Ovarian Stimulation Protocols Central Paradigm Minimize Maximize beneficial complications and effects of treatment risks High-quality Cycle cancellation, oocyte yield OHSS, multiple pregnancyEsteves, 4 Fauser et al., 2008
Theca externa cells Theca interna cells Granulosa cells Follicular antrum Zona pellucida Oocyte Cumulus Oophorus cells Capillary network Basement membraneEsteves, 5 Zeleznik et al 1974; Adashi 1996, Hillier 1994.
Rationale of LH suppression in COH Premature luteinization in IVF — Cycle cancellation — Low number of oocytes retrieved/atresia — Reduced fertilization rate and embryo quality — Poor prognosis for pregnancy — Psychological burden & Financial loss Reduced risk of Allows ovarian LH suppression premature LH surge and stimulation to be untimely ovulation controlled 1Loumaye, et al. Human Reprod 1990;5:357 2Balasch J. In: Female Infertility Therapy:Current Practice (Shoham, Howles, Jacobs, eds). Martin DunitzEsteves, 6 1998:189
Physiologic Actions of GnRH Stimulates synthesis and release of LH and FSH pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 Short Term Long Term U U U GnRH LH FSH U UEsteves, 7
LH Surge Prevention: GnRH Antagonists GnRH receptor activation Receptor affinity Biologic activity pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2Esteves, 8
Comparison of Long GnRH Agonist and GnRH Antagonist Protocols Prevent Can be OHSS by integrated in GnRH-a No flare spontaneous/OIGnRH antagonist Antagonist effect with No hormonal cycles protocol administration possible cyst withdrawal formation Gonadotropin administration Less gona- Can exclude dotropins early pregnancy Flare up Pituitary effect suppression Gonadotropin administration Long GnRH agonist Longer Agonist administration protocol treatment Pre-treatment cycle Treatment cycle
Why has introduction of antagonists in clinical practice has been slow? Experience with Agonists — Why change if it is working Clinicians´ concerns — E2 decrease — Not been able to program aspirations on weekdays — LH surge (more monitoring) — Difficult to useEsteves, 11
GnRH Antagonists in COH Clinical Results and Effects on Cycle Parameters Level Type of evidence 1a Obtained from meta-analysis of randomised trials 1b Obtained from at least one randomised trial 2a Obtained from one well-designed controlled study without randomisation 2b Obtained from at least one other type of well-designed quasi- experimental study 3 Obtained from well-designed non-experimental studies, such as comparative and correlation studies, and case reports 4 Obtained from expert committee reports or opinions or clinical experience of respected authoritiesEsteves, 12 Modified from Sackett et al. Oxford Centre for Evidence-based Medicine Levels of Evidence (2009)
GnRH Antagonist in COH 1a GnRH Antagonists vs Agonists Probability of Live birth Al-Inany et al (2011)1 Kolibianakis et al (2006)2 N studies 45 22 Included IUI cycles Yes No N patients 7,511 3,176 Primary outcome Ongoing PR or LBR LBR Odds ratio 0.86 0.86 (95% CI 0.69-1.08) (95% CI 0.72 to 1.02) *Live birth rate included ongoing pregnancies (Al-Inany) or calculated rates (Kolibianakis). 1. Al-Inany et al. Cochrane Database Syst Rev. 2011; 5:CD001750.Esteves, 13 2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.
GnRH Antagonist in COH 1a GnRH Antagonists vs Agonists Al-Inany et al1 Kolibianakis et al2 Duration of ovarian -1.13 days -1.54 days stimulation (-1.83; -0.44) (-2.42; -0.66; p=.0006) Oocytes retrieved -- -1.19 (-1.82; -0.56) Risk of severe 0.43* OR=0.61 OHSS (95% CI 0.33 to 0.57) (0.42; 0.89; p=.01) *For every 59 women treated with a GnRH agonist vs GnRH antagonist, one additional case of severe OHSS will occur. 1. Al-Inany et al. Cochrane Database Syst Rev. 2011; 5:CD001750.Esteves, 14 2. Kolibianakis et al. Hum Reprod Update. 2006;12:651.
GnRH Antagonist in COH OHSS – 3 levels of Protection 1st Level: Antagonist rather than Agonists. 2nd Level: In patients on antagonist protocol at risk of OHSS, replace hCG with GnRH-a for oocyte maturation trigger. 3rd Level: In patients with early OHSS onset, use of GnRH-ant luteal phase.Esteves, 15
GnRH Antagonist in COH Poor Responders 1a Pu D, Wu J, Liu J.. Hum Reprod. 2011; 26: 2742 Antagonist vs Duration of Oocytes Cycle CPR Agonist stimulation retrieved cancellation 14 RCT; 1127 -1.9 days -0.17 1.01 1.23 patients (-3.6; -0.12) (-2.42; -0.66) (0.71; 1.42) (0.92, 1.66) PCOS 1b Lainas et al. Hum Reprod. 2010; 25:683 Antagonist vs Duration of Oocytes Grades II + III CPR (%) Agonist stimulation; retrieved; N OHSS (%) days RCT; 220 10 vs 12 28 vs 27 65 vs 44 50.9 vs 47.3 patients (P<.001) (P=.22) (P=0.006) (P=.68)Esteves, 16
What is the Best Antagonist Protocol? Fixed or Flexible daily OCP pretreatment Day of hCG administration LH supplementationEsteves, 17
GnRH Antagonist in COH 1b Flexible or Fixed Cetrorelix 0.25mg P Flexible*; N=68 Fixed; N=72 value Duration of COH 9.7 ± 1.9 9.9 ± 2.7 .72 Age* 2,225 ± 1,128 2,190 ± 833 .84 Oocytes retrieved* 12 ± 6.6 10.3 ± 4.7 NS Metaphase II 11.7 ± 6.5 9.8 ± 5.2 .07 oocytes* Fertilization rate 54.9 ± 22.8 56.3 ± 21.4 .77 Pregnancy rate 24.7% 23.3% NS *Flexible: LH >10 IU/L, and/or mean follicle >12 mm, and/or serum E2 >150 pg/mL; Fixed: Day 6; No LH surge reported Kolibianakis EM, et al. Fertil Steril. 2011; 95:558-62Esteves, 18
GnRH Antagonist in COH 1b Day of hCG administration hCG administration ≥3 follicles of One day P ≥16mm later value 120 NG women 39 y-o undergoing antagonist COH protocol Mean ± Metaphase II 6.1 ± 4.9 9.2 ± 7.1 .009 oocytes Mean ± Fertilization 66.7 ± 23.4 70.1 ± 20.9 .44 rate Ongoing Pregnancy 34.6% 40.7% .55 rate Kyrou D et al. Fertil Steril. 2011; 96(5):1112-5.Esteves, 20
Is LH needed in a GnRH antagonist Protocol? 1b Sauer et al (2004) - multicenter study using 3mg flexible protocol (+OCP): no benefit of LH supplementation (150 IU r-hLH day 6 FSH) on MII oocytes or pregnancy rate vs no supplementation or GnRH agonist protocol Cédrin-Durnerin et al (2004) - multicenter study using 3mg flexible protocol (+OCP): no benefit of LH supplementation (75 IU r-hLH day antag) on oocytes or delivery rates Sauer et al, Reprod Biomed Online 2004;9:487–93;Esteves, 21 Cédrin-Durnerin et al, Hum Reprod 2004;19:1979–84.
Is LH needed for older women in GnRH antagonist Protocol? 292 NG women aged 36-39 1b Fixed (D6) antagonist COH protocol rFSH rFSH + rLH P=0.02 68% 61% OR=1.49 OR=1.56 95% CI 0.93-2.38 95% CI 1.04-2.33 33% 25% 27% 19% %2PN Ongoing PR ImplantationEsteves, 22 Bosch et al. Fertil Steril. 2011; 95:1031-6.
GnRH Antagonists in COH Summary Clinical Outcomes Evidence No difference in probability of live birth (overall and 1a subgroups) compared to agonists Significantly lower OHSS and duration of 1a stimulation No difference in Flexible or Fixed Antagonist 1b Protocols OCP programming or delaying hCG (+1 day) not 1a detrimental No need of LH supplementation overall; subgroup 1b analysis suggest that aged women may benefitEsteves, 23
Currently, >50% COH cycles use ANTAGONISTS Cycles with GnRH Antagonists 60% 15% 1999 2009Esteves, 24 REDLARA Registry; ART World Report (ICMART)
Practical Tips in GnRH Antagonist Cycle Management Avoid step-down rFSH/hMG in the first 48 hours after antagonist Use OCP for scheduling purposes — Make pill-free interval flexible Flexible GnRH antagonist no later than day 8 of stimulation or follicle size 14 mm; If >6 follicles 11-13 mm diameter start GnRH antagonist Use last antagonist injection on hCG dayEsteves, 25
Take-home Messages Agonists yield higher number of oocytes Antagonists are safer than agonists — Decreased moderate and severe OHSS rates Antagonists more patient-friendly — Shorter duration of COH Probability of live birth in COS is independent of the analog used for pituitary suppressionEsteves, 26