INCREASED RISK OF EARLYPREGNANCY LOSS AND LOWER LIVE BIRTH RATE WITH GNRH ANTAGONIST VS LONG GNRH AGONIST PROTOCOL IN PCOS WOMEN UNDERGOING CONTROLLED OVARIAN HYPERSTIMULATION.

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Published Dec 9, 2009
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Vol. 87 No. 12 (2009): Issue Dec 2009

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Moez Kdous
Anis Chaker
Maha Bouyahia
Fethi Zhioua

Abstract

Aim: to compare standard long GnRH agonist protocol (Triptorelin) and GnRH antagonist regimens (Cetrorelix) in polycystic ovary syndrome (PCOS) patients undergoing controlled ovarian stimulation (COS) for ICSI cycles.
Methods: Retrospective case-control study. 106 PCOS patients undergoing COS for ICSI with long GnRH agonist protocol (Triptorelin) were matched with age and BMI to 106 PCOS patients undergoing COS for ICSI with GnRH antagonist (Cetrorelix) during the same period. Ovarian stimulation with recombinant follicle stimulating hormone (rFSH) was used in the two groups. Oral contraceptive pill pretreatment was used in all patients undergoing ovarian stimulation using GnRH antagonists. ICSI was performed for male infertility in all cases. The main outcome measures evaluated were: cancellation of the cycles, number of aspirated follicles, oocyte maturity, fertilization rate, Embryo quality, pregnancy and implantation rates, clinical abortion rate, multiple pregnancy rate and the live birth rate rate. Kchi2 test and t Student test were used for differences between normo-ovulatory and PCOS patients and the limit of significance was set at p<0.05.
Results: There was no significant difference in term of cancellation rate (2.8% vs 1.8%; NS). Duration of gonadotrophin stimulation (9,7 ± 0,7 vs 11,2 ± 1,9 days; p<0,001) and gonadotrophin consumption ( 2209,0 ± 548,3 vs 1411,1 ± 217,9 UI : p<0,001) were significantly decreased with GnRH antagonist. The mean  oestradiol level on the triggering day was significantly higher in the agonist group (3347,85 ± 99 vs 2354,45 ± 839; p<0,001 ). A fall in LH level of ³ 50% from stimulation day 8 (S8) to S1 was observed in GnRH antagonist group. Risk of ovarian hyperstimulation syndrome (OHSS) was significantly decreased with GnRH antagonist (1.8% vs 10.7%; p=0.01). The mean number of retrival oocytes (15.9 ± 5.9 vs 17.3± 8.3; ns) and the mean number of mature oocytes (11.43±4.2 vs 11.9± 6.4; ns) were similar in the two groups. fertilization rate (73.3% vs 75.8%; NS), mean number of grade 1 and 2 embryos (6.3±2.7 vs 6.9±3.9; NS), mean number of transferred embryos (1.9±0,7 vs 1.8±0,7 ; NS), implantation rate (13.3% vs 18.45%; ns) and clinical pregnancy rate per transfer (28.6% vs 31.1% ; NS) did not differ statistically in the two groups. Twin and triplet pregnancies rates were also similar in the two groups (7.1% vs 9.3% ; NS) and (3.5% vs 3.1% ; NS) respectively. Live birth rate (12.2% vs 20.7%; p<0.001) was significantly lower in GnRH antagonist group and miscarrage rate was significantly higher in this same group (42.8% vs 18.7%; p<0.001).
Conclusion : GnRH antagonist protocol is a short and simple protocol with a significant reduction in incidence of OHSS and amount of gonadotrophins.
However, GnRH antagonist protocol provides a lower live birth rate and an increased risk of early pregnancy loss compared to the GnRH agonist long protocol. Further studies are necessary for more solid conclusions.

Keywords:

GnRH antagonists, GnRH agonists, PCOS, ICSI

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References

  1. [1]. Kolibianakis EM, Collins J, Tarlatzis BC, Devroey P, Diedrich K, Griesinger G. Among patients treated for IVF with gonadotrophins and GnRH analogues, is the probability of live birth dependent on the type of analogue used? A systematic review and meta-analysis. Hum Reprod Update 2006; 12: 651-71.
  2. [2]. Al-Inany HG, Abou-Setta AM, Aboulghar M. Gonadotrophinreleasing hormone antagonists for assisted conception. A Cochrane review. Reprrod Biomed Online 2007; 14:640-9.
  3. Lainas TG, Petsas GK, Zorzovilis IZ, Iliadis GS, Lainas GT, Cazlaris HE, Kolibianakis EM. Initiation of GnRH antagonist on Day 1 of stimulation as compared to the long agonist protocol in PCOS patients. A randomized controlled trial: effect on hormonal levels and follicular development. Hum Reprod 2007; 22 :1540-6.
  4. Sahu B, Ozturk O, Ranierri M, Serhal P. Comparison of oocyte quality and intracytoplasmic sperm injection outcome in women with isolated polycystic ovaries or polycystic ovarian syndrome. Arch Gynecol Obstet. 2008; 277: 239-44.
  5. The Rotterdam ESHRE/ASRM-Sponsored PCOS. Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome. Hum Reprod 2004; 81: 19-25.
  6. Navot D, Bergh PA, Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies : prevention and treatment. Fertil Steril 1992 ; 58 : 249-61.
  7. Ragni G, Vegetti W, Riccaboni A, Engl B, Brigante C, Crosignani PG. Comparaison of GnRH agonists in assisted reproduction cycles of patients at high risk of ovarian hyperstimulation syndrome. Human Reproduction 2005; 20: 2421-5.
  8. Bahceci M, Ulug U, Ben-Shlomo I, Erden HF, Akman M. Use of GnRH antagonist in controlled ovarian hyperstimulation for assisted conception in women with polycystic ovary disease: a randomized, prospective, pilot study. Journal of reproductive medicine 2005; 50: 84-90.
  9. The European and meaddle East Orgalutran Study Group. Comparable clinical outcome using the GnRH antagonist ganirelix or a long protocol of the GnRH agonist triptorelin for the prevention of premature LH surges in women undergoing ovarian stimulation. Hum Reprod 2001; 16: 644-51.
  10. The European Orgalutran Study Group. Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient results of a controlled, randomized, multicentre trial. Hum Reprod 2000; 15: 1490-8.
  11. The North American Ganirelix Study Group. Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation. Fertil Steril 2001; 75: 38-45.
  12. Griesinger G, Venetis CA, Marx T, Diedrich K, Tarlatzis BC, Kolibianakis EM. Oral contraceptive pill pretreatment in ovarian stimulation with GnRH antagonists for IVF. A systematic review and meta-analysis. Fertil Steril 2008; 90: 1055-63.
  13. Albano C, Felberbaum RE, Smitz J, et al. Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone-releasing hormone (LHRH)- antagonist cetrorelix and the LHRH-agonist buserelin. European Cetrorelix Study Group. Hum Reprod 2000; 15: 526-31.
  14. Olivennes F, Belaisch-Allart J, Emperaire JC et al. Prospective, randomized, controlled study of in vitro fertilization-embryo transfer with a single dose of luteinizing hormone-releasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LR-RH agonist (triptorelin). Fertil Steril 2000; 73: 314-20.
  15. Delvigne A, Dubois M, Battheu B, Bassil S, Meuleman C, De Sutter P, et al. The ovarian hyperstimulation syndrome in in-vitro fertilization. A Belgian multicentric study.II. Multiple descriminant analysis for risk prediction. Hum Reprod 1993; 8: 1361-6.
  16. Griesinger G, Diedrich K, Tarlatzis BC, Kolibianakis EM. GnRH antagonists in ovarian stimulation for IVF in patients with poor response to gonadotrophins, polycystic ovary syndrome, and risk of ovarian hyperstimulation. A meta-analysis. Reprod Biomed Online 2006; 13: 628-38.
  17. Mathur R, Kailsasam C, Jenkins J. Review of the evidence base of strategies to prevent ovarian hyperstimulation syndrome. Hum Fertil 2007;10:75-85.
  18. Alcione L.A. Silva, Lauriane G.A. Abreu, Ana Carolina J.S. Rosae- Silva, Rui A. Ferriani, Marcos F. Leuprolide acetate reduces both in vivo and in vitro ovarian steroidogenesis in infertile women. Steroids 2008; 73: 1475-1484.
  19. Aboulghar MA, Mansour RT, Amin YM, Al-Inany HG, Aboulghar MM, Serour GI. Prospective randomized study comparing coasting with GnRH antagonist administration in patients at risk for severe OHSS. Reprod Biomed Online 2007; 15: 271-9.
  20. Griesinger G, Kolibianakis EM, Papanikolaou EG, Diedrich K, Van steirteghem A, Devroey P. Triggering of final oocyte maturation with gonadotrophin-releasing hormone agonist or human chorionic gonadotropin. Live birth after frozen-thawed embryo replacement cycles. Fertil Steril 2007; 88: 616-21.
  21. Le Du A, Kadoch IJ, Bourcigaux N, Doumerc S, Bourrier MC, Chevalier N, et al. In vitro oocyte maturation for the treatment of infertility associated with polycystic ovarian syndrome. The french experience. Hum Reprod 2005; 20: 420-4.
  22. Felberbaum RE, Diedrich K. Gonadotrophin-releasing hormone antagonist: will they replace the agonists? Reprod Biomed Online 2003; 6: 43-53.
  23. Olivennes F, Fanchin R, Bouchard P, Taieb J, Frydman R. Triggering of ovulation by a gonadotropin-releasing hormone (GnRH) agonist in patients pretreated with a GnRH antagonist. Fertil Steril 1996; 66: 151-3.
  24. Devaux A, Pouly JL, Bachelot A, Mourouvin Z, De Mouzon J. Les antagonistes du GnRH: effets biologiques. Gynécol Obstét Fertil 2004 ; 32 : 741-47.
  25. Rajkumar K, Dheen T, Kresk M, Murphu LJ. Impaired estrogen action in the uterus og IGF binding protein-1 transgenic mice. Endocrinology 1996; 137: 1258-64.
  26. Ohlsson R, Holmgren L, Glaser A, Szpecht A, Pfeifer-Ohlsson S. IGFII and short- range stimulatory loops in control of human placental growth. EMBO J 1989; 8: 1993-9.
  27. Rashid MR, Ong FB, Omar MH, Ng SP, Nurshaireen A, Sharifah- Teh NS, Fazilah AH, Zamzarina MA. GnRH agonist and GnRH antagonist in intracytoplasmic injection cycles. Med J Malaysia 2008 ; 63:113-7.
  28. Rackow BW, Kliman HJ, Taylor HS. GnRH antagonists may affect endometrial receptivity.Fertil Steril 2008;89:1234-9.
  29. Franco Jr J, Baruffi RLR, Mauri AL, Petersen CG, Felipe V, Oliveira JBA. GnRH antagonists vs GnRH agonists in poor ovarian responders: a meta-analyse. Reprod Biomed Online. 2006; 13: 618- 27.
  30. Fasioloutis SJ, Laufer N, Sabbagh-Ehrlich S, Lewin A, Hurwitz A, Simon A. Gonadotropin-releasing hormone (GnRH)-antagonist versus GnRH-agonist in ovarian stimulation of poor responders undergoing IVF. J Assist Reprod Genet 2003 ; 20 : 455-60.
  31. Kurzawa R, Ciepiela P, Baczkowski T, Safranow K, Brelik P. Comparaison of embryological and clinical outcome in GnRH antagonist vs GnRH agonist protocols for in vitro fertilization in PCOS non-obese patients. A prospective randomized study. J Assist Reprod Genet 2008; 25: 365-74.
  32. Kim CH, Lee YJ, Hong SH et al. Efficacy of GnRH antagonist during early and controlled ovarian hyperstimulation period in women with polycystic ovary syndrome undergoing IVF-ET. Hum Reprod 2004; 19:105-109.
  33. Westergraad LG, Laursen SB, Andersen CY. Increeased risk of early pregnancy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotrophic women undergoing assisted reproduction. Human Reprod 2000; 15: 1003-8.
  34. Diedrich K, Diedrich E, Santos E et al. Suppression of the endogenous LH-Surge By The GnRH antagonist Cetrorelix during ovarian stimulation. Hum Reprod 1994; 9: 788-91.
  35. Lahood R, Al-Jefout M, Tyler J, Ryan J, Driscoll G. A relative reduction in mid-follicular LH concentrations during GnRH agonist IVF/ICSI cycles leads to lower live birth. Hum Reprod 2006; 10: 2645-49.
  36. Griesinger G, Diedrich K, Deveroy P, Kolibianakis EM. GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol. A systematic review and meta-analysis. Hum Reprod Update 2005; 20: 1213-20.
  37. [Cedrin-Durnerin I, Grange-Dujardin D, Laffy A, Parneix I, Massin N, Galey J, and al. Recombinant LH supplementation during GnRH antagonist administration in IVF/ICSI cycles. A prospective randomized study. Hum Reprod 2004; 19: 1979-84.
  38. Baruffi RL, Mauri AL, Petersen CG, Felipe V, Martins AM, Cornicelli J, Cavagna M, Oliveira JB, Franco JG Jr. Recombinant LH supplementation to recombinant FSH during induced ovarian stimulation in the GnRH-antagonist protocol: a meta-analysis. Reprod Biomed Online 2007 ;14:14-25.
  39. Fatemi H, Kolibianakis EM, Camus M, Tournaye H, Van Steirteghem A, Devroye P. Progesterone combined with estradiol as luteal support in cycles stimulated with GnRH antagonist/rec-FSH for IVF. A randomized clinical trial. Fertil Steril 2005; 84 (supplement 1), S322.