GnRH agonist instead of hCG to trigger GnRH agonist instead of hCG to trigger ovulation in GnRH antagonist cyclesovulation 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 (evidence).• 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 Triggering of ovulation by a GnRH agonist in patients pretreated with a GnRH antagonistpatients pretreated with a GnRH antagonist

•Pilot study, Pilot study, Ovulation inductionOvulation induction 5 5 patients.patients.•LH and FSH rise in all 5 patients.LH and FSH rise in all 5 patients.

Olivennes et al, Fertil Steril Olivennes et al, Fertil Steril 66:151, 199666:151, 1996

Use of a single bolus of GnRH agonist triptorelin Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist to trigger ovulation after GnRH antagonist

ganirelixganirelix treatment in women undergoing ovarian treatment in women undergoing ovarian stimulation for assisted reproduction with special stimulation for assisted reproduction with special reference to the prevention of reference to the prevention of OHSSOHSS: preliminary : preliminary

reportreport

Itskovitz-Eldor et al, Hum Reprod 15:1965, Itskovitz-Eldor et al, Hum Reprod 15:1965, 20002000

Materials and MethodsMaterials and Methods

• 8 Women considered at risk of developing OHSS: >20 follicles >11mm and/or E2 levels>3000ng/ml on the last stimulation day.

• 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

ResultsResults

• 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

pregnancies

Median values of serum LH and EMedian values of serum LH and E22 after after injection of triptorelin 0.2mginjection of triptorelin 0.2mg

Time after injection (n=8)

Serum LH (IU/l)

Serum estradiol (pg/ml)

Pre-dose 2.4 4775

0.5 h 12.7 4630

1 h 14.3 4505

2 h 73.7 5080

4 h 219 5540

10-12 h 71.0 6000

Day of OPU 7.9 2375

Day of ET 0.8 963

First week post-ET

1.0 145Itskovitz et al, 2000

Normal LH surgeNormal LH surge

Hoff et al, 1983

High respondersHigh 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.

SummarySummary

• 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 advantage.

Endocrine profiles after triggering of Endocrine profiles after triggering of final oocyte maturation with GnRH final oocyte maturation with GnRH agonist after cotreatment with the agonist after cotreatment with the GnRH antagonist GnRH antagonist ganirelixganirelix during during

ovarian hyperstimulation for ovarian hyperstimulation for in vitroin vitro fertilizationfertilization

Fauser BC, et alFauser BC, et al

J Clin Endoc Metab 87:709, 2002J Clin Endoc Metab 87:709, 2002

Fauser et al, 2002

Protocol(Randomized multicenter study)

0.2 mg

0.5 mg

10000IU

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 rate 61 ± 30% 62 ± 23% 56 ± 18%

No. of embryos obtained persubject, 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 18% 20% 13%

Fauser et al, 2002

Serum hormone concentrations (AUC) during triggering of final oocyte maturation

Triptorelin (n=15)

Leuprorelin (n=15) hCG (n=15)

LH(0–24h) (IU/L)159 ± 142 53 ± 142 2.7 ± 2.2

FSH(0–24h) (IU/L)114.5 ± 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

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 patients”.

• But…

Normal menstrual cycle

Yen and Jaffe 1991

1800 hCG (8 oocytes)

Agonists(9 oocytes)

Nonsupplemented luteal phase characteristics Nonsupplemented luteal phase characteristics after the administration of r-hCG, r-LH, or after the administration of r-hCG, r-LH, or

GnRH-agonist to induce final oocyte GnRH-agonist to induce final oocyte maturation in IVF patients after ovarian maturation in IVF patients after ovarian

stimulation with r-FSH and stimulation with r-FSH and GnRH antagonistGnRH antagonist

Beckers GM et al, J Clin Endoc Metab Beckers GM et al, J Clin Endoc Metab

88:4186, 200388:4186, 2003

• 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)

Study protocolStudy protocol

Beckers et al, 2003

ResultsResults• 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

(P<0.001) • 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

SummarySummary

• 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 antagonist.

Beckers et al, 2003

However…

• 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 triggerbiosynthesis of sex steroids by the CL is practically zero.Physiological range?Luteolysis?

Lower levels of inhibin A and pro-alpha C during Lower levels of inhibin A and pro-alpha C during the luteal phase after triggering oocyte maturation the luteal phase after triggering oocyte maturation

with GnRH agonist versus hCGwith GnRH agonist versus hCG

Nevo et al, Fertil Steril 79:1123, 2003Nevo et al, Fertil Steril 79:1123, 2003

Clinical characteristicsClinical characteristics

Nevo et al, 2003

Luteal phaseLuteal phase

Nevo et al, 2003

Natural cycle day 7-9=75 pg/ml vs. 18

Natural cycle day 7-9=

750 pg/ml vs. 184

SummarySummary

• 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

• 5 volunteers , mid-luteal agonist• Luteolysis occurred as indicated by parallel fall

in E2 and P4.• Suggested as “morning after” injection to

prevent pregnancy.

Casper and Yen, Science, 1979, 205:408

Suggested mechanism of luteolysis

• Aberrant LH surge sufficient for final oocyte maturation but insufficient for complete CL formation.– 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 0/9

• Lanzone FS, 1994: similar rate.• Fauser JCEM 2002: agonist 18%-

20%, hCG 13%

ESHRE 2004

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%

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%

• 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

group…

ESHRE 2004 (contd)

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 support.

• 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 cyclesRambam Medical Center

• Max E2=21,436 pmol/l, 23 oocytes, 11 embryos.

• 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 triggeropinion

• Primarily in the context of OHSS prevention.

• A major reason to use GnRH antagonists in ovarian stimulation: to keep the option of agonist trigger if needed.

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 Prevention of ovarian hyperstimulation syndrome: Cochrane databasesyndrome: Cochrane database

• Embryo freezing: insufficient evidence…

• 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 FSH.

• 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