Transcript Document

GnRH agonist instead of hCG to trigger
ovulation in GnRH antagonist cycles
Dec 10, 2004
Quick overview
• Does that trigger work? Yes (evidence).
• Is endogenous LH surge physiological? Not
exactly (evidence).
• Effect on the luteal phase? Complete luteolysis
• Clinical use? In the context of OHSS
prevention (evidence/opinion).
• Future? Establish use in OHSS prevention
(RCT), fine-tune trigger for other uses?
Triggering of ovulation by a GnRH agonist in
patients pretreated with a GnRH antagonist
•Pilot study, Ovulation induction 5
•LH and FSH rise in all 5 patients.
 Olivennes et al, Fertil Steril 66:151,
Use of a single bolus of GnRH agonist triptorelin
to trigger ovulation after GnRH antagonist
ganirelix treatment in women undergoing ovarian
stimulation for assisted reproduction with special
reference to the prevention of OHSS: preliminary
Itskovitz-Eldor et al, Hum Reprod 15:1965, 2000
Materials and Methods
• 8 Women considered at risk of developing
OHSS: >20 follicles >11mm and/or E2
levels>3000ng/ml on the last stimulation
• Ovarian stimulation with rFSH (150IU or
225 IU daily) and ganirelix 0.25mg daily
from day 6.
• Induction of LH surge with a single
injection of triptorelin 0.2mg SC ~30hr
after the last injection of ganirelix.
• Luteal support: E2+P
• Mean no. of follicles>11mm=25.1±4.5
• Median E2 (pg/ml)=3675 (range 2980–7670)
• Mean number of oocytes=23.4 (±15.4), 83% MII
• Mean number of embryos=15.4±6.6
• 7 ETs from fresh embryos: 1 pregnancy
• 17 ETs from frozen-thawed embryos: 4
Median values of serum LH and E2 after
injection of triptorelin 0.2mg
Time after injection
Serum LH
Serum estradiol
0.5 h
10-12 h
Day of OPU
Day of ET
First week post-ET
Itskovitz et al, 2000
Normal LH surge
Hoff et al, 1983
High responders
Itskovitz et al, 1991
Agonist-triggered LH surge vs.
natural surge
• Maximal LH at 4 h vs. 14h
• Surge duration 24 h vs. 48 h
• Surge amplitude – comparable.
• The ability of a single bolus of triptorelin
0.2mg to trigger an adequate LH surge in
stimulation cycles using a GnRH antagonist
protocol was demonstrated.
• The results suggest that this regimen may
prove highly effective in terms of OHSS
prevention, though further studies are
needed to establish this potential
Endocrine profiles after triggering of final
oocyte maturation with GnRH agonist
after cotreatment with the GnRH
antagonist ganirelix during ovarian
hyperstimulation for in vitro fertilization
Fauser BC, et al
J Clin Endoc Metab 87:709, 2002
(Randomized multicenter study)
0.2 mg
0.5 mg
Fauser et al, 2002
Clinical outcome (mean±SD)
Number of oocytes/subject
9.8 ± 5.4
8.7 ± 4.5
8.3 ± 3.3
Proportion of metaphase II oocyte
72 ± 18%
85 ± 17%
86 ± 17%
Fertilization rate
61 ± 30%
62 ± 23%
56 ± 18%
No. of embryos obtained per
subject, grades 1 and 2 pooled
2.7 ± 3.4
3.2 ± 2.6
3.3 ± 2.0
Implantation rate
15 ± 34%
18 ± 37%
7 ± 14%
Ongoing pregnancy rate
Fauser et al, 2002
Serum hormone concentrations (AUC)
during triggering of final oocyte maturation
LH(0–24h) (IU/L)1
59 ± 142
53 ± 142
2.7 ± 2.2
FSH(0–24h) (IU/L)1
14.5 ± 3.82
14.3 ± 3.72
5.0 ± 1.2
E2(0–2 wk) (pg/ml)1
252 ± 1542
196 ± 1113
515 ± 286
P(0–2 wk) (ng/ml)1
12.5 ± 7.72
15.2 ± 7.12
37.8± 17.1
PANCOVA < 0.001 comparing all three groups.
2 P = 0.0001 vs. hCG group (paired t test).
3 P = 0.0006 vs. hCG group (paired t test).
Fauser et al, 2002
Serum concentrations of LH (hCG), FSH, E2 and P
Fauser et al, 2002
Summary (abstract)
• “Corpus luteum formation is induced by
GnRH agonists with luteal phase steroid
levels closer to the physiological range
compared with hCG”.
• “This more physiological approach for
inducing oocyte maturation may represent
a successful and safer alternative for IVF
• But…
Normal menstrual cycle
Yen and Jaffe 1991
hCG (8 oocytes)
(9 oocytes)
Nonsupplemented luteal phase characteristics
after the administration of r-hCG, r-LH, or
GnRH-agonist to induce final oocyte
maturation in IVF patients after ovarian
stimulation with r-FSH and GnRH antagonist
Beckers GM et al, J Clin Endoc Metab
88:4186, 2003
Study protocol
• 40 Women
• Randomized two-center study
• Ovarian stimulation: r-FSH (150 IU/d,
fixed) combined with GnRH antagonist
(antide 1 mg/d). No luteal support.
• Induction of oocyte maturation by:
– r-hCG (Ovidrel, 250 g)
– r-LH (Luveris, 1 mg)
– GnRH agonist (triptorelin, 0.2 mg)
Beckers et al, 2003
• Median duration of the luteal phase:
r-hCG-13d, r-LH-10d, GnRHa–9d (P<0.005)
• Serum LH day of OPU (IU/l):
r-hCG-1.3, r-LH-50.6, GnRHa-5.5 (P<0.001)
• Median AUC per day for LH:
r-hCG-0.50, r-LH-2.35, GnRHa-1.07
• Median AUC per day for Progesterone:
r-hCG-269, r-LH-41, GnRHa-16 (P<0.001)
• Low pregnancy rate (overall 7.5%)
Beckers et al, 2003
• Luteal phase is insufficient after
ovarian stimulation for IVF in
combination with daily GnRH
antagonist in all three groups.
• Luteal support is mandatory after
ovarian stimulation with GnRH
Beckers et al, 2003
• There is a difference between the
groups: luteal E2 and P levels in the
agonist group are practically zero!
Based on the last 2 papers:
following GnRH-a trigger
biosynthesis of sex steroids
by the CL is practically zero.
Physiological range?
Lower levels of inhibin A and pro-alpha C during
the luteal phase after triggering oocyte maturation
with GnRH agonist versus hCG
Nevo et al, Fertil Steril 79:1123, 2003
Clinical characteristics
Nevo et al, 2003
Luteal phase
Natural cycle day 7-9=
75 pg/ml vs. 18
Natural cycle day 7-9=
750 pg/ml vs. 184
Nevo et al, 2003
• GnRH antagonist-based protocol for
ovulation induction enables the use of a
GnRH-a trigger.
• The lower levels of steroidal and
nonsteroidal hormones, which are secreted
by the corpora lutea, reflect luteolysis, and
may explain the mechanism of OHSS
prevention by GnRH-a.
• Pregnancy post agonist trigger does not
rescue the CL!!!
Nevo et al, 2003
Luteolysis post agonist: an old concept
Casper and Yen, Science, 1979, 205:408
• 5 volunteers , mid-luteal agonist
• Luteolysis occurred as indicated by parallel fall in
E2 and P4.
• Suggested as “morning after” injection to prevent
Suggested mechanism of luteolysis
• Aberrant LH surge sufficient for
final oocyte maturation but
insufficient for complete CL
– Repeated agonist dose does so not
prolong surge.
• Aberrant luteal LH secretion.
– Agonist given 6 days later – no LH
response (emperaire 1994).
Pregnancy rate
(normal responder)
• Segal FS, 1992: GnRH-a 20%, hCG 19%
• Gonen JCEM, 1990: GnRH-a 3/9, hCG
• Lanzone FS, 1994: similar rate.
• Fauser JCEM 2002: agonist 18%-20%,
hCG 13%
ESHRE 2004
Ossina et al: Triggering ovulation in GnRH antagonist
protocol: triptorelin 0.1 mg vs. hCG, randomized
multicenter trial. 101 patients, luteal support?
Pregnancy: 48% vs. 42%
Westergaard et al: Significant reduction of clinical
pregnancy by use of GnRH agonist compared to hCG to
induce ovulation in FSH/GnRH antagonist cycles.
96 patients, luteal support: Crinone, 4 mg estradiol.
Pregnancy: hCG=39%, agonist =7.5%
ESHRE 2004 (contd)
• Triggering ovulation with leuprolide acetate
(LA) is associated with lower pregnancy rates
(Bankowski et al, Johns Hopkins)
• May 2000 – July 2003: antagonist cycles,
trigger hCG 10,000 routinely, if E2>3000pg/ml:
trigger with 1 mg LA.
• hCG: 317 patients, LA: 97 patients
• Peak E2: 2050 vs. 4800.
• Oocytes: 10 vs. 21, embryos: 5.6 vs. 12.5
• Pregnancy: 21.5% vs. 11.3%
• Three cases of severe OHSS all in the hCG
ESHRE 2004 (contd)
• GnRH agonist as a novel luteal
support. Loumaye et al .
• 24 IUI patients. Ovulation triggered
with buserelin 0.2 mg.
• Luteal support with 0.1 mg daily.
• Normal luteal phase.
• Importance of dose, type of agonist.
The question of pregnancy rate
(normal responder)
• The importance of adequate luteal
• As with egg donation patients.
The question of pregnancy rate
(high responder)
• Pellicer FS 1996: Lower implantation
rates in high responders: 0% vs. 18.5%.
• Simon HR 1995: 16.3 vs. 33.3%
• Simon FS 1998: Increasing uterine
receptivity by decreasing estradiol
levels…with step-down regimen. Thin
rope: 17% cancellation..
Clinical experience, 40 cycles
Rambam Medical Center
• Max E2=21,436 pmol/l, 23 oocytes, 11
• Fresh ET: 13% pregnancy rate
• Thaw cycles: 23% pregnancy rate
Pregnancy rate per OPU
• Given the large number of oocytes
and embryos obtained (with no risk of
OHSS) the clinical rate per OPU
(fresh and thaw cycles combined) is
more relevant to the patient.
Clinical use of agonist trigger
• Primarily in the context of OHSS
• A major reason to use GnRH
antagonists in ovarian stimulation: to
keep the option of agonist trigger if
RCT: Catch 22…
• A large body of observational data
shows that agonist trigger completely
prevents OHSS.
• Unethical to randomize high risk
patients to hCG arm.
• No RCT, no formal recognition, no
endorsement, no implementation…
If not RCT let’s consider mechanism
• The origin of OHSS is hyper-function
of CL.
• No OHSS without CL.
• How to induce luteolysis?
• Surgical: “Bilateral partial
oophorectomy in the management of
severe OHSS. Amarin, HR 2003
• Medical: Trigger with a GnRH agonist.
Prevention of ovarian hyperstimulation
syndrome: Cochrane database
• Embryo freezing: insufficient
• Coasting: insufficient evidence…
• Albumin: clear benefit…
Further study
• Luteal LH secretion pattern post
agonist trigger.
• Fine-tuning GnRH agonist dose,
potency, route.
• Fine-tuning luteal support: keep
estradiol high?
• Freeze all embryos to increase
pregnancy rate, not to prevent OHSS…
Suggested protocol for the high responder
• Start stimulation with 150-225 IU rec
• Start antagonist on day 6 of stimulation.
Consider adding 1 rec LH (75 IU) daily.
• Ignore E2 levels! No need to step down!
Give all growing follicles full FSH support!
• Trigger with 0.2 mg triptorelin.
• Start luteal support on day of OPU.
• Use vaginal E2 and P.
Agonist trigger to OHSS
is like
ICSI to male factor infertility
Thank you