Molecular insights into sperm head shaping and its role in human male fertility

Abstract BACKGROUND Sperm head shaping, controlled by the acrosome-acroplaxome-manchette complex, represents a significant morphological change during spermiogenesis and involves numerous proteins expressed in a spatially and temporally specific manner. Defects in sperm head shaping frequently lead to teratozoospermia concomitant with oligozoospermia and asthenozoospermia, but the pathogenic mechanism underlying sperm head shaping, and its role in male infertility, remain poorly understood. OBJECTIVE AND RATIONALE This review aims to summarize the mechanism underlying sperm head shaping, reveal the relationship between gene defects associated with sperm head shaping and male infertility in humans and mice, and explore potential clinical improvements in ICSI treatment. SEARCH METHODS We searched the PubMed database for articles published in English using the keyword ‘sperm head shaping’ in combination with the following terms: ‘acrosome formation’, ‘proacrosomal vesicles (PAVs)’, ‘manchette’, ‘perinuclear theca (PT)’, ‘chromatin condensation’, ‘linker of nucleoskeleton and cytoskeleton (LINC) complex’, ‘histone-to-protamine (HTP) transition’, ‘male infertility’, ‘ICSI’, and ‘artificial oocyte activation (AOA)’. The selected publications until 1 August 2024 were critically summarized, integrated, and thoroughly discussed, and the irrelevant literature were excluded. OUTCOMES A total of 6823 records were retrieved. After careful screening, integrating relevant literature, and excluding articles unrelated to the topic of this review, 240 articles were ultimately included in the analysis. Firstly, we reviewed the important molecular events and structures integral to sperm head shaping, including PAV formation to fusion, acrosome attachment to the nucleus, structure and function of the manchette, PT, chromatin condensation, and HTP transition. Then, we set forth human male infertility associated with sperm head shaping and identified genes related to sperm head shaping resulting in teratozoospermia concomitant with oligozoospermia and asthenozoospermia. Finally, we summarized the outcomes of ICSI in cases of male infertility resulting from mutations in the genes associated with sperm head shaping, as well as the ICSI outcomes through AOA for infertile men with impaired sperm head. WIDER IMPLICATIONS Understanding the molecular mechanisms of sperm head shaping and its relationship with human male infertility holds profound clinical implications, which may contribute to risk prediction, genetic diagnosis, and the potential treatment of human male infertility.