In ART, GnRH antagonists are effective in preventing a premature LH surge and induce a shorter and more cost-effective ovarian stimulation compared to the long agonist protocol.

1. G N R H A G O N I S T V E R S U S
G N R H A N TA G O N I S T
D R . S N E H A L D H O B A L E K O H A L E
M . S . , D. N . B . ( O B G Y )
F E L L O W S H I P I N R E P R O D U C T I V E M E D I C I N E
C O N S U LTA N T R E P R O D U C T I V E M E D I C I N E

2. LH SURGE IS MEDIATED BY
ESTRADIOL AND GNRH

3. PREMATURE LUTEINIZATION IN IVF

4. LH SUPPRESSION IN COS
• Administration of GnRH analogues
– Synthetic versions of native GnRH
– Options are GnRH agonist and antagonist
• GnRH Agonist
– 1984
– Buserelin, nafarelin, triptorelin, leuprolide
• GnRH Antagonist
– 1999
– Cetrorelix, ganirelix

5. MECHANISM OF ACTION OF GNRH AGONIST
inhibition of endogenous LH surge

7. MECHANISM OF ACTION OF ANTAGONISTS
prevention of premature LH surge

9. MECHANISM OF ACTION
ANTAGONIST
• Receptor blockage
• Competitive inhibition
• Immediate suppression
• Rapid reversibility
AGONIST
• Initial flare-up
• Receptor down regulation
• Pituitary desensitization
• Slow reversibility

10. GNRH ANTAGONIST VS LONG GNRH
AGONIST CYCLES

12. ADVANTAGES OF ANTAGONIST
PROTOCOLS
• Shorter treatment
• Smaller doses of gonadotropins
• No ovarian cyst formation
• Lower incidence of OHSS
• Immediate recovery of pituitary

13. OHSS PROTECTION LEVELS BY ANTAGONIST
1st Level: Antagonist rather than agonists
2nd Level: In patients on antagonist protocol at risk of OHSS, replace
hCG with GnRH-a for oocyte maturation triggering
3rd Level: In patients with early OHSS onset, use GnRH antagonist luteal
phase.
Devroey et al. Hum Reprod 2011; 10:
2593-97.

14. Why antagonist did not replace
agonist for controlled ovarian
hyper stimulation in ART
cycles?

15. COCHRANE REVIEW: PREGNANCY OUTCOME
AL-INANY AND ABOULGHAR 2002
• The clinical pregnancy rate was significantly lower in the antagonist
group.
• The absolute treatment effect (ATE) was calculated to be 5%. The
number needed to treat (NNT) was 20.
• This means that for every 20 subfertile couples undergoing IVF/ ICSI
program, one additional successful pregnancy added to the 5-8
expected pregnancies in the GnRH agonist treated group

16. Lower pregnancy rate in
antagonist cycles??

17. THE DIFFERENCE IN STIMULATION:
AGONIST VS. ANTAGONIST
1.Synchronized follicles after GnRH down regulation
2.Day 2 ovary without any down-regulation (antagonist protocol)

18. EFFECT OF ANTAGONIST ON
ENDOMETRIUM AND IMPLANTATION
• Dose finding study: 2 mg of Ganirelix had very low pregnancy rate (1).
• Negative effect on endometrial receptivity (2). However, this was
criticized by Mannaerts and Gordon 2000(3).
• Pregnancies from frozen-thawed embryos from antagonist cycles are
similar to agonist cycles, suggesting an effect of antagonist on
endometrium and not on oocytes (4).
1.Ganirelix dose-finding study group 1998
2.Hernandez et al 2000
3.Mannaerts and Gordon 2000
4.Kol 1999

19. LEARNING CURVE AND FINE-TUNING
• Some major European clinics use antagonist only with good
results
• Meta-analysis comparing agonist and antagonist showed
the difference in pregnancy rate to be very small
Fauser and Devroey 2005

20. GNRH ANTAGONIST VS GNRH AGONIST:
SUCCESS RATES BETTER IN CENTERS WITH
EXPERIENCE

21. EFFECTS OF GNRH ANTAGONISTS
ON CYCLE PARAMETERS
CONCLUSIONS
• No negative impact of transitory E2 decline
• No need LH supplementation, but for aged women
• No negative impact endometrium
• Flexible similar to fixed, but less vials
• hCG day+1 not detrimental
• OCP seems to impact outcome

22. LIVE BIRTH AFTER IVF: AGONIST /
ANTAGONIST: A META ANALYSIS (2006)
• 22 RCT
• 3176 Subjects
• Live birth (from manuscript in 10 studies and by conversion of
pregnancy rate to live birth rate using special formula in 12 studies
(Arce et al 2005)
• Both long and flare up agonist protocols were included
• No significant difference between PR in agonist and antagonist
protocols (OR, 0.86; 95% CI, 0.72-1.02)
Kolibianakis et al Hum Reprod Update. 2006 Nov-Dec;12(6):651-71.

23. AL-INANY ET AL COCHRANE DATABASE SYST REVIEW
2006 JUL 19;3:CD001750
• 27 RCT included
• Only long GnRH protocol was included
• Clinical pregnancy rate was significantly lower in the antagonist group
(OR = 0.84, 95% CI = 0.72-0.97)
• Ongoing pregnancy rate and live birth rate showed the same
significant lower pregnancy rate in the antagonist group (P = 0.03; OR
0.82, 95% CI 0.69-0.98)
• OHSS was significantly lower in the antagonist arm (P=0.01, RR 0.61,
95% CI 0.42-0.89)

24. AUTHORS’ CONCLUSIONS
• GnRH antagonist protocol is a short and simple protocol
with good clinical outcome with significant reduction in
OHSS and amount of gonadotropins used, but with
significantly lower pregnancy rate.

25. NEW COCHRANE REVIEW
(AL-INANY ET AL. 2011)
• In a recent Cochrane review
• 45 RCT = 7511 cycles
• Comparing long GnRHs versus GnRH antagonist
• There was no significant difference in the live birth rate (9 RCT OR:
0.086, 95% CI 0.69-1.88)
Cochrane Database Syst Rev. 2011 May 11;(5):CD001750

26. NEW COCHRANE REVIEW
(AL-INANY ET AL. 2011)
• There was no significant difference in ongoing pregnancy rate (29 RCT
OR: 0.87, 95% CI 0.77-.099)
• There were a statistically significant lower incidence of OHSS in GnRH
antagonist group (29 RCT, OR: 0.43; 95% CI 0.33 – 0.57, P<0.00001)
Cochrane Database Syst Rev. 2011 May 11;(5):CD001750

27. META-ANALYSIS OF AGONIST VERSUS
ANTAGONIST IN POOR RESPONDERS
6 trials included, there was no significant difference between GnRH
antagonist and agonist long or flare-up protocol with respect to cycle
cancellation rate, number of oocytes and clinical pregnancy rate per
cycle initiated (Franco et al Reprod Biomed Online. 2006 Nov;13(5):618-
27.)

28. META-ANALYSES CONFIRM THAT GNRH
ANTAGONISTS HAVE A BETTER SAFETY PROFILE
VS GNRH AGONISTS
• For every 59 women treated with a GnRH agonist vs GnRH antagonist,
one additional case of severe OHSS will occur.
• ~ 2 times less risk for hospital admission due to OHSS with GnRH
antagonists
Al-Inany et al. Cochrane Database Syst Rev. 2006;3:CD001750.
Kolibianakis et al. Hum Reprod Update. 2006;12:651.

29. AN OHSS-FREE CLINIC BY
SEGMENTATION OF IVF TREATMENT
• GnRH antagonist protocol and trigger ovulation by a bolus of GnRHa
if there is a risk for OHSS, freeze all oocytes or embryos for later use.
This will prevent completely OHSS.
Devroey et al., 2011

30. ANTAGONIST FOR PREVENTION OF
OHSS
Aboulghar et al Reprod Biomed Online. 2007 Sep;15(3):271-9.

31. CONCLUSION
• GnRH antagonist protocol provides significant advantages:
–Shorter stimulation periods
–Option for the use of soft friendly protocol
–No cyst formation
–Lower incidence of OHSS
–Less stressful

32. CONCLUSION
• GnRH antagonist results in:
–Similar pregnancy rates compared to GnRHa long protocol.
–Similar pregnancy outcome.
–Similar babies’ outcome.

33. PRACTICAL TIPS IN GNRH ANTAGONIST CYCLE
MANAGEMENT
• Avoid gonadotropin step-down in the first 24h after antagonist
• Make pill-free interval more than 5 days if OCP for scheduling
purposes
• Start antagonist no later than stimulation day 8 or follicle size 14 mm
in flexible protocol!
• Start antagonist if >6 follicles 11-13 mm diameter regardless of
stimulation day!
• Use last antagonist injection on hCG day (17mm mean diameter or any
sign of endometrium luteinization)

35. SCHEDULING WITH OC PILLS

36. SCHEDULING WITH PROGESTERONE

37. SCHEDULING WITH ESTRADIOL

38. THANK YOU