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

Alberto Vaiarelli, Danilo Cimadomo, Elisabetta Trabucco, Roberta Vallefuoco, Laura Buffo, Ludovica Dusi, Fabrizio Fiorini, Nicoletta Barnocchi, Francesco Maria Bulletti, Laura Rienzi, Filippo Maria Ubaldi, Alberto Vaiarelli, Danilo Cimadomo, Elisabetta Trabucco, Roberta Vallefuoco, Laura Buffo, Ludovica Dusi, Fabrizio Fiorini, Nicoletta Barnocchi, Francesco Maria Bulletti, Laura Rienzi, Filippo Maria Ubaldi

Abstract

A panel of experts known as the POSEIDON group has recently redefined the spectrum of poor responder patients and introduced the concept of suboptimal response. Since an ideal management for these patients is still missing, they highlighted the importance of tailoring the ovarian stimulation based on the chance of each woman to obtain an euploid blastocyst. Interestingly, a novel pattern of follicle recruitment has been defined: multiple waves may arise during a single ovarian cycle. This evidence opened important clinical implications for the treatment of poor responders. For instance, double stimulation in the follicular (FPS) and luteal phase (LPS) of the same ovarian cycle (DuoStim) is an intriguing option to perform two oocyte retrievals in the shortest possible time. Here, we reported our 2-year experience of DuoStim application in four private IVF centers. To date, 310 poor prognosis patients completed a DuoStim protocol and underwent IVF with blastocyst-stage preimplantation-genetic-testing. LPS resulted into a higher mean number of oocytes collected than FPS; however, their competence (i.e., fertilization, blastocyst, euploidy rates, and clinical outcomes after euploid single-embryo-transfer) was comparable. Importantly, the rate of patients obtaining at least one euploid blastocyst increased from 42.3% (n = 131/310) after FPS to 65.5% (n = 203/310) with the contribution of LPS. A summary of the putative advantages and disadvantages of DuoStim was reported here through a Strengths-Weaknesses-Opportunities-Threats analysis. The strengths of this approach make it very promising. However, more studies are needed in the future to limit its weaknesses, shed light on its putative threats, and realize its opportunities.

Keywords: IVF; Poseidon; double stimulation; dual-stimulation; duostim; euploid blastocyst; low prognosis patients; poor responder.

Figures

Figure 1
Figure 1
Multicenter clinical experience at the G.EN.E.R.A. centers for reproductive medicine (Rome, Naples, Marostica, and Umbertide) with the application of a DuoStim approach. (A) Mean number of metaphase (MII) oocytes, fertilized embryos, blastocysts, and euploid blastocysts obtained per cycle after follicular phase stimulation (FPS) and luteal phase one (LPS); (B) Mean embryological results calculated per MII oocyte retrieved and inseminated in FPS- and LPS-derived cycles; (C) Overall embryological results of the MII oocytes collected after FPS and LPS, respectively. The stars identify statistically significant differences. The non-Gaussian distribution of the data was assessed through the Shapiro–Wilk test. Wilcoxon signed-rank test and Fisher’s exact test were used to test for significant differences between FPS- and LPS-derived data.
Figure 2
Figure 2
DuoStim SWOT analysis. Abbreviations: FPS, follicular phase stimulation; LPS, luteal phase stimulation; RCT, randomized controlled trial; COS, controlled ovarian stimulation.

References

    1. Ubaldi F, Vaiarelli A, D’Anna R, Rienzi L. Management of poor responders in IVF: is there anything new? Biomed Res Int (2014) 2014:352098.10.1155/2014/352098
    1. 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) 96:1058–61.e7.10.1016/j.fertnstert.2011.09.048
    1. Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L, et al. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod (2011) 26:1616–24.10.1093/humrep/der092
    1. Ferraretti AP, Gianaroli L. The Bologna criteria for the definition of poor ovarian responders: is there a need for revision? Hum Reprod (2014) 29:1842–5.10.1093/humrep/deu139
    1. Younis JS, Ben-Ami M, Ben-Shlomo I. The Bologna criteria for poor ovarian response: a contemporary critical appraisal. J Ovarian Res (2015) 8:76.10.1186/s13048-015-0204-9
    1. Ata B, Kaplan B, Danzer H, Glassner M, Opsahl M, Tan SL, et al. Array CGH analysis shows that aneuploidy is not related to the number of embryos generated. Reprod Biomed Online (2012) 24:614–20.10.1016/j.rbmo.2012.02.009
    1. Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR, et al. The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil Steril (2014) 101(3): 656–663.e1.10.1016/j.fertnstert.2013.11.004
    1. Ubaldi FM, Capalbo A, Colamaria S, Ferrero S, Maggiulli R, Vajta G, et al. Reduction of multiple pregnancies in the advanced maternal age population after implementation of an elective single embryo transfer policy coupled with enhanced embryo selection: pre- and post-intervention study. Hum Reprod (2015) 30:2097–106.10.1093/humrep/dev159
    1. Patrizio P, Vaiarelli A, Levi Setti PE, Tobler KJ, Shoham G, Leong M, et al. How to define, diagnose and treat poor responders? Responses from a worldwide survey of IVF clinics. Reprod Biomed Online (2015) 30:581–92.10.1016/j.rbmo.2015.03.002
    1. Iliodromiti S, Anderson RA, Nelson SM. Technical and performance characteristics of anti-Mullerian hormone and antral follicle count as biomarkers of ovarian response. Hum Reprod Update (2015) 21:698–710.10.1093/humupd/dmu062
    1. Poseidon Group (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) Alviggi C, Andersen CY, Buehler K, Conforti A, De Placido G, et al. A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil Steril (2016) 105:1452–3.10.1016/j.fertnstert.2016.02.005
    1. Glujovsky D, Farquhar C, Quinteiro Retamar AM, Alvarez Sedo CR, Blake D. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev (2016) (6):CD002118.10.1002/14651858.CD002118.pub5
    1. Dahdouh EM, Balayla J, Garcia-Velasco JA. Comprehensive chromosome screening improves embryo selection: a meta-analysis. Fertil Steril (2015) 104:1503–12.10.1016/j.fertnstert.2015.08.038
    1. Duffy JM, Ahmad G, Mohiyiddeen L, Nardo LG, Watson A. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev (2010) (1):CD000099.10.1002/14651858.CD000099.pub3
    1. Yeung T, Chai J, Li R, Lee V, Ho PC, Ng E. A double-blind randomised controlled trial on the effect of dehydroepiandrosterone on ovarian reserve markers, ovarian response and number of oocytes in anticipated normal ovarian responders. BJOG (2016) 123:1097–105.10.1111/1471-0528.13808
    1. Yeung TW, Chai J, Li RH, Lee VC, Ho PC, Ng EH. A randomized, controlled, pilot trial on the effect of dehydroepiandrosterone on ovarian response markers, ovarian response, and in vitro fertilization outcomes in poor responders. Fertil Steril (2014) 102:108–115.e1.10.1016/j.fertnstert.2014.03.044
    1. Yeung TW, Li RH, Lee VC, Ho PC, Ng EH. A randomized double-blinded placebo-controlled trial on the effect of dehydroepiandrosterone for 16 weeks on ovarian response markers in women with primary ovarian insufficiency. J Clin Endocrinol Metab (2013) 98:380–8.10.1210/jc.2012-3071
    1. Balasch J, Fabregues F, Penarrubia J, Carmona F, Casamitjana R, Creus M, et al. Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH. Hum Reprod (2006) 21:1884–93.10.1093/humrep/del052
    1. Fabregues F, Penarrubia J, Creus M, Manau D, Casals G, Carmona F, et al. Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial. Hum Reprod (2009) 24:349–59.10.1093/humrep/den428
    1. Bosdou JK, Venetis CA, Dafopoulos K, Zepiridis L, Chatzimeletiou K, Anifandis G, et al. Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial. Hum Reprod (2016) 31:977–85.10.1093/humrep/dew028
    1. Polyzos NP, Davis SR, Drakopoulos P, Humaidan P, De Geyter C, Vega AG, et al. Testosterone for poor ovarian responders: lessons from ovarian physiology. Reprod Sci (2016).10.1177/1933719116660849
    1. Adams GP, Singh J, Baerwald AR. Large animal models for the study of ovarian follicular dynamics in women. Theriogenology (2012) 78:1733–48.10.1016/j.theriogenology.2012.04.010
    1. Jacob JC, Gastal EL, Gastal MO, Carvalho GR, Beg MA, Ginther OJ. Follicle deviation in ovulatory follicular waves with one or two dominant follicles in mares. Reprod Domest Anim (2009) 44:248–54.10.1111/j.1439-0531.2007.01048.x
    1. Jacob JC, Gastal EL, Gastal MO, Carvalho GR, Beg MA, Ginther OJ. Temporal relationships and repeatability of follicle diameters and hormone concentrations within individuals in mares. Reprod Domest Anim (2009) 44:92–9.10.1111/j.1439-0531.2007.01003.x
    1. Ginther OJ, Knopf L, Kastelic JP. Temporal associations among ovarian events in cattle during oestrous cycles with two and three follicular waves. J Reprod Fertil (1989) 87:223–30.10.1530/jrf.0.0870223
    1. Ginther OJ, Jacob JC, Gastal MO, Gastal EL, Beg MA. Development of one vs multiple ovulatory follicles and associated systemic hormone concentrations in mares. Reprod Domest Anim (2009) 44:441–9.10.1111/j.1439-0531.2008.01109.x
    1. Ginther OJ. The mare: a 1000-pound guinea pig for study of the ovulatory follicular wave in women. Theriogenology (2012) 77:818–28.10.1016/j.theriogenology.2011.09.025
    1. Baerwald AR, Adams GP, Pierson RA. Ovarian antral folliculogenesis during the human menstrual cycle: a review. Hum Reprod Update (2012) 18:73–91.10.1093/humupd/dmr039
    1. Baerwald AR, Adams GP, Pierson RA. Characterization of ovarian follicular wave dynamics in women. Biol Reprod (2003) 69:1023–31.10.1095/biolreprod.103.017772
    1. Clancy KB, Baerwald AR, Pierson RA. Systemic inflammation is associated with ovarian follicular dynamics during the human menstrual cycle. PLoS One (2013) 8:e64807.10.1371/journal.pone.0064807
    1. Polyzos NP, Nwoye M, Corona R, Blockeel C, Stoop D, Haentjens P, et al. Live birth rates in Bologna poor responders treated with ovarian stimulation for IVF/ICSI. Reprod Biomed Online (2014) 28:469–74.10.1016/j.rbmo.2013.11.010
    1. La Marca A, Grisendi V, Giulini S, Sighinolfi G, Tirelli A, Argento C, et al. Live birth rates in the different combinations of the Bologna criteria poor ovarian responders: a validation study. J Assist Reprod Genet (2015) 32:931–7.10.1007/s10815-015-0476-4
    1. Busnelli A, Papaleo E, Del Prato D, La Vecchia I, Iachini E, Paffoni A, et al. A retrospective evaluation of prognosis and cost-effectiveness of IVF in poor responders according to the Bologna criteria. Hum Reprod (2015) 30:315–22.10.1093/humrep/deu319
    1. 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) 105:1488–95.e1.10.1016/j.fertnstert.2016.03.002
    1. 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):153–9.10.1097/GCO.0000000000000365
    1. 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) 29:684–91.10.1016/j.rbmo.2014.08.009
    1. 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):155–62.10.1097/GCO.0000000000000452
    1. 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:CD008528.10.1002/14651858.CD008528.pub3
    1. Heijnen EM, Eijkemans MJ, De Klerk C, Polinder S, Beckers NG, Klinkert ER, et al. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet (2007) 369:743–9.10.1016/S0140-6736(07)60360-2
    1. Revelli A, Casano S, Salvagno F, Delle Piane L. Milder is better? Advantages and disadvantages of “mild” ovarian stimulation for human in vitro fertilization. Reprod Biol Endocrinol (2011) 9:25.10.1186/1477-7827-9-25
    1. Maheshwari A, McLernon D, Bhattacharya S. Cumulative live birth rate: time for a consensus? Hum Reprod (2015) 30:2703–7.10.1093/humrep/dev263
    1. Domar AD, Smith K, Conboy L, Iannone M, Alper M. A prospective investigation into the reasons why insured United States patients drop out of in vitro fertilization treatment. Fertil Steril (2010) 94:1457–9.10.1016/j.fertnstert.2009.06.020
    1. Van den Broeck U, Holvoet L, Enzlin P, Bakelants E, Demyttenaere K, D’Hooghe T. Reasons for dropout in infertility treatment. Gynecol Obstet Invest (2009) 68:58–64.10.1159/000214839
    1. Bodri D, Kawachiya S, De Brucker M, Tournaye H, Kondo M, Kato R, et al. Cumulative success rates following mild IVF in unselected infertile patients: a 3-year, single-centre cohort study. Reprod Biomed Online (2014) 28:572–81.10.1016/j.rbmo.2014.01.002
    1. Brandes M, van der Steen JO, Bokdam SB, Hamilton CJ, de Bruin JP, Nelen WL, et al. When and why do subfertile couples discontinue their fertility care? A longitudinal cohort study in a secondary care subfertility population. Hum Reprod (2009) 24:3127–35.10.1093/humrep/dep340
    1. Roest J, van Heusden AM, Zeilmaker GH, Verhoeff A. Cumulative pregnancy rates and selective drop-out of patients in in-vitro fertilization treatment. Hum Reprod (1998) 13:339–41.10.1093/humrep/13.2.339
    1. Goswami M, Hyslop LA, Murdoch AP. NHS-funded IVF: consequences of NICE implementation. Hum Fertil (Camb) (2013) 16:121–7.10.3109/14647273.2013.786840
    1. Rustamov O, Smith A, Roberts SA, Yates AP, Fitzgerald C, Krishnan M, et al. Anti-Mullerian hormone: poor assay reproducibility in a large cohort of subjects suggests sample instability. Hum Reprod (2012) 27:3085–91.10.1093/humrep/des260
    1. Rustamov O, Smith A, Roberts SA, Yates AP, Fitzgerald C, Krishnan M, et al. The measurement of anti-Mullerian hormone: a critical appraisal. J Clin Endocrinol Metab (2014) 99:723–32.10.1210/jc.2013-3476
    1. Nelson SM. Biomarkers of ovarian response: current and future applications. Fertil Steril (2013) 99:963–9.10.1016/j.fertnstert.2012.11.051
    1. Tsampras N, Gould D, Fitzgerald CT. Double ovarian stimulation (DuoStim) protocol for fertility preservation in female oncology patients. Hum Fertil (Camb) (2017) 20:248–53.10.1080/14647273.2017.1287433
    1. Reynolds KA, Omurtag KR, Jimenez PT, Rhee JS, Tuuli MG, Jungheim ES. Cycle cancellation and pregnancy after luteal estradiol priming in women defined as poor responders: a systematic review and meta-analysis. Hum Reprod (2013) 28:2981–9.10.1093/humrep/det306
    1. Fanchin R, Salomon L, Castelo-Branco A, Olivennes F, Frydman N, Frydman R. Luteal estradiol pre-treatment coordinates follicular growth during controlled ovarian hyperstimulation with GnRH antagonists. Hum Reprod (2003) 18:2698–703.10.1093/humrep/deg516
    1. 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) 30:57–66.10.1016/j.rbmo.2014.09.012
    1. Capalbo A, Rienzi L, Cimadomo D, Maggiulli R, Elliott T, Wright G, et al. Correlation between standard blastocyst morphology, euploidy and implantation: an observational study in two centers involving 956 screened blastocysts. Hum Reprod (2014) 29:1173–81.10.1093/humrep/deu033
    1. Cobo A, Bellver J, Domingo J, Perez S, Crespo J, Pellicer A, et al. New options in assisted reproduction technology: the Cryotop method of oocyte vitrification. Reprod Biomed Online (2008) 17:68–72.10.1016/S1472-6483(10)60295-7
    1. Fatemi HM, Polyzos NP, van Vaerenbergh I, Bourgain C, Blockeel C, Alsbjerg B, et al. Early luteal phase endocrine profile is affected by the mode of triggering final oocyte maturation and the luteal phase support used in recombinant follicle-stimulating hormone-gonadotropin-releasing hormone antagonist in vitro fertilization cycles. Fertil Steril (2013) 100:742–7.10.1016/j.fertnstert.2013.05.028
    1. Yarali H, Polat M, Mumusoglu S, Yarali I, Bozdag G. Preparation of endometrium for frozen embryo replacement cycles: a systematic review and meta-analysis. J Assist Reprod Genet (2016) 33:1287–304.10.1007/s10815-016-0787-0
    1. Massin N. New stimulation regimens: endogenous and exogenous progesterone use to block the LH surge during ovarian stimulation for IVF. Hum Reprod Update (2017) 23:211–20.10.1093/humupd/dmw047
    1. Martinez F, Clua E, Devesa M, Rodriguez I, Arroyo G, Gonzalez C, et al. Comparison of starting ovarian stimulation on day 2 versus day 15 of the menstrual cycle in the same oocyte donor and pregnancy rates among the corresponding recipients of vitrified oocytes. Fertil Steril (2014) 102:1307–11.10.1016/j.fertnstert.2014.07.741
    1. Kuang Y, Hong Q, Chen Q, Lyu Q, Ai A, Fu Y, et al. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil Steril (2014) 101:105–11.10.1016/j.fertnstert.2013.09.007
    1. 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 (Oxf) (2016) 84:720–8.10.1111/cen.12983
    1. Lin LT, Wang PH, Tsui KH. The use of luteal-phase ovarian stimulation for poor ovarian responders undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer treatment. Taiwan J Obstet Gynecol (2016) 55:307–8.10.1016/j.tjog.2016.04.002
    1. Moffat R, Pirtea P, Gayet V, Wolf JP, Chapron C, de Ziegler D. Dual ovarian stimulation is a new viable option for enhancing the oocyte yield when the time for assisted reproductive technnology is limited. Reprod Biomed Online (2014) 29:659–61.10.1016/j.rbmo.2014.08.010

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