GnRH Agonists And Antagonists: Current Aspects

Abstract

GnRH agonists have been widely accepted in some clinical aspects such as symptomatic endometriosis or leimyomata. Since assisted reproductive technologies have been appeared, GnRH agonists have expanded its clinical usage. Although the flare up effect of agonists has been noted, its application during controlled ovarian hyperstimulation in order to inhibit premature ovulation had been valid without an alternative medication for a long period. Once the GnRH antagonists had been discovered which have been attributed to have no flare up effect with a lower ovarian hyperstimulation syndrome incidence and decrease in requirement of total exogenous gonadotrophin use, it is still controversial whether GnRH antagonists or agonists are more suitable for a optimum ovarian stimulation protocol. In this review, the performance of agonists and antagonists during controlled ovarian hyperstimulation and clinical or ongoing pregnancy rates have been detailed with clinical studies and recent recommendations. Key words: GnRH agonist, GnRH antagonist, In vitro fertilization, Assisted reproduction technics, Pregnancy.

Keywords

• GnRH agonist, GnRH antagonist, In vitro fertilization, Assisted reproduction technics, Pregnancy.

GnRH Agonistleri Ve Antagonistleri: Güncel Yönleri

Öz

Semptomatik endometriosis ve leimyoma gibi sebeplerden dolayı zaten kullanılmakta olan GnRH agonistleri, yardımcı üreme tekniklerinin ortaya çıkmasıyla birlikte kendisine daha da geniş kullanım alanı bulmuştur. İlk uygulandığında mevcut hipofizer gonadotropinlerin hızlıca salınmasına bağlı ortaya çıkan alevlendirici (flare up) etkisi aslında istenmeyen bir yan etkisi olsa da erken spontan ovulasyonu baskılamak amacıyla yakın zamana kadar alternatifsiz olarak kullanılagelmiştir. Alevlendirici etkisinin olmadığı, ovaryan hiperstimülasyon sendromunun daha az izlendiği, toplam eksojen gonadotropin ihtiyacının daha düşük olduğu iddia edilen GnRH antagonistlerinin ortaya çıkması ile birlikte, klinisyenler arasında hangisinin genel yönleriyle daha uygun olduğu hakkında ki tartışmalar yapılan karşılaştırmalı çalışmalar ile halen devam etmektedir. Yapılan bu derlemede, mevcut klinik çalışmalar ve güncel bilgiler çerçevesinde, GnRH agonist ve antagonistleri gerek kontrollü ovaryan stimülasyon performansları, gerekse de gebelik oranları açısından detaylıca değerlendirilmektedir. Anahtar kelimeler: GnRH agonist, GnRH antagonist, In vitro fertilizasyon, Yardımcı üreme teknikleri, Gebelik.

Anahtar Kelimeler

• GnRH agonist, GnRH antagonist, In vitro fertilizasyon, Yardımcı üreme teknikleri, Gebelik.

Kaynakça

1. King JA, Millar RP. Evolutionary aspects of gonadotropin-releasing hormone and its receptor. Cell Mol Neurobiol 1995;15:5-23.
2. White RB, Eisen JA, Kasten TL, Fernald RD. Second gene for gonadotropin- releasing hormone in humans. Proc Natl Acad Sci U S A 1998;95:305-9.
3. Grundker C, Gunthert AR, Millar RP, Emons G. Expression of gonadotropin- releasing hormone II (GnRH-II) receptor in human endometrial and ovarian cancer cells and effects of GnRH-II on tumor cell proliferation. J Clin Endocrinol Metab 2002;87:1427-30.
4. Tanriverdi F, Gonzalez-Martinez D, Silveira LF, Hu Y, Maccoll GS, Travers P, et al. Expression of gonadotropin-releasing hormone type-I (GnRH-I) and type-II (GnRH- II) in human peripheral blood mononuclear cells (PMBCs) and regulation of B- lymphoblastoid cell proliferation by GnRH-I and GnRH-II. Exp Clin Endocrinol Diabetes 2004;112:587-94.
5. Millar RP. GnRH II and type II GnRH receptors. Trends Endocrinol Metab 2003;14:35-43.
6. Loutradis D, Drakakis P, Kallianidis K, Bletsa R, Milingos S, Makris N, et al. The effect of the duration of GnRH-agonist down regulation before ovarian stimulation on the biological and clinical outcome after intracytoplasmic sperm injection. Eur J Obstet Gynecol Reprod Biol 1998;80:251-5.
7. Murase M, Uemura T, Gao M, Inada M, Funabashi T, Hirahara F. GnRH antagonist- induced down-regulation of the mRNA expression of pituitary receptors: comparisons with GnRH agonist effects. Endocr J 2005;52:131-7.
8. Malmusi S, La Marca A, Giulini S, Xella S, Tagliasacchi D, Marsella T, et al. Comparison of a gonadotropin-releasing hormone (GnRH) antagonist and GnRH agonist flare-up regimen in poor responders undergoing ovarian stimulation. Fertil Steril 2005;84:402-6.

9. Hazum E, Koch Y, Liscovitch M, Amsterdam A. Intracellular pathways of receptor- bound GnRH agonist in pituitary gonadotropes. Cell Tissue Res 1985;239:3-8.
10. Schally AV, Nair RM, Redding TW, Arimura A. Isolation of the luteinizing hormone and follicle-stimulating hormone-releasing hormone from porcine hypothalami. J Biol Chem 1971;246:7230-6.
11. Hoshiai H. Current guidelines for treatment of endometriosis. The present status in Japan. Drugs Today (Barc) 2005;41 Suppl A:17-21.
12. Furui T, Imai A, Takagi A, Tamaya T, Takagi H, Matsunami K, et al. Differential efficacy of gonadotropin-releasing hormone (GnRH) agonist treatment on pedunculated and degenerated myomas: a retrospective study of 630 women. J Obstet Gynaecol 2000;20:504-6.
13. Stanhope R, Traggiai C. Precocious puberty (complete, partial). Endocr Dev 2004;7:57-65.
14. Kupker W, Felberbaum RE, Krapp M, Schill T, Malik E, Diedrich K. Use of GnRH antagonists in the treatment of endometriosis. Reprod Biomed Online 2002;5:12-6.
15. Todd NF, Lieberman R, Gulley JL, Dahut W, Arlen PM. Prolonged response to nilutamide in a patient with stage D0.5 prostate cancer who previously failed androgen deprivation therapy. Am J Ther 2005;12:172-4.
16. Speroff L, editor. Clinical Gynecologic Endocrinology and Infertility. 7 ed. Philadelphia: Lippincott Willimas and Wilkins; 2005.
17. Ludwig M, Katalinic A, Diedrich K. Use of GnRH antagonists in ovarian stimulation for assisted reproductive technologies compared to the long protocol. Meta-analysis. Arch Gynecol Obstet 2001;265:175-82.
18. Olivennes F, Fanchin R, Ledee N, Righini C, Bouchard P, Frydman R. [GnRH antagonists in IVF]. J Gynecol Obstet Biol Reprod (Paris) 2001;30:657-62; discussion 662-3.
19. Albano C, Felberbaum RE, Smitz J, Riethmuller-Winzen H, Engel J, Diedrich K, 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.
20. Akman MA, Erden HF, Tosun SB, Bayazit N, Aksoy E, Bahceci M. Comparison of agonistic flare-up-protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders: results of a prospective randomized trial. Hum Reprod 2001;16:868-70.
21. 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.
22. de Jong D, Macklon NS, Eijkemans MJ, Mannaerts BM, Coelingh Bennink HJ, Fauser BC. Dynamics of the development of multiple follicles during ovarian stimulation for in vitro fertilization using recombinant follicle-stimulating hormone (Puregon) and various doses of the gonadotropin-releasing hormone antagonist ganirelix (Orgalutran/Antagon). Fertil Steril 2001;75:688-93.
23. Al-Inany H. GnRH agonist versus antagonist therapy. Hum Reprod 2002;17:1413; author reply 1413-4.
24. Borm G, Mannaerts B. 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. The European Orgalutran Study Group. Hum Reprod 2000;15:1490-8.
25. Olivennes F, Rongieres C, Fanchin R, Frydman R. [Perspectives in the use of GnRh antagonists]. Contracept Fertil Sex 1998;26:187-8.
26. Hernandez ER. Embryo implantation and GnRH antagonists: embryo implantation: the Rubicon for GnRH antagonists. Hum Reprod 2000;15:1211-6.
27. Wilcox J, Potter D, Moore M, Ferrande L, Kelly E. Prospective, randomized trial comparing cetrorelix acetate and ganirelix acetate in a programmed, flexible protocol for premature luteinizing hormone surge prevention in assisted reproductive technologies. Fertil Steril 2005;84:108-17.
28. Wikland M, Bergh C, Borg K, Hillensjo T, Howles CM, Knutsson A, et al. A prospective, randomized comparison of two starting doses of recombinant FSH in combination with cetrorelix in women undergoing ovarian stimulation for IVF/ICSI. Hum Reprod 2001;16:1676-81.
29. Fanchin R, Salomon L, Castelo-Branco A, Olivennes F, Frydman N, Frydman R. Luteal estradiol pre-treatment coordinates follicular growth during controlled ovarian hyperstimulation with GnRH antagonists. Hum Reprod 2003;18:2698-703.
30. Ortmann O, Weiss JM, Diedrich K. Embryo implantation and GnRH antagonists: ovarian actions of GnRH antagonists. Hum Reprod 2001;16:608-11.
31. Itskovitz-Eldor J, Kol S, Mannaerts B. Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH 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. Hum Reprod 2000;15:1965-8.
32. Fauser BC, de Jong D, Olivennes F, Wramsby H, Tay C, Itskovitz-Eldor J, et al. Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization. J Clin Endocrinol Metab 2002;87:709-15.
33. Ludwig M, Felberbaum RE, Devroey P, Albano C, Riethmuller-Winzen H, Schuler A, et al. Significant reduction of the incidence of ovarian hyperstimulation syndrome (OHSS) by using the LHRH antagonist Cetrorelix (Cetrotide) in controlled ovarian stimulation for assisted reproduction. Arch Gynecol Obstet 2000;264:29-32.
34. Kolibianakis E, Zikopoulos K, Albano C, Camus M, Tournaye H, Van Steirteghem A, et al. Reproductive outcome of polycystic ovarian syndrome patients treated with GnRH antagonists and recombinant FSH for IVF/ICSI. Reprod Biomed Online 2003;7:313-8.
35. Kolibianakis EM, Albano C, Camus M, Tournaye H, Van Steirteghem AC, Devroey P. Initiation of gonadotropin-releasing hormone antagonist on day 1 as compared to day 6 of stimulation: effect on hormonal levels and follicular development in in vitro fertilization cycles. J Clin Endocrinol Metab 2003;88:5632-7.
36. Kolibianakis EM, Albano C, Camus M, Tournaye H, Van Steirteghem AC, Devroey P. Relationship between LH and oestradiol in IVF cycles before GnRH antagonist initiation. Reprod Biomed Online 2003;7:190-3.
37. Surrey ES, Schoolcraft WB. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. Fertil Steril 2000;73:667-76.
38. Akman MA, Erden HF, Tosun SB, Bayazit N, Aksoy E, Bahceci M. Addition of GnRH antagonist in cycles of poor responders undergoing IVF. Hum Reprod 2000;15:2145-7.