertilization rate,Hum Reprod.2009 Sep;24(9):2293-302,multiple linear regression analyses：FF Hcy is an independent determinant of oocyte quality and

37、 embryo quality,Hum Reprod.2009 Sep;24(9):2293-302,PCOS pregnance after IVF or ICSI,FF Hcy levels negatively associated with FF E2The E2-enriched follicular fluid positively correlated with oocyte fertilization,cleavage and implantationhigher follicular fluid Hcy levels may suppress E2 production an

38、d interfere with the development of dominant follicles,oocyte maturation and fertilization in women with PCOS undergoing assisted reproduction,Hum Reprod.2009 Sep;24(9):2293-302,Leptin,16kDa protein hormoneregulating energy intake,energy expenditure,and their balancehigh FF and serum leptin levels c

39、losely associated with decreased oocyte maturity,poor fertilization and embryo quality,and lower pregnancy rates,Reproduction 2005;130:917921,PCOS undergoing ARTLeptin,ART success group:low FF and serum leptinPCOS group:higher FF and serum leptinelevated leptin levels may block E2 production,disturb

40、ing follicular development and oocyte maturation,Hum Reprod.2000 Mar;15(3):539-44,VEGF and FGF,Vascular endothelial growth factor(VEGF)a homodimeric glycoprotein angiogenesis,follicular vascularization and intrafollicular oxygenationFibroblast growth factors(FGF)A group of polypeptides play a fundam

41、ental role in development,cell growth,tissue,regulator of FSH action,Human Reproduction 2005;20,15621568,Expert Rev Endocrinol Metab 2007;2(2):215-223,PCOS patients undergoing IVFserum and follicular fluid VEGF and bFGF levels,Gynecol Endocrinol.2006 Aug;22(8):465-70,PCOSFGF,follicular fluid bFGF le

42、vels inversely correlated with the percentage of mature oocytes collected(p=0.034),bFGF seems to be an FSH-dependent growth factor,Gynecol Endocrinol.2006 Aug;22(8):465-70,PCOS undergoing ICSI using a GnRH antagonist or a GnRH agonist protocol,between the GnRH antagonist and the GnRH agonist MII ooc

43、ytes VEGF concentrations statistically significant(log 3.20 0.21 versus 3.34 0.15,corresponding mean VEGF 1774 and 2316 pg/ml,respectively)(P 0.001),Reprod Biomed Online.2009 Jan;18(1):21,PCOS undergoing ICSI using a GnRH antagonist or a GnRH agonist protocol,higher oestradiol concentrations were re

44、lated to embryos of higher quality(P=0.037)PCOS:GnRH antagonists decrease follicular oestradiol and VEGF concentrations and the number of retrieved MII oocytes,Reprod Biomed Online.2009 Jan;18(1):21,Conclusions,AgeCauses of infertilityResponsiveness to ovulation inductionDifferent stimulation protocolsEmbryo qualitySperm qualityEmbryo transfer techniqueLuteal phase support,Thank you for attention,