Clinical Efficacy and Hormonal Change of GnRH Antagonist in Controlled Ovarian Stimulation for IVF-ET

체외수정시술을 위한 과배란유도에 있어 GnRH Antagonist의 임상적 효용성과 혈중 호르몬 농도의 변화

  • Moon, Shin-Yong (Department of Obstetrics and Gynecology, College of Medicine, Seoul National University) ;
  • Chun, Eun-Kyung (Department of Obstetrics and Gynecology, College of Medicine, Seoul National University) ;
  • Kim, Sang-Don (Department of Obstetrics and Gynecology, College of Medicine, Seoul National University) ;
  • Choi, Young-Sik (Department of Obstetrics and Gynecology, College of Medicine, Seoul National University) ;
  • Jee, Byung-Chul (Department of Obstetrics and Gynecology, College of Medicine, Seoul National University) ;
  • Ku, Seung-Yup (Department of Obstetrics and Gynecology, College of Medicine, Seoul National University) ;
  • Suh, Chang-Suk (Department of Obstetrics and Gynecology, College of Medicine, Seoul National University) ;
  • Choi, Young-Min (Department of Obstetrics and Gynecology, College of Medicine, Seoul National University) ;
  • Kim, Jung-Gu (Department of Obstetrics and Gynecology, College of Medicine, Seoul National University) ;
  • Kim, Seok-Hyun (Department of Obstetrics and Gynecology, College of Medicine, Seoul National University)
  • 문신용 (서울대학교 의과대학 산부인과학교실) ;
  • 천은경 (서울대학교 의과대학 산부인과학교실) ;
  • 김상돈 (서울대학교 의과대학 산부인과학교실) ;
  • 최영식 (서울대학교 의과대학 산부인과학교실) ;
  • 지병철 (서울대학교 의과대학 산부인과학교실) ;
  • 구승엽 (서울대학교 의과대학 산부인과학교실) ;
  • 서창석 (서울대학교 의과대학 산부인과학교실) ;
  • 최영민 (서울대학교 의과대학 산부인과학교실) ;
  • 김정구 (서울대학교 의과대학 산부인과학교실) ;
  • 김석현 (서울대학교 의과대학 산부인과학교실)
  • Published : 2004.12.30

Abstract

Objectives: To evaluate the efficacy of GnRH antagonist cetrorelix in women undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) and to determine changes in serum hormone concentrations during cetrorelix administration. Methods: We performed a clinical trial on 30 patients undergoing COH with highly purified follicular stimulating hormone (HP-FSH) and gonadotropin releasing hormone antagonist (GnRHant), cetrorelix. FSH was administrated from day 2 or 3 of cycle with fixed dose and adjusted according to individual response. 0.25 mg of cetrorelix was injected daily subcutaneously from stimulation day 5 until the day of hCG administration. Daily ultrasound monitoring was performed for growing follicles and serum levels of luteinizing hormone (LH), estradiol ($E_2$) and progesterone were measured daily during cetrorelix administration. Up to 4 embryos were transferred. Results: Mean age of enrolled patients was $32.0{\pm}3.4$ years (mean $\pm$ S.D.). All of 30 patients underwent oocyte pick-up, and embryo transfer was done in 28 patients. The total and mean numbers of received oocytes were 196 and $6.5{\pm}4.7$, the number of fertilized eggs was 111, and the fertilization rate was 56.6%. Total duration of FSH administration was $9.2{\pm}2.2$ days and mean of $24.3{\pm}7.7$ ampules of HP-FSH was administered. Total duration of cetrorelix administration was $5.7{\pm}1.9$ days. Serum LH and progesterone levels were maintained in the range of $1.4{\sim}2.9\;mIU/mL$ and $0.3{\sim}0.6\;ng/mL$, which respectively reflected effective prevention of premature LH surge. Clinical pregnancies were achieved in 9 patients, and overall clinical pregnancy rate was 30.0% per oocyte retrieval, and 32.1% per embryo transfer. Conclusion: GnRH antagonist is safe and convenient for COH for IVF-ET and effective with optimal pregnancy rate.

Keywords

References

  1. Porter RN, Smith W, Craft LL. Induction of ovula-tion for in vitro fertilization using buserelin and gonadotrophin. Lancet 1984; 324: 1284-5
  2. MacLachlan V, Besanko M, O'Shea F, Wade H, Wood C, Trounson A, et al. A controlled study of luteinizing hormone-releasing hormone agonist (bu-serelin) for the induction of folliculogenesis before in vitro fertilization. N Engl J Med 1989; 320: 1233-7 https://doi.org/10.1056/NEJM198905113201902
  3. Juan CB Del Gadillo, Ernst S, Ralf D, Ludwig W, Norbert L. Comparison of GnRH agonist and anta-gonist in unselected IVF/ICSI patient treated with different controlled ovarian hyperstimulation proto-cols: a matched study. Eur J Obstet Gynecol Reprod Biol 2002; 102: 179-83 https://doi.org/10.1016/S0301-2115(01)00580-2
  4. Smitz J, Ron-El R, Tarlatzis BC. The use of gona-dotropin-releasing hormone agonists for in vitro fer-tilization and other assisted procreation techniques: experience from three centers. Hum Reprod 1992; 7: S49-66 https://doi.org/10.1093/humrep/7.suppl_1.49
  5. Hahn DW, McGuire JL, Vale WW, Rivier J. Reproductive/endocrine and anaphylactoid properties of an LHRH-antagonist, ORF 18260 [Ac-DNAL1(2), 4FDPhe2,D-Trp3,D-Arg6]-GnRH. Life Sci 1985; 37: 505-14. https://doi.org/10.1016/0024-3205(85)90462-X
  6. Behre HM, Klein B, Steinmeyer E, McGregor GP, Voigt K, Nieschlag E. Effective suppression of lute-inizing hormone and testosterone by single doses of the new gonadotropin-releasing hormone antagonist cetrorelix (SB-75) in normal men. J Clin Endocrinol Metab 1992; 75: 393-8 https://doi.org/10.1210/jc.75.2.393
  7. Albano C, Smitz J, Camus M, Riethmuller-Winzen H, Van Steirteghem A, Devroey P. Comparison of different doses of gonadotropin-releasing hormone antagonist Cetrorelix during controlled ovarian hyperstimulation. Fertil Steril 1997; 67: 917-22 https://doi.org/10.1016/S0015-0282(97)81407-0
  8. Reissmann TH, Felberbaum R, Diedrich K, Engel J, Comaru-Schally AM, Schally AV. Development and application of luteinizing hormone antagonists in treatment of infertility: an overview. Hum Reprod 1995; 10: 1974-81
  9. Albano C, Felberbaum RE, Smitz J, Riethmuller-Winzen H, Engel J, Diedrich K, et al. Ovarian sti-mulation with HMG: results of a prospective randomized phase III European study comparing the lute-inizing hormone-releasing hormone (LHRH)-anta-gonist cetrorelix and the LHRH-agonist buserelin. European Cetrorelix Study Group. Hum Reprod 2000; 15: 526-31. https://doi.org/10.1093/humrep/15.3.526
  10. Olivennes F, Belaisch-Allart J, Emperaire JC, De-chaud H, Alvarez S, Moreau L, et al. Prospective, randomized, controlled study of in vitro fertilization-embryo transfer with a single dose of a luteinizing hormone-releasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LH-RH agonist (triptorelin). Fertil Steril 2000; 73: 314-20 https://doi.org/10.1016/S0015-0282(99)00524-5
  11. Larry IB, Samuel JC, Bradley SH, Richard PD. A randomized prospective trial comparing GnRH anta-gonist/rFSH versus GnRH agonist/rFSH in women pretreated with oral contraceptives prior to IVF. Fertil Steril 2003; 80: S104-5
  12. Stanley GP, Judith LB, Milton WM, John KT, Hea-ther G, Renee M. Effect of GnRH antagonists on cancellation rates in IVF cycles. Fertil Steril 2003; 80: S182
  13. Sozos JF, Neri L, Shelley SE, Aby L, Arye H, Alex S. Gonadotropin-releasing hormone (GnRH)-anta-gonist versus GnRH-agonist in ovarian stimulation of poor responders undergoing IVF. J Assist Reprod Genet 2003; 20: 455-60 https://doi.org/10.1023/B:JARG.0000006707.88826.e7
  14. 김석현, 지병철, 정경남, 김희선, 류범용, 오선경 등. 체외수정시술시 다태임신의 예방에 관한 연구: 배아 등급과 누적배아지수의 의의. 대한산부회지 1995; 38: 2333-46
  15. 김석현, 오수영, 지병철, 정병준, 김희선, 류범용 등. 고식적 체외수정시술시 3일째 배아 이식술의 효용성에 관한 연구. 대한산부회지 1999; 42: 457-63
  16. 김석현, 심순섭, 지병철, 최성미, 김희선, 류범용 등. 난자 세포질내 정자 주입술을 이용한 체외수정시술시 누적 임신율에 관한 연구. 대한산부회지 2001; 44: 492-500
  17. 김석현, 구승엽, 지병철, 김은경, 천은경, 김희선 등. 체외수정시술시 5일간의 체외배양을 이용한 포배기 배아 이식술에 관한 연구. 대한산부회지 2001; 44: 2000-9
  18. Schally AV, Kastin AJ, Arimura A. Hypothalamic FSH and LH regulating hormone: structure, phy-siology and clinical studies. Fertil Steril 1971; 22: 703-21 https://doi.org/10.1016/S0015-0282(16)38580-6
  19. Maria EC, Ciro C, Gian LB, Gianfranco S. GnRH antagonist. Eur J Obstet Gynecol Reprod Biol 2004; 115: S44-56 https://doi.org/10.1016/j.ejogrb.2004.01.033
  20. Karen LH. Gonadotropin-releasing hormone anta-gonists. Curr Opin Pharmacol 2003; 3: 660-6 https://doi.org/10.1016/j.coph.2003.06.009
  21. Felberbaum RE, Reissmann T, Kupker W, Bauer O, al Hasani S, Diedrich C, et al. Preserved pituitary response under ovarian stimulation with HMG and GnRH antagonists (Cetrorelix) in women with tubal infertility. Eur J Obstet Gynecol Reprod Biol 1995; 61: 151-5 https://doi.org/10.1016/0301-2115(95)02138-W
  22. Reissmann T, Felberbaum R, Diedrich K, Engel J, Comaru-Schally AM, Schally AV. Development and applications of luteinizing hormone-releasing hor-mone antagonists in the treatment of infertility: an overview. Hum Reprod 1995; 10: 1974-81 https://doi.org/10.1093/oxfordjournals.humrep.a136219
  23. Albino C, Smitz J, Camus M, Bennink HC, Van Steiteghem AC, Devroey P. Hormonal profile during the follicular phase in cycles stimulated with a com-bination of human menopausagonadotrophin and gonadotrophin-releasing hormone antagonist cetro-relix. Hum Reprod 1996; 11: 2114-8 https://doi.org/10.1093/oxfordjournals.humrep.a019058
  24. Borm G, Mannaerts B. Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recom-binant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial. The European Orgalutran Study Group. Hum Reprod 2000; 15: 1490-8 https://doi.org/10.1093/humrep/15.7.1490
  25. Felberbaum RE, Albano C, Ludwig M, Riethmuller-Winzen H, Grigat M, Devroey P, et al. Ovarian stimulation for assisted reproduction with HMG and concomitant midcycle administration of the GnRH antagonist cetrorelix according to the multiple dose protocol: a prospective uncontrolled phase III study. Hum Reprod 2000; 15: 1015-20 https://doi.org/10.1093/humrep/15.5.1015
  26. Ludwig M, Felberbaum RE, Devroey P, Albino C, Riethmuller-Winzen H, Schuler A, et al. Significant reduction of the incidence of ovarian hyperstimula-tion syndrome (OHSS) by using the LHRH anta-gonist Cetrorelix (Cetrotide) in controlled ovarian stimulation for assisted reproduction. Arch Gynecol Obstet 2000; 264: 29-32 https://doi.org/10.1007/PL00007479
  27. Olivennes F, Mannaerts B, Struijs M, Bonduelle M, Devroey P. Perinatal outcome of pregnancy after GnRH antagonist (ganirelix) treatment during ovar-ian stimulation for conventional IVF or ICSI: a pre-liminary report. Hum Reprod 2001; 16: 1588-91 https://doi.org/10.1093/humrep/16.8.1588
  28. Boerrigter PJ, De Bie JJ, Mannaerts BM, Van Leeu-wen BP, Passier Timmermans DP. Obstetrical and neonatal outcome after controlled ovarian stimula-tion for IVF using the GnRH antagonist ganirelix. Hum Reprod 2002; 17: 2027-34 https://doi.org/10.1093/humrep/17.8.2027
  29. 이방현, 김정훈, 오영미, 김성훈, 채희동, 강병문. 체외수정시술을 위한 과배란유도에 있어 GnRH Antagonist 다회투여법과 GnRH Agonist 장기요법의 비교 연구. 대한산부회지 2003; 46: 1202-8
  30. 이은실, 김동호, 배도환, 이상훈. 저반응군 환자에서 GnRH Antagonist를 이용한 과배란유도의 효용성에 관한 연구. 대한산부회지 2003; 46: 1999-2004
  31. 정진호, 김동호, 이상훈. 보조 생식 시술의 과 배란유도에서 GnRH antagonist를 사용한 mini-malstimulation protocol의 임상적 효용성에 관한 연구. 대한산부회지 2004; 47: 38-44