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The approach to the PCOS patient undergoing IVF

The approach to the PCOS patient undergoing IVF. Roy Homburg Barzili Medical Centre, Ashkelon, Israel and Homerton University Hospital, London Antalya, October 2011. Problems – IVF for PCOS. Excessive ovarian response Low fertilization rates High number of immature oocytes

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The approach to the PCOS patient undergoing IVF

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  1. The approach to the PCOS patient undergoing IVF Roy Homburg Barzili Medical Centre, Ashkelon, Israel and Homerton University Hospital, London Antalya, October 2011

  2. Problems – IVF for PCOS • Excessive ovarian response • Low fertilization rates • High number of immature oocytes • Reduced cleavage rates • Low implantation rates • High miscarriage rates

  3. Overcoming the problems for PCOS in IVF Diagnosis and mild stimulation Agonist vs antagonist Oral contraceptive pre-treatment GnRH agonist to trigger ovulation Metformin Freeze embryos IVM

  4. no cyst formation early pregnancy? more physiologic less gona- dotropins longer treatment no hormonal withdrawal antagonist administration multiple dose protocol gonadotropin administration gonadotropin administration long protocol (mid-luteal) agonist administration Comparison of the long protocol and the antagonist protocols Patient-friendly Menses flare up effect pituitary suppression pre-treatment cycle treatment cycle

  5. O H S S 4.1% 2.6%

  6. Hospital admission due to OHSS RR: 0.47 ~50% less risk for hospital admission due to OHSS with GnRH antagonists Kolibianakis et al. Hum Reprod Update. 2006

  7. GnRH antagonists are safer than agonists: an update of a Cochrane review.Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit J, Abou-Setta AM.Hum Reprod Update, May 2011

  8. Finally…..no difference in live birth rate 2011 May 11, 2011 With new information available, authors of a Cochrane Systematic Review have revised their conclusions about the relative effectiveness of two different treatments used to help women become pregnant. They now conclude that giving women GnRH-antagonists leads to similar live-birth rates compared with GnRH agonists. Previously they had concluded that women who used antagonists tended to have lower birth-rates than those using agonists. [........] In 2006, when the researchers reached their earlier conclusion, they were only able to draw data from 27 trials. Since then more research has been published, allowing them to consider the findings of 45 randomised controlled studies that involved a total of 7,511 women. “This increased amount of data lets us get a much better idea of how well the two approaches compare,” says Dr Hesham Al-Inany, who was lead author of the research and works at Cairo University, Egypt. Dr Al-Inany led a multi-centre team, with researchers also based in the Netherlands and Canada. “The reduction in ovarian hyperstimulation combined with a comparable live-birth rate mean justifies a move away from the standard GnRH agonist to using GnRH antagonists,” says Dr Al-Inany. http://eu.wiley.com/WileyCDA/PressRelease/pressReleaseId-96357.html

  9. F&S 2008 18.1% vs 23.6%

  10. - OC pretreated • Starting with Gn on day 2/3 after the last OC intake • Fixed GnRH antagonist regimen (long-starting SD 1) Huirne et al, 2007

  11. Incidence of OHSS Objective:to determine OHSS incidence in 2,524 antagonist-based cycles (1801 patients). Results:fifty three patients (2%) were hospitalized because of OHSS. Conclusions: clinically significant OHSS is a limitation even in antagonist cycles. “There is more than ever an urgent need for alternative final oocyte maturation – triggering medication” F&S January 2006

  12. 0.25mg/day antagonist FSH Day 5 , 6 or 7 antagonist startFIXED hcg 0.25mg/day antagonist FSH hcg day 8/9 Follicle size 14mm- start antagonist Flexible regime FSH hcg

  13. 0.25mg/day antagonist FSH Day 5 , 6 or 7 antagonist startFIXED GnRH agonist 0.25mg/day antagonist FSH GnRH agonist day 8/9 Follicle size 14mm- start antagonist Flexible regime FSH hcg

  14. Agonist: 1932 patients, not a single case of OHSS! hCG: 84 cases in 1760 patients, 4.8%

  15. Agonist versus HCG for oocyte triggering • Youssef et al. Cochrane Review 2010

  16. 0.25mg/day antagonist FSH Day 5 start FIXED GnRH agonist Freeze and thaw cycles Luteal phase support FSH hcg

  17. Triggering of final oocyte maturation with GnRH-a or HCG: • Live birth after frozen-thawed embryo replacement cycles P = 0.02 Griesinger et al., FertilSteril 2007

  18. Frozen-thawed cycles Manzanares et al, 2009

  19. 0.25mg/day antagonist FSH Day 5 start FIXED GnRH agonist Luteal phase support: 1. Massive doses P +/- E2 2. 1500 IU hCG on day OPU (Humaidan 2009) FSH hcg

  20. GnRH agonist vs hCG in high risk IVF patients RCT, n=66 with PCO’s Antag + GnRH trigger vs Agonist + hCG trigger OHSS – 0% vs 31% Ongoing pregnancy rates – 53% vs 48% Adequate E2 , P supplementation in luteal phase Engmann et al, 2008

  21. 0.25mg/day antagonist FSH Day 5 start FIXED GnRH agonist Luteal phase support: 1500 IU hCG on day OPU (Humaidan 2009) No significant difference in outcome compared with hCG trigger FSH hcg

  22. Table 3. Pregnancy outcome in GnRHa vs. hCG-group. Humaidan et al, 2010

  23. Beyond the context of OHSS: Patient-friendly luteal phase • Abdominal pain and discomfort due to enlarged ovaries. • How to minimize ovarian volume post oocyte retrieval?

  24. Clinical use of agonist triggeropinion Primarily in the context of OHSS prevention. Prevention is total. A major reason to use GnRH antagonists in ovarian stimulation of high-risk patients: to keep the option of agonist trigger if needed.

  25. Metformin for IVF • n=73 PCOS for IVF/ICSI - metformin (2G/d) - placebo for 16 weeks • No difference in any stimulation, IVF or clinical criteria. • BUT in group with BMI < 28, pregnancy rates double on metformin. Kjotrod et al, 2004

  26. Metformin in IVF Tang, Bart & Balen, 2005 • Single centre, double-blind RCT • 94 patients, PCOS, BMI 27.8 101 IVF/ICSI cycles, long agonist protocol • Metformin (850mg bd) or placebo from start of agonist to OPU

  27. Metformin in IVF • No difference: Total dose FSH No. of oocytes Fertilisation rates • Tang, Barth & Balen, 2005

  28. Metformin for IVF in PCOS P = 0.02 Tang et al., Hum Reprod 2005

  29. Metformin in IVF • Short term co-treatment with metformin for PCOS in IVF/ICSI : • Does not improve response to stimulation • Improves pregnancy rates • Reduces the risk of OHSS Tang, Bart & Balen, 2005

  30. Endometrial dysfunction • Low luteal phase serum glycodelin and IGFBP-1 (Jacubowicz et al, 2001) • Plasma endothelin-1 levels high in PCOS (Diamantis-Kandarakis et al, 2005) • Inadequate endometrial blood flow (Orio et al, 2005) All induced by hyperinsulinemia and improved by metformin.

  31. IVM from unstimulated PCO N=118 women, PCOS. 152 cycles OPU day 9-14 ET – 140 cycles Clinical pregnancy rate – 40% / transfer 56 livebirths and another 10 ongoing. Zhao et al, F&S, 2008

  32. Summary –High responders IVF • The GnRH antagonist protocol appears to be an attractive option for PCOS patients undergoing IVF. • Ovulation triggering with GnRH-a may be a better option than cycle cancellation or prolonged coasting. • The addition of metformin to the treatment protocol • may be beneficial for PCOS. • Pretreatment with an OCP may be beneficial.

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