Advertisement

Artificial oocyte activation with ionomycin compared with A23187 among patients at risk of failed or impaired fertilization

Published:August 24, 2022DOI:https://doi.org/10.1016/j.rbmo.2022.08.105

      ABSTRACT

      Research question

      Do fertilization rates differ between intracytoplasmic sperm injection (ICSI) cycles treated with artificial oocyte activation (AOA) using 10 µmol/l ionomycin or commercial A23187 in women at risk of failed or impaired fertilization?

      Design

      This single-centre, 7-year retrospective cohort study included 157 couples with a history of total fertilization failure (TFF, 0%) or low fertilization (<30%) after ICSI, or with severe oligo-astheno-teratozoospermia (OAT) in the male partner. Couples and underwent 171 ICSI–AOA cycles using either 10 µmol/l ionomycin or commercial A23187. The embryological and clinical outcomes were compared.

      Results

      Fertilization rates in the ionomycin group were significantly higher than those in the A23187 group for all three subgroups (TFF, 46.9% versus 28.4%, P = 0.002; low fertilization, 67.7% versus 49.2%, P < 0.001; severe OAT, 66.4% versus 31.6%, P < 0.001). AOA with ionomycin significantly increased the day 3 cleavage rate (P = 0.009) when compared with A23187 in the low fertilization group, but not in the TFF or severe OAT group (both P > 0.05). The rates of day 3 good-quality embryos, clinical pregnancy, implantation and live birth, and the cumulative live birth, did not differ between the two groups (all P > 0.05). A total of 64 live births resulted in 72 healthy babies born.

      Conclusions

      AOA with 10 µmol/l ionomycin may be more effective than commercial A23187 in improving oocyte activation in patients at risk of failed or impaired fertilization, especially in cases of sperm-related defects.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Reproductive BioMedicine Online
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      REFERENCES

        • Berridge M.J.
        • Bootman M.D.
        • Lipp P.
        Calcium–a life and death signal.
        Nature. 1998; 395: 645-648https://doi.org/10.1038/27094
        • Bonte D.
        • Ferrer-Buitrago M.
        • Dhaenens L.
        • Popovic M.
        • Thys V.
        • De Croo I.
        • De Gheselle S.
        • Steyaert N.
        • Boel A.
        • Vanden Meerschaut F.
        • De Sutter P.
        • Heindryckx B.
        Assisted oocyte activation significantly increases fertilization and pregnancy outcome in patients with low and total failed fertilization after intracytoplasmic sperm injection: a 17-year retrospective study.
        Fertil. Steril. 2019; 112: 266-274https://doi.org/10.1016/j.fertnstert.2019.04.006
        • Borges Jr., E.
        • de Almeida Ferreira Braga D.P.
        • de Sousa Bonetti T.C.
        • Iaconelli Jr., A.
        • Franco Jr., J.G.
        Artificial oocyte activation with calcium ionophore A23187 in intracytoplasmic sperm injection cycles using surgically retrieved spermatozoa.
        Fertil. Steril. 2009; 92: 131-136https://doi.org/10.1016/j.fertnstert.2008.04.046
        • Cardona Barberan A.
        • Boel A.
        • Vanden Meerschaut F.
        • Stoop D.
        • Heindryckx B.
        Diagnosis and Treatment of Male Infertility-Related Fertilization Failure.
        J .Clin. Med. 2020; 9https://doi.org/10.3390/jcm9123899
        • Combelles C.M.
        • Morozumi K.
        • Yanagimachi R.
        • Zhu L.
        • Fox J.H.
        • Racowsky C.
        Diagnosing cellular defects in an unexplained case of total fertilization failure.
        Hum. Reprod. 2010; 25: 1666-1671https://doi.org/10.1093/humrep/deq064
        • Dedkova E.N.
        • Sigova A.A.
        • Zinchenko V.P.
        Mechanism of action of calcium ionophores on intact cells: ionophore-resistant cells.
        Membr. Cell Biol. 2000; 13: 357-368
        • Deemeh M.R.
        • Tavalaee M.
        • Nasr-Esfahani M.H.
        Health of children born through artificial oocyte activation: a pilot study.
        Reprod. Sci. 2015; 22: 322-328https://doi.org/10.1177/1933719114542017
        • Ebner T.
        • Montag M.
        • Montag M.
        • Van der Ven K.
        • Van der Ven H.
        • Ebner T.
        • Shebl O.
        • Oppelt P.
        • Hirchenhain J.
        • Krüssel J.
        • Maxrath B.
        • Gnoth C.
        • Friol K.
        • Tigges J.
        • Wünsch E.
        • Luckhaus J.
        • Beerkotte A.
        • Weiss D.
        • Grunwald K.
        • Struller D.
        • Etien C.
        Live birth after artificial oocyte activation using a ready-to-use ionophore: a prospective multicentre study.
        J. Reproductive biomedicine online. 2015; 30: 359-365https://doi.org/10.1016/j.rbmo.2014.11.012
        • Ebner T.
        • Koster M.
        • Shebl O.
        • Moser M.
        • Van der Ven H.
        • Tews G.
        • Montag M.
        Application of a ready-to-use calcium ionophore increases rates of fertilization and pregnancy in severe male factor infertility.
        Fertil. Steril. 2012; 98: 1432-1437https://doi.org/10.1016/j.fertnstert.2012.07.1134
        • Ebner T.
        • Moser M.
        • Sommergruber M.
        • Jesacher K.
        • Tews G.
        Complete oocyte activation failure after ICSI can be overcome by a modified injection technique.
        Hum. Reprod. 2004; 19: 1837-1841https://doi.org/10.1093/humrep/deh325
        • Ebner Thomas
        • Shebl Omar
        • Oppelt Peter
        First live births after application of a ready-to-use ionomycin in cases of failed artificial oocyte activation (aoa) using calcimycin.
        Fertil. Steril. 2021; 116https://doi.org/10.1016/j.fertnstert.2021.07.545
        • Egashira A.
        • Murakami M.
        • Haigo K.
        • Horiuchi T.
        • Kuramoto T.
        A successful pregnancy and live birth after intracytoplasmic sperm injection with globozoospermic sperm and electrical oocyte activation.
        Fertil. Steril. 2009; 92 (2037 e5-9)https://doi.org/10.1016/j.fertnstert.2009.08.013
        • Eppig J.J.
        • Schultz R.M.
        • O'Brien M.
        • Chesnel F.
        Relationship between the developmental programs controlling nuclear and cytoplasmic maturation of mouse oocytes.
        Dev. Biol. 1994; 164: 1-9https://doi.org/10.1006/dbio.1994.1175
        • ESHRE Special Interest Group of Embryology and Alpha Scientists in Reproductive Medicine
        The Vienna consensus: report of an expert meeting on the development of ART laboratory performance indicators.
        Reprod. Biomed. Online. 2017; 35: 494-510https://doi.org/10.1016/j.rbmo.2017.06.015
        • Fang C.
        • Huang R.
        • Wei L.N.
        • Jia L.
        Frozen-thawed day 5 blastocyst transfer is associated with a lower risk of ectopic pregnancy than day 3 transfer and fresh transfer.
        Fertil. Steril. 2015; 103 (655-61 e3)https://doi.org/10.1016/j.fertnstert.2014.11.023
        • Fawzy M.
        • Emad M.
        • Mahran A.
        • Sabry M.
        • Fetih A.N.
        • Abdelghafar H.
        • Rasheed S.
        Artificial oocyte activation with SrCl2 or calcimycin after ICSI improves clinical and embryological outcomes compared with ICSI alone: results of a randomized clinical trial.
        Hum. Reprod. 2018; 33: 1636-1644https://doi.org/10.1093/humrep/dey258
        • Ferrer-Buitrago M.
        • Bonte D.
        • De Sutter P.
        • Leybaert L.
        • Heindryckx B.
        Single Ca(2+) transients vs oscillatory Ca(2+) signaling for assisted oocyte activation: limitations and benefits.
        Reproduction. 2018; 155: R105-RR19https://doi.org/10.1530/REP-17-0098
        • Ferrer-Buitrago M.
        • Bonte D.
        • Dhaenens L.
        • Vermorgen S.
        • Lu Y.
        • De Sutter P.
        • Heindryckx B.
        Assessment of the calcium releasing machinery in oocytes that failed to fertilize after conventional ICSI and assisted oocyte activation.
        Reprod. Biomed. Online. 2019; 38: 497-507https://doi.org/10.1016/j.rbmo.2018.12.035
        • Ferrer-Buitrago M.
        • Dhaenens L.
        • Lu Y.
        • Bonte D.
        • Vanden Meerschaut F.
        • De Sutter P.
        • Leybaert L.
        • Heindryckx B.
        Human oocyte calcium analysis predicts the response to assisted oocyte activation in patients experiencing fertilization failure after ICSI.
        Hum. Reprod. 2018; 33: 416-425https://doi.org/10.1093/humrep/dex376
        • Gardner D.K
        • Schoolcraft W.B.
        In-vitro culture of human blastocyst.
        Towards reproductive certainty: Infertility and genetics beyond. 1999; 1999: 378-388
        • Guo Y.C.
        • Chen P.Y.
        • Li T.T.
        • Jia L.
        • Sun P.
        • Zhu W.S.
        • Deng C.C.
        • Fang C.
        • Liang X.Y.
        Different progestin-primed ovarian stimulation protocols in infertile women undergoing in vitro fertilization/intracytoplasmic sperm injection: an analysis of 1188 cycles.
        Arch. Gynecol. Obstet. 2019; 299: 1201-1212https://doi.org/10.1007/s00404-019-05065-4
        • Heindryckx B.
        • De Gheselle S.
        • Gerris J.
        • Dhont M.
        • De Sutter P.
        Efficiency of assisted oocyte activation as a solution for failed intracytoplasmic sperm injection.
        Reprod. Biomed. Online. 2008; 17: 662-668https://doi.org/10.1016/s1472-6483(10)60313-6
        • Heindryckx B.
        • Van der Elst J.
        • De Sutter P.
        • Dhont M.
        Treatment option for sperm- or oocyte-related fertilization failure: assisted oocyte activation following diagnostic heterologous ICSI.
        Hum. Reprod. 2005; 20: 2237-2241https://doi.org/10.1093/humrep/dei029
        • Kashir J.
        • Heindryckx B.
        • Jones C.
        • De Sutter P.
        • Parrington J.
        • Coward K.
        Oocyte activation, phospholipase C zeta and human infertility.
        Hum. Reprod. Update. 2010; 16: 690-703https://doi.org/10.1093/humupd/dmq018
        • Kim J.W.
        • Yang S.H.
        • Yoon S.H.
        • Kim S.D.
        • Jung J.H.
        • Lim J.H.
        Successful pregnancy and delivery after ICSI with artificial oocyte activation by calcium ionophore in in-vitro matured oocytes: a case report.
        J. Reproductive biomedicine online. 2015; 30: 373-377https://doi.org/10.1016/j.rbmo.2014.11.014
        • Kochhar P.K.
        • Ghosh P.
        Intracytoplasmic Sperm Injection with Assisted Oocyte Activation Resulting in Successful Pregnancies and Live Birth in Couples with Globozoospermia: A Report of Two Cases.
        J. Hum. Reprod. Sci. 2018; 11: 72-74https://doi.org/10.4103/jhrs.JHRS_47_17
        • Li B.
        • Zhou Y.
        • Yan Z.
        • Li M.
        • Xue S.
        • Cai R.
        • Fu Y.
        • Hong Q.
        • Long H.
        • Yin M.
        • Du T.
        • Wang Y.
        • Kuang Y.
        • Yan Z.
        • Lyu Q.
        Pregnancy and neonatal outcomes of artificial oocyte activation in patients undergoing frozen-thawed embryo transfer: a 6-year population-based retrospective study.
        Arch. Gynecol. Obstet. 2019; 300: 1083-1092https://doi.org/10.1007/s00404-019-05298-3
        • Li J.
        • Zheng X.
        • Lian Y.
        • Li M.
        • Lin S.
        • Zhuang X.
        • Chen L.
        • Liu P.
        • Qiao J.
        Artificial oocyte activation improves cycles with prospects of ICSI fertilization failure: a sibling oocyte control study.
        Reprod. Biomed. Online. 2019; 39: 199-204https://doi.org/10.1016/j.rbmo.2019.03.216
        • Liu C.
        • Hermann T.E.
        Characterization of ionomycin as a calcium ionophore.
        J. Biol. Chem. 1978; 253: 5892-5894
        • Liu F.
        • Zou S.S.
        • Zhu Y.
        • Sun C.
        • Liu Y.F.
        • Wang S.S.
        • Shi W.B.
        • Zhu J.J.
        • Huang Y.H.
        • Li Z.
        A novel micro-straw for cryopreservation of small number of human spermatozoon.
        Asian J. Androl. 2017; 19: 326-329https://doi.org/10.4103/1008-682X.173452
        • Lu Q.
        • Chen X.
        • Li Y.
        • Zhang X.H.
        • Liang R.
        • Zhao Y.P.
        • Wei L.H.
        • Shen H.
        A live birth of activated one-day-old unfertilized oocyte for a patient who experienced repeatedly near-total fertilization failure after intracytoplasmic sperm injection.
        Chin. Med. J. (Engl.). 2012; 125: 546-548
        • Malcuit C.
        • Knott J.G.
        • He C.
        • Wainwright T.
        • Parys J.B.
        • Robl J.M.
        • Fissore R.A.
        Fertilization and inositol 1,4,5-trisphosphate (IP3)-induced calcium release in type-1 inositol 1,4,5-trisphosphate receptor down-regulated bovine eggs.
        Biol. Reprod. 2005; 73: 2-13https://doi.org/10.1095/biolreprod.104.037333
        • Mason M.J.
        • Grinstein S.
        Ionomycin activates electrogenic Ca2+ influx in rat thymic lymphocytes.
        Biochem. J. 1993; 296: 33-39https://doi.org/10.1042/bj2960033
        • Mateizel I.
        • Verheyen G.
        • Van de Velde H.
        • Tournaye H.
        • Belva F.
        Obstetric and neonatal outcome following ICSI with assisted oocyte activation by calcium ionophore treatment.
        J. Assist. Reprod. Genet. 2018; 35: 1005-1010https://doi.org/10.1007/s10815-018-1124-6
        • Miyazaki S.
        • Shirakawa H.
        • Nakada K.
        • Honda Y.
        Essential role of the inositol 1,4,5-trisphosphate receptor/Ca2+ release channel in Ca2+ waves and Ca2+ oscillations at fertilization of mammalian eggs.
        Dev. Biol. 1993; 158: 62-78https://doi.org/10.1006/dbio.1993.1168
        • Moaz M.N.
        • Khattab S.
        • Foutouh I.A.
        • Mohsen E.A.
        Chemical activation of oocytes in different types of sperm abnormalities in cases of low or failed fertilization after ICSI: a prospective pilot study.
        Reprod. Biomed. Online. 2006; 13: 791-794https://doi.org/10.1016/s1472-6483(10)61025-5
        • Montag M.
        • Koster M.
        • van der Ven K.
        • Bohlen U.
        • van der Ven H.
        The benefit of artificial oocyte activation is dependent on the fertilization rate in a previous treatment cycle.
        Reprod. Biomed. Online. 2012; 24: 521-526https://doi.org/10.1016/j.rbmo.2012.02.002
        • Morgan A.J.
        • Jacob R.
        Ionomycin enhances Ca2+ influx by stimulating store-regulated cation entry and not by a direct action at the plasma membrane.
        Biochem. J. 1994; 300: 665-672https://doi.org/10.1042/bj3000665
        • Nasr-Esfahani M.H.
        • Deemeh M.R.
        • Tavalaee M.
        Artificial oocyte activation and intracytoplasmic sperm injection.
        Fertil. Steril. 2010; 94: 520-526https://doi.org/10.1016/j.fertnstert.2009.03.061
        • Nasr-Esfahani M.H.
        • Razavi S.
        • Javdan Z.
        • Tavalaee M.
        Artificial oocyte activation in severe teratozoospermia undergoing intracytoplasmic sperm injection.
        Fertil. Steril. 2008; 90: 2231-2237https://doi.org/10.1016/j.fertnstert.2007.10.047
        • Nasr-Esfahani M.H.
        • Razavi S.
        • Mardani M.
        • Shirazi R.
        • Javanmardi S.
        Effects of failed oocyte activation and sperm protamine deficiency on fertilization post-ICSI.
        Reprod. Biomed. Online. 2007; 14: 422-429https://doi.org/10.1016/s1472-6483(10)60888-7
        • Nikiforaki D.
        • Vanden Meerschaut F.
        • de Roo C.
        • Lu Y.
        • Ferrer-Buitrago M.
        • de Sutter P.
        • Heindryckx B.
        Effect of two assisted oocyte activation protocols used to overcome fertilization failure on the activation potential and calcium releasing pattern.
        Fertil. Steril. 2016; 105 (798-806.e2)https://doi.org/10.1016/j.fertnstert.2015.11.007
        • Ozil J.P.
        • Banrezes B.
        • Toth S.
        • Pan H.
        • Schultz R.M.
        Ca2+ oscillatory pattern in fertilized mouse eggs affects gene expression and development to term.
        Dev. Biol. 2006; 300: 534-544https://doi.org/10.1016/j.ydbio.2006.08.041
        • Ozil J.P.
        • Markoulaki S.
        • Toth S.
        • Matson S.
        • Banrezes B.
        • Knott J.G.
        • Schultz R.M.
        • Huneau D.
        • Ducibella T.
        Egg activation events are regulated by the duration of a sustained [Ca2+]cyt signal in the mouse.
        Dev. Biol. 2005; 282: 39-54https://doi.org/10.1016/j.ydbio.2005.02.035
        • Rawe V.Y.
        • Olmedo S.B.
        • Nodar F.N.
        • Doncel G.D.
        • Acosta A.A.
        • Vitullo A.D.
        Cytoskeletal organization defects and abortive activation in human oocytes after IVF and ICSI failure.
        Mol. Hum. Reprod. 2000; 6: 510-516https://doi.org/10.1093/molehr/6.6.510
        • Rybouchkin A.
        • Dozortsev D.
        • de Sutter P.
        • Qian C.
        • Dhont M.
        Intracytoplasmic injection of human spermatozoa into mouse oocytes: a useful model to investigate the oocyte-activating capacity and the karyotype of human spermatozoa.
        Hum. Reprod. 1995; 10: 1130-1135https://doi.org/10.1093/oxfordjournals.humrep.a136105
        • Saleh A.
        • Kashir J.
        • Thanassoulas A.
        • Safieh-Garabedian B.
        • Lai F.A.
        • Nomikos M.
        Essential Role of Sperm-Specific PLC-Zeta in Egg Activation and Male Factor Infertility: An Update.
        Front Cell Dev. Biol. 2020; 8: 28https://doi.org/10.3389/fcell.2020.00028
        • Sang Q.
        • Li B.
        • Kuang Y.
        • Wang X.
        • Zhang Z.
        • Chen B.
        • Wu L.
        • Lyu Q.
        • Fu Y.
        • Yan Z.
        • Mao X.
        • Xu Y.
        • Mu J.
        • Li Q.
        • Jin L.
        • He L.
        • Wang L.
        Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility.
        Am. J. Hum. Genet. 2018; 102: 649-657https://doi.org/10.1016/j.ajhg.2018.02.015
        • Santella L.
        • Dale B.
        Assisted yes, but where do we draw the line?.
        Reprod. Biomed. Online. 2015; 31: 476-478https://doi.org/10.1016/j.rbmo.2015.06.013
        • Shebl O.
        • Reiter E.
        • Enengl S.
        • Allerstorfer C.
        • Schappacher-Tilp G.
        • Trautner P.S.
        • Rechberger T.
        • Oppelt P.
        • Ebner T.
        Double ionophore application in cases with previous failed/low fertilization or poor embryo development.
        Reprod. Biomed. Online. 2022; 44: 829-837https://doi.org/10.1016/j.rbmo.2021.11.008
        • Swann K.
        • Lai F.A.
        Egg Activation at Fertilization by a Soluble Sperm Protein.
        Physiol. Rev. 2016; 96: 127-149https://doi.org/10.1152/physrev.00012.2015
        • Swanson C.A.
        • Arkin A.P.
        • Ross J.
        An endogenous calcium oscillator may control early embryonic division.
        Proc. Natl. Acad. Sci. USA. 1997; 94: 1194-1199https://doi.org/10.1073/pnas.94.4.1194
        • Tejera A.
        • Molla M.
        • Muriel L.
        • Remohi J.
        • Pellicer A.
        • De Pablo J.L.
        Successful pregnancy and childbirth after intracytoplasmic sperm injection with calcium ionophore oocyte activation in a globozoospermic patient.
        Fertil. Steril. 2008; 90 (1202 e1-5)https://doi.org/10.1016/j.fertnstert.2007.11.056
        • Terada Y.
        • Hasegawa H.
        • Takahashi A.
        • Ugajin T.
        • Yaegashi N.
        • Okamura K.
        Successful pregnancy after oocyte activation by a calcium ionophore for a patient with recurrent intracytoplasmic sperm injection failure, with an assessment of oocyte activation and sperm centrosomal function using bovine eggs.
        Fertil. Steril. 2009; 91 (935 e11-4)https://doi.org/10.1016/j.fertnstert.2008.09.043
        • Tesarik J.
        • Rienzi L.
        • Ubaldi F.
        • Mendoza C.
        • Greco E.
        Use of a modified intracytoplasmic sperm injection technique to overcome sperm-borne and oocyte-borne oocyte activation failures.
        Fertil. Steril. 2002; 78: 619-624https://doi.org/10.1016/s0015-0282(02)03291-0
        • Tesarik J.
        • Sousa M.
        • Testart J.
        Human oocyte activation after intracytoplasmic sperm injection.
        Hum. Reprod. 1994; 9: 511-518https://doi.org/10.1093/oxfordjournals.humrep.a138537
        • Toth S.
        • Huneau D.
        • Banrezes B.
        • Ozil J.P.
        Egg activation is the result of calcium signal summation in the mouse.
        Reproduction. 2006; 131: 27-34https://doi.org/10.1530/rep.1.00764
        • Vanden Meerschaut F.
        • Leybaert L.
        • Nikiforaki D.
        • Qian C.
        • Heindryckx B.
        • De Sutter P.
        Diagnostic and prognostic value of calcium oscillatory pattern analysis for patients with ICSI fertilization failure.
        Hum. Reprod. 2013; 28: 87-98https://doi.org/10.1093/humrep/des368
        • Wakai T.
        • Zhang N.
        • Vangheluwe P.
        • Fissore R.A.
        Regulation of endoplasmic reticulum Ca(2+) oscillations in mammalian eggs.
        J. Cell Sci. 2013; 126: 5714-5724https://doi.org/10.1242/jcs.136549
        • Yin M.
        • Yu W.
        • Li W.
        • Zhu Q.
        • Long H.
        • Kong P.
        • Lyu Q.
        DNA methylation and gene expression changes in mouse pre- and post-implantation embryos generated by intracytoplasmic sperm injection with artificial oocyte activation.
        Reprod. Biol. Endocrinol. 2021; 19: 163https://doi.org/10.1186/s12958-021-00845-7
        • Zhao S.
        • Chen T.
        • Yu M.
        • Bian Y.
        • Cao Y.
        • Ning Y.
        • Su S.
        • Zhang J.
        • Zhao S.
        Novel WEE2 gene variants identified in patients with fertilization failure and female infertility.
        Fertil. Steril. 2019; 111: 519-526https://doi.org/10.1016/j.fertnstert.2018.11.018

      Biography

      Lei Jia obtained her MS from Sun Yat-sen University, China, and since then has worked as a Clinical Embryologist at the Reproductive Medicine Centre, Sixth Affiliated Hospital of Sun Yat-sen University. Her research areas include oocyte activation, oocyte ageing and stem cells.
      Key message
      Artificial oocyte activation with 10 µM ionomycin may provide higher fertilization rates than with commercial A23187 in patients at risk of failed or impaired fertilization.