Artificial oocyte activation: physiological, pathophysiological and ethical aspects

Anifandis, George; Michopoulos, Alexandros; Daponte, Alexandros; Chatzimeletiou, Katerina; Simopoulou, Mara; Messini, Christina I.; Polyzos, Nikolas P; Vassiou, Katerina; Dafopoulos, Konstantinos; Goulis, Dimitrios G.

doi:10.1080/19396368.2018.1516000

Cited by 41 publications

(28 citation statements)

References 103 publications

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“…Given the complexity of cellular mechanisms regulated by intra-cytoplasmic Ca 2+ levels and oscillations ( Alberio et al , 2000 ), Ca 2+ ionophores have raised concerns of molecular downstream consequences, issues with long-term gene expression and epigenetic alterations (i.e. DNA methylation), with possible implications affecting embryonic development post-implantation ( Ebner et al , 2012 ; Vanden Meerschaut et al , 2014b ; Santella and Dale, 2015 ; Capalbo et al , 2016 ; Nikiforaki et al , 2016 ; Anifandis et al , 2019 ). For example, protein synthesis and degradation changes in the first cell cycle may occur as a result of AOA, based on data with parthenogenetically activated mammalian oocytes ( Ebner and Montag, 2016 ).…”

Section: Efficacy and Safety Of Aoamentioning

confidence: 99%

Oocyte activation deficiency and assisted oocyte activation: mechanisms, obstacles and prospects for clinical application

Kashir

Ganesh

Jones

et al. 2022

Human Reproduction Open

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Background Oocyte activation deficiency (OAD) is attributed to the majority of cases underlying failure of intracytoplasmic sperm injection (ICSI) cycles, the standard treatment for male factor infertility. Oocyte activation encompasses a series of concerted events, triggered by sperm-specific phospholipase C zeta (PLCζ), which elicits increases in free cytoplasmic calcium (Ca2+) in spatially and temporally specific oscillations. Defects in this specific pattern of Ca2+ release is directly attributable to most cases of OAD. Ca2+ release can be clinically mediated via assisted oocyte activation (AOA), a combination of mechanical, electrical and/or chemical stimuli which artificially promote an increase in the levels of intracytoplasmic Ca2+. However, concerns regarding safety and efficacy underlie potential risks that must be addressed before such methods can be safely widely used. Objective and Rationale Recent advances in current AOA techniques warrant a review of the safety and efficacy of these practices, to determine the extent to which AOA may be implemented in the clinic. Importantly, the primary challenges to obtaining data on the safety and efficacy of AOA must be determined. Such questions require urgent attention before widespread clinical utilisation of such protocols can be advocated. Search Methods A literature review was performed using databases including PubMed, Web of Science, Medline etc. using assisted oocyte activation, oocyte activation deficiency, calcium ionophores, intra-cytoplasmic sperm injection, phospholipase c zeta, oocyte activation, failed fertilisation, and fertilisation failure as keywords. Relevant articles published until June 2019 were analysed and included in the review, with an emphasis on studies assessing large scale efficacy and safety. Outcomes Contradictory studies on the safety and efficacy of AOA do not yet allow for the establishment of AOA as standard practice in the clinic. Heterogeneity in study methodology, inconsistent sample inclusion criteria, non-standardised outcome assessments, restricted sample size and animal model limitations render AOA strictly experimental. The main scientific concern impeding AOA utilisation in the clinic is the non-physiological method of Ca2+ release mediated by most AOA agents, coupled with a lack of holistic understanding regarding the physiological mechanism(s) underlying Ca2+ release at oocyte activation. Limitations, reasons for caution The number of studies with clinical relevance using AOA remains significantly low. A much wider range of studies examining outcomes using multiple AOA agents are required. Wider Implications In addition to addressing the five main challenges of studies assessing AOA safety and efficacy, more standardized, large-scale, multi-centre studies of AOA, as well as long term follow-up studies of children born from AOA, would provide evidence for establishing AOA as a treatment for infertility. The delivery of an activating agent that can more accurately recapitulate physiological fertilisation, such as recombinant PLCζ, is a promising prospect for the future of AOA. Further to PLCζ, many other avenues of physiological oocyte activation also require urgent investigation to assess other potential physiological avenues of AOA. Study Funding/Competing Interests DG was supported by Stanford University’s Bing Overseas Study Program. JK was supported by a Healthcare Research Fellowship Award (HF-14-16) made by Health and Care Research Wales (HCRW), alongside a National Science, Technology, and Innovation plan (NSTIP) project grant (15-MED4186-20) awarded by the King Abdulaziz City for Science and Technology (KACST). The authors have no competing interests to declare. Lay Summary At fertilisation, oocyte activation is triggered by sperm-specific phospholipase C zeta (PLCζ) by releasing calcium in specific patterns within the oocyte. A deficiency in this process underlies most cases of fertilisation failure in mammals. This process of calcium release can be clinically mimicked via assisted oocyte activation (AOA), involving a combination of mechanical, electrical and/or chemical stimuli. Recent advances in AOA techniques warrant a review of the safety and efficacy of these practices and of how AOA may be clinically implemented in the clinic. Herein, following a detailed literature review examining studies assessing large scale efficacy and safety, the main concern impeding clinical AOA implementation is its non-physiological nature, coupled with a lack of holistic understanding of physiological mechanism(s) underlying calcium release at fertilisation. We find that numerous questions require urgent attention before widespread clinical utilisation of such protocols can be advocated. We hope that this article will be able to aid the burgeoning number of researchers investigating the clinical efficacy of such methodology in further refining the practice until large scale utilisation can be achieved and accepted.

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Section: Efficacy and Safety Of Aoamentioning

confidence: 99%

Oocyte activation deficiency and assisted oocyte activation: mechanisms, obstacles and prospects for clinical application

Kashir

Ganesh

Jones

et al. 2022

Human Reproduction Open

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“…Total fertilization failure (TFF) is a devastating outcome for couples undergoing IVF or ICSI. In ICSI cycles, TFF has been reported to occur in about 3% of cycles (44). Risk factors for TFF can include globoozospermia.…”

Section: Artificial Oocyte Activationmentioning

confidence: 99%

“…Different protocols exist but have been based on either chemical, mechanical or electrical stimulation of the oocyte following ICSI. These all ultimately lead to an influx of calcium into the ooplasm, theoretically mimicking the natural oocyte activation which occurs with normal fertilization (44).…”

Section: Artificial Oocyte Activationmentioning

confidence: 99%

“…The process of oocyte activation is thought to ultimately influence normal embryo development, epigenetic imprinting and pregnancy outcome. The significant deviations from a normal oscillatory calcium changes, as well as probably unknown molecular events occurring in artificial oocyte activation, are potentially causes for abnormal pregnancy, obstetric or neonatal outcomes (44). There is limited data available regarding this.…”

Section: Artificial Oocyte Activationmentioning

confidence: 99%

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Add-ons in the laboratory: hopeful, but not always helpful

Armstrong

Atkinson

MacKenzie

et al. 2019

Fertility and Sterility

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All the steps in an in vitro fertilization cycle are important but none more so than those that occur in the laboratory. To improve the chance of success, adjuncts, commonly referred to as 'add-ons', are offered. Yet as with other new interventions, add-ons in the laboratory require justification by well-designed studies prior to being offered as routine practice. Add-ons aim to improve the chance of a take-home baby, but, their safety and efficacy is less than clear. In addition, the financial burden from the use of add-ons is often borne by the couple. This review of the most commonly used laboratory add-ons did not find any high-quality evidence to support their use in routine practice. (Fertil Steril Ò 2019;112:994-9. Ó2019 by American Society for Reproductive Medicine.

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“…Yet, these studies have mainly focused on investigating the effectiveness of AOA in reproductive medicine, while few studies reported on the safety of this approach. In fact, ionophores, including A23187, exert many effects on cell homeostasis that might have a long-term effect on gene expression, some of which might be a threat and possible risk for epigenetics [ 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?

Liang

Fang

et al. 2022

Open Medicine

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Assisted oocyte activation (AOA) has been proposed as an effective technique to overcome the problem of impaired fertilization after intracytoplasmic sperm injection (ICSI) but the safety of AOA remains a concern. We aimed to investigate if AOA induces imprinting effects on embryos. We used 13 cleavage embryos, nine blastocysts, and eight placentas from 15 patients. The subjects were divided into six groups by tissue type and with or without AOA. The methylation levels of imprinted genes (H19, paternally expressed gene [PEG3] and small nuclear ribonucleoprotein polypeptide N [SNRPN]) were tested by pyrosequencing. We observed different methylation levels among cleavage embryos. The variability was much more remarkable between cleavage embryos than blastocysts and placenta tissues. The methylation levels were especially higher in SNRPN and lower in the H19 gene in AOA embryos than those without AOA. No significant difference was found either among blastocysts or among placenta tissues regardless of AOA. The methylation levels of the three genes in blastocysts were very similar to those in the placenta. Compared to conventional ICSI, AOA changed imprinting methylation rates at H19 and SNRPN in cleavage embryos but not in the blastocyst stage and placenta. We recommend that blastocyst transfer should be considered for patients undergoing AOA during in vitro fertilization.

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Artificial oocyte activation: physiological, pathophysiological and ethical aspects

Cited by 41 publications

References 103 publications

Oocyte activation deficiency and assisted oocyte activation: mechanisms, obstacles and prospects for clinical application

Oocyte activation deficiency and assisted oocyte activation: mechanisms, obstacles and prospects for clinical application

Add-ons in the laboratory: hopeful, but not always helpful

Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?

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