北医三院生殖医学中心讲义英文版王志燮教授

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1、Peking University Third HospitalQiao JieFactors Affecting Conception Production of healthy sperm Healthy eggs by the woman Unblocked fallopian tubes The ability for the sperm to fertilize the egg The ability for the embryo to implant in the uterusIVF success rate Despite the progress in IVF,people u

2、ndertaking 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 results Different stimulation protocols Factors affecting IVF results Different stimulation proto

3、cols Endometriosis and IVF (Barnhart et al.,2002,P.Kuivasaari et al.2005,)Reduced fertilization rate (Bergendal et al.1998,Azem et al.,1999,)Azem et al.,1999;Barnhartet al.,2002;Kuivasaari et al.,2005;A lower number (Bergendal et al.1998,Azem et al.,1999,)A lower ovarian response to gonadotrophins (

4、Azem et al,1999;Al-Azemi et al,2000;Aboulghar,2003;Barnhart et al,2002;Kuivasaari et al,2005;)Endometriosis and IVFembryo quality (Barnhartet al.,2002;Kuivasaari et al.,2005;)Endometriosis and IVFEndometriosis and IVF Decreased expression of biomarkers of implantation-decreased expression of Wei Q e

5、t 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 3Wei Q et al,2009Lessey BA et

6、al,1994;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 rate (Sims et al.1993;Strandell et al,1994;Andersen et al,1994;Zeyneloglu HB et

7、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 developing (Freeman et al,1996)Improved pregnancy,implantation and delivery rat

8、es 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,prostaglandins or other inflammatory compounds.These compounds may have eith

9、er 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 effectsrate of of the embryos reaching the morula stage and the blastocyst stage (Schenk et al.1996;S

10、achdev 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 IVF Reduce en

11、dometrial 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 a

12、fter 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-multilayered endometrial pattern and significantly lower endometrial and subendomet

13、rial 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 oocytes Lower fertilization,cleavage rates Lower implantation rates Higher miscar

14、riage ratesPoor quality of oocytes and embryosHuman Reproduction Update,Vol.12,No.1 pp.1321,2006PCOS during folliculogenesis and follicle maturation abnormal endocrine/paracrine factors metabolic dysfunction intrafollicular microenvironment alterations Impaired oocyte maturation and embryonic develo

15、pmental competenceSeminar Reprod Med 2008;26:53-61 Transforming growth factors(TGF-)Anti-Mllerian hormone(AMH)Growth differentiation factor(GDF9)Inhibins Activitins Bone morphological protein-15(BMP15)TGF-AMHserum AMH levels reduces throughout reproductive lifeSerum AMH levels stable throughout the

16、menstrual cycleHuman Reproduction Update,Vol.16,No.2 pp.113130,2010Mean AMH serum levels significantly higher in PCOS patients associated with increased development of antral follicles and follicular arrest in PCOS patients lower in POF patientsTrends in Endocrinology and Metabolism Vol.19 No.9PCOS-

17、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):962-5 PCOS in IVF:Serum and FF AMH significantly higher PCOS in IVF:Serum and FF AMH significantly higher The AMH levels The AMH level

18、s 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 bec

19、ause of impaired access of FSH to folliclesfolliclesFertil Steril.2010 Jun;94(1):198-204TGF-InhibinsInhibins produced by the dominant follicle stimulate theca cell androgen production for E2 synthesisIn IVF patients,higher FF inhibin A and B levels(measured on the day of oocyte retrieval)better oocy

20、te maturity and fertilization rates higher pregnancy ratesEurop J Obstet Gynecol Reprod Biol 2004;115:194199 PCOSInhibins FF 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 compare

21、d 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 embr

22、yo qualityto embryo quality(Hum Reprod.2002 Jul;17(7):1724-8)TGF-GDF 9 GDF9,an oocyte-secreted factor promotes granulosa cell proliferation and preantral follicle growth its deficiency impairs granulosa cell proliferation and causes follicular arrest at the primary follicle stageSemin Reprod Med.200

23、8 January;26(1):5361PCOSGDF 9 PCOS oocytes GDF9 mRNA levels reduced Impaired follicle growth Lead to premature luteinization Decrease luteal generation Maybe altered granulosa cell-oocyte signalingJ Clin Endocrinol Metab 2002;87:1337-1344Insulin-like growth factorsmultifunctional polypeptides with i

24、nsulin-like activity two 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

25、 2007;2(2):215-223 IGF serum and follicular serum and follicular fluidfluid IGF-I/IGFBP-1 higher IGF-I/IGFBP-1 higher in women who became in women who became pregnantpregnant The ratio IGF-I/IGFBP-1 The ratio IGF-I/IGFBP-1 may reflect oocyte may reflect oocyte qualityqualityJ Assist Reprod Genet 200

26、3;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 decrease

27、d 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 regulators interleukins(IL135)Leukemia Inhibitory Factor(LIF)Tumor

28、necrosis factor-alpha(TNF)Soluble Fas(sFas)Soluble Fas ligand(sFasL)regulating ovarian function exerting an influence on proliferation,differentiation,follicular maturation,steroidogenesis and apoptosisBest Practice and Res Clinical Obste and Gynaecology.2004;18:755-771 PCOS undergoing IVF 1)higher

29、serum and FF interleukin-6 and TNF-1)higher serum and FF interleukin-6 and TNF-2)cytokine concentrations:FF 2)cytokine concentrations:FF serumserum 3)FF TNF-concentrations were inversely 3)FF TNF-concentrations were inversely correlated to the estradiol levelscorrelated to the estradiol levels，indic

30、ative 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

31、 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;93:9206CKLIF LIF enhances embryonic development and increases blastocyst formation,dec

32、reasing the rate of embryo degeneration FF concentrations of PCOS during IVFFF concentrations of PCOS during IVF The 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/m

33、l)2652658168167497490.0010.001Hum Reprod.2001 Oct;16(10):2073-8 CKFas FasL sFas and sFasL,anti-and pro-apoptotic factors,respectivelyPCOS in IVFPCOS in IVF serum sFas serum sFas treated with treated with metforminmetformin serum sFasserum sFas FF sFasL FF sFasL r reduceeduce GC DNA GC DNA fragmentat

34、ion 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 F

35、F 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 oocyte Grade 12 embryo fertilization rateHum Reprod.2009 Sep;24(9):2293-302 multiple linear regr

36、ession 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 ICSI FF Hcy levels negatively associated with FF E2FF Hcy levels negatively associated with FF E2 The E2-enriched follicular fluid positively correl

37、ated The E2-enriched follicular fluid positively correlated with oocyte fertilization,cleavage and implantationwith oocyte fertilization,cleavage and implantation higher follicular fluid Hcy levels may suppress E2 higher follicular fluid Hcy levels may suppress E2 production and interfere with the d

38、evelopment 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)

39、:2293-302 Leptin 16kDa protein hormone regulating energy intake,energy expenditure,and their balance high 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 ARTLeptin

40、variablevariableART 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

41、/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

42、and oocyte maturationHum Reprod.2000 Mar;15(3):539-44 VEGF and FGF Vascular endothelial growth factor(VEGF)a homodimeric glycoprotein angiogenesis,follicular vascularization and intrafollicular oxygenation Fibroblast growth factors(FGF)A group of polypeptides play a fundamental role in development,c

43、ell growth,tissue,regulator of FSH actionHuman Reproduction 2005;20,15621568 Expert Rev Endocrinol Metab 2007;2(2):215-223 PCOS patients undergoing IVF serum and follicular fluid VEGF and bFGF levelsGynecol Endocrinol.2006 Aug;22(8):465-70PCOSFGF follicular fluid bFGF levels inversely correlated wit

44、h the percentage of mature oocytes collected(p=0.034)bFGF seems to be an FSH-dependent growth factorGynecol Endocrinol.2006 Aug;22(8):465-70PCOS undergoing ICSI using a GnRH antagonist or a GnRH agonist protocol between the GnRH antagonist and the GnRH agonist between the GnRH antagonist and the GnR

45、H agonist MII oocytes VEGF concentrations statistically MII oocytes VEGF concentrations statistically significantsignificant(log 3.20(log 3.20 0.21 versus 3.34 0.21 versus 3.34 0.15,corresponding mean VEGF 1774 0.15,corresponding mean VEGF 1774 and 2316 pg/ml,respectively)(and 2316 pg/ml,respectivel

46、y)(P P 0.001)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 related to higher oestradiol concentrations were related to embryos of higher quality(embryos of higher quality(P=P=0.037)0.037)PCOS

47、:GnRH antagonists decrease follicular PCOS:GnRH antagonists decrease follicular oestradiol and VEGF concentrations and the number oestradiol and VEGF concentrations and the number of retrieved MII oocytesof retrieved MII oocytesReprod Biomed Online.2009 Jan;18(1):21 Conclusions Different stimulation protocolsThank you for attentionThank you for attention