gnrh agonist versus antagonist and impact on cycle outcome

Sandro Esteves, MD, PhD!Director, ANDROFERT!

Campinas, BRAZIL!!

GnRH Agonist vs. Antagonist in ICSI and Its Impact on

Cycle Outcome

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

ANDROFERT androfert.com.br

ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 APRIL

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http://www.androfert.com.br/review




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Why LH surge suppression is desirable in COS



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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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LH surge is mediated by estradiol and GnRH



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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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How GnRH analogues work



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GnRH Agonist

pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2

GnRH Antagonist

pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2



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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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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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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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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

Folli

cle

Size

(mm

)

Estr

adio

l (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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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)!

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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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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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)

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!

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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•  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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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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What we achieve by using GnRH Antagonist vs.

Agonist in COS



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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)

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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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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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

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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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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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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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)

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)

1999 2011

15%

65%

REDLARA Registry; ART World Report (ICMART)

Cycles with Antagonists in South America



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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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gnrh agonist versus antagonist and impact on cycle outcome

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