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ART FOR PCOS-DIFFICULTIES AND SOLUTIONS

ART FOR PCOS-DIFFICULTIES AND SOLUTIONS. Dr. Bulent Urman American Hospital, ISTANBUL Assisted Reproduction Unit Koç University, Faculty of Medicine Department of OB/GYN. Consensus on infertility treatment related to PCOS. R E S I S T A N C E. F A I L U R E. FIRST LINE

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ART FOR PCOS-DIFFICULTIES AND SOLUTIONS

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  1. ART FOR PCOS-DIFFICULTIES AND SOLUTIONS Dr. Bulent Urman American Hospital, ISTANBUL Assisted Reproduction Unit Koç University, Faculty of Medicine Department of OB/GYN

  2. Consensus on infertility treatment related to PCOS R E S I S T A N C E F A I L U R E FIRST LINE CLOMIPHENE CITRATE SECOND LINE LOD/GONADOTROPINS R E S I S T A N C E THIRD LINE IVF The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group March 2–3, 2007, Thessaloniki, Greece. Human Reproduction 2008

  3. Does Ovulation = Live Birth ? Legro et al Hum Reprod 2004

  4. Surgical induction of ovulation From Urman and Yakin JRM 2006

  5. Challenges of treating infertility with IVF in the PCOS/PCO patient • Propensity for an exaggerated ovarian response • Difficulties in titrating gonadotropin dose • Increased risk of cycle cancellation • Increased incidence of early and late OHSS • Increased risk of spontaneous pregnancy loss

  6. Optimal ovarian stimulation for IVF • Avoid understimulation • Avoid overstimulation • Minimize cycle cancellation • Minimize if not avoid altogether OHSS

  7. FSH

  8. Normal responder OVER STIMULATION OPTIMAL STIMULATION 300 225 150 UNDER STIMULATION

  9. Hyper responder OVER STIMULATION 187.5 OPTIMAL STIMULATION 150 UNDER STIMULATION 112.5

  10. PCOS AND OHSS

  11. Artini et al. Humanfertility 2009;12:40

  12. hCG VEGF induced permeability Nature Rev Cancer;2005:437:497

  13. VEGF inducedpermeability Nature Rev Cancer;2005:437:497

  14. Insulin resistance and OHSS • Insulin is a stimulator of VEGF secretion in vascular endothelial cells. Doronzo et al. Eur. J. Clin. Invest. 34(10); 664 - 673 • Effect of metformin on OHSS seems to be mediated by declined insulin levels

  15. Metformin and OHSS • Two meta-analyses found that metformin co-administration in PCOS women undergoing IVF decreased the incidence of OHSS • The beneficial effect was observed in all RCTs regardless of duration and dosage of metformin • Number of oocytes collected and peak E2 levels were unaffected by metformin Costello et al. 2006 Hum. Rep. 21(6);1387 – 1399 Moll et al. 2007 Hum. Reprod. Update 13(6); 527 - 537

  16. hCG VEGF induced permeability Cabergoline inhibits phosphorylation of VEGR2 Gomez et al Endocrinology 2006;147:5400 Nature Rev Cancer;2005:437:497

  17. PreIVF considerations • Weight loss in overweight women • Metformin • LOD

  18. Impact of weight on IVF outcome From Bellver et al. FertilSteril 2010

  19. Metformin co-treatment

  20. Metformin prior to and during IVF All patients treated with luteal long protocol Metformin started on the first day of down regulation Dose 2 x 850 mg/day From Tang et al. Hum Reprod 2006

  21. Metformin co-treatment From Moll et al. Hum Reprod Update 2007

  22. Laparoscopic ovarian drilling as an adjunct to IVF • May decrease the frequency and severity of OHSS in women with a previous episode of OHSS • May facilitate ovarian stimulation in the brittle PCOS patient (Ferraretti, Fertil Steril 2001)

  23. Ovarian stimulation for IVF in the PCOS patient • Type of gonadotropin? • How to suppress LH surge and premature luteinization (agonist vs antagonist)? • How to trigger final oocyte maturation? • Coasting

  24. Urinary vs recFSH in women with PCOS undergoing IVF-RCT

  25. Agonist vs antagonist From Kurzawa et al. J Assist Reprod Genet 2008

  26. Agonist vs antagonist-RCT From Lainas et al. Hum Reprod 2010

  27. GnRH triggering of final oocyte maturation

  28. GnRHa triggering of final oocyte maturation in patients at risk for OHSS

  29. GnRHa triggering of oocyte maturation-RCT From Engman et al. FertilSteril 2008

  30. GnRHa triggering of oocyte maturation-RCT From Engman et al. FertilSteril 2008

  31. Main characteristics, luteal phase support and reproductive outcome of published RCT on GnRHa triggering of final oocyte maturation Humaidan et al. Hum Reprod 2009

  32. Main characteristics, luteal phase support and reproductive outcome of published RCT on GnRHa triggering of final oocyte maturation (intention to treat) Humaidan et al. Hum Reprod 2009

  33. GnRHa triggering of oocyte maturation-hints and tips • Lower implantation rates reported in some studies may be attributed to the luteolytic effect of the GnRHa • Titration of the luteal phase support is important

  34. Optimal cycle management in the PCOS patient • Careful titration of the gonadotropin dose • Measures to prevent OHSS • Coasting • GnRHa for triggering final oocyte maturation • Single Blast transfer vs Cryopreservation of all embryos • Cabergoline

  35. Outcome of IVF in PCOS

  36. Outcome of IVF in women with PCOS vs controls PCOS TUBAL/OTHER From Urman et al. RBM Online 2004

  37. Outcome of IVF in women with PCOS vs controls From Urman et al. RBM Online 2004

  38. Cumulative PR in PCOS vs controls From Pirinen et al. Gynecol Endocrinol 2010

  39. From Heijnen Hum Reprod Update 2006

  40. IVM

  41. Clinical outcome of IVM in PCOS or PCO From Suikkari, Curr Opin Obstet Gynecol 2008

  42. IVM vs IVF in PCOS • Randomized trials do not exist • Comparative studies, noncomparative case series and randomized trials comparing different protocols of IVM show: • Favorable maturation, fertilization, pregnancy and live birth rates with IVM compared to IVF • The rate of congenital anomalies appear to be similar • Urgent randomized trials are needed

  43. Conclusions • PCOS patient is the most difficult to treat with IVF • Cycle cancellation rates and risk of OHSS are higher • Fine tailoring of ovarian stimulation is necessary to avoid complications • Treating physicians should be aware of the difficulties and remedies/solutions

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