How effective are the non-conventional ovarian stimulation protocols in ART? A systematic review and meta-analysis

Abstract

Purpose

To compare the effectiveness of starting the ovarian stimulation on the early follicular phase (“Conventional”) with the newer range of non-conventional approaches starting in the luteal phase (“Luteal”), random-start, and studies implementing them in DuoStim (“Conventional”+“Luteal”).

Methods

Systematic review. We searched CENTRAL, PubMed, and Embase, on March 2020. We included randomized and non-randomized controlled trials that compared “Luteal,” random-start ovarian stimulation or DuoStim with “Conventional”; we analyzed them by subgroups: oocyte freezing and patients undergoing ART treatments, both, in the general infertile population and among poor responders.

Results

The following results come from a sensitivity analysis that included only the low/moderate risk of bias studies. When comparing “Luteal” to “Conventional,” clinically relevant differences in MII oocytes were ruled out in all subgroups. We found that “Luteal” probably increases the COH length both, in the general infertile population (OR 2.00 days, 95% CI 0.81 to 3.19, moderate-quality evidence) and in oocyte freezing cycles (MD 0.85 days, 95% CI 0.53 to 1.18, moderate-quality evidence). When analyzing DuoStim among poor responders, we found that it appears to generate a higher number of MII oocytes in comparison with a single “Conventional” (MD 3.35, 95%CI 2.54–4.15, moderate-quality evidence).

Conclusion

Overall, this systematic review of the available data demonstrates that in poor responders, general infertile population and oocyte freezing for cancer stimulation in the late follicular and luteal phases can be utilized in non-conventional approaches such as random-start and DuoStim cycles, offering similar outcomes to the conventional cycles but potentially with increased flexibility, within a reduced time frame. However, more well-designed trials are required to establish certainty.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Data availability

Search strategies are included in supplemental tables.

References

  1. 1.

    Garcia-Velasco JA, Fatemi HM. To pill or not to pill in GnRH antagonist cycles: that is the question! Reprod Biomed Online. 2015;30(1472–6491 (Electronic)):39–42.

    Article  Google Scholar 

  2. 2.

    Cardoso MCA, Evangelista A, Sartorio C, Vaz G, Werneck CLV, Guimaraes FM, et al. Can ovarian double-stimulation in the same menstrual cycle improve IVF outcomes? JBRA Assist Reprod. 2017;21(3):217–21. https://doi.org/10.5935/1518-0557.20170042.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Practice Committee of the American Society for Reproductive Medicine. Electronic address aao. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil Steril. 2019;112(6):1022–33. https://doi.org/10.1016/j.fertnstert.2019.09.013.

    Article  Google Scholar 

  4. 4.

    Esteves SC, Carvalho JF, Bento FC, Santos J. A novel predictive model to estimate the number of mature oocytes required for obtaining at least one euploid blastocyst for transfer in couples undergoing in vitro fertilization/intracytoplasmic sperm injection: the ART calculator. Front Endocrinol (Lausanne). 2019;10:99. https://doi.org/10.3389/fendo.2019.00099.

    Article  Google Scholar 

  5. 5.

    Polyzos NP, Devroey P. A systematic review of randomized trials for the treatment of poor ovarian responders: is there any light at the end of the tunnel? Fertil Steril. 2011;96(5):1058–61 e7. https://doi.org/10.1016/j.fertnstert.2011.09.048.

    Article  PubMed  Google Scholar 

  6. 6.

    Cakmak H, Katz A, Cedars MI, Rosen MP. Effective method for emergency fertility preservation: random-start controlled ovarian stimulation. Fertil Steril. 2013;100(6):1673–80. https://doi.org/10.1016/j.fertnstert.2013.07.1992.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kuang Y, Chen Q, Hong Q, Lyu Q, Ai A, Fu Y, et al. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reprod BioMed Online. 2014;29(6):684–91. https://doi.org/10.1016/j.rbmo.2014.08.009.

    Article  PubMed  Google Scholar 

  8. 8.

    Kahraman S, Çil AP, Oğur Ç, Semiz A, Yilanlioglu C. Probability of finding at least one euploid embryo and the euploidy rate according to the number of retrieved oocytes and female age using FISH and array CGH. J Reprod Biotechnol Fertil. 2016;5:2058915816653277. https://doi.org/10.1177/2058915816653277.

    Article  Google Scholar 

  9. 9.

    Vaiarelli A, Cimadomo D, Trabucco E, Vallefuoco R, Buffo L, Dusi L, et al. Double stimulation in the same ovarian cycle (DuoStim) to maximize the number of oocytes retrieved from poor prognosis patients: a multicenter experience and SWOT analysis. Front Endocrinol (Lausanne). 2018;9:317. https://doi.org/10.3389/fendo.2018.00317.

    Article  Google Scholar 

  10. 10.

    Ubaldi FM, Capalbo A, Vaiarelli A, Cimadomo D, Colamaria S, Alviggi C, et al. Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation. Fertil Steril. 2016;105(6):1488–95 e1. https://doi.org/10.1016/j.fertnstert.2016.03.002.

    Article  PubMed  Google Scholar 

  11. 11.

    Sighinolfi G, Sunkara SK, La Marca A. New strategies of ovarian stimulation based on the concept of ovarian follicular waves: from conventional to random and double stimulation. Reprod BioMed Online. 2018;37(4):489–97. https://doi.org/10.1016/j.rbmo.2018.07.006.

    Article  PubMed  Google Scholar 

  12. 12.

    Vaiarelli A, Cimadomo D, Argento C, Ubaldi N, Trabucco E, Drakopoulos P, et al. Double stimulation in the same ovarian cycle (DuoStim) is an intriguing strategy to improve oocyte yield and the number of competent embryos in a short timeframe. Minerva Ginecol. 2019;71(5):372–6. https://doi.org/10.23736/S0026-4784.19.04390-9.

    Article  PubMed  Google Scholar 

  13. 13.

    Zhang J. Luteal phase ovarian stimulation following oocyte retrieval: is it helpful for poor responders? Reprod Biol Endocrinol. 2015;13:76. https://doi.org/10.1186/s12958-015-0076-2.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ubaldi FM, Vaiarelli A, Alviggi C, Trabucco E, Zullo F, Capalbo A, et al. Double stimulation in a single menstrual cycle increases the number of oocytes retrieved in poor prognosis patients undergoing IVF treatment. Prospective study with historical control. 71st Annual Meeting of the American Society for Reproductive Medicine. Fertil Steril. 2015;104(3):e322.

    Article  Google Scholar 

  15. 15.

    Tsampras N, Gould D, Fitzgerald CT. Double ovarian stimulation (DuoStim) protocol for fertility preservation in female oncology patients. Hum Fertil (Camb). 2017;20(4):248–53. https://doi.org/10.1080/14647273.2017.1287433.

    Article  Google Scholar 

  16. 16.

    La Marca A, Capuzzo M. Use of progestins to inhibit spontaneous ovulation during ovarian stimulation: the beginning of a new era? Reprod BioMed Online. 2019;39(2):321–31. https://doi.org/10.1016/j.rbmo.2019.03.212.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Sonmezer M, Turkcuoglu I, Coskun U, Oktay K. Random-start controlled ovarian hyperstimulation for emergency fertility preservation in letrozole cycles. Fertil Steril. 2011;95(6):2125 e9–11. https://doi.org/10.1016/j.fertnstert.2011.01.030.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated August 2019). Cochrane 2019.

  19. 19.

    Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Cakmak H, Rosen MP. Random-start ovarian stimulation in patients with cancer. Curr Opin Obstet Gynecol. 2015;27(3):215–21. https://doi.org/10.1097/GCO.0000000000000180.

    Article  PubMed  Google Scholar 

  21. 21.

    Massin N. New stimulation regimens: endogenous and exogenous progesterone use to block the LH surge during ovarian stimulation for IVF. Hum Reprod Update. 2017;23(2):211–20. https://doi.org/10.1093/humupd/dmw047.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Covidence systematic review software. Melbourne, Australia: Veritas Health Innovation.

  23. 23.

    Babineau J. Product review: Covidence (systematic review software). J Can Health Libr Assoc / J Assoc Bibl Santé Can. 2014;35(2). https://doi.org/10.5596/c14-016.

  24. 24.

    Higgins J, Green S, (editors). Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Confidence intervals. 2011.

  25. 25.

    Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94. https://doi.org/10.1016/j.jclinepi.2010.04.026.

    Article  PubMed  Google Scholar 

  26. 26.

    Higgins J, Green S, (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration 2011.

  27. 27.

    Sterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919. https://doi.org/10.1136/bmj.i4919.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    EPOC Cochrane group. What study designs should be included in an EPOC review? EPOC Resources for review authors, 2017. http://epoc.cochrane.org/resources/epoc-resources-review-authors. Accessed 23 Jan 2018.

  29. 29.

    Schünemann H, Brożek J, Guyatt G, Oxman A. GRADE handbook for grading quality of evidence and strength of recommendations. 2013.

  30. 30.

    Buendgen NK, Schultze-Mosgau A, Cordes T, Diedrich K, Griesinger G. Initiation of ovarian stimulation independent of the menstrual cycle: a case-control study. Arch Gynecol Obstet. 2013;288(4):901–4. https://doi.org/10.1007/s00404-013-2794-z.

    Article  PubMed  Google Scholar 

  31. 31.

    Cavagna F, Pontes A, Cavagna M, Dzik A, Donadio NF, Portela R, et al. Specific protocols of controlled ovarian stimulation for oocyte cryopreservation in breast cancer patients. Curr Oncol. 2018;25(6):e527–e32. https://doi.org/10.3747/co.25.3889.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Checa MA, Brassesco M, Sastre M, Gomez M, Herrero J, Marque L, et al. Random-start GnRH antagonist for emergency fertility preservation: a self-controlled trial. Int J Women's Health. 2015;7:219–25. https://doi.org/10.2147/IJWH.S66743.

    CAS  Article  Google Scholar 

  33. 33.

    Jin B, Niu Z, Xu B, Chen Q, Zhang A. Comparison of clinical outcomes among dual ovarian stimulation, mild stimulation and luteal phase stimulation protocols in women with poor ovarian response. Gynecol Endocrinol. 2018;34(8):694–7. https://doi.org/10.1080/09513590.2018.1435636.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Lin LT, Vitale SG, Chen SN, Wen ZH, Tsai HW, Chern CU, et al. Luteal phase ovarian stimulation may improve oocyte retrieval and oocyte quality in poor ovarian responders undergoing in vitro fertilization: preliminary results from a single-center prospective pilot study. Adv Ther. 2018;35(6):847–56. https://doi.org/10.1007/s12325-018-0713-1.

    Article  PubMed  Google Scholar 

  35. 35.

    Martazanova B, Mishieva N, Bogatyreva K, Veyukova M, Kodileva T, Burmenskaya O, et al. Double stimulation in a single menstrual cycle in patients with reduced ovarian reserve: hormonal characteristics, cumulus cell gene expression, embryological and clinical outcome. Abstracts of the 34rd Annual Meeting of the European Society of Human Reproduction and Embryology. Hum Reprod. 2018;33(Suppl 1):i80.

    Google Scholar 

  36. 36.

    Muteshi C, Child T, Ohuma E, Fatum M. Ovarian response and follow-up outcomes in women diagnosed with cancer having fertility preservation: comparison of random start and early follicular phase stimulation - cohort study. Eur J Obstet Gynecol Reprod Biol. 2018;230:10–4. https://doi.org/10.1016/j.ejogrb.2018.09.007.

    Article  PubMed  Google Scholar 

  37. 37.

    Qin N, Chen Q, Hong Q, Cai R, Gao H, Wang Y, et al. Flexibility in starting ovarian stimulation at different phases of the menstrual cycle for treatment of infertile women with the use of in vitro fertilization or intracytoplasmic sperm injection. Fertil Steril. 2016;106(2):334–41 e1. https://doi.org/10.1016/j.fertnstert.2016.04.006.

    Article  PubMed  Google Scholar 

  38. 38.

    von Wolff M, Capp E, Jauckus J, Strowitzki T, Germeyer A. Ferti Psg. Timing of ovarian stimulation in patients prior to gonadotoxic therapy: an analysis of 684 stimulations. Eur J Obstet Gynecol Reprod Biol. 2016;199:146–9. https://doi.org/10.1016/j.ejogrb.2016.02.006.

    CAS  Article  Google Scholar 

  39. 39.

    Llacer J, Moliner B, Luque L, Bernabeu A, Lledo B, Castillo JC, et al. Luteal phase stimulation versus follicular phase stimulation in poor ovarian responders: results of a randomized controlled trial. Reprod Biol Endocrinol. 2020;18(1):9. https://doi.org/10.1186/s12958-020-00570-7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Zhang W, Wang M, Wang S, Bao H, Qu Q, Zhang N, et al. Luteal phase ovarian stimulation for poor ovarian responders. JBRA Assist Reprod. 2018;22(3):193–8. https://doi.org/10.5935/1518-0557.20180045.

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Vaiarelli A, Cimadomo D, Conforti A, Schimberni M, Giuliani M, D'Alessandro P, et al. Luteal phase after conventional stimulation in the same ovarian cycle might improve the management of poor responder patients fulfilling the Bologna criteria: a case series. Fertil Steril. 2020;113(1):121–30. https://doi.org/10.1016/j.fertnstert.2019.09.012.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Wang N, Wang Y, Chen Q, Dong J, Tian H, Fu Y, et al. Luteal-phase ovarian stimulation vs conventional ovarian stimulation in patients with normal ovarian reserve treated for IVF: a large retrospective cohort study. Clin Endocrinol. 2016;84(5):720–8. https://doi.org/10.1111/cen.12983.

    CAS  Article  Google Scholar 

  43. 43.

    Sfakianoudis K, Pantos K, Grigoriadis S, Rapani A, Maziotis E, Tsioulou P, et al. What is the true place of a double stimulation and double oocyte retrieval in the same cycle for patients diagnosed with poor ovarian reserve? A systematic review including a meta-analytical approach. J Assist Reprod Genet. 2020;37(1):181–204. https://doi.org/10.1007/s10815-019-01638-z.

    Article  PubMed  Google Scholar 

  44. 44.

    Liu C, Jiang H, Zhang W, Yin H. Double ovarian stimulation during the follicular and luteal phase in women >/=38 years: a retrospective case-control study. Reprod BioMed Online. 2017;35(6):678–84. https://doi.org/10.1016/j.rbmo.2017.08.019.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

Thanks, Daniel Comandé, for helping in the search strategy.

Author information

Affiliations

Authors

Contributions

DG: participation in study design, execution, analysis, manuscript drafting, and critical discussion.

RP: participation in study design, execution, analysis, manuscript drafting, and critical discussion.

MM: participation in execution, analysis, and manuscript drafting.

CS: participation in study design, manuscript drafting, and critical discussion.

KL: participation in execution, analysis, manuscript drafting, and critical discussion.

AC: participation in study design, analysis, manuscript drafting, and critical discussion.

Corresponding author

Correspondence to Demian Glujovsky.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Glujovsky, D., Pesce, R., Miguens, M. et al. How effective are the non-conventional ovarian stimulation protocols in ART? A systematic review and meta-analysis. J Assist Reprod Genet 37, 2913–2928 (2020). https://doi.org/10.1007/s10815-020-01966-5

Download citation

Keywords

  • Double ovarian stimulation
  • DuoStim
  • Random-start ovarian stimulation
  • Luteal-phase stimulation
  • Systematic review