Strategies for Pituitary Down-regulation to Optimize IVF/ICSI Outcome in Poor Ovarian Responders

Badawy, Ahmed; Wageah, Alaa; EL-Gharib, Mohamed; Osman, Ezz Eldin

Strategies for Pituitary Down-regulation to Optimize IVF/ICSI Outcome in Poor Ovarian Responders

Authors

Ahmed Badawy

Alaa Wageah

Mohamed EL-Gharib

Ezz Eldin Osman

College of Medicine, Al-Jouf University, Mansoura, Egypt

Abstract

The ovarian stimulation of poor responders still remains a challenging task for clinicians. There are numerous strategies that have been suggested to improve the outcome in poor responders but there is still no one pituitary down-regulation protocol that best suits all women with such condition. Traditional GnRH agonist flare and long luteal phase protocols do not appear to be advantageous. Reduction of GnRH agonist doses, "stop" protocols, and microdose GnRH agonist flare regimes all appear to improve outcomes, although the proportional benefit of one approach over another has not been convincingly established. GnRH antagonists improve outcomes in this patient population, although, in general, pregnancy rates appear to be lower in comparison to microdose GnRH agonist flare regimes.

Keywords

ICSI

IVF

Poor ovarian response

Howles CM, Macnamee MC, Edwards RG. Short term use of an LHRH agonist to treat poor responders entering an in-vitro fertilization programme. Hum Reprod. 1987;2(8):655-6.

Marcus SF, Brinsden PR, Macnamee M, Rainsbury PA, Elder KT, Edwards RG. Comparative trial between an ultra-short and long protocol of luteinizing hormone-releasing hormone agonist for ovarian stimulation in in-vitro fertilization. Hum Reprod. 1993;8(2):238-43.

Scott RT, Neal GS, Illions EH, Hayslip CA, Hofmann GE. The duration of leuprolide acetate administration prior to ovulation induction does not impact ovarian responsiveness to exogenous gonadotropins. Fertil Steril. 1993;60(2):247-53.

Deaton JL, Bauguess P, Huffman CS, Miller KA. Pituitary response to early follicular-phase minidose gonadotropin releasing hormone agonist (GnRHa) therapy: evidence for a second flare. J Assist Reprod Genet. 1996;13(5):390-4.

Padilla SL, Dugan K, Maruschak V, Shalika S, Smith RD. Use of the flare-up protocol with high dose human follicle stimulating hormone and human menopausal gonadotropins for in vitro fertilization in poor responders. Fertil Steril. 1996;65(4):796-9.

Toth TL, Awwad JT, Veeck LL, Jones HW Jr, Muasher SJ. Suppression and flare regimens of gonadotropin-releasing hormone agonist. Use in women with different basal gonadotropin values in an in vitro fertilization program. J Reprod Med. 1996;41 (5):321-6.

Karande V, Morris R, Rinehart J, Miller C, Rao R, Gleicher N. Limited success using the "flare" protocol in poor responders in cycles with low basal follicle-stimulating hormone levels during in vitro fertilization. Fertil Steril. 1997;67(5):900-3.

Surrey ES, Bower J, Hill DM, Ramsey J, Surrey M W. Clinical and endocrine effects of a microdose GnRH agonist flare regimen administered to poor responders who are undergoing in vitro fertilization. Fertil Steril. 1998;69(3):419-24.

Schoolcraft W, Schlenker T, Gee M, Stevens J, Wagley L. Improved controlled ovarian hyperstimulation in poor responder in vitro fertilization patients with a microdose follicle-stimulating hormone flare, growth hormone protocol. Fertil Steril. 1997;67(1): 93-7.

Leondires MP, Escalpes M, Segars JH, Scott RT Jr, Miller BT. Microdose follicular phase gonadotropin-releasing hormone agonist (GnRH-a) compared with luteal phase GnRH-a for ovarian stimulation at in vitro fertilization. Fertil Steril. 1999;72 (6):1018-23.

Scott RT, Navot D. Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization. Fertil Steril. 1994;61 (5):880-5.

Kyrou D, Kolibianakis EM, Venetis CA, Papanikolaou EG, Bontis J, Tarlatzis BC. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Fertil Steril. 2009;91(3): 749-66.

Weissman A, Farhi J, Royburt M, Nahum H, Glezerman M, Levran D. Prospective evaluation of two stimulation protocols for low responders who were undergoing in vitro fertilization-embryo transfer. Fertil Steril. 2003;79(4):886-92.

Latouche J, Crumeyrolle-Arias M, Jordan D, Kopp N, Augendre-Ferrante B, Cedard L, et al. GnRH receptors in human granulosa cells: anatomical localization and characterization by autoradiographic study. Endocrinology. 1989;125(3):1739-41.

Kowalik A, Barmat L, Damario M, Liu HC, Davis O, Rosenwaks Z. Ovarian estradiol production in vivo. Inhibitory effect of leuprolide acetate. J Reprod Med. 1998;43(5):413-7.

Dirnfeld M, Fruchter O, Yshai D, Lissak A, Ahdut A, Abramovici H. Cessation of gonadotropin-releasing hormone analogue (GnRH-a) upon down-regulation versus conventional long GnRH-a protocol in poor responders undergoing in vitro fertilization. Fertil Steril. 1999;72(3):406-11.

Garcia-Velasco JA, Isaza V, Requena A, Martínez-Salazar FJ, Landazábal A, Remohí J, et al. High doses of gonadotrophins combined with stop versus non-stop protocol of GnRH analogue administration in low responder IVF patients: a prospective, randomized, controlled trial. Hum Reprod. 2000;15(11):2292-6.

Faber BM, Mayer J, Cox B, Jones D, Toner JP, Oehninger S, et al. Cessation of gonadotropin-releasing hormone agonist therapy combined with high-dose gonadotropin stimulation yields favorable pregnancy results in low responders. Fertil Steril. 1998;69(5):826-30.

Wang PT, Lee RK, Su JT, Hou JW, Lin MH, Hu YM. Cessation of low-dose gonadotropin releasing hormone agonist therapy followed by high-dose gonadotropin stimulation yields a favorable ovarian response in poor responders. J Assist Reprod Genet. 2002;19(1):1-6.

Schachter M, Friedler S, Raziel A, Strassburger D, Bern O, Ron-el R. Improvement of IVF outcome in poor responders by discontinuation of GnRH analogue during the gonadotropin stimulation phase--a function of improved embryo quality. J Assist Reprod Genet. 2001;18(4):197-204

Pinkas H, Orvieto R, Avrech OM, Rufas O, Ferber A, Ben-Rafael Z, et al. Gonadotropin stimulation following GnRH-a priming for poor responders in in vitro fertilization-embryo transfer programs. Gynecol Endocrinol. 2000;14(1):11-4.

Olivennes F, Righini C, Fanchin R, Torrisi C, Hazout A, Glissant M, et al. A protocol using a low dose of gonadotrophin-releasing hormone agonist might be the best protocol for patients with high follicle-stimulating hormone concentrations on day 3. Hum Reprod. 1996;11(6):1169-72.

Feldberg D, Farhi J, Ashkenazi J, Dicker D, Shalev J, Ben-Rafael Z. Minidose gonadotropin-releasing hormone agonist is the treatment of choice in poor responders with high follicle-stimulating hormone levels. Fertil Steril. 1994;62(2):343-6.

Albuquerque LE, Saconato H, Maciel MC, Baracat EC, Freitas V. Depot versus daily administration of GnRH agonist protocols for pituitary desensitization in assisted reproduction cycles: a Cochrane Review. Hum Reprod. 2003;18(10):2008-17.

Halmos G, Schally AV. Changes in subcellular distribution of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) after treatment with the LH-RH antagonist cetrorelix. Proc Natl Acad Sci U S A. 2002;99(2):961-5.

Kovacs M, Schally AV, Csernus B, Rekasi Z. Luteinizing hormone-releasing hormone (LH-RH) antagonist Cetrorelix down-regulates the mRNA expression of pituitary receptors for LH-RH by counteracting the stimulatory effect of endogenous LH-RH. Proc Natl Acad Sci U S A. 2001;98(4): 1829-34.

Al-Inany HG, Abou-Setta AM, Aboulghar M. Gonadotrophin-releasing hormone antagonists for assisted conception. Cochrane Database Syst Rev. 2006;(3):CD001750.

Mahutte NG, Arici A. Role of gonadotropin-releasing hormone antagonists in poor responders. Fertil Steril. 2007;87(2):241-9.

Craft I, Gorgy A, Hill J, Menon D, Podsiadly B. Will GnRH antagonists provide new hope for patients considered 'difficult responders' to GnRH agonist protocols? Hum Reprod. 1999;14(12): 2959-62.

Nikolettos N, Al-Hasani S, Felberbaum R, Demirel LC, Kupker W, Montzka P, et al. Gonadotropin-releasing hormone antagonist protocol: a novel method of ovarian stimulation in poor responders. Eur J Obstet Gynecol Reprod Biol. 2001;97(2): 202-7.

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(10):2145-7.

Sunkara SK, Coomarasamy A, Khalaf Y, Braude P. A three-arm randomised controlled trial comparing Gonadotrophin Releasing Hormone (GnRH) agonist long regimen versus GnRH agonist short regimen versus GnRH antagonist regimen in women with a history of poor ovarian response undergoing in vitro fertilisation (IVF) treatment: Poor responders intervention trial (PRINT). Reprod Health. 2007;4:12.

Akman MA, Erden HF, Tosun SB, Bayazit N, Aksoy E, Bahceci M. Comparison of agonistic flareup-protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders: results of a prospective randomized trial. Hum Reprod. 2001;16(5):868-70.

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(2):402-6.

Demirol A, Gurgan T. Comparison of microdose flare-up and antagonist multiple-dose protocols for poor-responder patients: a randomized study. Fertil Steril. 2009;92(2):481-5.

Martinez F, Coroleu B, Marques L, Parera N, Buxaderas R, Tur R, et al. [Comparison of “Short Protocol” versus “Antagonists” with or without Clomiphene Citrate for stimulation in IVF of patients with “low response”]. Rev Iberoam Fertil Reprod Hum. 2003;20:355–60. Italian.

Schmidt DW, Bremner T, Orris JJ, Maier DB, Benadiva CA, Nulsen JC. A randomized prospective study of microdose leuprolide versus ganirelix in in vitro fertilization cycles for poor responders. Fertil Steril. 2005;83(5):1568-71.

Kahraman K, Berker B, Atabekoglu CS, Sonmezer M, Cetinkaya E, Aytac R, et al. Microdose gonadotropin-releasing hormone agonist flare-up protocol versus multiple dose gonadotropin-releasing hormone antagonist protocol in poor responders undergoing intracytoplasmic sperm injection-embryo transfer cycle. Fertil Steril. 2009;91(6):2437-44.

Devesa M, Martínez F, Coroleu B, Tur R, González C, Rodríguez I, et al. Poor prognosis for ovarian response to stimulation: results of a randomised trial comparing the flare-up GnRH agonist protocol vs. the antagonist protocol. Gynecol Endocrinol. 2010;26(7):509-15.

Berin I, Stein DE, Keltz MD. A comparison of gonadotropin-releasing hormone (GnRH) antagonist and GnRH agonist flare protocols for poor responders undergoing in vitro fertilization. Fertil Steril. 2010;93(2):360-3.

Lainas TG, Sfontouris IA, Papanikolaou EG, Zorzovilis JZ, Petsas GK, Lainas GT, et al. Flexible GnRH antagonist versus flare-up GnRH agonist protocol in poor responders treated by IVF: a randomized controlled trial. Hum Reprod. 2008;23(6): 1355-8.

Cheung LP, Lam PM, Lok IH, Chiu TT, Yeung S Y, Tjer CC, et al. GnRH antagonist versus long GnRH agonist protocol in poor responders undergoing IVF: a randomized controlled trial. Hum Reprod. 2005;20(3):616-21.

Marci R, Caserta D, Dolo V, Tatone C, Pavan A, Moscarini M. GnRH antagonist in IVF poor-responder patients: results of a randomized trial. Reprod Biomed Online. 2005;11(2):189-93.

Tazegül A, Görkemli H, Ozdemir S, Aktan TM. Comparison of multiple dose GnRH antagonist and minidose long agonist protocols in poor responders undergoing in vitro fertilization: a randomized controlled trial. Arch Gynecol Obstet. 2008;278(5): 467-72.

Sun Y, Zhu YM. [Gonadotropin-releasing hormone antagonist protocol in patients with risk of poor response to ovarian stimulation in IVF-ET]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2009;38(3):305-10. Chinese.

Tehraninejad ES, Fazel A, Samiei A, Rashidi B, Kiani K. Flexible multi-dose GnRH antagonist versus long GnRH agonist protocol in poor responders: A randomized controlled trial. Int J Fertil Stril. 2009;2(4):165-8.

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(5):628-38.

Franco JG Jr, Baruffi RL, Mauri AL, Petersen CG, Felipe V, Cornicelli J, et al. GnRH agonist versus GnRH antagonist in poor ovarian responders: a meta-analysis. Reprod Biomed Online. 2006;13(5): 618-27.