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

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Progesterone for luteal phase support in IVF cycles

  1. 1. PROGESTERONE FOR LPS: META- ANALYSIS AND COST BENEFIT ANALYSIS Hesham Al-Inany, M.D, PhD
  2. 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. 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. 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. 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. 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. 7 WHY RCTS? Participants RandomlyAssigned Intervention Group Control Group Follow-up Follow-up Intervention Group Control Group
  8. 8. ADVANTAGES OF SR  Larger numbers & power  Critical appraisal of studies
  9. 9. THE USE OF PROGESTERONE IN IVF Nosarka et al. 2005.
  10. 10. Cochrane Review 2011 Pregnancy rates are significantly reduced in ovarian stimulation without luteal phase support
  11. 11. DOES THE PROTOCOL AFFECT???  Both agonists & Antagonists protocols require luteal phase support (Kahraman et al, 2010)
  12. 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. 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. 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. 15. (Cochrane Rev., 2011)
  16. 16. A SYSTEMATIC REVIEW: P+E2 VS. P (GELBAYA ET AL, 2008)
  17. 17. PROGESTERONE PLUS PREDNISOLONE & LOW DOSE ASPIRIN No benefit on CPR (Mollo et al,2003, Ezzeldin et al, 2003).
  18. 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. 19. WHICH TYPE OF PROGESTERONE???
  20. 20. Progesterone in LPS IM P Oral P Vaginal P ROUTE .
  21. 21. COMPOSITION
  22. 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. 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. 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. 25. OUR SR: Vaginal vs. IM progesterone - CPR Vaginal vs. IM progesterone – Ongoing pregnancy rate Vaginal vs. IM progesterone – Live birth rate
  26. 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. 27. VAGINAL P4: 65% OF THE USE  http://www.ivf-worldwide.com/survey/survey- progesterone-results.html , August 2009
  28. 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. 29. Vaginal vs. oral progesterone - Clinical pregnancy rate Vaginal vs. oral progesterone – Ongoing pregnancy rate OUR SR
  30. 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. 31. ORAL DG VS MICRONISED PROGESTERONE
  32. 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. 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. 34. UTEROGESTAN VS CRINONE: LARGEST STUDY Ganesh et al, Fertil Steril 2011
  35. 35. Our SR : Vaginal progesterone vs. Crinone 8% gel - Clinical pregnancy rate Vaginal progesterone vs. Crinone 8% gel – Live birth rate
  36. 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. 37. MINOR SIDE EFFECTS  (perineal irritation, leaking out, interference with coitus) may limit the gel in favor of capsules Pezino et al (2004)
  38. 38. HOW TO MAKE DECISION ABOUT DRUG Crinone vs Uterogestan
  39. 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. 40. ECONOMIC ANALYSIS  IVF/ICSI cycle, there are probabilities - Pregnancy - No pregnancy - Abortion - Repeat trial (usually up to 3 cycles) - Stop trial
  41. 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. 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. 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. 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. 45. IN ALL CONDITIONS  cost-effectiveness is optimal with Vaginal progesterone caps regimen (Polyzos et al, 2009)
  46. 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. 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. 48. THANK YOU!

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