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BACKGROUND: Infertility affects between 10 and 16% of couples worldwide. Twenty to 30% of cases of infertility are due to a male factor, 20-35% to a female factor, and 25-40% are due to both male and female factors. In ∼10-25% of cases, the precise underlying cause remains unclear. IVF or ICSI followed by embryo transfer can be very appropriate treatment options in cases of female tubal damage, ovulatory failure or male-factor infertility. While the use of IVF has been reported to be suitable for many infertile couples, normal IVF cycles can fail in some cases. While ICSI can represent a powerful alternative in cases of IVF failure, complete fertilization failure can still occur in 1-5% of ICSI cycles. This can be due to a variety of factors and while commonly attributed to deficiency of sperm factors, it is very likely that abnormalities in crucial oocyte factors could also play a key role. METHODS: A critical literature review using PubMed was performed between April 2014 and July 2015 targeting studies concerning sperm and oocyte factors that could account for oocyte activation deficiency, and including studies of in vitro oocyte maturation in human oocytes, and animal models. RESULTS: Accumulating evidence indicates that phospholipase C zeta (PLCζ) is the sperm oocyte activation factor, although recent studies claim that another sperm protein known as post-acrosomal WWP-binding domain protein could also play a significant role in the activation of oocytes. The present review discusses our current understanding of these two proteins but emphasizes that defects in the molecular machinery within the oocyte that interacts with such sperm proteins may also represent an underlying cause of fertilization failure and infertility, especially in cases where there is no obvious indication for sperm deficiency. Abnormalities in such mechanisms are highly likely to exert influence over the pulsatile release of calcium within the ooplasm, the critical signal that controls oocyte activation events. These molecular targets within the oocyte are rarely, if ever, considered clinically. We therefore recommend that future diagnostic assays should be developed to consider the inositol triphosphate receptor, protein kinase C, proteins associated with stored operated calcium entry calcium/calmodulin-dependent protein kinase II and mitogen-activated protein kinase. Development of such assays would represent a significant step forward in the diagnosis of oocyte activation deficiency and may identify a series of potential therapeutic targets. CONCLUSIONS: The present review provides a general overview of how a combination of sperm and oocyte factors can underlie oocyte activation deficiency, but pays particular attention to the less appreciated role of the oocyte. Enhanced research within this realm is much warranted and may establish new approaches for the diagnosis and treatment of infertility.

Original publication




Journal article


Hum Reprod Update

Publication Date





23 - 47


Ca2+ homeostasis, infertility, oocyte activation deficiency, phospholipase C zeta, post-acrosomal WWP-binding domain protein, protein kinase C, sperm-borne oocyte activation factor, Animals, Embryo Transfer, Female, Fertilization, Humans, In Vitro Oocyte Maturation Techniques, Infertility, Female, Infertility, Male, Male, Oocytes, Sperm Injections, Intracytoplasmic, Spermatozoa