Presentation on theme: "GnRH agonist instead of hCG to trigger ovulation in GnRH antagonist cycles Dec 10, 2004."— Presentation transcript:
1GnRH agonist instead of hCG to trigger ovulation in GnRH antagonist cycles Dec 10, 2004
2Quick 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?
3Triggering 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
4Itskovitz-Eldor et al, Hum Reprod 15:1965, 2000 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 reportItskovitz-Eldor et al, Hum Reprod 15:1965, 2000
5Materials and Methods8 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
6Results 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% MIIMean number of embryos=15.4±6.67 ETs from fresh embryos: 1 pregnancy17 ETs from frozen-thawed embryos: 4 pregnancies
7Median values of serum LH and E2 after injection of triptorelin 0.2mg Time after injection (n=8)Serum LH (IU/l)Serum estradiol (pg/ml)Pre-dose2.447750.5 h12.746301 h14.345052 h73.750804 h219554010-12 h71.06000Day of OPU7.92375Day of ET0.8963First week post-ET1.0145Itskovitz et al, 2000
10Agonist-triggered LH surge vs. natural surge Maximal LH at 4 h vs. 14hSurge duration 24 h vs. 48 hSurge amplitude – comparable.
11SummaryThe 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.
12Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilizationFauser BC, et alJ Clin Endoc Metab 87:709, 2002
14Clinical outcome (mean±SD) Triptorelin (n=17)Leuprorelin (n=15)hCG(n=15)Number of oocytes/subject9.8 ± 5.48.7 ± 4.58.3 ± 3.3Proportion of metaphase II oocyte72 ± 18%85 ± 17%86 ± 17%Fertilization rate61 ± 30%62 ± 23%56 ± 18%No. of embryos obtained persubject, grades 1 and 2 pooled2.7 ± 3.43.2 ± 2.63.3 ± 2.0Implantation rate15 ± 34%18 ± 37%7 ± 14%Ongoing pregnancy rate18%20%13%Fauser et al, 2002
15Serum hormone concentrations (AUC) during triggering of final oocyte maturationTriptorelin (n=15)Leuprorelin (n=15)hCG (n=15)LH(0–24h) (IU/L)159 ± 14253 ± 1422.7 ± 2.2FSH(0–24h) (IU/L)114.5 ± 3.8214.3 ± 3.725.0 ± 1.2E2(0–2 wk) (pg/ml)1252 ± 1542196 ± 1113515 ± 286P(0–2 wk) (ng/ml)112.5 ± 7.7215.2 ± 7.1237.8± 17.11 PANCOVA < comparing all three groups.2 P = vs. hCG group (paired t test).3 P = vs. hCG group (paired t test).Fauser et al, 2002
16Serum concentrations of LH (hCG), FSH, E2 and P Fauser et al, 2002
18Summary (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…
21Beckers GM et al, J Clin Endoc Metab 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 antagonistBeckers GM et al, J Clin Endoc Metab88:4186, 2003
22Study 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
23Results 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
24SummaryLuteal 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
25However…There is a difference between the groups: luteal E2 and P levels in the agonist group are practically zero!
28Based on the last 2 papers: following GnRH-a triggerbiosynthesis of sex steroidsby the CL is practically zero.Physiological range?Luteolysis?
29Nevo et al, Fertil Steril 79:1123, 2003 Lower levels of inhibin A and pro-alpha C during the luteal phase after triggering oocyte maturation with GnRH agonist versus hCGNevo et al, Fertil Steril 79:1123, 2003
31Luteal phase Natural cycle day 7-9= 75 pg/ml vs. 18 Nevo et al, 2003
32SummaryGnRH 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
33Luteolysis post agonist: an old concept Casper and Yen, Science, 1979, 205:4085 volunteers , mid-luteal agonistLuteolysis occurred as indicated by parallel fall in E2 and P4.Suggested as “morning after” injection to prevent pregnancy.
34Suggested 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).
36ESHRE 2004Ossina et al: Triggering ovulation in GnRH antagonist protocol: triptorelin 0.1 mg vs. hCG, randomized multicenter trial 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%
37ESHRE 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 patientsPeak E2: 2050 vsOocytes: 10 vs. 21, embryos: 5.6 vs. 12.5Pregnancy: 21.5% vs. 11.3%Three cases of severe OHSS all in the hCG group…
38ESHRE 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.
39The question of pregnancy rate (normal responder) The importance of adequate luteal support.As with egg donation patients.
40The 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..
41Clinical experience, 40 cycles Rambam Medical Center Max E2=21,436 pmol/l, 23 oocytes, 11 embryos.Fresh ET: 13% pregnancy rateThaw cycles: 23% pregnancy rate
42Pregnancy rate per OPUGiven 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.
43Clinical use of agonist trigger opinion 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.
44RCT: 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…
45If 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 2003Medical: Trigger with a GnRH agonist.
47Further 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…
48Suggested protocol for the high responder Start stimulation with 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.
49Agonist trigger to OHSS ICSI to male factor infertility is likeICSI to male factor infertility