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

Abstract

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.

Effect of calcium ionophore (A23187) on embryo development and its safety in PGT cycles

“…Sperm induce Ca 2+ signaling in the oocyte cytoplasm, and the generation of Ca 2+ signals trigger a subsequent series of physiological changes, such as the rapid depolarization of the oocyte oocyte membrane potential, release of cortical granules, chromosomal segregation, extrusion of the second polar body, decreased activity of kinases such as MPF/MAPK, translation of egg mRNA, pronucleus formation, and DNA replication. The orderly occurrence of these molecular events is also a hallmark of successful oocyte activation ( 22 ). Thus, the induction of an elevated intracellular Ca 2+ concentration in oocytes through AOA is an alternative treatment for patients with recurrent fertilization failure in ICSI and can result in normal embryos.…”

Role of Antioxidants of Natural Herbs in Management of Male Infertility

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What Does Intracytoplasmic Sperm Injection Change in Embryonic Development? The Spermatozoon Contribution

“…Compared to non-globozoospermic sperm, the fertilization rate is diminished. Oocyte activation fails due to sperm-specific phospholipase PLCζ under-expression or inactivity [ 46 ], defective sperm chromatin condensation, and sperm DNA damage [ 47 ].…”