The document discusses changing protocols for in vitro fertilization (IVF) from gonadotropin-releasing hormone (GnRH) agonists to GnRH antagonists. Some key points discussed include: 1) GnRH antagonists are associated with a lower risk of ovarian hyperstimulation syndrome (OHSS) compared to GnRH agonists. 2) While efficacy outcomes like live birth and pregnancy rates are similar between the two protocols, GnRH antagonists require fewer gonadotropin ampoules and have a shorter duration of stimulation. 3) Based on multiple randomized controlled trials and meta-analyses, it is justified to shift from GnRH agonists to GnRH antagonists for IVF

1. kasr al ainy school of Medicine Cairo University CHANGING ATTITUDES IN OVARIAN STIMULATION

2. CHANGING ATTITUDE IS A FACT OF LIFE To improve efficacy : better results: pregnancy To improve safety : less complications: OHSS

3. THE BEST MODEL Breech Trial

4. WHAT ABOUT GYNECOLOGY HRT: WHI study

5. IVF Safety comes first

6. 16 follicles 12 mature oocytes 14 oocytes Extras frozen if good 2 to 3 transferred 9 fertilize normally 5 divide normally 30-40% of couples 4 stop dividing & sperm Typical progression

7. OHSS is the most serious complication of ovulation induction.

8. PROTOCOLS FOR IVF GnRH Antagonist Protocols GnRH Agonist Protocols 225 IU per day (150 IU Europe ) Individualized Dosing of FSH/HMG 250 mg per day antagonist Individualized Dosing of FSH/HMG GnRHa 1.0 mg per day up to 21 days 0.5 mg per day of GnRHa 225 IU per day (150 IU Europe ) Day 6 of FSH/HMG Day of hCG Day 1 of FSH/HMG Day 6 of FSH/HMG Day of hCG 7 – 8 days after estimated ovulation Down regulation Day 2 or 3 of menses Day 1 FSH/HMG

9. SHOULD BE EVIDENCE BASED RCT Systematic Reviews

10. AL-INANY & ABOULGHAR, 2001

11. AL-INANY ET AL., 2006 O.R = 0.82, 95% CI = 0.68 to 0.97

12. AL-INANY ET AL., 2010 45 RCTs 7532 participants Many subgroup analyses: - Poor responders - PCOS - OCP pretreatment - LH stability examined - Cetrotide vs. ganerilix - Fixed vs. flexible protocol Conclusion differed

13. IT IS JUSTIFIED TO Shift from GnRH agonist to GnRH antagonist for IVF/ ICSI cycles

14. WHY: (AL-INANY ET AL, 2010)

15. HOW TO EXPLAIN OHSS is an uncommon complication Uncommon complications need large number of participants to show if there is a real difference between two drugs In our current situation: agonist vs. antagonist OHSS in agonist group: 3.74% (84/3165) OHSS in antagonist group: 1.91% (149/ 2252)

16. NUMBER NEEDED TO HARM NNH= 25 (95%CI = 19 to 36) This clinically means : for every 25 women underoing downregulation by Agonist , you may expect one more case of severe OHSS

17. CANCELLATION FOR RISK OF OHSS

18. CONSIDERING CYCLES CANCELLED FOR RISK OF OHSS Then the difference will more statistically significant if cancellation was not done This difference is highly significant both from statistical significance and clinical significance

19. So we may say confidently that GnRH antagonist is safer than GnRH agonist in IVF/ ICSI cycles

20. LIVE BIRTH RATE

21. CPR

22. MISCARRIAGE RATE

23. IN FAVOR OF ANTAGONIST much shorter duration of GnRH analogue treatment (OR -20.90, 95% CI -22.20 to -19.60) less days of stimulation (OR -1.54, 95% CI -2.42 to -0.66). reduction in the amount of gonadotrophins (OR -4.27, 95% CI -10.19 to 1.65)

24. 3. 0 ampoules less with GnRH antagonists p<0.0 7 FSH requirement

25. 1. 1 less days with antagonists p<0.001 Duration of FSH treatment

26. HOW TO EXPLAIN IMPROVED EFFICACY LH-instability incidence per woman randomised: defined as any fluctuation in LH-level, either a LH-surge or rise in LH-concentration as defined by the study protocol

27. LH STABILITY: AGONIST VS. ANATGONIST

28. FIXED DOSE PROTOCOL

29. Flexible antagonist stimulation

30. Meta-analysis of clinical pregnancy rate in fixed and flexible protocols for GnRH antagonist protocols Al-Inany et al. 2005

31. FURTHER ANALYSIS LH instability is more reported in studies using flexible antagonist protocol Al-Inany et al, 2005 showed fixed protocol achieve better results than flexible Clinicians tend to use fixed protocol more now Thus better LH stability

32. SO OUR CONCLUSION: There are no significant differences in the efficacy of GnRH antagonist and long agonist protocols with a significant reduction in the incidence of severe OHSS with the antagonist.

33. BUT NOT ALL DOCTORS WOULD GO FOR ANTAGONIST

34. (GNRH) ANTAGONISTS: OFF LABEL INDICATION unique Idea Administration during GnRH agonist cycle when follicle reach ~16mm and E2 level > 4000pmol Decrease but Continue hMG (step down protocol) Monitor by E2 Not more than 3 days

35. VALUE allow continued stimulation while rapidly decreasing the E2 level to a range that is clinically acceptable.

37. OUR RESULTS Parameter Coasting (n = 96) Antagonist (n = 94) P-value Age (years) 30.0 ± 4.9 29.6 ± 4.6 NS Duration of infertility (years) 6.64 ± 4.45 7.07 ± 4.3 NS No. of HMG injections 30.52 ± 8.9 29.94 ± 8.8 NS Days of stimulation 1 9.1 ± 1.5 9.4 ± 1.5 NS Peak oestradiol (pg/ml) 5087 ± 1589 5305 ± 1680 NS Oestradiol on day of HCG (pg/ml) 2605 ± 790 2721 ± 699 NS Range of oestradiol on day of HCG (pg/ml) 1110–4136 1223–4093 NS Day of intervention 2.82 ± 0.97 1.74 ± 0.91 <0.0001 No. of oocytes 14.06 ± 5.20 16.5 ± 7.60 0.02 No. of MII oocytes 11.13 ± 4.60 13.14 ± 6.60 NS No. of fertilized oocytes 7.97 ± 3.80 9.14 ± 4.70 NS No. of high quality embryos 2.21 ± 1.10 2.87 ± 1.20 0.0001 No. of embryos transferred 2.83 ± 0.50 2.79 ± 0.40 NS No. of cryopreserved embryos 4.50 ± 3.93 5.77 ± 4.87 NS Clinical pregnancy (%) 46/96 (47.9) 52/94 (55.3) NS Multiple pregnancy (%) 15/46 (32.6) 17/52 (32.7) NS

38. THE FUTURE Simplifying IVF procedure ELONVA

39. JUST A QUESTION Would u change ur protocol from agonist to antagonist??

40. SIMPLE, SHORTER SAFER

41. WHY CHANGING ATTITUDE For Tomorrow Better Health

42. THANK YOU Dr. Hesham Al-Inany MD, PhD e-mail : hesham@khosoba.com