RECOMBINANT LH RECOMBINANT HCG AND GNRH AGONIST TO
RECOMBINANT LH, RECOMBINANT HCG AND GNRH AGONIST TO TRIGGER OVULATION IN ANTAGONIST CYCLES: A CRITICAL EVALUATION SHAHAR KOL AUGUST 2014
THE NATURAL CYCLE üLH surge goes together with FSH surge.
HOW TO IMITATE NATURE? üUse recombinant LH
RECOMBINANT LH FOR FINAL OOCYTE MATURATION European Recombinant LH Study Group. J Clin Endocrinol Metab 2001; 86: 2607– 2618
Treatment arm 5000 IU 15, 000 IU 30, 000 IU rh. LH (n=39) u-h. CG (n=34) No. of follicles >10 mm 14. 03 ± 5. 32 16. 44 ± 6. 95 No. of oocytes retrieved 10. 23 ± 4. 70 11. 74 ± 6. 27 Oocytes in metaphase II 85. 5% 77. 8% No. of oocytes inseminated 9. 82 ± 4. 74 11. 26 ± 5. 73 11. 63 ± 7. 52 11. 57 ± 6. 57 12. 38 ± 6. 25 No. of embryos 5. 42 ± 3. 33 7. 00 ± 4. 68 6. 65 ± 5. 02 6. 36 ± 4. 68 2. 39 ± 0. 60 2. 48 ± 0. 85 2. 58 ± 0. 6 Implantation rate 6. 0 ± 0. 16% 15. 0 ± 0. 31% Pregnancy (total) 15. 4% (n=6) Clinical pregnancy 15, 000 + 10, 000 IU rh. LH (n=39) u-h. CG (n=41) rh. LH (n=26) u-h. CG (n=22) rh. LH (n=25) u-h. CG (n=24) p (linearity) 15. 17 ± 8. 34 15. 46 ± 6. 75 14. 23 ± 5. 61 14. 00 ± 4. 90 a a 0. 3007 11. 84 ± 7. 53 11. 78 ± 6. 75 12. 62 ± 6. 22 10. 82 ± 5. 70 a a 0. 1702 a a 0. 183 10. 55 ± 5. 74 a a 0. 1687 7. 67 ± 4. 34 6. 33 ± 5. 19 a a 0. 0983 2. 52 ± 0. 62 2. 78 ± 0. 8 2. 67 ± 0. 73 a a 0. 4310 6. 0 ± 0. 19% 9. 0 ± 0. 24% 11. 0 ± 0. 26% 3. 0 ± 0. 09% 19. 0 ± 0. 33% 17. 0 ± 0. 33% 0. 1373 26. 5% (n=9) 10. 3% (n=4) 24. 4% (n=10) 23. 1% (n=6) 13. 6% (n=3) 32. 0% (n=8) 37. 5% (n=9) 0. 2689 10. 3% (n=4) 23. 5% (n=8) 7. 7% (n=3) 14. 6% (n=6) 15. 4% (n=4) 13. 6% (n=3) 28. 0% (n=7) 25. 0% (n=6) 0. 1479 Live birth 5. 1% (n=2) 17. 6% (n=6) 7. 7% (n=3) 12. 2% (n=5) 15. 4% (n=4) 4. 5% (n=1) 20. 0% (n=5) 16. 7% (n=4) 0. 0606 Cryopreserved embryos 4. 42 ± 2. 65 6. 81 ± 3. 67 7. 93 ± 4. 18 4. 90 ± 3. 24 6. 27 ± 2. 96 4. 80 ± 3. 19 5. 75 ± 2. 49 9. 89 ± 3. 22 0. 2645 3. 42 ± 1. 83 5. 67 ± 2. 65 3. 50 ± 1. 84 3. 27 ± 1. 49 3. 00 ± 1. 41 2. 17 ± 0. 98 2. 50 ± 0. 71 4. 75 ± 2. 43 0. 9092 16. 7% (n=2/12) 0. 0% (n=0/9) 50. 0% (n=5/10) 27. 3% (n=3/11) 62. 5% (n=5/8) 33. 3% (n=2/6) 0. 0% (n=0/2) 0. 0% (n=0/8) b 8. 3% (n=1/12) 0. 0% (n=0/9) 40. 0% (n=4/10) 27. 3% (n=3/11) 50. 0% (n=4/8) 16. 7% (n=1/6) 0. 0% (n=0/2) 0. 0% (n=0/8) b 8. 3% (n=1/12) 0. 0% (n=0/9) 30. 0% (n=3/10) 18. 2% (n=2/11) 12. 5% (n=1/8) 0. 0% (n=0/6) 0. 0% (n=0/2) 0. 0% (n=0/8) b Parameters examined No. of embryos transferred Cryopreserved embryos transferred Pregnancy from cryopreserved embryos (total) Clinical pregnancy from cryopreserved embryos Live birth from cryopreserved embryos 90. 8% 88. 6% 57. 6% 84. 5% ● 15, 000 + 10, 000 IU gave 20% live birth rate but with a 12% OHSS rate
• High P during implantation window: after h. CG or 2 LH boluses 3 days apart
CONCLUSIONS üThe results show that a single dose of rh. LH is effective in inducing final follicular maturation and early luteinization in vitro fertilization and embryo transfer patients and is comparable with 5, 000 IU u-h. CG. A single dose of rh. LH results in a highly significant reduction in OHSS compared with h. CG.
“TRIAL 21447” ü a double-blind large (437 patients) multicenter randomized study (Trial 21447), compared the implantation and pregnancy rates following triggering ovulation by r-h. LH versus HCG. ü pregnancy rates and clinical pregnancy rates were significantly lower in the r-h. LH group than in the u-HCG group (P = 0. 018 and P = 0. 023 respectively). ü In order for r-h. LH to be as efficacious as u-HCG, the dose would have to be increased to a point where the cost/benefit ratio may become adverse. ü The study was not published and the manufacturer of r-h. LH decided not to register or manufacture the high dose of r-h. LH used for triggering ovulation. Aboulghar & Al-Inany RBMOnline, 2005
HCG AS TRIGGER üThe default trigger agent üRecombinant human h. CG or urinary h. CG üQuestion of dose
üRecombinant h. CG is better in: • More mature oocytes (9. 4 vs. 7. 1) • Higher luteal progesterone • Better injection tolerance
“There is no evidence of a difference in the clinical outcomes of life birth/ongoing pregnancy, miscarriage and OHSS between urinary and recombinant gonadotrophins for induction of final follicular maturation”. Same conclusions in a Cochrane review 2011.
WHAT ARE THE PROBLEMS WITH HCG AS TRIGGER? üNo FSH surge üLong half life
POTENTIAL BENEFIT OF FSH SURGE üPromotes LH receptor formation in luteinizing granulosa cells üPromotes nuclear maturation (i. e. resumption of meiosis) üPromotes cumulus expansion Eppig JJ. Nature 1979; 281: 483– 484 Strickland Beers. J Biol Chem 1976; 251: 5694– 5702 Yding Andersen C. Reprod Biomed Online 2002; 5: 232– 239 Yding Andersen C, et al. Mol Hum Reprod 1999; 5: 726– 731 Zelinski-Wooten MB, et al. Human Reprod 1995; 10: 1658– 1666
Conclusions: ü Adding a bolus of FSH 450 IU at the time of h. CG improves oocyte recovery and fertilization rate. Lamb at al, F&S 2011
h. CG long half life
HCG AND LUTEAL PHASE DEFECT ü Supraphysiologic stimulation of CL in early luteal phase ü Supraphysioloigc levels of E 2 and P ü Negative feedback at the pituitary level ü Low endogenous LH secretion ü Luteal phase defect ü Need of luteal phase supplementation
GNRH AGONIST TRIGGER ü This possibility was first introduced in 1988: “Induction of LH surge and oocyte maturation by Gn. RH analogue (Buserelin) in women undergoing ovarian stimulation for IVF. ” Itskovitz et al, Gynecological Endocrinology 1988, 2: Suppl 1, 165 .
THE PHYSIOLOGY OF AGONIST TRIGGER LH surge 1 FSH surge 2 1. Humaidan P, et al. Reprod Biomed Online 2011 2. Gonen Y, et al. J Clin Endocrinol Metab 1990
CAN AGONIST TRIGGER WORK IN ANTAGONIST-BASED OVARIAN STIMULATION? ü Can the agonist displace the antagonist from the receptor? ü Can a short LH surge promote final oocyte maturation? antagonist
Endocrine Profiles after Triggering of Final Oocyte Maturation with Gn. RH Agonist after Cotreatment with the Gn. RH Antagonist Ganirelix during Ovarian Hyperstimulation for in Vitro Fertilization The study was designed to examine whether, after daily late follicular phase treatment with 0. 25 mg ganirelix, administration of a single dose of Gn. RH agonist is at least as effective as h. CG in inducing final oocyte maturation in patients undergoing ovarian hyperstimulation for IVF Fauser et al, 2002
CLINICAL OUTCOME (MEAN±SD) Triptorelin (n=17) Leuprorelin (n=15) h. CG (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 61 ± 30% 62 ± 23% 56 ± 18% No. of embryos obtained per subject, grades 1 and 2 pooled 2. 7 ± 34% 3. 2 ± 2. 6 3. 3 ± 2. 0 Implantation rate 15 ± 34% 18 ± 37% 7 ± 14% 18% 20% 13% Ongoing pregnancy rate Fauser et al, 2002
What is the advantage of agonist trigger? üAgonist trigger causes quick and irreversible luteolysis. üThis leaves the clinician with the options to specifically control the luteal phase.
CLINICAL USE OF AGONIST TRIGGER üEgg donors üPrevention of OHSS üPatient comfort üSpecial cases
No OHSS! Bodri et al, Fertil Steril. 2010
Melo et al RBMonline 2009
…and when OHSS is not the main issue? "We did find differences in the duration of the luteal phase: The period to menstrual onset in the non-h. CG group was significantly shorter (10. 2 days vs. 5. 2 days; P<. 001). Also, 42% of those who received h. CG reported subjective complaints (mostly abdominal discomfort), whereas this percentage was 0% in those who received Gn. RH agonist to trigger ovulation. No OHSS was observed in either cohort. " Cerrillo et al, 2009, IVI Madrid
AGONIST TRIGGER IN THE CONTEXT OF OHSS PREVENTION üThe dream of OHSS-free IVF treatment is real!
ANTAGONIST ERA Use of a single bolus of Gn. RH agonist triptorelin to trigger ovulation after Gn. RH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: Short communication. Itskovitz-Eldor et al, 2000
Gn. RH agonist versus h. CG for oocyte triggering in Gn. RH antagonist ART cycles Total events 0 (Gn. RH) 21 (h. CG) Youssef MA, et al. Human Reprod Update 2010; 16: 459– 466
16 publications Ovulation trigger n OHSS % (n) RCT, high risk Oocyte source own Gn. RHa h. CG Engamnn et al 2008 RCT, high risk own Gn. RHa h. CG Acevedo et al 2006 RCT donors Gn. RHa h. CG Bodri et al 2009 Retrospective donors Gn. RHa h. CG Griesinger et al 2010 Observational, High risk RCT own Gn. RHa 15 13 33 32 30 30 1046 1031 40 0 (0/13) 31(4/13) 0 (0/33) 31 (10/32) 0 (0/30) 17 (5/30) 0 (0/1046) 1. 3 (13/1031) 0 (0/40) own Gn. RHa h. CG Engmann et al 2006 Retrospective, casecontrolled, high risk own Gn. RHa h. CG 152 150 23 23 0 (0/152) 2 (3/150) 0 (0/23) 4 (1/23) Manzanares et al 2009 Retrospective casecontrol, high risk own Gn. RHa h. CG - cancelled 42 0 (0/42) Hernandez et al 2009 Retrospective donors Gn. RHa h. CG Orvieto et al 2006 Retrospective, high risk: agonist arm only own Gn. RHa h. CG donors Gn. RHa h. CG 254 175 82 69 32 42 0 (0/254) 6 (10/175) 0 (0/82) 7 (5/69) 0 (0/32) 1 (1/42) Sismanoglu et al 2009 RCT donors Gn. RHa h. CG Humaidan et al 2009 Observational, high risk own Galindo et al 2009 RCT donors Gn. RHa h. CG Melo at al 2009 RCT donors Gn. RHa h. CG Shahrokh et al 2010 RCT, high risk own Gn. RHa h. CG Reference Trial type Babayof et al 2006 Humaidan et al 2009 Agonist: 2, 005 patients, not a single case of OHSS! h. CG: 92 cases in 1, 810 patients, 5. 1% Shapiro et al 2007 44 44 Gn. RH, luteal rescue 12 0 (0/44) 7 (3/44) 8 (1/12) with h. CG 1500 IU 106 50 50 45 45 0 (0/106) 8 (9/106) 0 (0/50) 16(8/50) 0 (0/45) 15 (33)
A safe and OHSS-free clinical environment
PREGNANCY RATE POST AGONIST TRIGGER ü We showed that agonist trigger causes quick and irreversible luteolysis. ü Therefore, the right luteal support is crucial. ü The evolution of post agonist luteal support.
ü The concept of “tailored” luteal phase support: • Extreme response (>25 follicles >11 mm): freeze all • High response (15 -25 follicles): a bolus of 1, 500 IU h. CG on retrieval day • Normal response: an alternative to h. CG trigger Humaidan and plyzos F&S 2014
THE ADVANTAGE FOR THE ‘NORMAL RESPONDER’ Antagonist FSH/h. MG Agonist trigger OPU 36 hours 1500 IU h. CG ET 4 days 1500 IU h. CG Kol S, et al. Human Reprod 2011; 26: 2874– 2877
Stimulation characteristics and embryology data Stimulation (days) 9. 3 ± 2. 0 Gn. RH antagonist (days) 3. 8 ± 0. 9 FSH (units) 2443 ± 925 E 2 day of trigger (pmol/L) 3764 ± 1227 P day of trigger (nmol/L) 2. 4 ± 1. 65 LH day of trigger (IU/L) 1. 9 ± 1. 3 Oocytes retrieved 6. 7 ± 2. 5 Embryos obtained 3. 6 ± 1. 7 Embryos transferred 2. 9 ± 0. 9 Embryos frozen 0. 8 ± 1. 5 Beta h. CG (IU/L) 152 ± 86 E 2 (day of pregnancy test, pmol/L) 6607 ± 3789 P (day of pregnancy test, nmol/L) 182 ± 50 Values are mean ± SD Reproductive outcomes Positive h. CG/cycle, n (%) 11/15 (73) Clinical ongoing pregnancy, n (%) 7/15 (47) Early pregnancy loss, n (%) 4/11 (36) Kol S, et al. Human Reprod 2011; 26: 2874– 2877
Dual trigger improves: • Implantation rate • Clinical pregnancy rate • Live birth rate Lin et al, 2013
SPECIAL CASES üEmpty follicles üRecurrent IVF failure
IS FSH SURGE REDUNDANT IN ALL WOMEN? ? ? Beck-Fruchter at al 2012
SURVEY RESULTS: Triggering of ovulation with Gn. RH-a in ART: Worldwide feedback on an emerging new option with great potential Take home message “The results of this survey indicate that Gn. RH trigger is widely used worldwide and therefore has become part of the standard of care today. Hence, doctors are entitled to prescribe it just as patients may ask that this option is considered in their case. ”
“Agonist triggering is viewed as one of the major advances in ovarian stimulation, with the potential to eliminate OHSS…”
Revolution in the making In Out Antagonist-based protocols “long agonist” protocols Agonist trigger h. CG trigger LH activity-based luteal support Progesterone-based luteal support Total OHSS elimination ~1% severe OHSS Patient friendly luteal phase Painful P injections or leaky, messy vaginal P. Thank you
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