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Progesterone for luteal phase support in IVF cycles

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Luteal phase support is essential for IVF cycles. Progesterone has many forms and modalities: which to use? this talk is an attempt to answer this question

Luteal phase support is essential for IVF cycles. Progesterone has many forms and modalities: which to use? this talk is an attempt to answer this question

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  • 1. PROGESTERONE FOR LPS: META- ANALYSIS AND COST BENEFIT ANALYSIS Hesham Al-Inany, M.D, PhD
  • 2. OUTLINE OF THIS TALK  What is the problem?  How to deliver solid evidence if available  Different modalities for LPS  Vaginal capsules vs gel  Conclusion
  • 3. LUTEAL PHASE IN ART CYCLES  Iatrogenic luteal phase defect due to supraphysiological steroid levels in stimulated cycles Fatemi et al. Hum Reprod Update. 2007
  • 4. QUESTIONS TO BE ANSWERED  What is the best strategy for LPS  Is combined strategy more effective  How to choose between different modalities :- (Safety, Effectiveness / convenience/ cost)
  • 5. OUTLINE OF THIS TALK  What is the problem?  How to deliver solid answer for these questions?  Different modalities for LPS  Vaginal capsules vs gel  Comments  Conclusion
  • 6. THE BEST EVIDENCE FOR DIFFERENT TYPES OF QUESTION Level Treatment Prognosis Diagnosis I Systematic Review of … Systematic Review of … Systematic Review of … II Randomised trial Cohort studies Cross sectional III
  • 7. 7 WHY RCTS? Participants RandomlyAssigned Intervention Group Control Group Follow-up Follow-up Intervention Group Control Group
  • 8. ADVANTAGES OF SR  Larger numbers & power  Critical appraisal of studies
  • 9. THE USE OF PROGESTERONE IN IVF Nosarka et al. 2005.
  • 10. Cochrane Review 2011 Pregnancy rates are significantly reduced in ovarian stimulation without luteal phase support
  • 11. DOES THE PROTOCOL AFFECT???  Both agonists & Antagonists protocols require luteal phase support (Kahraman et al, 2010)
  • 12. OUTLINE OF THIS TALK  What is the problem?  How to deliver solid evidence if available  Different modalities for LPS  Vaginal capsules vs gel  Conclusion
  • 13. ELEMENTS OF LUTEAL PHASE SUPPORT  HCG: 1500-2000 IU i.m. q3d for 4 doses from oocyte retrieval  P4: from oocyte retrieval to 7-10 weeks 1) Progesterone in oil 25-100 mg i.m. qd 2) Utrogestan® 200 mg p.o. or vag. tid 3) Crinone® gel 90 mg vag. aod or bid Combined strategy hCG + P4 E2 + P4 Prednisolone + P4
  • 14. PRITTS, 2002 – hCG versus no treatment: significantly better – IM and vaginal progesterone and versus no treatment: significantly better – hCG = vaginal and IM progesterone BUT increased risk of OHSS associated with hCG use!
  • 15. (Cochrane Rev., 2011)
  • 16. A SYSTEMATIC REVIEW: P+E2 VS. P (GELBAYA ET AL, 2008)
  • 17. PROGESTERONE PLUS PREDNISOLONE & LOW DOSE ASPIRIN No benefit on CPR (Mollo et al,2003, Ezzeldin et al, 2003).
  • 18. ROLE OF PROGESTERONE 2.0 2.5 3.0 3.5 4.0 4.5 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 UC Frequency/min 0% 5% 10% 15% 20% 25% <3.0 3.1-4.0 4.1-5.0 >5.0 (Fanchin et al, 1998)(De Ziegler et al, 1996) UC/min UC = uterine contractions.
  • 19. WHICH TYPE OF PROGESTERONE???
  • 20. Progesterone in LPS IM P Oral P Vaginal P ROUTE .
  • 21. COMPOSITION
  • 22. AVAILABLE IN THE MARKET  Synthetic Natural Micronised  Provera - Cyclogest - Utrogestan caps  Depo-provera - Utrogest caps  Norplant - Prontogest - Progestan caps  Megestrol acetate - Ellios caps  Nomegestrol acetate - Endometrin tab  Northinderone - Crinone 8% gel  Duphaston
  • 23. IM PROGESTERONE  Effective  Painful (long, thick needles)  Occasional sterile abscess  Occasional allergic reaction (oil vehicle)*  Needs to be administered by nurse, husband  Acute eosinophilic pneumonia associated with IM administration of progesterone as luteal phase support after IVF: 5case reports * Bouckaert et al. Human Reproduction 2004; 19(8), 1806-1810
  • 24. ENDOMETRIAL DIFFUSION: TARGETED DELIVERY MICRONISED VAGINAL PROGESTERONE Four hours after application Bulletti et al. Hum Reprod. 1997;12:1073. Progressive diffusion of progesterone from the cervix to the fundus of the uterus One hour after application
  • 25. OUR SR: Vaginal vs. IM progesterone - CPR Vaginal vs. IM progesterone – Ongoing pregnancy rate Vaginal vs. IM progesterone – Live birth rate
  • 26. IN OOCYTE DONATION RECIPIENTS  vaginal progesterone showed better results than intramuscular injection  The study was small and retrospective • Berger BM, Phillips JA., 2012
  • 27. VAGINAL P4: 65% OF THE USE  http://www.ivf-worldwide.com/survey/survey- progesterone-results.html , August 2009
  • 28. ORAL PROGESTERONE  the convenience of oral administration is attractive,  However, the first-pass hepatic metabolism after oral administration requires higher doses  The clinical efficacy of oral progesterone has been debated  The vaginal administration of P results in a greater bioavailability with less relative variability than oral P (Levine & Watson, 2000).
  • 29. Vaginal vs. oral progesterone - Clinical pregnancy rate Vaginal vs. oral progesterone – Ongoing pregnancy rate OUR SR
  • 30. Statistically significant retarded endometrial development (“out phase endometrium”) in artificial cycles treated with oral dydrogesterone has been reported in several studies Pellicer et al, 1989; Li et al, 1994, Fatemi et al, 2007 DG Side effects  Sedation  Drowsiness  DG can not be given vaginal
  • 31. ORAL DG VS MICRONISED PROGESTERONE
  • 32. AUTHORISED BODIES APPROVAL  neither Duphaston nor Cyclogest are approved (worldwide) for Luteal Phase Support indication in ART Only few trials available for Cyclogest:
  • 33. OUTLINE OF THIS TALK  What is the problem?  How to deliver solid evidence if available  Different modalities for LPS  Vaginal : Capsules vs gel  Conclusion
  • 34. UTEROGESTAN VS CRINONE: LARGEST STUDY Ganesh et al, Fertil Steril 2011
  • 35. Our SR : Vaginal progesterone vs. Crinone 8% gel - Clinical pregnancy rate Vaginal progesterone vs. Crinone 8% gel – Live birth rate
  • 36. DOSE ??  Sensitivity analysis performed by excluding one trial in which vaginal P gel was administered twice instead of once on a daily basis did not reveal any difference (OR 1.30, 95% CI 0.93–1.81; P¼.118).  Our meta-analysis confirm previous findings from other trials that there is no difference in effectiveness between vaginal P gel and vaginal capsules when used in IVF/ICSI cycles
  • 37. MINOR SIDE EFFECTS  (perineal irritation, leaking out, interference with coitus) may limit the gel in favor of capsules Pezino et al (2004)
  • 38. HOW TO MAKE DECISION ABOUT DRUG Crinone vs Uterogestan
  • 39. Utrogestan® (200mg/caps) 400-600 mg/day 0.96 - 1.44€/day Endometrin® (100 mg tablet) 200-300 mg/day 8.86 – 13.29€/day Crinone® (8% vaginal gel) 90-180 mg/day 3.83 - 7.66€/day i.e Gel is at least 4 times more expensive than Capsules 4 € x 2weeks of LPS = ~65€ difference If repeated 3 cycles: 195 € COST
  • 40. ECONOMIC ANALYSIS  IVF/ICSI cycle, there are probabilities - Pregnancy - No pregnancy - Abortion - Repeat trial (usually up to 3 cycles) - Stop trial
  • 41. EXAMPLE : 1ST CYCLE Start Cycle 10,000 Ovum Pickup No OHSS Ovum Pickup OHSS 9810 190 Fertilization & Transfer No Oocytes 373+7=380 9437+183=9620 Clinical Pregnancy -ve βHCG 2982 6638 Ongoing Pregnancy Miscarriage 405 2577 3246 3392 Continue Stop Goal ! Therefore, for a cohort of 10,000 individuals the expected, mathematically exact, outcome at the end of the 1st cycle is 380+405+3392 = 4177 patients who will restart the cycle, and 2577 who achieved ongoing pregnancy, and 3246 who gave up on IVF from the first trial
  • 42. END RESULTS  10,000 cohort women will cost at least 1,400,000€ difference in case of gel over capsule  What would be the impact of such difference???  With crinone: lower number of women restarting cycle, and higher number of women stopping cycle  With Uterogestan: higher number of women restarting the cycle and lower number of women stopping cycle
  • 43. WHEN DO YOU START PROGESTERONE? 1. Day of hCG 2. Day of OPU 3. Day of ET (day 3) 4. Day of ET (day 5) Polling Question
  • 44. HOW LONG SHOULD PROGESTERONE BE ADMINISTERED? 1. Positive hCG 2. Up to 7 wks pregnancy 3. Up to 12 wks pregnancy 4. Up to 34 ws if multiple pregnancy Polling Question
  • 45. IN ALL CONDITIONS  cost-effectiveness is optimal with Vaginal progesterone caps regimen (Polyzos et al, 2009)
  • 46. PATIENT PREFERENCES  A recent era of developing patient preferences studies to evaluate the patient acceptability and satisfaction for a certain modality of treatment ove r the other  Unfortunately, no studies have been done in the field of luteal phase support.
  • 47. CONCLUSIONS (BY EVIDENCE)  LPS is important in IVF/ICSI cycles  hCG better not used in LPS as it increases OHSS  IM progesterone has many side effects  Oral progesterone is debatable  Micronised progesterone has solid evidence of effectiveness and convenience  Micronised capsules are more cost effective than progesterone gel
  • 48. THANK YOU!