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Factors influencing IVF outcomes

Factors influencing IVF outcomes. Peking University Third Hospital Qiao Jie. Factors 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 uterus.

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Factors influencing IVF outcomes

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  1. Factors influencing IVF outcomes Peking University Third Hospital Qiao Jie

  2. Factors 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 uterus

  3. IVF success rate Despite 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

  4. Factors affecting IVF results • Age • Causes of infertility • Responsiveness to ovulation induction • Different stimulation protocols • Embryoquality • Sperm quality • Embryo transfer • technique • Luteal phase support

  5. Factors affecting IVF results • Age • Causes of infertility • Responsiveness to ovulation induction • Different stimulation protocols • Embryoquality • Sperm quality • Embryo transfer • technique • Luteal phase support

  6. 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 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 et al,2000; Aboulghar,2003;Barnhart et al,2002;Kuivasaari et al,2005;Al-Fadhli R,et al,2006; Kumbak B et al,2008)

  7. 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 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 )

  8. Endometriosis and IVF Lower VEGF gene expression in granulosa cells may adversely affect oocyte development and maturation (Yamashita Y, et al,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)

  9. Endometriosis and IVF Decreased expression of biomarkers of implantation -- decreased expression of HOXA10 (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 integrin (Lessey BA et al,1994; Khorram O et al,2002) Alterations in endometrial apoptosis (Gebel HM et al,1998; Bergqvist A et al,1993)

  10. 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 al,1998 ) Lower ongoing pregnancy rate (Sims et al,1993)

  11. 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 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)

  12. Hydrosalpinx and IVF Hydrosalpinx 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)

  13. Hydrosalpinx and IVF Embryotoxic effects -- 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)

  14. Hydrosalpinx and IVF Reduce endometrial receptivity -- lower levels of integrins αVβ3 in the endometrium (Lessey et al. 1994; Meyer W et al,1997) --diminished expression of HOXA10in 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 αVβ3 expression after surgical correction of hydrosalpinx (Meyer W et al,1997)

  15. 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 subendometrial blood flows Ng EHY. et al, 2006

  16. Intra-ovarian Factors in Polycystic Ovary Syndrome (PCOS): Impact on Oocyte Maturation and Embryo Developmental Competence

  17. PCOS patients’ typical characterization In IVF • Increased number of oocytes • Lower fertilization, cleavage rates • Lower implantation rates • Higher miscarriage rates Poor quality of oocytes and embryos Human Reproduction Update, Vol.12, No.1 pp. 13–21, 2006

  18. PCOS during folliculogenesis and follicle maturation • abnormal endocrine/paracrine factors • metabolic dysfunction • intrafollicular microenvironment alterations Impaired oocyte maturation and embryonic developmental competence Seminar Reprod Med 2008; 26:53-61

  19. Transforming growth factors (TGF-β) • Anti-Müllerian hormone (AMH) • Growth differentiation factor (GDF9) • Inhibins • Activitins • Bone morphologicalprotein-15 (BMP15)

  20. TGF-β——AMH serum AMH levels reduces throughout reproductive life Serum AMH levels stable throughout the menstrual cycle Human Reproduction Update, Vol.16, No.2 pp. 113–130, 2010

  21. significantly higher in PCOS patients associated with increased development of antral follicles and follicular arrest in PCOS patients lower in POF patients Mean AMH serum levels Trends in Endocrinology and Metabolism Vol.19 No.9

  22. PCOS-IVF——AMH 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

  23. PCOS in IVF: Serum and FF AMH significantly higher • 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

  24. TGF-β——Inhibins Inhibins • produced by the dominant follicle • stimulate theca cell androgen production for E2 synthesis In IVF patients,higher FF inhibin A and B levels(measured on the day of oocyte retrieval) • better oocyte maturity and fertilization rates • higher pregnancy rates Europ J Obstet Gynecol Reprod Biol 2004; 115: 194–199

  25. PCOS——Inhibins • FF inhibin A and inhibin 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 )

  26. TGF-β——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 stage Semin Reprod Med. 2008 January ; 26(1): 53–61

  27. PCOS——GDF 9 • PCOS oocytes GDF9 mRNA levels reduced • Impaired follicle growth • Lead to premature luteinization • Decrease luteal generation • Maybe altered granulosa cell-oocyte signaling J Clin Endocrinol Metab 2002;87:1337-1344

  28. Insulin-like growth factors multifunctional polypeptides with insulin-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 arrest Expert Rev Endocrinol Metab 2007; 2(2):215-223

  29. serum and follicular fluid IGF-I/IGFBP-1 higher in women who became pregnant The ratio IGF-I/IGFBP-1 may reflect oocyte quality IGF J Assist Reprod Genet 2003; 20:167-176

  30. PCOS——IGF PCOS patients :Mean serum IGF-I and IGFBP-3 levels increased during stimulation • Serum IGFBP-3 levels increase • greater pregnant (P.03) • ongoing pregnancy (P.02) • Serum IGF-I levels decreased • higher mean number of immature oocytes retrieved (4.8±1.1 vs. 2.4±0.4; P.02) • IGF-I plays a key role in oocyte maturation in PCOS patients • Alterations in IGFBP-3 concentration during stimulation may be a critical mechanism in modulating IGF-I activity Fertil Steril 2007;88:139–44

  31. Cytokine Family a large family of soluble polypeptide regulators • interleukins (IL1~35) • Leukemia Inhibitory Factor (LIF) • Tumor necrosis factor-alpha (TNFα) • Soluble Fas (sFas) • Soluble Fas ligand (sFasL) • regulating ovarian function • exerting an influence on proliferation, differentiation, follicular maturation, steroidogenesis and apoptosis Best Practice and Res Clinical Obste and Gynaecology. 2004; 18:755-771

  32. PCOS undergoing IVF • 1) higher serum and FF interleukin-6 and TNF-α • 2) cytokine concentrations : FF ＞serum • 3) FF TNF-α concentrations were inversely correlated to the estradiol levels，indicative poor quality oocytes and embryos Obstet Gynecol 2003; 101:1177– 82

  33. CK——TNFα 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 Fertil Steril 2010;93:920–6 • PCOS patients treated with pioglitazone during COS • FF TNF-a and IL-6 levels significantly lower • The clinical pregnancy rate higher Fert Steril 2009; 92(suppl) :s104-105

  34. 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 correlated with LIF PCOS: Implatation rates lower FF LIF appears to function as an embryotrophic agent CK——LIF Hum Reprod. 2001 Oct;16(10):2073-8

  35. sFas and sFasL ,anti-and pro-apoptotic factors, respectively PCOS in IVF serum sFas ↓ treated with metformin serum sFas ↑ FF sFasL ↓ reduceGC DNA fragmentation increase implantation and clinical pregnancy rates CK——Fas FasL Hum Reprod. 2005 Sep;20(9):2391-5

  36. 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; 21:1725–1733

  37. 52 PCOS patients underwent GnRHagonist / r-FSH treatment higher FF Hcy group: Grade 3 oocyte↓ Grade 1–2 embryo↓ fertilization rate↓ PCOS——Hcy Hum Reprod. 2009 Sep;24(9):2293-302

  38. multiple linear regression analyses： FF Hcy is an independent determinant of oocyte quality and embryo quality Hum Reprod. 2009 Sep;24(9):2293-302

  39. PCOS pregnance after IVF or ICSI • FF Hcy levels negatively associated with FF E2 • The E2-enriched follicular fluid positively correlated with oocyte fertilization, cleavage and implantation • higher follicular fluid Hcy levels may suppress E2 production and 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

  40. 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 rates Reproduction 2005; 130: 917–921

  41. PCOS undergoing ART——Leptin • ART success group: low FF and serum leptin • PCOS group: higher FF and serum leptin • elevated leptin levels may block E2 production, disturbing follicular development and oocyte maturation Hum Reprod. 2000 Mar;15(3):539-44

  42. 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, cell growth, tissue, regulator of FSH action Human Reproduction 2005; 20, 1562–1568 Expert Rev Endocrinol Metab 2007; 2(2):215-223

  43. PCOS patients undergoing IVF • serum and follicular fluid VEGF and bFGF levels Gynecol Endocrinol. 2006 Aug;22(8):465- 70

  44. follicular fluid bFGF levels inversely correlated with the percentage of mature oocytes collected (p=0.034) bFGF seems to be an FSH-dependent growth factor PCOS——FGF Gynecol Endocrinol. 2006 Aug;22(8):465- 70

  45. PCOS undergoing ICSI using a GnRH antagonist or a GnRH agonist protocol • between the GnRH antagonist and the GnRH agonist • MII oocytes 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

  46. PCOS undergoing ICSI using a GnRH antagonist or a GnRH agonist protocol • higher oestradiol concentrations were related 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

  47. Conclusions Age Causes of infertility Responsiveness to ovulation induction Different stimulation protocols Embryoquality Sperm quality Embryo transfer technique Luteal phase support

  48. Thank you for attention

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