Dose and timing of GnRH antagonist administration
Transcript of Dose and timing of GnRH antagonist administration
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