Abstract
Infertility affects approximately 15% of reproductive-aged couples worldwide, of which up to 30% of the cases are caused by male factors alone. The origin of male infertility is mostly attributed to sperm abnormalities, of which many are caused by genetic defects. The development of intracytoplasmic sperm injection (ICSI) has helped to circumvent most male infertility conditions. However, there is still a challenging group of infertile males whose sperm, although having normal sperm parameters, are unable to activate the oocyte, even after ICSI treatment. While ICSI generally allows fertilization rates of 70 to 80%, total fertilization failure (FF) still occurs in 1 to 3% of ICSI cycles. Phospholipase C zeta (PLCζ) has been demonstrated to be a critical sperm oocyte activating factor (SOAF) and the absence, reduced, or altered forms of PLCζ have been shown to cause male infertility-related FF. The purpose of this review is to (i) summarize the current knowledge on PLCζ as the critical sperm factor for successful fertilization, as well as to discuss the existence of alternative sperm-induced oocyte activation mechanisms, (ii) describe the diagnostic tests available to determine the cause of FF, and (iii) summarize the beneficial effect of assisted oocyte activation (AOA) to overcome FF.
Highlights
Infertility is a worldwide health problem defined by the World Health Organization as the inability of a couple to achieve pregnancy after one year of regular, unprotected intercourses [1]
Further examples include mutations in SPATA16 and DPY19L2 causing globozoospermia [17,18] and the gene causing cystic fibrosis, CFTR [19], whose defect is correlated to congenital bilateral absence of the vas deferens (CBAVD), a form of obstructive azoospermia
PLCζ deficiency has been confirmed as a clear cause of fertilization failure (FF) after intracytoplasmic sperm injection (ICSI), it seems undeniable that other sperm factors or alternative oocyte activation mechanisms are contributing to the oocyte activation process as well, at least during in vitro fertilization (IVF) and in vivo fertilization
Summary
Infertility is a worldwide health problem defined by the World Health Organization as the inability of a couple to achieve pregnancy after one year of regular, unprotected intercourses [1]. In vivo mating experiments of PLCζ KO mice with WT females showed that PLCζ-null mice are not infertile, but surprisingly subfertile, as they are able to have offspring albeit at lower efficiency [87,88] These results validated the role of PLCζ as the SOAF necessary during ICSI and pointed to the potential existence of alternative sperm factors or independent oocyte activation mechanisms being active in mouse when PLCζ is absent during IVF and in vivo fertilization. There are a couple of tests available to determine the cause of the oocyte-activating deficiency These assays directly investigate the male gamete due to its easy accessibility and include the study of the activation rate and Ca2+ oscillatory capacity of the spermatozoa (in heterologous and homologous ICSI tests) as well as the evaluation of altered PLCζ presence (by genetic screening, gene expression analysis, and protein localization and quantification assays) [30]. A detailed description of the diagnostic tests used to detect sperm factors causing fertilization failure is given
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