gnrh antagonists in controlled ovarian stimulation

Insight’12 – Lite, Coimbatore, India – May 2012

Lecture Overview

Importance of LH suppression in COH

LH suppresion using GnRH-antagonists

Clinical Results

Take-Home Messages

Esteves, 2

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Ovarian Stimulation

Protocols

High-quality oocyte yield

Cycle cancellation,

OHSS,

multiple pregnancy

Central Paradigm

Minimize complications and

risks

Maximize beneficial effects of treatment

Esteves, 4 Fauser et al., 2008

Theca externa cells

Theca interna cells

Capillary network Basement membrane

Cumulus Oophorus cells

Oocyte

Zona pellucida

Granulosa cells Follicular

antrum

Esteves, 5 Zeleznik et al 1974; Adashi 1996, Hillier 1994.

Rationale of LH suppression in COH

Premature luteinization in IVF

— Cycle cancellation

— Low number of oocytes retrieved/atresia

— Reduced fertilization rate and embryo quality

— Poor prognosis for pregnancy

— Psychological burden & Financial loss

1Loumaye, et al. Human Reprod 1990;5:357 2Balasch J. In: Female Infertility Therapy:Current Practice (Shoham, Howles, Jacobs, eds). Martin Dunitz

1998:189

Esteves, 6

LH suppression Reduced risk of

premature LH surge and untimely ovulation

Allows ovarian stimulation to be

controlled

U GnRH

LH

FSH

Short Term Long Term

U

U

U

U

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

Physiologic Actions of GnRH

Stimulates synthesis and release of LH and FSH

Esteves, 7

LH Surge Prevention: GnRH Antagonists

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

GnRH receptor activation Receptor affinity Biologic activity

Esteves, 8

Start Administration

The difference in LH suppression

Follicular

Luteal

E2

, P

4

LH

, F

SH

0

10

20

30

2-4

weeks

Synchronized follicles

Agonist

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

Esteves, 9

Comparison of Long GnRH Agonist

and GnRH Antagonist Protocols

Agonist administration

Gonadotropin administration Long GnRH

agonist

protocol

Antagonist

administration

Gonadotropin administration

GnRH antagonist

protocol

Longer

treatment

Can exclude

early

pregnancy

Can be

integrated in

spontaneous/OI

cycles

Pre-treatment cycle Treatment cycle

Flare up

effect

No flare

effect with

possible cyst

formation

Pituitary

suppression

No hormonal

withdrawal

Less gona-

dotropins

Prevent

OHSS by

GnRH-a

Why has introduction of antagonists

in clinical practice has been slow?

Experience with Agonists

— Why change if it is working

Clinicians´ concerns

— E2 decrease

— Not been able to program

aspirations on weekdays

— LH surge (more monitoring)

— Difficult to use

Esteves, 11

GnRH Antagonists in COH

Clinical Results and

Effects on Cycle Parameters

Esteves, 12

Level Type of evidence

1a Obtained from meta-analysis of randomised trials

1b Obtained from at least one randomised trial

2a Obtained from one well-designed controlled study without

randomisation

2b Obtained from at least one other type of well-designed quasi-

experimental study

3 Obtained from well-designed non-experimental studies, such as

comparative and correlation studies, and case reports

4 Obtained from expert committee reports or opinions or clinical

experience of respected authorities

Modified from Sackett et al. Oxford Centre for Evidence-based Medicine Levels of Evidence (2009)

GnRH Antagonists vs Agonists

Al-Inany et al (2011)1 Kolibianakis et al (2006)2

N studies 45 22

Included IUI cycles Yes No

N patients 7,511 3,176

Primary outcome Ongoing PR or LBR LBR

Odds ratio 0.86

(95% CI 0.69-1.08)

0.86

(95% CI 0.72 to 1.02)

*Live birth rate included ongoing pregnancies (Al-Inany) or calculated rates (Kolibianakis).

1. Al-Inany et al. Cochrane Database Syst Rev. 2011; 5:CD001750.

2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.

Probability of Live birth

Esteves, 13

1a

GnRH Antagonist in COH

Al-Inany et al1 Kolibianakis et al2

Duration of ovarian

stimulation

-1.13 days

(-1.83; -0.44)

-1.54 days

(-2.42; -0.66; p=.0006)

Oocytes retrieved -- -1.19 (-1.82; -0.56)

Risk of severe

OHSS

0.43*

(95% CI 0.33 to 0.57)

OR=0.61

(0.42; 0.89; p=.01)

*For every 59 women treated with a GnRH agonist vs GnRH

antagonist, one additional case of severe OHSS will occur.

1. Al-Inany et al. Cochrane Database Syst Rev. 2011; 5:CD001750.

2. Kolibianakis et al. Hum Reprod Update. 2006;12:651. Esteves, 14

GnRH Antagonists vs Agonists

1a



OHSS – 3 levels of Protection

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 trigger.

3rd Level: In patients with early OHSS onset,

use of GnRH-ant luteal phase.

Esteves, 15

Esteves, 16

Poor Responders


Pu D, Wu J, Liu J.. Hum Reprod. 2011; 26: 2742

Antagonist vs

Agonist

Duration of

stimulation

Oocytes

retrieved

Cycle

cancellation

CPR

14 RCT; 1127

patients

-1.9 days

(-3.6; -0.12)

-0.17

(-2.42; -0.66)

1.01

(0.71; 1.42)

1.23

(0.92, 1.66)

1a

PCOS Lainas et al. Hum Reprod. 2010; 25:683

Antagonist vs

Agonist

Duration of

stimulation;

days

Oocytes

retrieved; N

Grades II + III

OHSS (%)

CPR (%)

RCT; 220

patients

10 vs 12

(P<.001)

28 vs 27

(P=.22)

65 vs 44

(P=0.006)

50.9 vs 47.3

(P=.68)

1b

What is the Best

Antagonist Protocol?

Fixed or Flexible daily

OCP pretreatment

Day of hCG administration

LH supplementation

Esteves, 17

Cetrorelix 0.25mg Flexible*; N=68 Fixed; N=72

P

value

Duration of COH 9.7 ± 1.9 9.9 ± 2.7 .72

Age* 2,225 ± 1,128 2,190 ± 833 .84

Oocytes retrieved* 12 ± 6.6 10.3 ± 4.7 NS

Metaphase II

oocytes* 11.7 ± 6.5 9.8 ± 5.2 .07

Fertilization rate 54.9 ± 22.8 56.3 ± 21.4 .77

Pregnancy rate 24.7% 23.3% NS

Kolibianakis EM, et al. Fertil Steril. 2011; 95:558-62


Esteves, 18

*Flexible: LH >10 IU/L, and/or mean follicle >12 mm, and/or serum

E2 >150 pg/mL; Fixed: Day 6; No LH surge reported

1b Flexible or Fixed

Esteves, 19

4 RCT; 847 patients

Duration of stimulation (days) +1.41 (+1.13; +1.68)

Gonadotropin consumption (UI) +542 (+127; +956)

Oocytes retrieved (n) 1.63 (-0.34; 3.61)

Ongoing Pregnancy (%) 0.74 (0.53; 1.03)

Griesinger et al. Fertil Steril 2008; 90: 1055-63.


Pretreatment with OCP

1a

hCG administration ≥3 follicles of

≥16mm

One day

later

P

value

120 NG women 39 y-o undergoing antagonist COH protocol

Mean ± Metaphase II

oocytes 6.1 ± 4.9 9.2 ± 7.1 .009

Mean ± 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.


Esteves, 20

Day of hCG administration

1b

Is LH needed in a GnRH antagonist

Protocol?

Sauer et al (2004) - multicenter study using 3mg flexible

protocol (+OCP): no benefit of LH supplementation

(150 IU r-hLH day 6 FSH) on MII oocytes or pregnancy

rate vs no supplementation or GnRH agonist protocol

Cédrin-Durnerin et al (2004) - multicenter study using

3mg flexible protocol (+OCP): no benefit of LH

supplementation (75 IU r-hLH day antag) on oocytes or

delivery rates

Esteves, 21

1b

Sauer et al, Reprod Biomed Online 2004;9:487–93;

Cédrin-Durnerin et al, Hum Reprod 2004;19:1979–84.

61%

25% 19%

68%

33% 27%

%2PN Ongoing PR Implantation

rFSH rFSH + rLH

Is LH needed for older women in

GnRH antagonist Protocol?

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. Esteves, 22

1b

GnRH Antagonists in COH

Summary

Esteves, 23

Clinical Outcomes Evidence

No difference in probability of live birth (overall and

subgroups) compared to agonists

1a

Significantly lower OHSS and duration of

stimulation

1a

No difference in Flexible or Fixed Antagonist

Protocols

1b

OCP programming or delaying hCG (+1 day) not

detrimental

1a

No need of LH supplementation overall; subgroup

analysis suggest that aged women may benefit

1b

Currently, >50% COH cycles use

ANTAGONISTS

Esteves, 24

19992009

15%

60%

Cycles with GnRH Antagonists

REDLARA Registry; ART World Report (ICMART)

Practical Tips in GnRH

Antagonist Cycle

Management

Avoid step-down rFSH/hMG in the first 48 hours after

antagonist

Use OCP for scheduling purposes

— Make pill-free interval flexible

Flexible GnRH antagonist no later than day 8 of

stimulation or follicle size 14 mm;

If >6 follicles 11-13 mm diameter start GnRH antagonist

Use last antagonist injection on hCG day Esteves, 25

Take-home Messages

Agonists yield higher number of oocytes

Antagonists are safer than agonists

— Decreased moderate and severe OHSS rates

Antagonists more patient-friendly

— Shorter duration of COH

Probability of live birth in COS is independent of the analog used for pituitary suppression

Esteves, 26

gnrh antagonists in controlled ovarian stimulation

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