1. Use of GnRH antagonists for IVF
Dr. Hakan Özörnek
EUROFERTIL IVF Center

2. Structures of GnRH-antagonists in comparison to native GnRH

3. Agonist - Initial Phase: Stimulation
GnRH
Agonist
Increased secretion of LH/FSH

4. Chronic Administration agonist
Blockade post receptor mechanisms
Some loss of receptors

5. Antagonist: Immediate Suppression
GnRH
Antagonist
Receptor blocked no micro aggregation
No effect immediate decrease of LH (FSH)

6. Hormon levels
days

7. Hormon levels
days

8. Advantages of GnRH-antagonists
no flare-up effect
no withdrawl symptoms
shorter stimulation
reduced gonadotrophin consumption
fast reversibility

9. Long Agonist vs Antagonist

10. Antagonist protocols

11. Timing of Antagonist Administration

12. Suggested protocol

13. Discontinuation of IVF therapy
Treatment burden
Length of treatment
Side effects
Burden of risk
OHSS

14. Advantages of Antagonists
No initial flare up
Shorter treatment duration
Less gonadotrophin consumption
Less clinic attendances
Lower risk of OHSS
No hypooestrogenemic effects
Weight gain, headache, hot flushes, mood changes, vomiting

15. Agonist
Antagonist

16. Disadvantages of Antagonists
Lower pregnancy rates ?

17. Normoresponder-Antagonist
Tubal infertility - DIR
Cycles
CPR/ET
Agonist
7712
37.8
Antagonist
1852
36.1
Engel, et al., 2006

18. Normoresponder-Antagonist
Patient 36
113
HMG/FSH ampoules
35.6
24.3*
E2 level
2549
1786*
Nr of oocytes
12.6
9.2
Transferred embryos
2.7
2.6
PR/ET
27.3
21.2
OHSS rate
11.1
3.5*
Olivennes, et al., 2000

19. Normoresponder-Antagonist
Patients
109
226
Gonadotropin usage
1800
1350*
Stimulation length 26 9*
E2 level
1370
1090
Nr of oocytes
9.6
7.9
PR/ET
41.7
35.8
The European and Middle East Orgalutran Study Group, 2001

20. Duration of stimulation (PCOS)
Grisinger G, RBM Online, 2006

21. Gonadotrophin consumption (poor)
Grisinger G, RBM Online, 2006

22. Gonadotropin consumption (PCOS)
Grisinger G, RBM Online, 2006

23. Gonadotrophin consumption
Al-Inany HG, RBM Online, 2007

24. Cancelled cycles (poor)

25. Number of oocytes
Al-Inany HG, RBM Online, 2007

26. Number of oocytes (PCOS)
Grisinger G, RBM Online, 2006

27. Miscarriage rate
Al-Inany HG, RBM Online, 2007

28. OHSS
Al-Inany HG, RBM Online, 2007

29. OHSS
In a Cochrane rewiev the relative odds of hospital admission for OHSS was reduced bye 54 % with antagonists compared with agonists.
Kolibianakis EM, Human Reprod Update, 2006

30. Hiperresponder-Antagonist
Lower E2 levels by antagonist cycles.
Ovulation can be triggered by agonist instead of HCG.

31. Clinical pregnancy rate
Al-Inany HG, RBM Online, 2007

32. Clinical pregnancy rate (PCOS)
Grisinger G, RBM Online, 2006

33. Clinical pregnancy rate (Poor)
Grisinger G, RBM Online, 2006

34. Live Birth Rate

35. Live birth rate(poor)
Kolibianakis EM, Human Reprod Update, 2006

36. Live birth rate (PCOS)
Kolibianakis EM, Human Reprod Update, 2006

37. Live birth rate (Gonadotropin type)
Kolibianakis EM, Human Reprod Update, 2006

38. Live birth rate (protocol type)
Kolibianakis EM, Human Reprod Update, 2006

39. Live birth rate (agonist type)
Kolibianakis EM, Human Reprod Update, 2006

40. Live birth rate (antagonist protocol)
Kolibianakis EM, Human Reprod Update, 2006

41. Live birth rate (antagonist type)
Kolibianakis EM, Human Reprod Update, 2006

42. Live birth rate
Al-Inany HG, RBM Online, 2007

43. Live birth rate
Al-Inany HG, RBM Online, 2007

44. Live birth rate
Kolibianakis EM, Human Reprod Update, 2006

45. Live birth rate
Kolibianakis EM, Human Reprod Update, 2006

46. Analog use in EUROFERTIL

47. Analog use in EUROFERTIL 2006-08
Agonist
Antagonist
Cycles
537
2033
Age
28.4
31.5*
Mean oocytes
12.5
9.7*
Transferred embryos
2.9
2.6
CPR/ET
43.7
45.0

48. CPR in antagonist cycles

49. Conclusions
Compared with GnRH agonists, GnRH antagonists are associated with reduced treatment duration and reduced risk of ovarian hyperstimulation syndrome
Use of GnRH antagonists avoids pituitary down-regulation, which is associated with hypo-estrogenic adverse events.

50. Conclusions
Meta-analyses comparing GnRH agonists and antagonists have calculated almost identical odds ratios ( ) for the probability of live birth, although the difference was statistically significant in one analysis and not in another. The difference is unlikely to be of clinical significance.

51. Take home message
The patient’s experience of IVF can often be marred by treatment burden, exposure to risk and psychological distress. Ovarian stimulation with antagonists co-treatment can provide live birth rates comparable to those achieved with the standart long agonist protocol and has advantages in terms of tolerability and safety.