Dose and timing of GnRH

antagonist administration

Nick MacklonDepartment of Reproduction and Gynaecology,

UMC Utrecht

The Netherlands

How do GnRH antagonists work?

■ Compete directly with endogenous GnRH for receptor binding

■ Need to constantly block receptors: HIGHER DOSES than agonists

■ Pure antagonists at the pituitary

■ May act as agonists in peripheral reproductive systems

■ Orally active non-peptide pure antagonists

■ Some compounds suppress LH but not FSH

Hara et al, JCEM 2003 88:1697

Tarlatzis et al, Hum Reprod Update 2006, 12:340

Dose and timing: Many roads lead to Rome

Low or high dose?

Adjust dose for BMI?

Fixed or flexible?

Early or late start?

Increase FSH dose?

Supplement LH?

Need luteal support?

Adjust for regimen?

Low dose or high dose?

■ Phase 2 Multi-centre RCT dose finding study: 1998

■ 6 doses from 0.025- 2.0mg tested in 329 women

■ Stimulation protocol: Fixed dose 150IU recFSH from day 2

■ GnRH antagonist commenced on stimulation day 6

■ PRINCIPAL OUTCOMES:

LH suppression dose dependent: minimal reliable dose: 0.25mg

Above dose of 0.25mg, implantation rates fall

The Ganerelix Study Group, Hum Reprod 1998, 13:3023

Effect of GnRH antagonist dose on E2, LH

and follicle development

0.625mg

2 mg

>17mm

15-17mm

11-14mm

>17mm

15-17mm

11-14mm

E2 levels

LH levels

De Jong et al.

Fertil Steril 2001;75:688

Single or multiple dose?

■ 3mg dose cetrorelix on day 8 or day 9

■ Prevents LH rise in 80% of cases

Olivennes et al, Hum Reprod 1998, 13:2211

Engel et al RBM Online 2003,6:482

Retrospective analysis of data from 5 studies, n=1881

3 studies: Multiple dose protocol

2 studies: Single-dose protocol

■ No difference in pregnancy rates between multiple and single dose regimens

■ No effect of body weight on pregnancy rates

Dose in lower weight Asian women

RCT in 58 women of 40-50kg Mean BMI 19.1

0.20mg/day Cetrorelix 0.15mg/dayStimulation day 6

2 or more follicles>18mm 5000IU hCG 5000IU hCG

Cycle day 3 150-225IU recFSH

LH surge on day of hCG 6% 27%*

Oocytes retrieved (mean) 10.5 8.3*

Clinical pregnancy rate per cycle 29% 20%*

*p<0.05

Chang et al. Taiwanese JOG 2006,45:317

Is a flexible regimen better than fixed?

Advantages of fixed regimen:

Simple monitoring

Tendency to better outcomes

Lower chance of premature LH rise?

Commence when leading follicle = 14mm vs stimulation day 6

Al Inany et al. 2005

Premature progesterone elevation and outcomes

Venetis et al Hum Reprod Update 2007, 13: 343High responders poorer outcomes?

Starting GnRH antagonist on stimulation day 1?

■ High exposure to LH and E2 in the early folicular phase detrimental (Kolibianakis et al Fertil Steril 2003;79:873, Howles et al Lancet

1986,30:521)

■ Risk of premature luteinization in flexible protocols

STUDY■ 63 women, <39 years, BMI 18-29, no PCOS, normal CD3 FSH

■ rec FSH 200IU/day and Ganerelix 0.25mg/day from cycle day 2

RATIONALE

Kolibianakis et al Fertil Steril 2004;82:223

Stimulation day 1 start GnRH antagonist

•Duration FSH treatment: 9 days

•Mean 12.1 oocytes

•Ongoing pregnancy rate per cycle

39.7%

LH levels (IU/L)

E2 levels (pg/L)

P levels (ng/L)

FSH levels (IU/L)

Kolibianakis et al

Fertil Steril 2004;82:223

ROLE in PCOS?

Is there an optimal

gonadotropin

stimulation regimen

for GnRH antagonist cycles?

Should the FSH dose be increased on commencing

GnRH antagonist?

Aboulghar et al RBMOnline 2004

•151 patients

•Randomized:HMG dose increased by 75IU or not at antagonist initiation

•Daily dose antagonist initiated by a follicle of 15mm

Parameter Group A (n=72) Group B (n=79) p-value(no dose increase) (dose increased)

Oocytes 0.1 ± 3.8 9.2 ±5.5 NSEmbryos transferred 2.9 ± 0.7 2.8 ±0.9 NSClinical pregnancy rate (%) 32.1 36.2 NSImplantation rate (%) 17.2 19.1 NS

Should the FSH dose be increased on commencing

GnRH antagonist?

Propst et al Fertil Steril 2006, 86:58

•60 patients

•Randomized: recFSH increased by 75IU or not at antagonist initiation

•Daily dose antagonist initiated by a follicle of 13-14mm

Parameter Control (n=30) Step up (n=30) p-value

Oocytes 14.6 ± 7.5 16.7±10.4 NSEmbryos transferred 2.1± 0.4 2.2 ±0.5 NSClinical pregnancy rate (%) 70% 60% NSImplantation rate (%) 50% 39% NS

Is profound LH suppression after GnRH

antagonist detrimental?

Kolibianakis Hum Reprod 2004;19:2490N=116

Percentile LH on day 8 Ongoing pregnancy rate per OPU

0-25th 0.3 (0.1-0.5) 56%

25-75th 1.0 (0.6-1.9) 40%

75-100th 3.3 (1.9-8.4) 24%

Does LH supplementation improve live-birth rate?

Kolibianakis et al, Hum Reprod Update 2007 13:445

Does LH supplementation improve live-birth rate?

Baruffi et al, RBM Online 2007

Does LH supplementation improve live-birth rate?

Baruffi et al, RBM Online 2007

RCT in 39 women <38 years, no PCOS or previous poor response

Is luteal support required?

Beckers et al. JCEM 2003

NO luteal supportNO luteal support

GnRH antagGnRH antag

rFSHrFSH (150 IU/d)(150 IU/d)

rhCG (250 ug, sc)rhCG (250 ug, sc)

rLH (1 mg, sc)rLH (1 mg, sc)

GnRH agonist (0.2 mg, sc)GnRH agonist (0.2 mg, sc)

(n=11)

(n=13)

(n=15)

Day 2

14mm foll

Luteal support is required after GnRH

antagonist

hCG(n=11)

LH(n=13)

GnRH -a(n=15)

P value

# Oocytes retrieved 7 (3-23) 7 (1-26) 10 (1-17) 0.90

Duration luteal phase(days)

13 (12-15) 10 (4-16) 9 (6-15) 0.005

Pregnancy(number (PR))

2 (18%) 1 (8%) 2 (13%) 0.74

Ongoing Pregnancy(number (PR))

2 (18%) 0 (0%) 1 (7%) 0.25

(medians and ranges)Beckers et al. JCEM 2003

■ Antagonists facilitate

development of mild stimulation

regimens threshold

Stimulation day

Exogenous HMG/FSH

1 7 14

window

Conventional stimulated cycle

1 7 14

window

Exogenous HMG/FSH

Mild stimulated cycle

Stimulation day

Macklon et al, Endocr Rev 2006, 27:170

Mild Stimulation Regimens

Are standard GnRH antagonist regimens optimal in mild stimulation?

What is the optimal number of oocytes?

GnRH Agonist Long Protocol

Number of oocytes

3020100

Pre

dic

ted

im

pla

nta

tio

n r

ate

40%

30%

20%

10%

0%

Protocol

Antagonist CD 5

Agonist long

Verberg et al,Hum Reprod 2007

GnRH Antagonist Mild Protocol

Van der Gaast et al RBM Online 2006;13, 376

Where are we now?

■ Dose: 0.25mg/day

■ Fixed protocol :start on stimulation day 5-6

■ Earlier start may improve outcomes

■ Increase of FSH dose probably not necessary

■ LH supplementation probably not necessary

■ Luteal support is necessary

Tarlatzis et al, Hum Reprod Update 2006,12:333

■ NEED TO INDIVIDUALIZE REGIMENS

Which road to Rome?

Low or high dose?

Adjust dose for BMI?

Fixed or flexible?

Early or late start?

Increase FSH dose?

Supplement LH?

Need luteal support?

Adjust for regimen?

Age

Expected response

Indication

BMI

Stimulation regimen

Other factors?

Acknowledgements

Diederick de Jong

Mark van der Gaast

Nicole Beckers

Marieke Verberg

Renee Eijkemans

Bernadette Mannaerts

Frank Broekmans

Bart Fauser