The principle of microbeam radiotherapy (MRT) is the delivery of a single high-dose fraction to a large treatment area divided into several smaller fields, to reduce the treatment's overall toxicity. Since the fundamental concept of MRT was first established, a notable tissue-sparing effect (TSE) has been confirmed in a large variety of species and tissue types, although the underlying biological mechanism in this process remains unclear. By coupling high-precision MRT with an ex-vivo mouse spermatogenesis model, we demonstrated the significant testicular TSE for maintaining spermatogenesis following MRT. To our knowledge, this was the first TSE identified in reproductive tissue. Our high-precision microbeam analysis also revealed that an efficient TSE for spermatogenesis relies on the size of the non-irradiated germ stem cell pool in the irradiated testicular tissues, suggesting the involvement of stem cell migration/competition. These findings of testicular TSE indicate that radiation infertility is not dose-dependent, but instead depends on micro-dosimetric conditions, and that the limit of the TSE is a potential threshold for radiation-induced male infertility.

Spermatogonial stem cells (SSCs) constitute the foundation of male sperm production and fertility. SSCs are characterised by their capacity for self-renewal and differentiation into spermatozoa throughout a male's reproductive life, thereby transmitting genetic information to subsequent generations. During embryonic development, SSCs are derived from postnatal testicular gonocytes, which originate from long-lived primordial germ cells. A large proportion of men's infertility is detected by sperm analysis. Unusual sperm parameters include sperm concentration, morphology and motility. Male infertility is mainly due to hormone deficits, physical causes, sexually transmitted diseases, environment, lifestyle and hereditary factors. The most severe form of male infertility is non-obstructive azoospermia (NOA), which is defined as no sperm in the ejaculate because of spermatogenesis failure. The first-line treatment for these individuals has been testicular sperm extraction under an operating microscope (micro-TESE). SSCs are also considered a promising pathway for regenerating impaired or damaged spermatogenesis. This review addresses SSC transplantation as a potential method for treating male infertility and restoring spermatogenesis in patients with degenerative diseases such as cancer, radiotherapy and chemotherapy.

Male infertility presents significant heterogeneity, yet traditional assessments primarily rely on semen parameters and endocrine, imaging, and genetic screening. Although these methods can identify some definitive etiologies, a mechanistic explanatory gap persists in large populations with mild to moderate oligoasthenoteratozoospermia, elevated sperm DNA fragmentation, or recurrent adverse reproductive outcomes. The testis maintains a dynamic immune-privileged balance by balancing infection defense against tolerance to post-pubertal germ cell antigens. In this context, infections, varicocele-induced hypoxia or thermal stress, metabolic abnormalities, and environmental factors, trigger innate immune recognition via PAMPs or DAMPs. Notably, most mechanistic insights discussed are derived from animal models and in vitro studies; direct high-level clinical evidence in humans remains limited, and the proposed framework requires prospective validation. This is proposed to drive myeloid amplification, complement cascades, and inflammasome activation, which may in turn mutually reinforce oxidative stress. Based on current evidence, this may consequently compromise blood-testis barrier integrity, cause immune tolerance thresholds to decline, and induce tissue remodeling, collectively impairing the spermatogenic microenvironment, sperm maturation, and DNA integrity. This article reviews these immunological mechanisms and proposes a hypothesis-driven intervention framework driven by immune endophenotypes, aiming to provide an actionable clinical roadmap for the precision management of male infertility.

Ionizing radiation impairs male fertility, but the ultrastructural lesions linking radiation to sperm dysfunction remain unclear. The sperm annulus, a ring structure essential for flagellar integrity, is a potential but unresolved target. Here, we integrate synchrotron X-ray ptychography, cryogenic soft X-ray tomography, electron microscopy, and confocal imaging for cross-scale visualization of radiation-induced injury. Ptychography enables quantitative imaging of the annulus at ∼40-nm resolution, bridging light and electron microscopy. In irradiated mice, we find annulus fracture, loss of cytomembrane coverage, and disruption at the midpiece-principal piece junction. These defects worsen during maturation, correlating with reduced motility and increased abnormalities. Protein analyses show down-regulation of SEPT12 and AKAP4, indicating compromised annulus and fibrous sheath. Cryogenic tomography confirms ultrastructural deterioration in the axoneme, fibrous sheath, and mitochondria. These findings identify the sperm annulus and fibrous sheath as primary radiation targets, defining a structural basis for radiation-induced male infertility. This multimodal approach offers a generalizable strategy for nanoscale 3D cellular architecture analysis.

Mycotoxins are widespread food contaminants, and urinary biomarkers reflect recent dietary exposure. Although mycotoxins have been implicated in reproductive toxicity, their impact on human oocyte and embryo development remains poorly characterized. This single-center, retrospective observational study investigated the association between urinary mycotoxin exposure, infertility subtypes, and embryo developmental parameters in women undergoing assisted reproductive technology (ART). A total of 124 women undergoing ART cycles between November 2024 and September 2025 were included. Infertile patients were stratified according to infertility diagnosis (endometriosis, polycystic ovary syndrome, poor ovarian response, advanced maternal age, unexplained infertility) and compared with female controls from couples with male-factor infertility. First-morning urine samples collected on the day of oocyte retrieval were analyzed for a panel of 25 mycotoxins using LC-MS/MS. Embryo development was monitored by time-lapse imaging to assess embryo quality and morpho-kinetic parameters. Urinary mycotoxins were frequently detected, with higher detection rates and levels observed in infertile women than controls, and distinct exposure profiles across infertility subtypes. Aflatoxin G1 (AFG1) was uniquely associated with impaired blastocyst quality, including reduced expansion and altered inner cell mass and trophectoderm morphology, independently of clinical predictors. Other mycotoxins were associated with alterations in early embryo cleavage kinetics prior to embryonic genome activation, while later developmental timings were unaffected. These findings suggest that dietary mycotoxin exposure may influence early human embryo development in ART, supporting the relevance of environmental biomonitoring in reproductive medicine. Further studies are required to confirm these findings and support future strategies to minimize potential reproductive risks.

Ionizing radiation poses a significant risk to male fertility by inducing testicular damage, yet effective protective strategies remain limited. The tripeptide Met-Ser-Arg (MSA) has demonstrated potential in alleviating radiation-induced oxidative stress and lipid metabolic disorders, prompting investigation into its protective effects on the male reproductive system. Male BALB/c mice were exposed to X-ray irradiation (0.5 Gy/day for 5 days) to establish a testicular injury model, followed by MSA treatment. Testicular structure and function were evaluated through histology, electron microscopy, computer-assisted sperm analysis (CASA), and quantitative PCR. MSA significantly alleviated radiation-induced testicular damage, restoring the structural integrity and function of spermatogenesis tubules while increasing both the height of the spermatogenic epithelium and germ cell number. Sperm quality and motility were markedly improved, and the expression of several sperm cell molecular markers was favorably adjusted. Mechanistic investigations revealed that MSA regulated lipid metabolism by upregulating fatty acid β-oxidation enzymes, including ACSL3 and CPT1A, while downregulating the lipid synthase DGAT2, thereby reducing lipid droplet accumulation. MSA also attenuated radiation-induced reactive oxygen species and malondialdehyde levels, enhanced antioxidant capacity through upregulation of NRF2 and HO-1, and preserved mitochondrial structure and function via upregulation of PGC1A. Furthermore, MSA reduced apoptosis by lowering the levels of Cleaved-caspase 3 and γH2AX. Collectively, these findings demonstrate that MSA ameliorates radiation-induced testicular injury and improves sperm quality through coordinated regulation of lipid metabolism, antioxidant pathway activation, mitochondrial protection, and apoptosis inhibition, providing a theoretical basis for its potential clinical application in the context of radiotherapy.

Advanced maternal age (AMA) is a major challenge in reproductive medicine, compounded by coexisting conditions such as adenomyosis and endometriosis, which impair oocyte competence and endometrial receptivity. Prolonged gonadotropin-releasing hormone agonist (GnRHa) protocols have been proposed to improve in vitro fertilization-embryo transfer (IVF-ET) outcomes. We report the case of a 41-year-old Indonesian woman with 13 years of primary infertility, AMA, adenomyosis, endometriosis, and male factor infertility. Following laparoscopic excision of endometriosis, she underwent a prolonged GnRH agonist protocol with depot triptorelin, followed by controlled ovarian stimulation using recombinant FSH and LH. Despite an initially modest response, eight oocytes were retrieved and all fertilized via ICSI. Two good-quality day-3 embryos were transferred fresh, and three blastocysts were cryopreserved. Intensive luteal support with hCG, progesterone, dydrogesterone, and estradiol was administered. Serial β-hCG confirmed early pregnancy, and at the time of reporting, she is 35+6 weeks pregnant with a viable singleton and unremarkable antenatal course. This case demonstrates that prolonged GnRHa protocols may offer favorable outcomes in women with AMA and multiple adverse prognostic factors, including adenomyosis, endometriosis, and male factor infertility. While encouraging, such results require cautious interpretation, and further prospective studies incorporating preimplantation genetic testing and cumulative live birth rate are needed to clarify their broader applicability.

The etiological contribution of male factors to infertility remains a significant concern in reproductive health. Natural dietary products are gaining attention as promising interventions to improve male infertility. This study investigates the effects of aqueous extract of Sesamum indicum L. (S. indicum) on male reproductive parameters and potential anti-infertility mechanisms. Male Sprague-Dawley rats were randomly assigned to five groups: a control group (distilled water), two treatment groups receiving aqueous S. indicum extract (1.5 and 3.0 g/kg) for 30 days, and corresponding recovery groups. Reproductive organs were assessed for weight and sperm parameters. Blood serum was analyzed for luteinizing hormone (LH), testosterone, and lipid profile parameters. Incorporating in silico approaches, bioactive compounds of S. indicum were screened from a database, and their targets were predicted via network pharmacology, followed by functional enrichment analyses and molecular docking. Findings show that S. indicum significantly increased (p < 0.05) the weights of the hearts, adrenal glands, livers, and accessory reproductive organs. Sperm count and morphology, as well as LH and testosterone levels, were significantly increased (p < 0.05). Network pharmacology identified linoleic acid, oleic acid, biotin, and esculentic acid as key contributors to the extract's anti-infertility effects, potentially via interactions with EGFR, HIF1, BCL2, TNF, and AKT1. These interactions, supported by favorable binding affinities, may involve antioxidative pathways. Although the exposure duration, differences in extraction methods, paucity of experimental molecular data, and algorithmic constraints represent potential limitations, the present findings provide pharmacological insights into the therapeutic role of S. indicum in male infertility.