To compare the efficacy of mild ovarian stimulation protocol and conventional controlled ovarian stimulation (COS) protocol for poor ovarian response (POR) patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).
This single-center prospective randomized controlled trial conducted from September 2013 to September 2015, including 191 patients who met the Bologna criteria of POR. Ninety-seven patients allocated to the mild ovarian stimulation group (MS group) were stimulated according to the letrozole/antagonist protocol, while 94 patients in the controlled ovarian stimulation group (COS group) were stimulated according to a high dose of gonadotropin (Gn) combined with gonadotropin-releasing hormone agonist (GnRH-a) stop protocol. The cumulative live birth rate was the primary outcome. Chinese clinical trial number ChiCTR-TRC-13003454.
Comparing with the COS group, both the stimulation duration and the total gonadotropin dose were significantly shorter and lower in the MS group (P < 0.001). A higher number of retrieved oocytes (P = 0.003) and transferrable embryos (P = 0.029) were obtained in the COS group. The cumulative live birth rates (OR 1.103; 95% CI 0.53 to 2.28; P = 0.791) were comparable between the two groups.
The increase of Gn dose during ovulation stimulation was associated with a higher number of transferrable embryos for POR patients, but this increase did not lead to a concomitant improvement of reproductive outcome, especially in terms of the cumulative live birth rate. Using a mild stimulation protocol was economically preferential while it was as effective as higher doses of Gn stimulation protocol in reproductive outcome for POR patients.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Biljan MM, Buckett WM, Dean N, Phillips SJ, Tan SL (2000) The outcome of IVF-embryo transfer treatment in patients who develop three follicles or less. Hum Reprod 15(10):2140–2144. https://doi.org/10.1093/humrep/15.10.2140
Roman R, Mussarat N, Detti L (2017) Ovarian stimulation in poor responders: have we made progress? Curr Pharm Biotechnol 18(8):614–618. https://doi.org/10.2174/1389201018666171002132853
Practice Committee of the American Society for Reproductive Medicine. Electronic address Aao (2018) Comparison of pregnancy rates for poor responders using IVF with mild ovarian stimulation versus conventional IVF: a guideline. Fertil Steril 109(6):993–999. https://doi.org/10.1016/j.fertnstert.2018.03.019
Pal L, Jindal S, Witt BR, Santoro N (2008) Less is more: increased gonadotropin use for ovarian stimulation adversely influences clinical pregnancy and live birth after in vitro fertilization. Fertil Steril 89(6):1694–1701. https://doi.org/10.1016/j.fertnstert.2007.05.055
Revelli A, Chiado A, Dalmasso P, Stabile V, Evangelista F, Basso G, Benedetto C (2014) "Mild" vs. "long" protocol for controlled ovarian hyperstimulation in patients with expected poor ovarian responsiveness undergoing in vitro fertilization (IVF): a large prospective randomized trial. J Assist Reprod Genet 31(7):809–815. https://doi.org/10.1007/s10815-014-0227-y
Faber BM, Mayer J, Cox B, Jones D, Toner JP, Oehninger S, Muasher SJ (1998) Cessation of gonadotropin-releasing hormone agonist therapy combined with high-dose gonadotropin stimulation yields favorable pregnancy results in low responders. Fertil Steril 69(5):826–830. https://doi.org/10.1016/s0015-0282(98)00040-5
Garcia-Velasco JA, Isaza V, Requena A, Martinez-Salazar FJ, Landazabal A, Remohi J, Pellicer A, Simon C (2000) 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 15(11):2292–2296. https://doi.org/10.1093/humrep/15.11.2292
Youssef MA, van Wely M, Al-Inany H, Madani T, Jahangiri N, Khodabakhshi S, Alhalabi M, Akhondi M, Ansaripour S, Tokhmechy R, Zarandi L, Rizk A, El-Mohamedy M, Shaeer E, Khattab M, Mochtar MH, van der Veen F (2017) A mild ovarian stimulation strategy in women with poor ovarian reserve undergoing IVF: a multicenter randomized non-inferiority trial. Hum Reprod 32(1):112–118. https://doi.org/10.1093/humrep/dew282
Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, Macklon NS, Fauser BC (2007) Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod 22(4):980–988. https://doi.org/10.1093/humrep/del484
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(1):231–235. https://doi.org/10.1016/j.fertnstert.2008.04.057
Abdel Mohsen I, Ezz El Din R (2013) Minimal stimulation protocol using letrozole versus microdose flare up GnRH agonist protocol in women with poor ovarian response undergoing ICSI. Gynecol Endocrinol 29(2):105–108. https://doi.org/10.3109/09513590.2012.730569
Siristatidis C, Salamalekis G, Dafopoulos K, Basios G, Vogiatzi P, Papantoniou N (2017) Mild versus conventional ovarian stimulation for poor responders undergoing IVF/ICSI. Vivo 31(2):231–237. https://doi.org/10.21873/invivo.11050
Ochin H, Ma X, Wang L, Li X, Song J, Meng Y, Shen J, Cui YG, Liu J (2018) Low dose clomiphene citrate as a mild stimulation protocol in women with unsuspected poor in vitro fertilization result can generate more oocytes with optimal cumulative pregnancy rate. J Ovarian Res 11(1):37. https://doi.org/10.1186/s13048-018-0408-x
Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, Chakravarty BN, Kabir SN (2004) A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod 19(9):2031–2035. https://doi.org/10.1093/humrep/deh359
Hu L, Bu Z, Guo Y, Su Y, Zhai J, Sun Y (2014) Comparison of different ovarian hyperstimulation protocols efficacy in poor ovarian responders according to the Bologna criteria. Int J Clin Exp Med 7(4):1128–1134
Kuroda K, Kitade M, Kumakiri J, Jinushi M, Shinjo A, Ozaki R, Ikemoto Y, Katoh N, Takeda S (2016) Minimum ovarian stimulation involving combined clomiphene citrate and estradiol treatment for in vitro fertilization of Bologna-criteria poor ovarian responders. J Obstet Gynaecol Res 42(2):178–183. https://doi.org/10.1111/jog.12862
Kushnir VA, Barad DH, Albertini DF, Darmon SK, Gleicher N (2017) Systematic review of worldwide trends in assisted reproductive technology 2004–2013. Reprod Biol Endocrinol 15(1):6. https://doi.org/10.1186/s12958-016-0225-2
Wong KM, Mastenbroek S, Repping S (2014) Cryopreservation of human embryos and its contribution to in vitro fertilization success rates. Fertil Steril 102(1):19–26. https://doi.org/10.1016/j.fertnstert.2014.05.027
Tilborg CV, Oudshoorn SC, Eijkemans MJC, Manger PAP, Brinkhuis E, van Heusden AM, Kuchenbecker WKH, Smeenk JMJ, Kwee J, Verhoeve HR, Lambalk CB, van der Veen F, Mol BWJ, Torrance HL, Broekmans FJM (2016) Optimization of outcome through individualized dosing in predicted poor responders undergoing IVF/ICSI; the OPTIMIST randomized controlled trial, NTR2657. Hum Reprod 31:16–17
Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L, EwgoPOR D (2011) ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod 26(7):1616–1624. https://doi.org/10.1093/humrep/der092
Racowsky C, Ohno-Machado L, Kim J, Biggers JD (2009) Is there an advantage in scoring early embryos on more than one day? Hum Reprod 24(9):2104–2113. https://doi.org/10.1093/humrep/dep198
Gardner DK, Lane M, Stevens J, Schlenker T, Schoolcraft WB (2000) Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil Steril 73(6):1155–1158. https://doi.org/10.1016/s0015-0282(00)00518-5
Bastu E, Buyru F, Ozsurmeli M, Demiral I, Dogan M, Yeh J (2016) A randomized, single-blind, prospective trial comparing three different gonadotropin doses with or without addition of letrozole during ovulation stimulation in patients with poor ovarian response. Eur J Obstet Gynecol Reprod Biol 203:30–34. https://doi.org/10.1016/j.ejogrb.2016.05.027
Xu B, Chen Y, Geerts D, Yue J, Li Z, Zhu G, Jin L (2018) Cumulative live birth rates in more than 3,000 patients with poor ovarian response: a 15-year survey of final in vitro fertilization outcome. Fertil Steril 109(6):1051–1059. https://doi.org/10.1016/j.fertnstert.2018.02.001
Sato F, Marrs RP (1986) The effect of pregnant mare serum gonadotropin on mouse embryos fertilized in vivo or in vitro. J In Vitro Fert Embryo Transf 3(6):353–357. https://doi.org/10.1007/bf01133247
Xu YW, Peng YT, Wang B, Zeng YH, Zhuang GL, Zhou CQ (2011) High follicle-stimulating hormone increases aneuploidy in human oocytes matured in vitro. Fertil Steril 95(1):99–104. https://doi.org/10.1016/j.fertnstert.2010.04.037
Murray AA, Gosden RG, Allison V, Spears N (1998) Effect of androgens on the development of mouse follicles growing in vitro. J Reprod Fertil 113(1):27–33. https://doi.org/10.1530/jrf.0.1130027
Haas J, Casper RF (2017) In vitro fertilization treatments with the use of clomiphene citrate or letrozole. Fertil Steril 108(4):568–571. https://doi.org/10.1016/j.fertnstert.2017.08.017
Pandian Z, McTavish AR, Aucott L, Hamilton MPR, Bhattacharya S (2010) Interventions for 'poor responders' to controlled ovarian hyper stimulation (COH) in in-vitro fertilisation (IVF). Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD004379.pub3
The authors thank Shen Chen for providing language help and writing assistance, also we want to thank the participating infertile women and all doctors, laboratory staff, nurses and clerks at the Reproductive Medicine Research Center, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
There was no funding in this study.
Conflict of interest
The authors declare that they have no conflict of interest.
This study was approved by the Sixth Affiliated Hospital of Sun Yat-sen University Ethical Committee, and all eligible patients received a detailed informed consent form that they signed to allow recruitment. The study was registered with a Chinese Clinical Trial Number, ChiCTR-TRC-13003454.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Liu, X., Li, T., Wang, B. et al. 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 (2020). https://doi.org/10.1007/s00404-020-05513-6
- Cumulative live birth rate
- Poor ovarian response
- Mild ovarian stimulation
- Conventional controlled ovarian stimulation
- Randomized controlled trial