GnRH antagonists

safer drug with similar live birth rates

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

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 transferred9 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 AntagonistGnRH Antagonist
ProtocolsProtocols
GnRH GnRH AgonistAgonist
ProtocolsProtocols
225 IU per day225 IU per day
(150 IU Europe(150 IU Europe))
Individualized Dosing of FSH/HMGIndividualized Dosing of FSH/HMG
250 mg per day antagonist250 mg per day antagonist
Individualized Dosing of FSH/HMGIndividualized Dosing of FSH/HMG
GnRHa 1.0 mg per day GnRHa 1.0 mg per day
up to 21 daysup to 21 days
0.5 mg per day of GnRHa0.5 mg per day of GnRHa
225 IU per day225 IU per day
(150 IU Europe(150 IU Europe))
Day 6Day 6
of FSH/HMGof FSH/HMG
DayDay
of of hCGhCG
Day 1 Day 1
of FSH/HMGof FSH/HMG
Day 6Day 6
of FSH/HMGof FSH/HMG
DayDay
of hCGof hCG
7 – 8 days7 – 8 days
after estimated ovulationafter estimated ovulation
Down regulationDown regulation
Day 2 or 3Day 2 or 3
of mensesof menses
Day 1 Day 1
FSH/HMGFSH/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<0.07
FSH requirement

25. 1.1 less days with antagonists
p<0.001
Duration of FSH treatment
Review: GnRH Antagonists vs. GnRH agonists
Comparison: 05 Duration of stimulation
Outcome: 01 Duration of stimulation
Study Antagonists Agonists WMD (random) Weight WMD (random)
or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI Year
Albano 181 10.60(2.30) 77 11.40(1.80) 7.01 -0.80 [-1.32, -0.28] 2000
Olivennes 115 9.40(1.40) 36 10.70(1.70) 6.91 -1.30 [-1.91, -0.69] 2000
European 448 9.00(2.01) 224 10.00(2.35) 7.16 -1.00 [-1.36, -0.64] 2001
Middle East 215 9.00(1.46) 106 11.00(1.80) 7.13 -2.00 [-2.39, -1.61] 2001
Martinez 21 9.30(2.10) 23 10.40(2.60) 5.65 -1.10 [-2.49, 0.29] 2003
Hwang 25 9.90(2.10) 24 10.80(2.20) 5.99 -0.90 [-2.11, 0.31] 2004
Sauer 21 9.30(1.10) 23 9.70(1.70) 6.60 -0.40 [-1.24, 0.44] 2004
Badrawi 47 10.32(1.38) 50 11.42(2.31) 6.73 -1.10 [-1.85, -0.35] 2005
Bahceci 59 11.97(2.30) 70 13.92(1.40) 6.84 -1.95 [-2.62, -1.28] 2005
Barmat 36 9.10(1.80) 41 9.00(1.28) 6.79 0.10 [-0.61, 0.81] 2005
Cheung 19 10.50(2.70) 21 11.50(2.40) 5.29 -1.00 [-2.59, 0.59] 2005
Loutradis 58 10.80(1.80) 58 10.30(1.30) 6.96 0.50 [-0.07, 1.07] 2005
Marci 29 9.80(0.80) 26 14.60(1.20) 6.99 -4.80 [-5.35, -4.25] 2005
Schmidt 14 10.10(0.30) 12 10.10(0.60) 7.15 0.00 [-0.37, 0.37] 2005
Xavier 53 9.50(1.70) 59 10.60(2.10) 6.79 -1.10 [-1.80, -0.40] 2005
Total (95% CI) 1341 850 100.00 -1.13 [-1.83, -0.44]
Test for heterogeneity: Chi² = 281.57, df = 14 (P < 0.00001), I² = 95.0%
Test for overall effect: Z = 3.19 (P = 0.001)
-10 -5 0 5 10
Favor antagonists Favor agonists

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 ± 0.971.74 ± 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 ± 1.200.0001
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




(GnRHantagonist
0.25 mg )
O.P.U
↓ ↓ ↓ ↓ ↓ ↓


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑

(…….…………recFSH/hMG…………..)

Decapeptyl
(0.2 mg)
Luteal support
2x progesteron

41. WHY CHANGING ATTITUDE
For Tomorrow Better
Health

42. THANK
YOU
Dr. Hesham Al-Inany MD, PhD
e-mail : [email protected]