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). 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 patients. LH and FSH rise in all 5 patients. Olivennes et al, Fertil Steril 66:151, 1996

Itskovitz-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 report 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 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 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 E2 after injection 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 1.0 145 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.

Summary 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 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) Protocol (Randomized multicenter study) 10000IU 0.2 mg 0.5 mg 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 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 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)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 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

hCG (8 oocytes) 1800 Agonists (9 oocytes)

Beckers 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 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

Results 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

Summary 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 trigger biosynthesis of sex steroids by the CL is practically zero. Physiological range? Luteolysis?

Nevo 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 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 Nevo et al, 2003

Summary 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 pregnancy.

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 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 group…

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 cycles Rambam 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 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.

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 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 ICSI to male factor infertility is like ICSI to male factor infertility

Thank you