Male factors contribute to approximately half of infertility cases, yet much remains unknown about the mechanisms of spermatogenic disorders. A wide range of research is being conducted at the animal and clinical levels to further elucidate the mechanisms of spermatogenic disorders. Spermatogenesis is initiated by meiosis originating from spermatogonial cells and is completed by a change in sperm morphology (spermiogenesis). Finally, sperm cells are uniquely shaped and functionally specialized to swim efficiently, reach the egg, and transmit male genetic traits. In recent RMB journal, Yogo and colleagues (2022 DOI: 10.1002/rmb2.12466) published a review summarizing the molecular basis of head and flagellum formation in mouse sperm. This review elucidates the molecular mechanisms behind the formation of sperm head and flagellum, contributing to a deeper understanding of sperm morphology and the causes of male infertility.

Various molecular functions essential for spermatogenesis are reported in RMB journal. Hiradate and colleagues (2022 DOI: 10.1002/rmb2.12452) found that Axdnd1 mutations cause infertility due to abnormalities in the elongation step of spermatogenesis, as well as nuclear shaping and manchette. AXDND1 is abundantly expressed in the testes, localizing from mid-pachytene spermatocytes to early spermatids. Given that deleterious heterozygous mutations in AXDND1 have been found in non-obstructive azoospermia (NOA) patients, this study may provide clues to understanding one of the mechanisms of spermatogenesis in NOA patients. Tulp2 has been reported to play a critical role in sperm tail morphology. Oyama and colleagues (2022 DOI: 10.1002/rmb2.12467) discovered that Tulp2 KO mice show abnormalities in the outer dense fiber (ODF) structure in the testes, which is considered a cause of sperm tail morphology abnormalities and motility disorders. Zelinda and colleagues (2023 DOI: 10.1002/rmb2.12542) evaluated the temporal expression and localization of the RSPH6A protein, a component of the flagellar axoneme. They confirmed that RSPH6A contributes to the initiation of fertilization capability by affecting sperm motility, suggesting that RSPH6A could be a useful marker for normal fertility in the general population.

Besides the studies investigating sperm tails, several articles are published focusing on sperm head morphology abnormalities. Sultana and colleagues (2023 DOI: 10.1002/rmb2.12520) focused on the protein TSNAXIP1, which is expressed in the testes. TSNAXIP1 deficiency induces sperm head malformations, resulting in distinctive flower-shaped sperm heads. Additionally, abnormal anchorage of the sperm neck was frequently observed in TSNAXIP1 null sperm.

Matsukura and colleagues (2023 DOI: 10.1002/rmb2.12514) evaluated the expression of PROM1, a protein involved in cell morphology and migration control, in the testes. PROM1 is localized to dividing spermatocytes in seminiferous epithelial cells, sperm, and the columnar epithelium in the epididymis. In Prom1 KO mice, the number of morphologically abnormal and poorly motile epididymal sperm significantly increased, indicating that PROM1 is also involved in sperm motility and fertilization capability. These basic animal researches will be useful to elucidate the mechanism of spermatogenesis in more detail. Concurrently, recent RMB journals also report clinical study more directly related to the clinical practice of male infertility.

In patients with cryptozoospermia undergoing intra cytoplasmic sperm injection (ICSI), there may be uncertainty about whether to use ejaculated sperm or testicular sperm. Hibi and colleagues (2023 DOI: 10.1002/rmb2.12546) analyzed approximately 200 cases of cryptozoospermia, demonstrating that pregnancy via ICSI with ejaculated sperm can be expected if appropriate sperm selection and processing are performed without testicular sperm extraction (TESE).

However, in cases of azoospermia, TESE is usually required. Klinefelter syndrome is one major cause of non-obstructive azoospermia, which has mosaic and non-mosaic types. Tsukamoto and colleagues (2024 DOI: 10.1002/rmb2.12579) compared ICSI outcomes between mosaic and non-mosaic Klinefelter syndrome patients when sperm was retrieved. The mosaic group had a higher rate of motile sperm for ICSI and a significantly higher blastocyst formation rate than the non-mosaic group.

Micro-TESE for non-obstructive azoospermia is often the only option for those wishing to conceive, but the sperm retrieval rate is not always satisfactory, and there are concerns about postoperative complications such as decreased testosterone levels. While methods to predict the state of spermatogenesis in the testes have been researched, Kuribayashi and colleagues (2023 DOI: 10.1002/rmb2.12507) reported a new technology using MRI to evaluate testicular creatine distribution, aiming to assess spermatogenesis non-invasively. If focal spermatogenesis can be visualized in the future, it would be clinically valuable, and further research developments are anticipated.

Tai and colleagues (2024 DOI: 10.1002/rmb2.12566) proposed “Micro-mapping testicular sperm extraction method” (MMTSE) to achieve a less invasive sperm retrieval technique in clinical practice. The authors divided testis into four parts and extracted sperm by creating multiple small needle punctures in the seminiferous tubules, potentially offering a less invasive sperm retrieval method for certain cases.

This virtual issue will provide new insights for researchers involved in male infertility and contribute to the future research for readers.

Editor
Koji Chiba