Gnrh agonist instead of hcg to trigger ovulation in gnrh antagonist cycles
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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 (evidence).

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Quick overview l.jpg
Quick overview antagonist cycles

  • 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?


Slide3 l.jpg

Triggering of ovulation by a GnRH agonist in patients pretreated with a GnRH antagonist

  • Pilot study, Ovulation induction 5 patients.

  • LH and FSH rise in all 5 patients.

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


Slide4 l.jpg

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 report

Itskovitz-Eldor et al, Hum Reprod 15:1965, 2000


Materials and methods l.jpg
Materials and Methods ovulation after GnRH antagonist

  • 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


Results l.jpg
Results ovulation after GnRH antagonist

  • 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 e 2 after injection of triptorelin 0 2mg l.jpg
Median values of serum LH and E ovulation after GnRH antagonist 2 after injection of triptorelin 0.2mg

Itskovitz et al, 2000


Slide8 l.jpg

Normal LH surge ovulation after GnRH antagonist

Hoff et al, 1983


Slide9 l.jpg

High responders ovulation after GnRH antagonist

Itskovitz et al, 1991


Agonist triggered lh surge vs natural surge l.jpg
Agonist-triggered LH surge vs. natural surge ovulation after GnRH antagonist

  • Maximal LH at 4 h vs. 14h

  • Surge duration 24 h vs. 48 h

  • Surge amplitude – comparable.


Summary l.jpg
Summary ovulation after GnRH antagonist

  • 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.


Slide12 l.jpg

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


Slide13 l.jpg

Protocol maturation with GnRH agonist after cotreatment with the GnRH antagonist

(Randomized multicenter study)

10000IU

0.2 mg

0.5 mg

Fauser et al, 2002


Clinical outcome mean sd l.jpg
Clinical outcome (mean±SD) maturation with GnRH agonist after cotreatment with the GnRH antagonist

Fauser et al, 2002


Slide15 l.jpg

Triptorelin maturation with GnRH agonist after cotreatment with the GnRH antagonist (n=15)

Leuprorelin (n=15)

hCG (n=15)

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

Serum hormone concentrations (AUC)

during triggering of final oocyte maturation

1PANCOVA < 0.001 comparing all three groups.

2P = 0.0001 vs. hCG group (paired t test).

3P = 0.0006 vs. hCG group (paired t test).

Fauser et al, 2002


Slide16 l.jpg

Serum concentrations of LH (hCG), FSH, E2 and P maturation with GnRH agonist after cotreatment with the GnRH antagonist

Fauser et al, 2002


Summary abstract l.jpg
Summary (abstract) maturation with GnRH agonist after cotreatment with the GnRH antagonist

  • “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…


Slide19 l.jpg

Normal menstrual cycle maturation with GnRH agonist after cotreatment with the GnRH antagonist

Yen and Jaffe 1991


Slide20 l.jpg

hCG (8 oocytes) maturation with GnRH agonist after cotreatment with the GnRH antagonist

1800

Agonists

(9 oocytes)


Slide21 l.jpg

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


Slide22 l.jpg

Study protocol administration of r-hCG, r-LH, or GnRH-agonist to induce final oocyte maturation in IVF patients after ovarian stimulation with r-FSH and

  • 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


Results23 l.jpg
Results administration of r-hCG, r-LH, or GnRH-agonist to induce final oocyte maturation in IVF patients after ovarian stimulation with r-FSH and

  • 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


Summary24 l.jpg
Summary administration of r-hCG, r-LH, or GnRH-agonist to induce final oocyte maturation in IVF patients after ovarian stimulation with r-FSH and

  • 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 l.jpg
However… administration of r-hCG, r-LH, or GnRH-agonist to induce final oocyte maturation in IVF patients after ovarian stimulation with r-FSH and

  • There is a difference between the groups: luteal E2 and P levels in the agonist group are practically zero!


Slide28 l.jpg

Based on the last 2 papers: administration of r-hCG, r-LH, or GnRH-agonist to induce final oocyte maturation in IVF patients after ovarian stimulation with r-FSH and

following GnRH-a trigger

biosynthesis of sex steroids

by the CL is practically zero.

Physiological range?

Luteolysis?


Slide29 l.jpg
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


Slide30 l.jpg

Clinical characteristics phase after triggering oocyte maturation with GnRH agonist versus hCG

Nevo et al, 2003


Slide31 l.jpg

Luteal phase phase after triggering oocyte maturation with GnRH agonist versus hCG

Natural cycle day 7-9=

75 pg/ml vs. 18

Natural cycle day 7-9=

750 pg/ml vs. 184

Nevo et al, 2003


Summary32 l.jpg
Summary phase after triggering oocyte maturation with GnRH agonist versus hCG

  • 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 l.jpg
Luteolysis post agonist: an old concept phase after triggering oocyte maturation with GnRH agonist versus hCG

  • 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 l.jpg
Suggested mechanism of luteolysis phase after triggering oocyte maturation with GnRH agonist versus hCG

  • 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 l.jpg
Pregnancy rate phase after triggering oocyte maturation with GnRH agonist versus hCG(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 l.jpg
ESHRE 2004 phase after triggering oocyte maturation with GnRH agonist versus hCG

  • 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 l.jpg
ESHRE 2004 (contd) phase after triggering oocyte maturation with GnRH agonist versus hCG

  • 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 contd38 l.jpg
ESHRE 2004 (contd) phase after triggering oocyte maturation with GnRH agonist versus hCG

  • 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 l.jpg
The question of pregnancy rate phase after triggering oocyte maturation with GnRH agonist versus hCG(normal responder)

  • The importance of adequate luteal support.

  • As with egg donation patients.


The question of pregnancy rate high responder l.jpg
The question of pregnancy rate phase after triggering oocyte maturation with GnRH agonist versus hCG(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 l.jpg
Clinical experience, 40 cycles phase after triggering oocyte maturation with GnRH agonist versus hCGRambam 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 l.jpg
Pregnancy rate per OPU phase after triggering oocyte maturation with GnRH agonist versus hCG

  • 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 opinion l.jpg
Clinical use of agonist trigger phase after triggering oocyte maturation with GnRH agonist versus hCGopinion

  • 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 l.jpg
RCT: Catch 22… phase after triggering oocyte maturation with GnRH agonist versus hCG

  • 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 l.jpg
If not RCT let’s consider mechanism phase after triggering oocyte maturation with GnRH agonist versus hCG

  • 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.


Slide46 l.jpg

Prevention of ovarian hyperstimulation syndrome: Cochrane database

  • Embryo freezing: insufficient evidence…

  • Coasting: insufficient evidence…

  • Albumin: clear benefit…


Further study l.jpg
Further study database

  • 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 l.jpg
Suggested protocol for the high responder database

  • 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.


Slide49 l.jpg

Agonis databaset trigger to OHSS

is like

ICSI to male factor infertility


Slide50 l.jpg

Thank you database