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Ovarian stimulation protocols for poor ovarian responders: a network meta-analysis of randomized controlled trials

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Abstract

Objective

To evaluate the efficacy of manifold ovarian stimulation protocols for patients with poor ovarian response.

Methods

PubMed, Embase, Cochrane Library and Web of Science were systematically searched until February 14, 2021. Primary outcomes included clinical pregnancy rate per initiating cycle and low risk of cycle cancellation. Secondary outcomes included number of oocytes retrieved, number of metaphase II (MII) oocytes, number of embryos obtained, number of transferred embryos, endometrial thickness on triggering day and estradiol (E2) level on triggering day. The network plot, league table, rank probabilities and forest plot of each outcome measure were drawn. Therapeutic effects were displayed as risk ratios (RRs) or mean differences (MDs) with 95% confidence intervals (CIs).

Results

This network meta-analysis included 15 trials on 2173 participants with poor ovarian response. Delayed start GnRH antagonist was the best regimen in terms of clinical pregnancy rate per initiating cycle (74.04% probability of being the optimal), low risk of cycle cancellation (75.30%), number of oocytes retrieved (68.67%), number of metaphase II (MII) oocytes (97.98%) and endometrial thickness on triggering day (81.97%), while for E2 level on triggering day, microdose GnRH agonist (99.25%) was the most preferred. Regarding number of embryos obtained and number of transferred embryos, no statistical significances were found between different ovarian stimulation protocols.

Conclusion

Delayed start GnRH antagonist and microdose GnRH agonist were the two superior regimens in the treatment of poor ovarian response, providing favorable clinical outcomes. Future investigation is needed to confirm and enrich our findings.

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References

  1. Abu-Musa A, Haahr T, Humaidan P (2020) Novel physiology and definition of poor ovarian response. Clinical Recommendations. Int J Mol Sci 21:2110

    Article  PubMed  Google Scholar 

  2. Giannelou P, Simopoulou M, Grigoriadis S et al (2020) The conundrum of poor ovarian response: from diagnosis to treatment. Diagnostics (Basel, Switzerland) 10:687

    PubMed  Google Scholar 

  3. Tarlatzis BC, Zepiridis L, Grimbizis G, Bontis J (2003) Clinical management of low ovarian response to stimulation for IVF: a systematic review. Hum Reprod Update 9:61–76

    Article  CAS  PubMed  Google Scholar 

  4. Surrey ES, Schoolcraft WB (2000) Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. Fertil Steril 73:667–676

    Article  CAS  PubMed  Google Scholar 

  5. Loh S, Wang JX, Matthews CD (2002) The influence of body mass index, basal FSH and age on the response to gonadotrophin stimulation in non-polycystic ovarian syndrome patients. Hum Reprod 17:1207–1211

    Article  CAS  PubMed  Google Scholar 

  6. Jang S, Kim KH, Jun JH, You S (2020) Acupuncture for in vitro fertilization in women with poor ovarian response: a systematic review. Integr Med Res 9:100395

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zhang Y, Zhang C, Shu J et al (2020) Adjuvant treatment strategies in ovarian stimulation for poor responders undergoing IVF: a systematic review and network meta-analysis. Hum Reprod Update 26:247–263

    Article  CAS  PubMed  Google Scholar 

  8. Arslan M, Bocca S, Mirkin S, Barroso G, Stadtmauer L, Oehninger S (2005) Controlled ovarian hyperstimulation protocols for in vitro fertilization: two decades of experience after the birth of Elizabeth Carr. Fertil Steril 84:555–569

    Article  CAS  PubMed  Google Scholar 

  9. Ashrafi M, Arabipoor A, Yahyaei A, Zolfaghari Z, Ghaffari F (2018) Does the “delayed start” protocol with gonadotropin-releasing hormone antagonist improve the pregnancy outcome in Bologna poor responders? a randomized clinical trial. Reprod Biol Endocrinol 16:124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cakmak H, Tran ND, Zamah AM, Cedars MI, Rosen MP (2014) A novel “delayed start” protocol with gonadotropin-releasing hormone antagonist improves outcomes in poor responders. Fertil Steril 101:1308–1314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Surrey ES, Bower J, Hill DM, Ramsey J, Surrey MW (1998) Clinical and endocrine effects of a microdose GnRH agonist flare regimen administered to poor responders who are undergoing in vitro fertilization. Fertil Steril 69:419–424

    Article  CAS  PubMed  Google Scholar 

  12. Ghaffari F, Jahangiri N, Madani T, Khodabakhshi S, Chehrazi M (2020) Randomized controlled trial of gonadotropin-releasing hormone agonist microdose flare-up versus flare-up among poor responders undergoing intracytoplasmic sperm injection. Int J Gynaecol Obstet 148:59–64

    Article  CAS  PubMed  Google Scholar 

  13. Scott RT, Navot D (1994) Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization. Fertil Steril 61:880–885

    Article  CAS  PubMed  Google Scholar 

  14. Lerman T, Depenbusch M, Schultze-Mosgau A et al (2017) Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study. Reprod Biomed Online 34:534–540

    Article  CAS  PubMed  Google Scholar 

  15. Lee TH, Wu MY, Chen HF, Chen MJ, Ho HN, Yang YS (2005) Ovarian response and follicular development for single-dose and multiple-dose protocols for gonadotropin-releasing hormone antagonist administration. Fertil Steril 83:1700–1707

    Article  CAS  PubMed  Google Scholar 

  16. Tazegül A, Görkemli H, Ozdemir S, Aktan TM (2008) 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 278:467–472

    Article  PubMed  Google Scholar 

  17. Liu X, Li T, Wang B, Xiao X, Liang X, Huang R (2020) Mild stimulation protocol vs conventional controlled ovarian stimulation protocol in poor ovarian response patients: a prospective randomized controlled trial. Arch Gynecol Obstet 301:1331–1339

    Article  CAS  PubMed  Google Scholar 

  18. Sunkara SK, Coomarasamy A, Khalaf Y, Braude P (2007) 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 4:12

    Article  PubMed  PubMed Central  Google Scholar 

  19. Anckaert E, Smitz J, Schiettecatte J, Klein BM, Arce JC (2012) The value of anti-Mullerian hormone measurement in the long GnRH agonist protocol: association with ovarian response and gonadotrophin-dose adjustments. Hum Reprod 27:1829–1839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sunkara SK, Coomarasamy A, Faris R, Braude P, Khalaf Y (2014) Long gonadotropin-releasing hormone agonist versus short agonist versus antagonist regimens in poor responders undergoing in vitro fertilization: a randomized controlled trial. Fertil Steril 101:147–153

    Article  CAS  PubMed  Google Scholar 

  21. Hamdine O, Eijkemans MJ, Lentjes EW et al (2015) Ovarian response prediction in GnRH antagonist treatment for IVF using anti-Müllerian hormone. Hum Reprod 30:170–178

    Article  CAS  PubMed  Google Scholar 

  22. Pu D, Wu J, Liu J (2011) Comparisons of GnRH antagonist versus GnRH agonist protocol in poor ovarian responders undergoing IVF. Hum Reprod 26:2742–2749

    Article  CAS  PubMed  Google Scholar 

  23. Fatemi HM, Doody K, Griesinger G, Witjes H, Mannaerts B (2013) High ovarian response does not jeopardize ongoing pregnancy rates and increases cumulative pregnancy rates in a GnRH-antagonist protocol. Hum Reprod 28:442–452

    Article  CAS  PubMed  Google Scholar 

  24. Qin Y (2021) Effects of using letrozole in combination with the GnRH antagonist protocol for patients with poor ovarian response: a meta-analysis. J Gynecol Obstet Hum Reprod 50:102139

    Article  PubMed  Google Scholar 

  25. Yarali H, Esinler I, Polat M, Bozdag G, Tiras B (2009) Antagonist/letrozole protocol in poor ovarian responders for intracytoplasmic sperm injection: a comparative study with the microdose flare-up protocol. Fertil Steril 92:231–235

    Article  CAS  PubMed  Google Scholar 

  26. Chen Q, Chai W, Wang Y et al (2019) Progestin vs. gonadotropin-releasing hormone antagonist for the prevention of premature luteinizing hormone surges in poor responders undergoing in vitro fertilization treatment: a randomized controlled trial. Front Endocrinol (Lausanne) 10:796

    Article  PubMed  Google Scholar 

  27. Huang P, Tang M, Qin A (2019) Progestin-primed ovarian stimulation is a feasible method for poor ovarian responders undergoing in IVF/ICSI compared to a GnRH antagonist protocol: a retrospective study. J Gynecol Obstet Hum Reprod 48:99–102

    Article  PubMed  Google Scholar 

  28. De Placido G, Mollo A, Clarizia R, Strina I, Conforti S, Alviggi C (2006) Gonadotropin-releasing hormone (GnRH) antagonist plus recombinant luteinizing hormone vs. a standard GnRH agonist short protocol in patients at risk for poor ovarian response. Fertil Steril 85:247–250

    Article  PubMed  Google Scholar 

  29. Schimberni M, Ciardo F, Schimberni M, Giallonardo A, De Pratti V, Sbracia M (2016) Short gonadotropin-releasing hormone agonist versus flexible antagonist versus clomiphene citrate regimens in poor responders undergoing in vitro fertilization: a randomized controlled trial. Eur Rev Med Pharmacol Sci 20:4354–4361

    CAS  PubMed  Google Scholar 

  30. Farquhar C, Rishworth JR, Brown J, Nelen WL, Marjoribanks J (2015) Assisted reproductive technology: an overview of Cochrane Reviews. Cochrane Database Syst Rev 7:Cd010537

    Google Scholar 

  31. Nikolakopoulou A, Mavridis D, Furukawa TA et al (2018) Living network meta-analysis compared with pairwise meta-analysis in comparative effectiveness research: empirical study. BMJ 360:k585

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kraemer HC (2017) Multiple-treatments meta-analysis: are the conclusions supported by the data? J Clin Oncol 35:565–566

    Article  PubMed  Google Scholar 

  33. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, Montori V, Akl EA, Djulbegovic B, Falck-Ytter Y, Norris SL, Williams JW, Atkins D, Meerpohl J, Schünemann HJ (2011) GRADE guidelines: 4. Rating the quality of evidence–study limitations (risk of bias). J Clin Epidemiol 64:407–415

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  35. Schoolcraft WB, Surrey ES, Minjarez DA, Stevens JM, Gardner DK (2008) Management of poor responders: can outcomes be improved with a novel gonadotropin-releasing hormone antagonist/letrozole protocol? Fertil Steril 89:151–156

    Article  CAS  PubMed  Google Scholar 

  36. Davar R, Neghab N, Naghshineh E (2018) Pregnancy outcome in delayed start antagonist versus microdose flare GnRH agonist protocol in poor responders undergoing IVF/ICSI: An RCT. Int J Reprod Biomed 16:255–260

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Prapas Y, Petousis S, Dagklis T et al (2013) GnRH antagonist versus long GnRH agonist protocol in poor IVF responders: a randomized clinical trial. Eur J Obstet Gynecol Reprod Biol 166:43–46

    Article  CAS  PubMed  Google Scholar 

  38. Kahraman K, Berker B, Atabekoglu CS et al (2009) 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 91:2437–2444

    Article  CAS  PubMed  Google Scholar 

  39. Zarei A, Parsanezhad ME, Kutenaei MA, Jahromi BN, Esfahani PS, Bakhshaei P (2018) Delayed start protocol with gonadotropin-releasing hormone antagonist in poor responders undergoing in vitro fertilization: a randomized, double-blinded, clinical trial. Oman Med J 33:506–511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Maged AM, Nada AM, Abohamila F, Hashem AT, Mostafa WA, Elzayat AR (2015) Delayed start versus conventional GnRH antagonist protocol in poor responders pretreated with estradiol in luteal phase: a randomized controlled trial. Reprod Sci 22:1627–1631

    Article  CAS  PubMed  Google Scholar 

  41. Aflatoonian A, Hosseinisadat A, Baradaran R, Farid Mojtahedi M (2017) Pregnancy outcome of “delayed start” GnRH antagonist protocol versus GnRH antagonist protocol in poor responders: a clinical trial study. Int J Reprod Biomed 15:231–238

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lainas TG, Sfontouris IA, Papanikolaou EG et al (2008) Flexible GnRH antagonist versus flare-up GnRH agonist protocol in poor responders treated by IVF: a randomized controlled trial. Hum Reprod 23:1355–1358

    Article  CAS  PubMed  Google Scholar 

  43. Davar R, Oskouian H, Ahmadi S, Firouzabadi RD (2010) GnRH antagonist/letrozole versus microdose GnRH agonist flare protocol in poor responders undergoing in vitro fertilization. Taiwan J Obstet Gynecol 49:297–301

    Article  PubMed  Google Scholar 

  44. Cheung LP, Lam PM, Lok IH et al (2005) GnRH antagonist versus long GnRH agonist protocol in poor responders undergoing IVF: a randomized controlled trial. Hum Reprod 20:616–621

    Article  CAS  PubMed  Google Scholar 

  45. Ebrahimi M, Akbari-Asbagh F, Ghalandar-Attar M (2017) Letrozole+ GnRH antagonist stimulation protocol in poor ovarian responders undergoing intracytoplasmic sperm injection cycles: An RCT. Int J Reprod Biomed 15:101–108

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Rosen MP, Shen S, Dobson AT, Rinaudo PF, McCulloch CE, Cedars MI (2008) A quantitative assessment of follicle size on oocyte developmental competence. Fertil Steril 90:684–690

    Article  PubMed  PubMed Central  Google Scholar 

  47. Cozzolino M, Franasiak J, Andrisani A, Ambrosini G, Vitagliano A (2020) “Delayed start” gonadotropin-releasing hormone antagonist protocol in Bologna poor-responders: a systematic review and meta-analysis of randomized controlled trials. Eur J Obstet Gynecol Reprod Biol 244:154–162

    Article  CAS  PubMed  Google Scholar 

  48. Yang S, Liu N, Li Y, Zhang L, Yue R (2021) Efficacy of the delayed start antagonist protocol for controlled ovarian stimulation in Bologna poor ovarian responders: a systematic review and meta-analysis. Arch Gynecol Obstet 303:347–362

    Article  PubMed  Google Scholar 

  49. Frankfurter D, Dayal M, Dubey A, Peak D, Gindoff P (2007) Novel follicular-phase gonadotropin-releasing hormone antagonist stimulation protocol for in vitro fertilization in the poor responder. Fertil Steril 88:1442–1445

    Article  CAS  PubMed  Google Scholar 

  50. Younis JS, Soltsman S, Izhaki I, Radin O, Bar-Ami S, Ben-Ami M (2010) Early and short follicular gonadotropin-releasing hormone antagonist supplementation improves the meiotic status and competence of retrieved oocytes in in vitro fertilization-embryo transfer cycles. Fertil Steril 94:1350–1335

    Article  CAS  PubMed  Google Scholar 

  51. Lee H, Choi HJ, Yang KM, Kim MJ, Cha SH, Yi HJ (2018) Efficacy of luteal estrogen administration and an early follicular Gonadotropin-releasing hormone antagonist priming protocol in poor responders undergoing in vitro fertilization. Obstet Gynecol Sci 61:102–110

    Article  PubMed  Google Scholar 

  52. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB (2006) A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 12:685–718

    Article  CAS  PubMed  Google Scholar 

  53. Uppangala S, Fernandes G, Salian SR et al (2020) Reduced ovarian response to controlled ovarian stimulation is associated with increased oxidative stress in the follicular environment. Reprod Biol 20:402–407

    Article  PubMed  Google Scholar 

  54. Ozcan Cenksoy P, Ficicioglu C, Kizilkale O et al (2014) The comparison of effect of microdose GnRH-a flare-up, GnRH antagonist/aromatase inhibitor letrozole and GnRH antagonist/clomiphene citrate protocols on IVF outcomes in poor responder patients. Gynecol Endocrinol 30:485–489

    Article  CAS  PubMed  Google Scholar 

  55. Mohsen IA, El Din RE (2013) Minimal stimulation protocol using letrozole versus microdose flare up GnRH agonist protocol in women with poor ovarian response undergoing ICSI. Gynecol Endocrinol 29:105–108

    Article  PubMed  Google Scholar 

  56. San Roman GA, Surrey ES, Judd HL, Kerin JF (1992) A prospective randomized comparison of luteal phase versus concurrent follicular phase initiation of gonadotropin-releasing hormone agonist for in vitro fertilization. Fertil Steril 58:744–749

    Article  CAS  PubMed  Google Scholar 

  57. Gelety TJ, Pearlstone AC, Surrey ES (1995) Short-term endocrine response to gonadotropin-releasing hormone agonist initiated in the early follicular, midluteal, or late luteal phase in normally cycling women. Fertil Steril 64:1074–1080

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, No. 569 Xinsi Road, Baqiao District, Xi’an, 710038, Shaanxi, People’s Republic of China

    Man Di, Xiaohong Wang, Jing Wu & Hongya Yang

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  1. Man Di
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  2. Xiaohong Wang
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  3. Jing Wu
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  4. Hongya Yang
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Contributions

MD and HY designed the study. XW and JW analyzed the data obtained. MD and XW wrote the paper. HY and JW reviewed and edited the paper. All of them read and approved the final manuscript.

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Correspondence to Hongya Yang.

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Di, M., Wang, X., Wu, J. et al. Ovarian stimulation protocols for poor ovarian responders: a network meta-analysis of randomized controlled trials. Arch Gynecol Obstet 307, 1713–1726 (2023). https://doi.org/10.1007/s00404-022-06565-6

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