Skip to main content
SpringerLink
Log in

Management of the poor responder: the role of GnRH agonists and antagonists

  • Symposium of the Aging Ovary
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Evaluate the relative benefit of various doses and regimens of GnRH agonists (GnRHa) and antagonists (GnRHant) in the management of the poor responder.

Methods

Review of English language publications with an emphasis on prospective randomized trials where available.

Results

The lack of a uniformly applied definition of the poor responder and dearth of prospective randomized trials make data analysis difficult. Traditional GnRHa flare and long luteal phase protocols do not appear to be beneficial. Reduction of GnRHa doses, “stop” protocols, and microdose GnRHa flare regimes all appear to enhance outcomes, although the relative benefit of one approach over another has not been conclusively demonstrated. GnRHant does improve outcomes in this patient population, although, in general, pregnancy rates appear to be lower in comparison to microdose GnRHa flare regimes.

Conclusions

There is no one controlled ovarian hyperstimulation (COH) protocol which is best suited for all poor responders. Low dose GnRHa regimes appear to be most advantageous. Prediction of compromised response prior to cycle initiation by a thorough assessment of ovarian reserve as well as a careful review of past response should allow for selection of an appropriate COH protocol for each individual patient.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Surrey E, Schoolcraft W. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive technologies. Fertil Steril 2000;73:667–76.

    Article  PubMed  CAS  Google Scholar 

  2. McKenna K, Foster P, McBain J, Martin M, Johnston W. Combined treatment with gonadotropin-releasing hormone agonist and gonadotropins in poor responders to hyperstimulation for in vitro fertilization (IVF): clinical and endocrine results. Aust NZ J Obstet Gynaecol 1989;29:428–32.

    CAS  Google Scholar 

  3. de Ziegler D, Cedars M, Randle D, Lu J, Judd H, Meldrum D. Suppression of the ovary using a gonadotropin releasing hormone agonist prior to stimulation for oocyte retrieval. Fertil Steril 1987;48:807–10.

    PubMed  Google Scholar 

  4. Serafini P, Stone B, Kerin J, Batzofin J, Quinn P, Marrs R. An alternate approach to controlled ovarian hyperstimulation in “poor responders”: pretreatment with a gonadotropin-releasing hormone analog. Fertil Steril 1988;49:90–5.

    PubMed  CAS  Google Scholar 

  5. Droesch K, Muasher S, Brzyski R, Jones G, Simonetti S, Liu H-C, et al. Value of suppression with a gonadotropin-releasing hormone agonist prior to gonadotropin stimulation for in vitro fertilization. Fertil Steril 1989;51:292–7.

    PubMed  CAS  Google Scholar 

  6. Cummins J, Yovich J, Edirisinghe W, Yovich J. Pituitary down-regulation using leuprolide for the intensive ovulation management of poor prognosis patients having in vitro fertilization treatments. J In Vitro Fert Embryo Transfer 1989;6:345–52.

    Article  CAS  Google Scholar 

  7. Horvath P, Styler M, Hammond J, Shelden R, Kemmann E. Exogenous gonadotropin requirements are increased in leuprolide suppressed women undergoing ovarian stimulation. Fertil Steril 1988;49:159–62.

    PubMed  CAS  Google Scholar 

  8. 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;62:343–6.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  10. Faber B, Mayer J, Cox B, Jones D, Toner J, 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;69:826–30.

    Article  PubMed  CAS  Google Scholar 

  11. Garcia-Velasco J, Isaza V, Requeria A, et al. High doses of gonadotropins combined with stop versus non-stop protocol of GnRH analogue administration in low responder IVF patients: a prospective, randomized, controlled trial. Hum Reprod 2000;15:2292–6.

    Article  PubMed  CAS  Google Scholar 

  12. Garcia J, Padilla S, Bargati J, Baramki T. Follicular phase gonadotropin-releasing hormone agonist and human gonadotropins: a better alternative for in vitro fertilization. Fertil Steril 1990;53:302–5.

    PubMed  CAS  Google Scholar 

  13. Katayama K, Roesler M, Gunnarson G, Stehlik E, Jagusch S. Short-term use of gonadotropin-releasing hormone agonist (leuprolide) for in vitro fertilization. J In Vitro Fert Embryo Transfer 1988;5:332–7.

    Article  CAS  Google Scholar 

  14. Toth T, Awwad J, Veeck L, Jones H, Muasher S. 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;41:321–6.

    PubMed  CAS  Google Scholar 

  15. Padilla S, Dugan K, Shalika S, Smith R. Use of the flare-up protocol with high dose follicle stimulating hormone and human menopausal gonadotropins for in vitro fertilization in poor responders. Fertil Steril 1996;65:796–9.

    PubMed  CAS  Google Scholar 

  16. Karande V, Jones G, Veeck L, Muasher S. High dose follicle stimulating hormone at the onset of the menstrual cycle does not improve the in vitro fertilization outcome in low-responder patients. Fertil Steril 1990;53:486–9.

    PubMed  CAS  Google Scholar 

  17. Gindoff P, Hall J, Stillman R. Ovarian suppression with leuprolide acetate comparison of luteal, follicular, and flare-up administration in controlled ovarian hyperstimulation for oocyte retrieval. J In Vitro Fert Embryo Transfer 1990;7:94–7.

    Article  CAS  Google Scholar 

  18. Anserini P, Magnasco A, Remorgida V, Gaggero G, Testa D, Capitanio G. Comparison of blocking vs. a flare-up protocol in poor responders with a normal and abnormal clomiphene citrate challenge test. Gynecol Endocrinol 1997;11:321–6.

    Article  PubMed  CAS  Google Scholar 

  19. Spandorfer S, Navarro J, Kump L, Liu H-C, Davis O, Rosenwaks Z. “Co-flare” stimulation in the poor responder patient: value of the flare response. J Assist Reprod Genet 2001;18:629–33.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  21. Brzyski R, Muasher S, Droesch K, Simonetti S, Jones G, Rosenwaks Z. Follicular atresia associated with concurrent initiation of gonadotropin-releasing hormone agonist and follicle-stimulating hormone for oocyte recruitment. Fertil Steril 1988;50:917–21.

    PubMed  CAS  Google Scholar 

  22. San Roman G, Surrey E, Judd H, Kerin J. A prospective randomized comparison of luteal phase versus concurrent follicular phase initiation of gonadotropin-releasing hormone agonist for in vitro fertilization. Fertil Steril 1992;58:744–9.

    PubMed  CAS  Google Scholar 

  23. Gelety T, Pearlstone A, Surrey E. Short-term endocrine response to gonadotropin-releasing hormone agonist initiated in the early follicular, mid luteal or late luteal phase in normally cycling women. Fertil Steril 1995;64:1074–80.

    PubMed  CAS  Google Scholar 

  24. Deaton J, Baugness P, Huffman C, Miller K. Pituitary response to early follicular phase minidose gonadotropin releasing hormone agonist (GnRH-a) therapy: evidence for a second flare. J Assist Reprod Genet 1996;13:390–4.

    Article  PubMed  CAS  Google Scholar 

  25. Scott R, Carey K, Leland M, Navot D. Gonadotropin responsiveness to ultra low-dose leuprolide acetate in baboons. Fertil Steril 1993;59:1124–8.

    PubMed  CAS  Google Scholar 

  26. Lindheim S, Barad D, Witt B, Ditkoff E, Sauer M. Short-term gonadotropin suppression with oral contraceptives benefits poor responders prior to controlled ovarian hyperstimulation. J Assist Reprod Genet 1996;16:745–7.

    Article  Google Scholar 

  27. Cedrin-Durnerin I, Bulwa S, Herve F, Martin-Pont B, Uzan M, Hugues J. The hormonal flare-up following gonadotropin-releasing hormone agonist administration is influenced by a progestogen pretreatment. Hum Reprod 1996;11:1859–63.

    PubMed  CAS  Google Scholar 

  28. Scott R, Navot D. Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonists during ovulation induction for in vitro fertilization. Fertil Steril 1994;61:880–5.

    PubMed  CAS  Google Scholar 

  29. 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;67:93–7.

    Article  PubMed  CAS  Google Scholar 

  30. Surrey E, Bower J, Hill D, Ramsey J, Surrey M. Clinical effects of a microdose GnRH agonist flare regimen administered to poor responders who are undergoing in vitro fertilization. Fertil Steril 1998;69:419–24.

    Article  PubMed  CAS  Google Scholar 

  31. Sharara F, McClamrock H. Use of microdose GnRH agonist protocol in women with low ovarian volumes undergoing IVF. Hum Reprod 2001;16:500–3.

    Article  PubMed  CAS  Google Scholar 

  32. Morgia F, Sbracia M, Schimberni M, Giallouardo A, Piscitelli C, Giannini P, Aragone C. A controlled trial of natural cycle versus microdose gonadotropin-releasing hormone analog flare cycles in poor responders undergoing in vitro fertilization. Fertil Steril 2004;81:1542–7.

    Article  PubMed  CAS  Google Scholar 

  33. Detti L, Williams D, Robbins J, Maxwell R, Thomas M. A comparison of three down regulation approaches for poor responders undergoing in vitro fertilization. Fertil Steril 2005;84:1401–5.

    Article  PubMed  CAS  Google Scholar 

  34. Kaufmann R, Wade R, Patton G. Very low dose luteal lupron and microdose lupron flare offer comparable outcomes in poor responders. Fertil Steril 2000;74:S232.

    Article  Google Scholar 

  35. Diedrich K, Diedrich C, Santos E, Zoll C, al-Hasani S, Reissman T, et al. Suppression of the endogenous luteinizing hormone surge by the gonadotropin-releasing hormone antagonist cetrorelix during ovarian stimulation. Hum Reprod 1994;9:788–91.

    PubMed  CAS  Google Scholar 

  36. Craft I, Giorgy A, Hill J, Menon D, Podscadly B. Will GnRH antagonists provide new hope for patients considered “difficult responders” to GnRH agonist protocols? Hum Reprod 1999;14:2959–62.

    Article  PubMed  CAS  Google Scholar 

  37. Takahashi K, Mukaida T, Tomiyama T, Goto T, Oka C. GnRH antagonist improved blastocyst quality and pregnancy outcome after multiple failures of IVF/ICSI-ET with a GnRH agonist protocol. J Assist Reprod Genet 2004;21:317–22.

    Article  PubMed  Google Scholar 

  38. Akman M, Erden H, Tosun S, Bayazat N, Aksoy E, Bahceci M. Addition of GnRH antagonist in cycles of poor responders undergoing IVF. Hum Reprod 2000;15:2145–7.

    Article  PubMed  CAS  Google Scholar 

  39. Dragasic K, Davis O, Fasouliotis S, Rosenwaks Z. Use of a luteal estradiol patch and a gonadotropin-releasing hormone antagonist suppression protocol before gonadotropin stimulation for in vitro fertilization in poor responders. Fertil Steril 2005;84:1023–6.

    Article  CAS  Google Scholar 

  40. Cheung L-P, Lam P-M, Lok I, Chiu T, Yeung S-Y, Tjer C-C, Haine SC. GnRH antagonist versus long GnRH agonist protocol in poor responders undergoing IVF: a randomized controlled trial. Hum Reprod 2005;20:616–21.

    Article  PubMed  CAS  Google Scholar 

  41. D’Amato G, Groppo E, Pasquadibisceglie A, Carone D, Vitti A, Vizziello G. A novel protocol of ovulation induction with delayed gonadotropin-releasing hormone antagonist administration combined with high-dose recombinant follicle-stimulating hormone and clomiphene citrate for poor responders and women over 35 years. Fertil Steril 2004;81:1572–7.

    Article  PubMed  CAS  Google Scholar 

  42. Schmidt D, Bremner T, Orris J, Maier D, Benadiva C, Nielsen J. A randomized prospective study of microdose leuprolide versus ganerelix in in vitro fertilization cycles for poor responders. Fertil Steril 2005;83:1568–71.

    Article  PubMed  CAS  Google Scholar 

  43. Akman M, Erden H, Tosus S, 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.

    Article  PubMed  CAS  Google Scholar 

  44. Malmusi S, La Marca A, Giulini S, Xella S, Tagliasacchi D, Marsella T, Volpe A. 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.

    Article  PubMed  CAS  Google Scholar 

  45. Schoolcraft W, Surrey E, Minjarez D, Stevens J, Gardner D. Management of poor responders: can outcomes be improved with a novel GnRH antagonist/letrozole protocol? Fertil Steril 2008 (in press).

  46. Mahutte N, Arici A. Role of gonadotropin-releasing hormone antagonists in poor responders. Fertil Steril 2007;87:241–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Colorado Center for Reproductive Medicine, 799 E Hampden Ave., #300, Englewood, CO, 80113, USA

    Eric S. Surrey

Authors
  1. Eric S. Surrey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric S. Surrey.

Additional information

Capsule

GnRH antagonists and low dose GnRH agonists have been employed with varying degrees of success in the management of the poor responder.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Surrey, E.S. Management of the poor responder: the role of GnRH agonists and antagonists. J Assist Reprod Genet 24, 613–619 (2007). https://doi.org/10.1007/s10815-007-9180-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-007-9180-3

Keywords

Search

Navigation