This document summarizes a lecture on using GnRH agonists versus antagonists in ICSI cycles and the impact on cycle outcomes. It discusses that LH suppression is desirable in controlled ovarian stimulation to prevent premature ovulation and luteinization. While GnRH agonists were initially used for this starting in 1984, GnRH antagonists introduced in 1999 provide LH suppression without an initial flare effect and allow for a flexible treatment protocol. The summary reviews the findings that GnRH antagonists have no negative impact on estradiol levels, endometrial receptivity, or cycle parameters compared to agonists and provide a better safety profile with shorter treatment duration.

1. Sandro Esteves, MD, PhD!
Director, ANDROFERT!
Campinas, BRAZIL!
!
GnRH Agonist vs. Antagonist
in ICSI and Its Impact on
Cycle Outcome

2. Lecture Outline
1. Why LH suppression is desirable in COS!
2. How GnRH analogues work !
3. What we achieve by using GnRH
antagonists vs. agonists in COS!
GnRH Agonist vs. Antagonists in ICSI and
its Impact on Cycle Outcome
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3. http://www.androfert.com.br/review
GnRH Agonist vs. Antagonists in ICSI and
its Impact on Cycle Outcome
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4. Why LH surge suppression
is desirable in COS
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5. Ovulation leading to cycle cancellation
Low number oocytes retrieved/atresia
Reduced fertilization and embryo quality
Poor prognosis for pregnancy
Psychological burden & financial loss
Premature Luteinization in IVF
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6. LH surge is mediated by
estradiol and GnRH
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7. 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!
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8. How GnRH analogues work
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GnRH Agonist
pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2

10. GnRH Antagonist
pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2
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11. 0
1
2
3
4
5
6
-6 0 6 12 18 24 30 36 42 48
Hours
LH(IU/L)
Antagonist
Antagonist • Half-­‐life
~20h
(Cetrorelix)
•
Suppress
LH
by
80%
of
baseline
levels
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12. GnRH Agonist vs. Antagonist in COS
Antagonist
Protocol
Gonadotropin administration
Can exclude early
pregnancy
Can be integrated
in spontaneous/OI
cycles
No flare
effect with
possible cyst
formation
Long GnRH Agonist Protocol
Gonadotropin administration
Pre-treatment cycle Treatment cycle
Flare up
effect
Pituitary
suppression
No
hormonal
withdrawal
Allow GnRH-a
trigger
Longer
treatment
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13. GnRH Antagonists in COS
Effects on Cycle Parameters!
§ Impact of estradiol level decline upon
antagonist administration
§ Need of LH supplementation
§ Impact on endometrium
§ Fixed vs. flexible protocol
§ Day of hCG administration
§ OCP pre-treatment
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14. Impact of E2 Decline Following
Antagonist Administration
Olivennes, et al. Fertil Steril 1998;70:S14
Days post Cetrorelix 3 mg
0
400
800
1200
1600
Day 0
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
0
5
10
15
20
FollicleSize(mm)
Estradiol(pg/ml)
Lead Follicle
E2
Although some patients experience a decline or
plateau in E2 following antagonist administration,
there is no evidence of negative impact on
treatment outcome.
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15. Is LH Needed in Antagonist Protocol?
Estradiol levels
hCG day!
WMD: 571!
(95% CI: 259; 882) !
-! WMD: 514 !
(95% CI: 368; 660)!
No. retrieved
oocytes!
WMD: 0.50!
(95% CI: -0.68; 1.68) !
-!
WMD: 0.41 !
(95% CI -0.44; 1.3) !
No. mature
oocytes!
-! -!
WMD: 0.88 !
(95% CI: 0.21; 1.54 ) !
Clinical PR! OR: 0.79 !
(95% CI: 0.26; 2.43)!
-!
OR: 0.89 !
(95% CI: 0.57; 1.39!
Live birth! OR 0.86!
(0.04; 1.85)!
r-hFSH+rLH vs. r-hFSH alone in antagonist cycles
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Mochtar et al,
2007!
3 RCT (N=216)!
Kolibianakis
et al, 2007!
2 RCT (N=176)!
Baruffi et al, 2007!
5 RCT (N= 434)!

16. 61%
25%
19%
68%
33%
27%
%2PN
Ongoing
PR
ImplantaLon
rFSH
rFSH
+
rLH
292 NG women aged 36-39
Fixed (D6) antagonist COH protocol
P=0.02
OR=1.49
95% CI 0.93-2.38
OR=1.56
95% CI 1.04-2.33
Bosch et al. Fertil Steril. 2011; 95:1031-6
Is LH needed in Antagonist Protocol?
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17. Cetrorelix 0.25mg! Flexible*; N=68! Fixed; N=72 !
P
value!
Duration of COS! 9.7 ± 1.9! 9.9 ± 2.7! NS!
Total gonadotropin dose! 2,225 ± 1,128! 2,190 ± 833! NS!
No. oocytes retrieved! 12 ± 6.6! 10.3 ± 4.7! NS!
No. metaphase II oocytes! 11.7 ± 6.5! 9.8 ± 5.2! NS!
% Fertilization rate! 54.9 ± 22.8! 56.3 ± 21.4! NS!
% Pregnancy rate! 24.7%! 23.3%! NS!
No. antagonist injections! 3.4 ± 1.1! 5.3 ± 1.8! <.05!
Kolibianakis EM, et al. Fertil Steril. 2011; 95:558-62
Flexible:
LH
>10
IU/L,
and/or
mean
follicle
>12
mm,
and/or
serum
E2
>150
pg/mL;
Fixed:
Day
6
Flexible vs. Fixed Antagonist
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18. GnRH Antagonist and
Endometrium Receptivity
!
Prapas N et al, RBM Online. 2009; 18:276.!
Recipients
(n=49)
Endometrial
priming
with
estradiol
+
antagonist
0.25mg
daily
Recipients
(n=49)
Endometrial
priming
with
estradiol
only
Pregnancy
55.1%
59.1%
ImplantaLon
26.1%
24.4
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Oocyte
donors
(n=49)

19. Metaphase II oocytes! 6.1 ± 4.9! 9.2 ± 7.1! .009!
% Fertilization rate! 66.7 ± 23.4! 70.1 ± 20.9! .44!
% Ongoing
Pregnancy rate! 34.6% ! 40.7%! .55!
Kyrou D et al. Fertil Steril. 2011; 96(5):1112-5.
Antagonist Protocol and Day
hCG Administration
RCT involving 120 NG women <39 yo.
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hCG administration!
≥3 follicles of
≥16mm!
One day
later !
P
value!

20. 6 RCT; 1,343 patients
Duration of stimulation (days)! WMD: +1.33 (+0.61; +2.05)!
Total gonadotropin dose (UI)! WMD: +360 (+158; +563)!
Oocytes retrieved (n)! WMD: +0.63 (-0.08; +1.25)!
Ongoing Pregnancy (%)! RR: 0.80 (0.66; 0.97)!
OR: 0.74 (0.58; 0.96)!
Griesinger et al. Fertil Steril 2010 !
Antagonist Protocol and OCP
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21. • 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!
Conclusions!
Effects of GnRH Antagonists
on cycle parameters
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22. Practical Tips in GnRH
Antagonist Cycle
Management
• Avoid gonadotropin step-down in the first 24h after
antagonist !
• Make pill-free interval flexible 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)!
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23. What we achieve by using
GnRH Antagonist vs.
Agonist in COS
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24. Similar live birth rates
Cochrane 2011 (N=7,511)
Al-Inany et al. Cochrane Database Syst Rev. 2011; 5:CD001750.
OR: 0.86
(95% CI 0.69-1.08)

25. GnRH antagonists have a better
safety profile vs GnRH Agonists
Al-Inany1 Kolibianakis2
Duration of
ovarian
stimulation
−1.54 days
(95% CI −2.42, −0.66;
P=0.0006)
−1.13 days
(95% CI −1.83, −0.44)
Risk of
severe OHSS
OR 0.61
(95% CI –0.42, 0.89; P=0.01)
RR 0.46*
(95% CI 0.26, 0.82; P=0.01)
Interventions
to prevent OHSS
OR 0.44
(95% CI 0.21, 0.93; P=0.03)
*For every 59 women treated with a GnRH agonist vs GnRH antagonist, 1 additional case of
severe OHSS will occur; RR = risk ratio.
1. Al-Inany et al. Cochrane Database Syst Rev. 2006;3:CD001750.
2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.
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26. Pundir et al, 2012!
9 RCT; N=966!
Xiao et al, 2013!
7 RCT; N=755!
Clinical PR!
RR: 1.01 !
(95% CI 0.88; 1.15)!
OR: 1.08 !
(95% CI 0.80-1.45)!
Miscarriage
rate!
RR: 0.79 !
(95% CI 0.49; 1.28)!
OR: 0.91!
(95% CI: 0.54-1.53)!
Pundir
J
et
al.
RBM
Online
2012;
24:
6-­‐22.;
Xiao
et
al,
Gynecol
Endocrinol.
2013;
;29(3):187-­‐91
.
PCOS: No difference in
ongoing pregnancy rate
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27. Pundir et al, 2012!
9 RCT; N=966!
Xiao et al, 2013!
7 RCT; N=755!
Duration of COS! -0.74 (95% CI -1.12; -0.36)! -!
Gonadotropin
dose!
MD: -0.28 !
(95% CI -0.43; -0.13)!
MD = -2.05 !
(95% CI -4.14; 0.05)!
Oocytes retrieved! WMD: 0.01!
(95% CI -0.24; 0.26)!
MD = -0.38 !
(95% CI -2.32; 1.56)!
Risk of OHSS! 20% vs 32% ! OR = 0.36 !
(95% CI 0.25; 0.52)!
Moderate and
Severe!
RR: 0.59 !
(95% CI 0.45-0.76)!
-!
PCOS: Antagonists have better
safety profile
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40% reduction in moderate/severe
OHSS by using antagonists compared to
agonists

28. GnRH-agonist vs hCG: 11 RCT – 1,055 women
Fresh
autologous
cycles (8 RCT)
Live birth
Pregnancy
Moderate/
severe OHSS
OR 0.44
(0.29 - 0.68)
OR 0.45
(0.31 - 0.65)
OR 0.10,
(0.01 to 0.82)
Youssef et al. Cochrane Database Syst Rev. 2011
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29. Humaidan et al. Fertil Steril 2012;
Engmann & Benadiva Fertil Steril 2012
Modified LPS
hCG bolus OPU day (1,500 UI) or 3x 500 UI
boluses; recLH; progesterone +
estradiol; combined
Risk difference for pregnancy
(hCG vs. GnRHa)
18% (Before) vs 6% (After) Modified LPS
LH Trigger with GnRH-agonist
Freeze all
Vitrification vs. Slow-freezing
Meta-analysis of 5 RCT
OPR = 35% x 27%;
OR: 1.82; 95% CI: 1.04-3.20
IR = 29% x 24%;
OR: 1.49, 95% CI: 1.03-2.15
AbdelFahez et al . RBM Online 2010
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30. GnRH Antagonist in COS
OHSS Protection Levels
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.
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31. Poor responder: No difference CPR
Pu,
et
al.
Hum
Reprod.
2011.
Pu D et al. Hum Reprod. 2011
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OR = 1.23 (95% CI 0.92; 1.66)

32. Poor responder: No difference in
No. oocytes
Pu,
et
al.
Hum
Reprod.
2011.
Pu D et al. Hum Reprod. 2011
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OR = -0.17 (95% CI -0.69; 0.34)

33. 1999
2011
15%
65%
REDLARA Registry; ART World Report (ICMART)
Cycles with Antagonists in
South America
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34. GnRH Agonist vs. Antagonists in ICSI
and its Impact on Cycle Outcome
Take-home messages!
GnRH analogues allow ovarian stimulation
to be controlled!
Safety, duration of treatment pro antagonist!
No difference in number of oocytes and live
birth rate between antagonist and agonist!
Protocol of first choice for PCOS patients
!and high responders !
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