RECOMBINANT LH, RECOMBINANT HCG
AND GNRH AGONIST TO TRIGGER
OVULATION IN ANTAGONIST CYCLES: A
CRITICAL EVALUATION
SHAHAR KOL
AUGUST 2014
THE NATURAL CYCLE
LH surge goes together with FSH surge.
HOW TO IMITATE NATURE?
Use recombinant LH
RECOMBINANT LH FOR FINAL OOCYTE MATURATION
European Recombinant LH Study Group. J Clin Endocrinol Metab 2001;86:2607–2618
Treatment arm
5000 IU
15,000 IU
Parameters examined
rhLH
(n=39)
u-hCG
(n=34)
No. of follicles >10 mm
14.03 ± 5.32
16.44 ± 6.95
No. of oocytes retrieved
10.23 ± 4.70
11.74 ± 6.27
Oocytes in metaphase II
85.5%
77.8%
No. of oocytes
inseminated
9.82 ± 4.74
No. of embryos
30,000 IU
15,000 + 10,000 IU
rhLH
(n=39)
u-hCG
(n=41)
rhLH
(n=26)
u-hCG
(n=22)
rhLH
(n=25)
u-hCG
(n=24)
p
(linearity)
15.17 ± 8.34
15.46 ± 6.75
14.23 ± 5.61
14.00 ± 4.90
a
a
0.3007
11.84 ± 7.53
11.78 ± 6.75
12.62 ± 6.22
10.82 ± 5.70
a
a
0.1702
90.8%
88.6%
57.6%
84.5%
a
a
0.183
11.26 ± 5.73
11.63 ±
7.52
11.57 ±
6.57
12.38 ±
6.25
10.55 ±
5.74
a
a
0.1687
5.42 ± 3.33
7.00 ± 4.68
6.65 ± 5.02
6.36 ± 4.68
7.67 ± 4.34
6.33 ± 5.19
a
a
0.0983
2.39 ± 0.60
2.48 ± 0.85
2.58 ± 0.6
2.52 ± 0.62
2.78 ± 0.8
2.67 ± 0.73
a
a
0.4310
Implantation rate
6.0 ± 0.16%
15.0 ± 0.31%
6.0 ± 0.19%
9.0 ± 0.24%
11.0 ±
0.26%
3.0 ± 0.09%
17.0 ±
0.33%
0.1373
Pregnancy (total)
15.4% (n=6)
26.5% (n=9)
10.3% (n=4)
24.4%
(n=10)
23.1% (n=6)
13.6% (n=3)
32.0% (n=8)
37.5% (n=9)
0.2689
Clinical pregnancy
10.3% (n=4)
23.5% (n=8)
7.7% (n=3)
14.6% (n=6)
15.4% (n=4)
13.6% (n=3)
28.0% (n=7)
25.0% (n=6)
0.1479
Live birth
5.1% (n=2)
17.6% (n=6)
7.7% (n=3)
12.2% (n=5)
15.4% (n=4)
4.5% (n=1)
16.7% (n=4)
0.0606
Cryopreserved embryos
4.42 ± 2.65
6.81 ± 3.67
7.93 ± 4.18
4.90 ± 3.24
6.27 ± 2.96
4.80 ± 3.19
5.75 ± 2.49
9.89 ± 3.22
0.2645
3.42 ± 1.83
5.67 ± 2.65
3.50 ± 1.84
3.27 ± 1.49
3.00 ± 1.41
2.17 ± 0.98
2.50 ± 0.71
4.75 ± 2.43
0.9092
16.7%
(n=2/12)
0.0%
(n=0/9)
50.0%
(n=5/10)
27.3%
(n=3/11)
62.5%
(n=5/8)
33.3%
(n=2/6)
0.0%
(n=0/2)
0.0%
(n=0/8)
b
8.3%
(n=1/12)
0.0%
(n=0/9)
40.0%
(n=4/10)
27.3%
(n=3/11)
50.0%
(n=4/8)
16.7%
(n=1/6)
0.0%
(n=0/2)
0.0%
(n=0/8)
b
0.0%
(n=0/9)
30.0%
(n=3/10)
18.2%
(n=2/11)
12.5%
(n=1/8)
0.0%
(n=0/6)
0.0%
(n=0/2)
0.0%
(n=0/8)
b
No. of embryos
transferred
Cryopreserved embryos
transferred
Pregnancy from
cryopreserved embryos
(total)
Clinical pregnancy from
cryopreserved embryos
Live birth from
cryopreserved embryos
8.3%
(n=1/12)
19.0 ±
0.33%
20.0% (n=5)
● 15,000 + 10,000 IU gave 20% live birth rate but with a 12% OHSS rate
• High P during implantation window:
after hCG or 2 LH boluses 3 days apart
CONCLUSIONS
The results show that a single dose of rhLH is effective in inducing
final follicular maturation and early luteinization in vitro
fertilization and embryo transfer patients and is comparable with
5,000 IU u-hCG. A single dose of rhLH results in a highly significant
reduction in OHSS compared with hCG.
“TRIAL 21447”
 a double-blind large (437 patients) multicenter randomized study (Trial 21447), compared the
implantation and pregnancy rates following triggering ovulation by r-hLH versus HCG.
 pregnancy rates and clinical pregnancy rates were significantly lower in the r-hLH group than
in the u-HCG group (P = 0.018 and P = 0.023 respectively).
 In order for r-hLH to be as efficacious as u-HCG, the dose would have to be increased to a
point where the cost/benefit ratio may become adverse.
 The study was not published and the manufacturer of r-hLH decided not to register or
manufacture the high dose of r-hLH used for triggering ovulation.
Aboulghar & Al-Inany RBMOnline, 2005
HCG AS TRIGGER
The default trigger agent
Recombinant human hCG or urinary hCG
Question of dose
Recombinant hCG is better in:
• More mature oocytes (9.4 vs. 7.1)
• Higher luteal progesterone
• Better injection tolerance
“There is no evidence of a difference in the clinical
outcomes of life birth/ongoing pregnancy, pregnancy,
miscarriage and OHSS between urinary and recombinant
gonadotrophins for induction of final follicular maturation”.
Same conclusions in a Cochrane review 2011.
WHAT ARE THE PROBLEMS WITH HCG AS TRIGGER?
No FSH surge
Long half life
POTENTIAL BENEFIT OF FSH SURGE
Promotes LH receptor formation in luteinizing granulosa cells
Promotes nuclear maturation (i.e. resumption of meiosis)
Promotes cumulus expansion
Eppig JJ. Nature 1979;281:483–484
Strickland and Beers. J Biol Chem 1976;251:5694–5702
Yding Andersen C. Reprod Biomed Online 2002;5:232–239
Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–731
Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666
Conclusions:
 Adding a bolus of FSH 450 IU at the
time of hCG improves oocyte
recovery and fertilization rate.
Lamb at al, F&S 2011
hCG long half life
HCG AND LUTEAL PHASE DEFECT
 Supraphysiologic stimulation of CL in early luteal phase
 Supraphysioloigc levels of E2 and P
 Negative feedback at the pituitary level
 Low endogenous LH secretion
 Luteal phase defect
 Need of luteal phase supplementation
GNRH AGONIST TRIGGER
 This possibility was first introduced in 1988:
“Induction of LH surge and oocyte maturation by GnRH analogue
(Buserelin) in women undergoing ovarian stimulation for IVF.”
Itskovitz et al, Gynecological Endocrinology 1988, 2:Suppl1, 165
.
THE PHYSIOLOGY OF AGONIST TRIGGER
LH surge1
1. Humaidan P, et al. Reprod Biomed Online 2011
FSH surge2
2. Gonen Y, et al. J Clin Endocrinol Metab 1990
CAN AGONIST TRIGGER WORK IN ANTAGONIST-BASED
OVARIAN STIMULATION?
 Can the agonist displace the
antagonist from the receptor?
 Can a short LH surge promote final
oocyte maturation?
antagonist
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
The study was designed to examine whether, after daily late follicular phase treatment
with 0.25 mg ganirelix, administration of a single dose of GnRH agonist is at least as
effective as hCG in inducing final oocyte maturation in patients undergoing ovarian
hyperstimulation for IVF
Fauser et al, 2002
CLINICAL OUTCOME (MEAN±SD)
Triptorelin
(n=17)
Leuprorelin
(n=15)
hCG
(n=15)
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
61 ± 30%
62 ± 23%
56 ± 18%
No. of embryos obtained per
subject, grades 1 and 2 pooled
2.7 ± 34%
3.2 ± 2.6
3.3 ± 2.0
Implantation rate
15 ± 34%
18 ± 37%
7 ± 14%
18%
20%
13%
Ongoing pregnancy rate
Fauser et al, 2002
What is the advantage of agonist trigger?
Agonist trigger causes quick and irreversible luteolysis.
This leaves the clinician with the options to specifically control the
luteal phase.
CLINICAL USE OF AGONIST TRIGGER
Egg donors
Prevention of OHSS
Patient comfort
Special cases
No OHSS!
Bodri et al, Fertil Steril. 2010
Melo et al RBMonline 2009
…and when OHSS is not the main issue?
"We did find differences in the duration of the luteal phase:
The period to menstrual onset in the non-hCG group was
significantly shorter (10.2 days vs. 5.2 days; P<.001). Also, 42%
of those who received hCG reported subjective complaints
(mostly abdominal discomfort), whereas this percentage was
0% in those who received GnRH agonist to trigger ovulation.
No OHSS was observed in either cohort."
Cerrillo et al, 2009, IVI Madrid
AGONIST TRIGGER IN THE CONTEXT OF OHSS PREVENTION
The dream of OHSS-free IVF treatment is real!
ANTAGONIST ERA
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 ovarian
hyperstimulation syndrome: preliminary report:
Short communication .
Itskovitz-Eldor et al, 2000
GnRH agonist versus hCG for oocyte triggering
in GnRH antagonist ART cycles
Total events 0 (GnRH)
21 (hCG)
Youssef MA, et al. Human Reprod Update
2010;16:459–466
16 publications
Ovulation
trigger
n
OHSS % (n)
RCT, high risk
Oocyte
source
own
GnRHa
hCG
Engamnn et al 2008
RCT, high risk
own
GnRHa
hCG
Acevedo et al 2006
RCT
donors
GnRHa
hCG
Bodri et al 2009
Retrospective
donors
GnRHa
hCG
Griesinger et al 2010
Observational,
High risk
RCT
own
GnRHa
15
13
33
32
30
30
1046
1031
40
0 (0/13)
31(4/13)
0 (0/33)
31 (10/32)
0 (0/30)
17 (5/30)
0 (0/1046)
1.3 (13/1031)
0 (0/40)
own
GnRHa
hCG
Engmann et al 2006
Retrospective, casecontrolled, high risk
own
GnRHa
hCG
152
150
23
23
0 (0/152)
2 (3/150)
0 (0/23)
4 (1/23)
Manzanares et al 2009
Retrospective casecontrol, high risk
own
GnRHa
hCG - cancelled
42
0 (0/42)
Hernandez et al 2009
Retrospective
donors
GnRHa
hCG
Orvieto et al 2006
Retrospective, high
risk
Retrospective, high
risk: agonist arm only
own
GnRHa
hCG
donors
GnRHa
hCG
254
175
82
69
32
42
0 (0/254)
6 (10/175)
0 (0/82)
7 (5/69)
0 (0/32)
1 (1/42)
Sismanoglu et al 2009
RCT
donors
GnRHa
hCG
Humaidan et al 2009
Observational, high
risk
own
GnRH, luteal rescue
with hCG 1500IU
44
44
12
0 (0/44)
7 (3/44)
8 (1/12)
Galindo et al 2009
RCT
donors
GnRHa
hCG
Melo at al 2009
RCT
donors
GnRHa
hCG
Shahrokh et al 2010
RCT, high risk
own
GnRHa
hCG
106
106
50
50
45
45
0 (0/106)
8 (9/106)
0 (0/50)
16(8/50)
0 (0/45)
15 (33)
Reference
Trial type
Babayof et al 2006
Humaidan et al 2009
Agonist: 2,005 patients,
not a single case of
OHSS!
hCG: 92 cases in 1,810
patients, 5.1%
Shapiro et al 2007
A safe and OHSS-free clinical environment
PREGNANCY RATE POST AGONIST TRIGGER
 We showed that agonist trigger causes quick and
irreversible luteolysis.
 Therefore, the right luteal support is crucial.
 The evolution of post agonist luteal support.
 The concept of “tailored” luteal phase support:
• Extreme response (>25 follicles >11 mm): freeze all
• High response (15-25 follicles): a bolus of 1,500 IU hCG on retrieval day
• Normal response: an alternative to hCG trigger
Humaidan and plyzos F&S 2014
THE ADVANTAGE FOR THE ‘NORMAL RESPONDER’
Antagonist
FSH/hMG
Agonist
trigger
OPU
36 hours
1500 IU hCG
ET
4 days
1500 IU hCG
Kol S, et al. Human Reprod 2011;26:2874–2877
Stimulation characteristics and embryology data
Stimulation (days)
9.3 ± 2.0
GnRH antagonist (days)
3.8 ± 0.9
FSH (units)
2443 ± 925
E2 day of trigger (pmol/L)
3764 ± 1227
P day of trigger (nmol/L)
2.4 ± 1.65
LH day of trigger (IU/L)
1.9 ± 1.3
Oocytes retrieved
6.7 ± 2.5
Embryos obtained
3.6 ± 1.7
Embryos transferred
2.9 ± 0.9
Embryos frozen
0.8 ± 1.5
Beta hCG (IU/L)
152 ± 86
E2 (day of pregnancy test, pmol/L)
6607 ± 3789
P (day of pregnancy test, nmol/L)
182 ± 50
Values are mean ± SD
Reproductive outcomes
Positive hCG/cycle, n (%)
11/15 (73)
Clinical ongoing pregnancy, n (%)
7/15 (47)
Early pregnancy loss, n (%)
4/11 (36)
Kol S, et al. Human Reprod 2011;26:2874–2877
Dual trigger improves:
• Implantation rate
• Clinical pregnancy rate
• Live birth rate
Lin et al, 2013
SPECIAL CASES
Empty follicles
Recurrent IVF failure
IS FSH SURGE REDUNDANT IN ALL WOMEN???
Beck-Fruchter at al 2012
SURVEY RESULTS:
Triggering of ovulation with GnRH-a in ART:
Worldwide feedback on an emerging new option with great potential
Take home message
“The results of this survey indicate that GnRH trigger is widely used worldwide
and therefore has become part of the standard of care today. Hence, doctors are
entitled to prescribe it just as patients may ask that this option is considered in
their case.”
“Agonist triggering is viewed as one of the major advances in ovarian
stimulation, with the potential to eliminate OHSS…”
Revolution in the making
In
Out
Antagonist-based protocols
“long agonist” protocols
Agonist trigger
hCG trigger
LH activity-based luteal support
Progesterone-based luteal support
Total OHSS elimination
~1% severe OHSS
Patient friendly luteal phase
Painful P injections or leaky, messy
vaginal P.
Thank you