The comparison of microdose flare up and flexible antagonist protocols in poor responders undergoing IVF treatment: A prospective randomized controlled trial


  • Serdinç Özdoğan
  • Özlem Özdeğirmenci
  • Serdar Dilbaz
  • Berfu Demir
  • Özgür Çınar
  • Berna Dilbaz
  • Ümit Göktolga


Poor responders, Microdose flare up, Antagonist, In vitro fertilization


Aim: Ovarian reserve is one of the most important prognostic factors to predict probability of pregnancy in in vitro fertilization (IVF) cycles. Poor ovarian response is associated with high cycle cancellation rate and diminished pregnancy rates. Therefore, the management of women who demonstrate an inadequate response to controlled ovarian hyperstimulation (COH) are a challenge to treat with IVF. 

Methods: A hundred consecutive infertile women, defined as poor responder, were recruited to this study. It was conducted at the assisted reproductive technology (ART) unit of the Ankara Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital during the period September 2009 to September 2011. All patients in Group 1(n=50) were treated by using flexible gonadotropin releasing hormone (GNRH) antagonist protocol and in Group 2 (n=50) were treated by using GnRH microdose flare-up protocol. Exogenous gonadotropin (Gonal F, Serono, Istanbul, Turkey) was initiated on the second day of menstruation in all patients in Group 1(n=50) and GnRH antagonist (0.25 mg, Cetrotide; Serono, Geneva, Switzerland) was started when the leading follicle reached 12 mm in mean diameter and were continued until the day of hCG administration. 

Results: Total dosage of gonadotropins was significantly higher in group 2 (2625 IU in group 1 vs 4050 IU in group 2; p<0.001). The pregnancy rate was higher in group 2 but not statistically significant (25.7% in group 1 vs 33.3% in group 2; p=0.501).

Conclusion: There is no consensus on the best standard treatment option for assisted reproductive technology (ART) cycles of poor responders. GnRH antagonist and microdose flare-up protocols seem to have similar outcomes in poor responder patients in intracytoplasmic sperm injection (ICSI) cycles except consumption of gonadotropins. Further prospective randomized trials with large sample size are needed to assess the efficacy of the two protocols in the poor responders.


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Strandell A, Bergh C, Lundin K. Selection of patients suitable for one-embryo transfer may reduce the rate of multiple births by half without impairment of overall birth rates. Hum Reprod 2000;15: 2520–5

Hoozemans DA, Schats R, Lambalk CB, Homburg R, Hompes PG. Human embryo implantation: current knowledge and clinical implications in assisted reproductive technology. Reprod Biomed Online 2004; 9:692–715

Schoolcraft WB, Surrey ES, Gardner DK. Embryo transfer: techniques and variables affecting success. Fertil Steril 2001;76:863–70

Schoolcraft WB, Surrey ES, Minjarez DA, Stevens JM, Gardner DK. Management of poor responders: can outcomes be improved with a novel gonadotropin-releasing hormone antagonist/letrozole protocol? Fertil Steril 2008;89:151–6

Surrey ES, Schoolcraft WB. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. Fertil Steril 2000;73:667–76

Manno M, Tomei F, Cervi M, Favretti C, Adamo V. Comparison of protocols efficacy in poor responders: differences in oocytes/embryos competence with different protocols, a retrospective study. Fertil Steril 2009;91:1431-1433

Veeck LL. Oocyte assessment and biological performance.Ann N Y cad Sci 1988;541:259–274

Balaban B, Urman B, Sertac A, Alatas C, Aksoy S, Mercan R. Oocyte morphology does not affect fertilization rate, embryo quality and implantation rate after intracytoplasmic sperm injection. Hum Reprod 1998;13:3431–3433

Rienzi L, Ubaldi FM, Iacobelli M, Minasi MG, Romano S, Ferrero S, Sapienza F, Baroni E, Litwicka K, Greco E. Significance of metaphase II human oocyte morphology on ICSI outcome. Fertil Steril 2008;90:1692–1700

Baczkowski T, Kurzawa R, Głabowski W. Methods of embryo scoring in in vitro fertilization. Reprod Biol 2004;4:5–22

Demirol A, Gurgan T. Comparison of microdose flare-up and antagonist multiple dose protocols for poor responder patients: a randomized study. Fertil Steril 2009;92:481-485

Kahraman K, Berker B, Atabekoglu, CS, Sonmezer M, Cetinkaya E, Aytac R, Satiroglu H. 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;91:2437-2444

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;61:880–5

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

Loutradis D, Vomvolaki E, Drakakis P. Poor responder protocols for in-vitro fertilization: options and results. Curr Opin Obstet Gynecol. 2008;20(4):374-816. Mahutte MG, Arici A. Role of gonadotropin-releasing hormone antagonists in poor responders. Fertil Steril 2007;87:241–9

De Placido G, Mollo A, Clarizia R, Strina I, Conforti S, Alviggi C. Gonadotropin-releasing hormone (GnRH) antagonist plus recombinant luteinizing hormone vs. a standard GnRH agonist short protocol in patients at risk for poor response. Fertil Steril. 2006;85(1):247-50

Akman M, Erden H, Tosus S, Bayazıt 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

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.

Galey-Fontaine J, Cedrin-Durnerin I, Chaibi R, Massin N, Hugues JN. Age and ovarian reserve are distinct predictive factors of cycle outcome in low responders. Reprod Biomed Online. 2005;10(1):94-9

Bahceci M, Ulug U, Ciray HN, Akman MA, Erden HF. Efficiency of changing the embryo transfer time from day 3 to day 2 among women with poor ovarian response: a prospective randomized trial. Fertil Steril. 2006;86(1):81-5

Duffy JM, Ahmad G, Mohiyiddeen L, Nardo LG, Watson A. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev 2010;(1): CD00099

Racowsky C, Jackson KV, Cekleniak NA, Fox JH, Hornstein MD, Ginsburg ES. The number of eight-cell embryos is a key determinant for selecting day 3 or day 5 transfer. Fertil Steril. 2000;73(3):558-64

Pritts EA, Atwood AK. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. Hum Reprod. 2002;17(9):2287-99

Surrey ES. Management of the poor responder: the role of GnRH agonists and antagonists. J Assist Reprod Genet 2007;24:613-619






Research Article

How to Cite

Özdoğan S, Özdeğirmenci Özlem, Dilbaz S, Demir B, Çınar Özgür, Dilbaz B, Göktolga Ümit. The comparison of microdose flare up and flexible antagonist protocols in poor responders undergoing IVF treatment: A prospective randomized controlled trial. J Surg Med [Internet]. 2019 Feb. 25 [cited 2022 Dec. 7];3(2):134-8. Available from: