Post on 07-May-2015
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
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
GnRH Antagonist in COH
GnRH Antagonist in COH
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
GnRH Antagonist in COH
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
GnRH Antagonist in COH
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.
GnRH Antagonist in COH
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.
GnRH Antagonist in COH
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