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Agonists and antagonists in controlled ovarian stimulation
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Agonists and antagonists in controlled ovarian stimulation

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"Serono Meeting for Assisted Reproductive Technology (SMART VI)", Cape Town, South Africa, April 2010 …

"Serono Meeting for Assisted Reproductive Technology (SMART VI)", Cape Town, South Africa, April 2010

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  • 1. SMART VI – Cape Town, South Africa – April 2010
  • 2. Overview
    • Importance of LH suppression in COS
    • Strategies to suppress LH
      • GnRH Agonists and Antagonists
    • Clinical Studies
      • GnRH Agonists and Antagonists
    Esteves,
  • 3. Rationale to LH suppression in ART
    • Reduced risk of premature LH surge and untimely ovulation
      • Allows ovarian stimulation to be controlled
    • Premature luteinization/ovulation in IVF
      • Cycle cancellation
      • Low number of oocytes retrieved/atresia
      • Reduced fertilization rate and embryo quality
      • Poor prognosis for pregnancy
    • Prior to LH suppression, up to 35% CX 1
      • Psychological burden & Financial loss
    1 Loumaye, et al. Human Reprod 1990;5:357 2 Balasch J. In: Female Infertility Therapy:Current Practice (Shoham, Howles, Jacobs, eds). Martin Dunitz 1998:189 Esteves,
  • 4. Physiologic Actions of GnRH
    • Stimulates synthesis and release of LH and FSH
    Esteves, U GnRH LH FSH Short Term Long Term U U U U U U U U U U U U U U U U U U U U U U pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH 2
  • 5. LH suppression in COS
    • Administration of GnRH analogues
      • Synthetic versions of native GnRH
      • Available as GnRH agonists and antagonists
    • GnRH Agonists
      • 1984
      • Buserelin, nafarelin, triptorelin, leuprolide acetate
    • GnRH Antagonists
      • 1999
      • Cetrorelix, ganirelix
    Esteves,
  • 6. LH Surge Prevention: GnRH Agonists Esteves, pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH 2
  • 7. LH Surge Prevention: Antagonists Esteves, pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH 2 GnRH receptor activation Receptor affinity Biologic activity
  • 8. The difference in LH suppression Start Administration Follicular Luteal E 2 , P 4 LH, FSH 0 10 20 30 2-4 weeks Synchronized follicles Agonist Antagonist
    • Half-life ~20h (Cetrorelix)
    • Suppress LH by 80% of baseline levels
  • 9. Agonists: Clinical Challenges (1)
    • By 1995, 85% of IVF cycles worldwide used agonists
    • Initial stimulatory (“flare”) on gonadotropins
      • Ovarian cyst formation ~10-20%
        • Cycle cancellation or negative impact on oocytes/embryos
    • Pretreatment takes 10-14 days for down-regulation
      • Requires monitoring
      • Sometimes difficult to predict date of OCP
      • Side effects (estrogen withdrawal)
    Shaker AD, et al. Fertil Steril 1995;64:791 Damario MA, et al. Hum Reprod 1997;12:2359 Esteves,
  • 10. Agonists: Clinical Challenges (2)
    • Risk of OHSS in high responders
      • Increased cancellation
      • Embryo cryopreservation
    • Longer duration of treatment
      • ~25-30 days
    • Longer interval between treatment cycles
    Shaker AD, et al. Fertil Steril 1995;64:791 Damario MA, et al. Hum Reprod 1997;12:2359 Esteves,
  • 11.
    • Unselected group of NG down-regulated women
    • Group A (hMG; N=299)
    • Group B (HP-hMG; N=330)
    • Group C (r-hFSH; N=236)
    Esteves, Reprod Biol Endocrinol. 2009; 7:111 Individualized dose Agonist (nasal spray): Nafarelin acetate (400 mcg/day; fixed) Gonadotropin dose 112.5-450 UI Day 1 of rFSH/hMG Day 6 of rFSH/hMG Day of hCG Cycle day 21 Day 2-5 of menses menses Vaginal progesterone
  • 12. Esteves et al, Reprod Biol Endocrinol. 2009; 7:111 Parameter HMG n=299 HP-hMG N=330 r-hFSH n=236 p value No. days stimulation 9.6 10.0 10.1 <0.01 Gonadotropin dose (IU) % Step-down 2,685 18.7 2,903 20.3 2,268 53.4 <0.01 No. retrieved oocytes 10.9 10.7 10.8 NS No. MII oocytes 8.9 8.9 8.7 NS 2PN fertilization (%) 72 72 71 NS Top quality embryos (%) 40 47 39 0.004 Implantation rate (%) 24 27 23 NS Live birth rate per cycle (%) 24.4 32.4 30.1 NS OHSS (%) 2.3 1.8 1.3 NS
  • 13. Esteves et al, Reprod Biol Endocrinol. 2009; 7:111
  • 14. Cycle Programming in GnRH Antagonist Cycles hCG or GnRH-a bolus Stimulation day hCG or GnRH-a bolus Cetrorelix; Ganirelix 0 1 2 3 4 5 6 7 8 9 10 11 12 13 gonadotropin 0.25 mg multiple dose protocol (fixed or flexible) Stimulation day Cetrorelix 0 1 2 3 4 5 6 7 8 9 10 11 12 13 gonadotropin 3 mg single dose protocol 2 CD1 OC OC Scheduling 14-28 days 2-5 pill-free days 2-5 pill-free days
  • 15. Comparison of Long GnRH Agonist and GnRH Antagonist Protocols Agonist administration Gonadotropin administration Long GnRH agonist protocol Antagonist administration Gonadotropin administration Single or multiple dose GnRH antagonist protocol Flare up effect Pituitary suppression Pre-treatment cycle Treatment cycle Less gona- dotropins? Prevent OHSS by GnRH-a
  • 16. Why has introduction of antagonists in clinical practice been slow?
    • Experience with Agonists
      • Why change if it is working
    • Initial studies suggesting lower PR
    • Adverse effect on endometrial receptivity
    • Several concerns
      • E2 decrease
      • Not been able to program aspirations on weekdays
      • LH surge (more monitoring)
      • Difficult to use
    Esteves,
  • 17. GnRH Antagonists Effects on Cycle Parameters and Clinical Study Results Esteves,
  • 18. Impact of E 2 Change Following Antagonist Administration Olivennes, et al. Fertil Steril 1998;70:S14 Although some patients experience a decline or plateau in E 2 following antagonist administration, there is no evidence of negative impact on treatment outcome. Esteves, Days post Cetrorelix 3 mg 0 400 800 1200 1600 Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 0 5 10 15 20 Follicle Size (mm) Estradiol (pg/ml) Lead Follicle E 2
  • 19. Is LH needed in a GnRH antagonist Protocol?
    • 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
    • Cedrin 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
    Esteves,
  • 20. Antagonists and Endometrium Receptivity GnRH antagonists and endometrial receptivity in oocyte recipients: a prospective randomized trial Prapas N et al, RBM Online. 2009; 18:276. NS Pregnancy 55.1% 59.1% Implantation 26.1% 24.4
  • 21. What is the Best Antagonist Protocol?
    • Fixed or Flexible daily
      • Follicle 14 or 15 mm
      • Day 6 FSH
    • Fixed single dose
      • 3mg day 7 FSH
    • OC pretreatment
      • 2-5 day interval before starting FSH
    Esteves,
  • 22. Antagonist Protocols Flexible or Fixed? Mansour, et al. Human Reprod 2002;17(Suppl 1):33 *Mean ± SD; NS = not significant Esteves, Cetrorelix 0.25mg Flexible (15 mm) N=64 Fixed (day 6) N=59 P value Age* 28.2 ± 3.7 27.3 ± 4.6 NS Oocytes retrieved* 12 ± 6.6 10.3 ± 4.7 NS Metaphase II oocytes* 9.6 ± 5.2 8.5 ± 4.2 NS Fertilization rate 79.2% 75.8% NS Pregnancy rate 51.6% 44.1% NS Implantation rate 27.3% 25.9% NS Number of cetrorelix vials used* 3.4 ± 1.1 5.3 ± 1.8 <0.05
  • 23. Cycle Programming in GnRH Antagonist Cycles Using OCs
    • Goals not different from OC use with GnRH agonists
        • Ability to plan and predict egg retrieval
        • Avoid weekend retrievals
        • Ability to schedule workload
        • Improve follicular homogeneity
    Esteves, Barmat L, et al. Fertil Steril 2005;83:321
  • 24. Treatment Outcomes of OC Pretreatment with GnRH Agonist or Antagonist Barmat L, et al. Fertil Steril 2005;83:321 *Mean ± SD; NS = non-significant Esteves, AG ANT P -value
      • LH (IU/L) on hCG
    3.2 ± 0.5 1.0 ± 0.2 <0.001
      • E 2 (pg/mL) on hCG
    2,103 ± 116 1,430 ± 131 <0.001 Total IUs r-hFSH 2,724 ± 130 2,706 ± 146 NS Days of r-hFSH 9.0 ± 0.2 9.1 ± 0.3 NS # oocytes retrieved 15 (6-33) 12.5 (2.3-22.0) NS Ongoing PR/cycle started (%) 43.9 36.8 NS
  • 25. Antagonist Protocols Single vs. Multiple? Fixed vs. Flexible? OC pre-treatment? Conclusions
    • All of them offer similar efficacy and safety
    • Less antagonist vials is needed in the flexible regimen despite similar outcomes
    Esteves,
  • 26. Kolibianakis et al . Hum Reprod Update . 2006;12:651 Meta-Analyses of GnRH Antagonists vs GnRH Agonists Cumulative meta-analyses on live birth rates
  • 27. Meta-Analyses of GnRH Antagonists vs GnRH Agonists *Live birth rate included ongoing pregnancies (Al-Inany) or calculated rates (Kolibianakis). 1. Al-Inany et al . Cochrane Database Syst Rev . 2006;3:CD001750. 2. Kolibianakis et al . Hum Reprod Update . 2006;12:651. Probability of Live birth *2.7% reduction in LBR (NS) Esteves, Al-Inany et al (2006) 1 Kolibianakis et al (2006) 2 N studies 27 22 Included non peer-reviewed data Yes No Included IUI cycles Yes No N patients 3865 3176 Primary outcome Ongoing PR or LBR LBR Odds ratio 0.82 (0.69-0.98; p=.03) 0.86 (0.72-1.02; p=.08)*
  • 28. Griesinger et al. Reprod Biomed Online . 2006;13:628. Meta-Analyses of GnRH Antagonists vs GnRH Agonists Esteves, Poor Responders PCOS
  • 29. Meta-Analyses of GnRH Antagonists vs GnRH Agonists *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 . 2006;3:CD001750. 2. Kolibianakis et al . Hum Reprod Update . 2006;12:651. Esteves, Al-Inany et al 1 Kolibianakis et al 2 Duration of ovarian stimulation -1.13 days (-1.83; -0.44) -1.54 days (-2.42; -0.66; p=.0006) Oocytes retrieved -- -1.19 (-1.82; -0.56) Risk of severe OHSS RR=0.46* (0.26; 0.82; p=.01) OR=0.61 (0.42; 0.89; p=.01)
  • 30. The time is for the introduction of antagonists in clinical practice Esteves, Myths Facts E2 decrease is detrimental No evidence Need LH supplementation No evidence; works well irrespective of gonadotropin Not been able to program OCP Use of OC with similar results LH surge No evidence; last dose on hCG day Difficult to use There is a learning curve Adverse effect on endometrium No evidence Lower LBR Probability of LB is independent of analog used for pituitary suppression
  • 31. Conclusions
    • Both analogs of similar efficacy for COS in IVF
    • Agonists yield higher number of oocytes
    • Antagonists associated with better safety profile
      • Reduced severe OHSS
    • Antagonists more patient-friendly
      • Shorter duration of ovarian stimulation
    • Probability of live birth in COS is independent of the analog used for pituitary suppression
    Esteves,
  • 32. Points to Consider in Cycle Management
    • Avoid step-down rFSH/hMG in the first 48 hours after antagonist
    • Use OCP for scheduling purposes (no impact on outcome)
      • 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
    • Patient selection (risk of OHSS)
    • Use last antagonist injection on hCG day
    Esteves,