Investigating Ovulation Induction Outcomes in Patients with Decreased Ovarian Reserve Treated with Double Stimulation during The Follicular and Luteal Phases Compared to The Conventional Antagonist Cycle: A Randomized Clinical Trial

Document Type : Original Article

Authors

1 Department of Obstetrics and Gynaecology, Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran

2 Department of Biostatistics and Epidemiology, Infectious Diseases and Tropical Medicine Research Centre, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran

3 Department of Obstetrics, Gynaecology and Infertility, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

4 Department of Obstetrics and Gynaecology, Molud Infertility Centre, Zahedan University of Medical Sciences, Zahedan, Iran

5 Pregnancy Health Research Centre, Zahedan University of Medical Sciences, Zahedan, Iran

6 Cellular and Molecular Research Centre, Research Institute of Cellular and Molecular Science in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran

Abstract

Background: It is difficult to obtain healthy oocytes in poor ovarian responders with conventional treatment methods.
Thus, the need to investigate new methods is essential. This study aims to investigate ovulation induction outcomes
in patients with decreased ovarian reserve (DOR) in two groups treated with double stimulation (DuoStim) during the
follicular and luteal phases in comparison with the antagonist cycle.
Materials and Methods: This was a randomised clinical trial that enrolled the patients with reduced ovarian reserve. The
patients referred for in vitro fertilisation (IVF) at Molud Infertility Clinic, Ali Ebn Abitalib (AS) Hospital, Zahedan, Iran
from 2020 to 2021. Participants were randomly divided into two groups, those who underwent treatment with DuoStim
during the follicular and luteal phase (case group) and those who received the conventional antagonist cycle (control group).
Results: The mean number of metaphase II (MII) eggs was 7.7 ± 3.1 in the case group and 6.1 ± 3.9 in the control
group (P=0.063). The mean total number of retrieved eggs in the case group was 9.2 ± 3.7 and in the control group, it
was 6.9 ± 4.4 (P=0.023). The mean number of embryos obtained in the case group was 6.5 ± 3.9; in the control group,
it was 4.7 ± 2.8 (P=0.016).
Conclusion: The DuoStim method can effectively play a role in increasing the total number of retrieved eggs and embryos
(registration number: IRCT20120817010617N8).

Keywords


  1.  

    1. Polat M, Mumusoglu S, Yarali Ozbek I, Bozdag G, Yarali H. Double or dual stimulation in poor ovarian responders: where do we stand? Ther Adv Reprod Health. 2021; 15: 26334941211024172.
    2. Gleicher N, Weghofer A, Barad DH. Anti-Müllerian hormone (AMH) defines, independent of age, low versus good live-birth chances in women with severely diminished ovarian reserve. Fertil Steril. 2010; 94(7): 2824-2827.
    3. Briggs R, Kovacs G, MacLachlan V, Motteram C, Baker HW. Can you ever collect too many oocytes? Hum Reprod. 2015; 30(1): 81- 87.
    4. Drakopoulos P, Blockeel C, Stoop D, Camus M, de Vos M, Tournaye H, et al. Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod. 2016; 31(2): 370-376.
    5. Ubaldi FM, Rienzi L, Ferrero S, Baroni E, Sapienza F, Cobellis L, et al. Management of poor responders in IVF. Reprod Biomed Online. 2005; 10(2): 235-246.
    6. Mahutte NG, Arici A. Poor responders: does the protocol make a difference? Curr Opin Obstet Gynecol. 2002; 14(3): 275-281.
    7. Maranhão KDS, Mariz MEGSM, Araújo EAD, Souza GR, Taveira KVM, Morais DB. Factors related to infertility in Brazil and their relationship with success rates after assisted reproduction treatment: an integrative review. JBRA Assist Reprod. 2021; 25(1): 136-149.
    8. Wiweko B, Afdi QF, Harzif AK, Pratama G, Sumapradja K, Muharam R, et al. Analysis of factors associated with ovarian reserve in a group of poor responders to in vitro fertilization: a cross-sectional study. Int J Reprod Biomed. 2020; 18(12): 1065-1072.
    9. 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): 1488-1495. e1.
    10. Vaiarelli A, Venturella R, Vizziello D, Bulletti F, Ubaldi FM. Dual ovarian stimulation and random start in assisted reproductive technologies: from ovarian biology to clinical application. Curr Opin Obstet Gynecol. 2017; 29(3): 153-159.
    11. Vaiarelli A, Cimadomo D, Ubaldi N, Rienzi L, Ubaldi FM. What is new in the management of poor ovarian response in IVF? Curr Opin Obstet Gynecol. 2018; 30(3): 155-162.
    12. 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): 684-691.
    13. Kamath MS, Maheshwari A, Bhattacharya S, Lor KY, Gibreel A. Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation. Cochrane Database Syst Rev. 2017; 11(11): CD008528.
    14. 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): 678-684.
    15. Li J, Lyu S, Lyu S, Gao M. Pregnancy outcomes in double stimulation versus two consecutive mild stimulations for IVF in poor ovarian responders. J Clin Med. 2022; 11(22): 6780.
    16. Vaiarelli A, Cimadomo D, Gennarelli G, Guido M, Alviggi C, Conforti A, et al. Second stimulation in the same ovarian cycle: an option to fully-personalize the treatment in poor prognosis patients undergoing PGT-A. J Assist Reprod Genet. 2022; 39(3): 663-673.
    17. 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): 121-130.
    18. Bacchetti P, Leung JM. Sample size calculations in clinical research. Anesthesiology. 2002; 97(4): 1028-1029.
    19. Kang M, Ragan BG, Park JH. Issues in outcomes research: an overview of randomization techniques for clinical trials. J Athl Train. 2008; 43(2): 215-221.
    20. Ubaldi F, Vaiarelli A, D'Anna R, Rienzi L. Management of poor responders in IVF: is there anything new? Biomed Res Int. 2014; 2014: 352098.
    21. Pirtea P, de Ziegler D, Poulain M, Ayoubi JM. New twists in ovarian stimulation and their practical implications. Front Med (Lausanne). 2019; 6: 197.
    22. Roberts J, Ronn R, Tallon N, Holzer H. Fertility preservation in reproductive-age women facing gonadotoxic treatments. Curr Oncol. 2015; 22(4): e294-304.
    23. Ozcan MC, Snegovskikh V, Adamson GD. Oocyte and embryo cryopreservation before gonadotoxic treatments: Principles of safe ovarian stimulation, a systematic review. Womens Health (Lond). 2022; 18: 17455065221074886.
    24. Rienzi L, Capalbo A, Stoppa M, Romano S, Maggiulli R, Albricci L, et al. No evidence of association between blastocyst aneuploidy and morphokinetic assessment in a selected population of poor-prognosis patients: a longitudinal cohort study. Reprod Biomed Online. 2015; 30(1): 57-66.
    25. Luo Y, Sun L, Dong M, Zhang X, Huang L, Zhu X, et al. The best execution of the DuoStim strategy (double stimulation in the follicular and luteal phase of the same ovarian cycle) in patients who are poor ovarian responders. Reprod Biol Endocrinol. 2020; 18(1): 102.
    26. 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): 193-198.
    27. de Almeida Cardoso MC, Evangelista A, Sartório C, Vaz G, Werneck CLV, Guimarães FM, et al. Can ovarian double-stimulation in the same menstrual cycle improve IVF outcomes? JBRA Assist Reprod. 2017; 21(3): 217-221.
    28. 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): 372-376.