Search Results (1,035)

Prostate cancer (PCa) is the second most frequently diagnosed malignancy in men worldwide. Although traditionally considered a disease of older men, the incidence of early-onset PCa (diagnosis < 55 years) is steadily rising. Advances in screening and therapy have significantly improved survival, creating a growing cohort of younger survivors for whom post-treatment quality of life—notably reproductive function—is paramount. Curative treatments such as radical prostatectomy, pelvic radiotherapy, androgen-deprivation therapy (ADT), and chemotherapy often cause irreversible infertility via multiple mechanisms, including surgical disruption of the ejaculatory tract, endocrine suppression of spermatogenesis, direct gonadotoxic injury to the testes, and oxidative sperm DNA damage. Despite these risks, fertility preservation is frequently overlooked in pre-treatment counseling, leaving many patients unaware of their options. This narrative review synthesizes current evidence on how PCa therapies impact male fertility, elucidates the molecular and physiological mechanisms of iatrogenic infertility, and evaluates both established and emerging strategies for fertility preservation and restoration. Key interventions covered include sperm cryopreservation, microsurgical testicular sperm extraction (TESE), and assisted reproductive technologies (ART). Psychosocial factors influencing decision-making, novel biomarkers predictive of post-treatment spermatogenic recovery, and long-term offspring outcomes are also examined. The review underscores the urgent need for timely, multidisciplinary fertility consultation as a routine component of PCa care. As PCa increasingly affects men in their reproductive years, proactively integrating preservation into standard oncologic practice should become a standard survivorship priority. Full article

Sperm count, motility, and morphology are semen parameters that directly affect male fertility. The presence of cytokines in seminal plasma negatively or positively influences these parameters. Interleukins and prostaglandins are proinflammatory cytokines present in human seminal plasma and play crucial roles in fertilization, in general and after intracytoplasmic sperm injection (ICSI) procedures. This study aimed to investigate the possible influence of interleukins IL-17 and IL-18, and prostaglandins PGE2 and PGF2α on male infertility. Semen samples were collected from 58 males who underwent the ICSI procedure. An enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of IL-17, IL-18, PGE2, and PGF2α, and these concentrations were then correlated with semen parameters and the rate of fertilization. Furthermore, the chromatin integrity of the sperm was evaluated with an Acridine Orange (AO) assay. The results showed an inversely proportional relationship between the AO binding intensity and fertilization rate (r = −0.394; p ≤ 0.002). Furthermore, a negative correlation was observed between the IL-18 concentration and positive AO (p ≤ 0.021). Moreover, the IL-18 concentration was positively correlated with the fertilization rate (p ≤ 0.05). In contrast, IL-17 did not significantly correlate with any semen parameters or with the fertilization rate. Seminal PGE2 levels were significantly correlated with embryo cleavage at 72 h (p ≤ 0.05). To conclude, this study revealed that denaturation of sperm nuclear deoxyribonucleic acid (DNA) contributes to low fertilization rates. In addition, this study proposed a potential role for IL-18 in fertilization. PGE2 likely influences embryo development, but further studies are needed to examine the impact of seminal PGE2 on the oocyte to fully elucidate its contribution to this complex biological process. Full article

Background/Objectives: Male infertility is a major health concern with a complex etiopathology, yet a substantial proportion of cases remain idiopathic. Mitochondrial dysfunction and non-coding RNA (ncRNA) deregulation have both been implicated in impaired spermatogenesis, but their interplay remains poorly understood. This study aimed to identify infertility-specific variants in ncRNAs that affect mitochondrial dynamics and homeostasis and to explore their roles. Methods: Whole-genome sequencing (WGS) was performed on genomic DNA samples from teratozoospermic, asthenozoospermic, oligozoospermic, and normozoospermic men. Variants uniquely present in infertile individuals and mapped to ncRNAs that affect mitochondrial dynamics were selected and prioritized using bioinformatics tools. An independent transcriptomic validation was conducted using RNA-sequencing data from testicular biopsies of men with non-obstructive azoospermia (NOA) to determine whether the ncRNAs harboring WGS-derived variants were transcriptionally altered. Results: We identified several infertility-specific variants located in lncRNAs known to interact with mitochondrial regulators, including GAS5, HOTAIR, PVT1, MEG3, and CDKN2B-AS1. Transcriptomic analysis confirmed significant deregulation of these lncRNAs in azoospermic testicular samples. Bioinformatic analysis also implicated the disruption of lncRNA–miRNA–mitochondria networks, potentially contributing to mitochondrial membrane potential loss, elevated reactive oxygen species (ROS) production, impaired mitophagy, and germ cell apoptosis. Conclusions: Our integrative genomic and transcriptomic analysis highlights lncRNA–mitochondrial gene interactions as a novel regulatory layer in male infertility, while the identified lncRNAs hold promise as biomarkers and therapeutic targets. However, future functional studies are warranted to elucidate their mechanistic roles and potential for clinical translation in reproductive medicine. Full article

Male infertility is a multifactorial condition often associated with disruptions in sperm metabolism and mitochondrial function, yet traditional semen analysis provides limited insight into these molecular mechanisms. Understanding sperm bioenergetics and metabolic dysfunctions is crucial for improving the diagnosis and treatment of conditions such as asthenozoospermia and azoospermia. This systematic review synthesizes recent literature, focusing on advanced tools and techniques—including omics technologies, advanced imaging, spectroscopy, and functional assays—that enable comprehensive molecular assessment of sperm metabolism and development. The reviewed studies highlight the effectiveness of metabolomics, proteomics, and transcriptomics in identifying metabolic biomarkers linked to male infertility. Non-invasive imaging modalities such as Raman and magnetic resonance spectroscopy offer real-time metabolic profiling, while the seminal microbiome is increasingly recognized for its role in modulating sperm metabolic health. Despite these advances, challenges remain in clinical validation and implementation of these techniques in routine infertility diagnostics. Integrating molecular metabolic assessments with conventional semen analysis promises enhanced diagnostic precision and personalized therapeutic approaches, ultimately improving reproductive outcomes. Continued research is needed to standardize biomarkers and validate clinical utility. Furthermore, these metabolic tools hold significant potential to elucidate the underlying causes of previously misunderstood and unexplained infertility cases, offering new avenues for diagnosis and treatment. Full article

Varicocele is a common, potentially correctable condition associated with impaired male fertility. Despite being frequently encountered in clinical andrology, its pathophysiological mechanisms, diagnostic criteria, and therapeutic approaches remain areas of active investigation and debate. The authors conducted a comprehensive literature search, using the PubMed database, covering clinical studies, systematic reviews, meta-analyses, and current international guidelines from the past ten years. Emphasis was placed on studies investigating novel diagnostic modalities, therapeutic innovations, and prognostic markers. Emerging evidence supports the multifactorial pathophysiology of varicocele, involving oxidative stress, hypoxia, inflammatory pathways, and potential genetic predisposition. Biomarkers, including microRNAs, antisperm antibodies, and sperm DNA fragmentation, offer diagnostic and prognostic utility, though their routine clinical implementation requires further validation. Advances in imaging, such as shear wave elastography, may improve diagnostic accuracy. While microsurgical subinguinal varicocelectomy remains the gold standard, technological refinements and non-surgical alternatives are being explored. Indications for treatment have expanded to include selected cases of non-obstructive azoospermia, hypogonadism, and optimization for assisted reproduction, though high-level evidence is limited. Full article

Background/Objectives: Infertility, defined as the failure to achieve pregnancy after one year of regular unprotected intercourse, represents a significant global health challenge, with male factors contributing to approximately 50% of cases. In this epidemiological context, both primary male infertility (the inability to conceive a first child) and secondary male infertility (which occurs when a man who has already fathered a child faces difficulty conceiving again) remain poorly understood at the genetic level. This study explored the role of single-nucleotide polymorphisms (SNPs) in mitochondrial genes (MT-ND3, MT-ND4L, and MT-ND4) in primary and secondary male infertility. Methods: This study analyzed the genotype distributions of SNPs in 68 infertile males (49 with primary infertility and 19 with secondary infertility) using Sanger sequencing. Results: Key findings revealed that studied SNPs were significantly associated with infertility type. Specifically, rs2857285 (T>C,G) in the ND4 gene showed a significant correlation (p = 0.023) with the TT genotype, which is prominent in primary infertility. Another SNP, rs28358279 (T>A,C) in the ND4L gene, also demonstrated a significant correlation (p = 0.046) with the TT genotype, being more common in primary infertility. In addition, rs869096886 (A>G) in the ND4 gene had a borderline correlation (p = 0.051), indicating a possible association between this SNP and reproductive duration. Conclusions: This study emphasizes the potential relevance of mitochondrial malfunction in male infertility, specifically the effects of studied SNPs on sperm survival and function over time. These findings suggest that certain mitochondrial SNPs might be potential biomarkers for infertility risk. Larger studies are needed to confirm these associations and examine the functional effects of these SNPs. Combining genetic analysis with environmental and lifestyle factors could enhance our understanding of male infertility and improve diagnostic and therapeutic strategies. Full article

Mitochondria are central to energy production and redox regulation in spermatozoa, supporting key functions such as progressive motility, capacitation, and the acrosome reaction. These processes are essential for successful fertilization and embryo development. However, species-specific differences exist in the reliance on oxidative phosphorylation versus glycolysis. Mitochondria also generate reactive oxygen species, which at physiological levels aid in sperm function but can cause oxidative stress and damage when overproduced. Mitochondrial dysfunction and excessive ROS can impair membrane potential, induce apoptosis, and damage nuclear and mitochondrial DNA, ultimately compromising sperm quality. Sperm mitochondrial DNA is highly susceptible to mutations and deletions, contributing to reduced motility and fertility. Targeted antioxidant strategies have emerged as promising therapeutic interventions to mitigate oxidative damage. This article provides a comprehensive overview of mitochondrial regulation in spermatozoa, the consequences of redox imbalance, and the potential of mitochondria-targeted antioxidants to improve sperm function and male fertility outcomes. The paper aims to deepen our understanding of mitochondrial roles in sperm physiology and contribute to the advancement of strategies for addressing male infertility. Full article

Male-factor infertility accounts for approxiamately half of all infertility cases globally, yet therapeutic options remain limited for individuals with no retrievable spermatozoa, such as those with non-obstructive azoospermia (NOA). In recent years, artificial gametogenesis has emerged as a promising avenue for fertility restoration, driven by advances in two complementary strategies: organotypic in vitro spermatogenesis (IVS), which aims to complete spermatogenesis ex vivo using native testicular tissue, and in vitro gametogenesis (IVG), which seeks to generate male gametes de novo from pluripotent or reprogrammed somatic stem cells. To evaluate the current landscape and future potential of these approaches, a narrative, semi-systematic literature search was conducted in PubMed and Scopus for the period January 2010 to February 2025. Additionally, landmark studies published prior to 2010 that contributed foundational knowledge in spermatogenesis and testicular tissue modeling were reviewed to provide historical context. This narrative review synthesizes multidisciplinary evidence from cell biology, tissue engineering, and translational medicine to benchmark IVS and IVG technologies against species-specific developmental milestones, ranging from rodent models to non-human primates and emerging human systems. Key challenges—such as the reconstitution of the blood–testis barrier, stage-specific endocrine signaling, and epigenetic reprogramming—are discussed alongside critical performance metrics of various platforms, including air–liquid interface slice cultures, three-dimensional organoids, microfluidic “testis-on-chip” devices, and stem cell-derived gametogenic protocols. Particular attention is given to clinical applicability in contexts such as NOA, oncofertility preservation in prepubertal patients, genetic syndromes, and reprocutive scenarios involving same-sex or unpartnered individuals. Safety, regulatory, and ethical considerations are critically appraised, and a translational framework is outlined that emphasizes biomimetic scaffold design, multi-omics-guided media optimization, and rigorous genomic and epigenomic quality control. While the generation of functionally mature sperm in vitro remains unachieved, converging progress in animal models and early human systems suggests that clinically revelant IVS and IVG applications are approaching feasibility, offering a paradigm shift in reproductive medicine. Full article

Background: Oxidative stress is a critical factor contributing to male infertility, impairing spermatogonial stem cells (SSCs) and disrupting normal spermatogenesis. This study aimed to isolate and characterize human SSCs and to investigate oxidative stress-related gene expression, protein interaction networks, and developmental trajectories involved in SSC function. Methods: SSCs were enriched from human orchiectomy samples using CD49f-based magnetic-activated cell sorting (MACS) and laminin-binding matrix selection. Enriched cultures were assessed through morphological criteria and immunocytochemistry using VASA and SSEA4. Transcriptomic profiling was performed using microarray and single-cell RNA sequencing (scRNA-seq) to identify oxidative stress-related genes. Bioinformatic analyses included STRING-based protein–protein interaction (PPI) networks, FunRich enrichment, weighted gene co-expression network analysis (WGCNA), and predictive modeling using machine learning algorithms. Results: The enriched SSC populations displayed characteristic morphology, positive germline marker expression, and minimal fibroblast contamination. Microarray analysis revealed six significantly upregulated oxidative stress-related genes in SSCs—including CYB5R3 and NDUFA10—and three downregulated genes, such as TXN and SQLE, compared to fibroblasts. PPI and functional enrichment analyses highlighted tightly clustered gene networks involved in mitochondrial function, redox balance, and spermatogenesis. scRNA-seq data further confirmed stage-specific expression of antioxidant genes during spermatogenic differentiation, particularly in late germ cell stages. Among the machine learning models tested, logistic regression demonstrated the highest predictive accuracy for antioxidant gene expression, with an area under the curve (AUC) of 0.741. Protein oxidation was implicated as a major mechanism of oxidative damage, affecting sperm motility, metabolism, and acrosome integrity. Conclusion: This study identifies key oxidative stress-related genes and pathways in human SSCs that may regulate spermatogenesis and impact sperm function. These findings offer potential targets for future functional validation and therapeutic interventions, including antioxidant-based strategies to improve male fertility outcomes. Full article

Background: Complete environmental adaptation requires both survival and reproductive success. The hypoxic Qinghai-Tibet Plateau (>3000 m) challenges reproduction in indigenous species. Tibetan sheep, a key plateau-adapted breed, possess remarkable hypoxic tolerance, yet the genetic basis of their reproductive success remains poorly understood. Methods: We integrated transcriptomic and genomic data from Tibetan sheep and two lowland breeds (Small-tailed Han sheep and Hu sheep) to identify Tibetan sheep reproduction-associated genes (TSRGs). Results: We identified 165 TSRGs: four genes were differentially expressed (DEGs) versus Small-tailed Han sheep, 77 DEGs versus Hu sheep were found, and 73 genes were annotated in reproductive pathways. Functional analyses revealed enrichment for spermatogenesis, embryonic development, and transcriptional regulation. Notably, three top-ranked selection signals (VEPH1, HBB, and MEIKIN) showed differential expression. Murine Gene Informatics (MGI) confirmed that knockout orthologs exhibit significant phenotypes including male infertility, abnormal meiosis (male/female), oligozoospermia, and reduced neonatal weight. Conclusions: Tibetan sheep utilize an evolved suite of genes underpinning gametogenesis and embryogenesis under chronic hypoxia, ensuring high reproductive fitness—a vital component of their adaptation to plateaus. These genes provide valuable genetic markers for the selection, breeding, and conservation of Tibetan sheep as a critical genetic resource. Full article

The epigenetic landscape plays a pivotal role in regulating the functions of both germ and somatic cells (Sertoli and Leydig cells) within the testis, which are essential for male fertility. While somatic cells support germ cell maturation and testosterone synthesis, the epigenetic regulation of germ cells is critical for proper spermatogenesis and function. Epigenetic modifications such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs (ncRNAs) are crucial for regulating gene expression that is essential for spermatogenesis and reproductive function. Although numerous studies have highlighted the significance of the epigenome and its implications for male reproductive health, a comprehensive overview of the existing literature and knowledge is lacking. This review aims to provide an in-depth analysis of the role of epigenetics in spermatogenesis and reproductive health, with a specific focus on DNA methylation, histone remodeling, and small noncoding RNAs (sncRNAs). Additionally, we examine the impact of lifestyle and environmental factors, such as diet, smoking, physical activity, and exposure to endocrine-disrupting chemicals, on the sperm epigenome. We emphasize how these factors influence fertility, embryonic development, and potential transgenerational inheritance. This review underscores how recent advances in the understanding of the epigenetic modulation of testicular function can inform the pathophysiology of male infertility, thereby paving the way for the development of targeted diagnostic and therapeutic strategies. Full article

Cattle–yak, a hybrid of yak and cattle, exhibits significant heterosis but male infertility, hindering heterosis fixation. Although extensive research has been conducted on transcriptional mechanisms in the testes of cattle–yak, the understanding of their translational landscape remains limited. In this study, we characterized the translational landscape of yak and cattle–yak based on Ribo-seq technology integrated with RNA-seq data. The results revealed that gene expression was not fully concordant between transcriptional and translational levels, whereas cattle–yak testes exhibited a stronger correlation across these two regulatory layers. Notably, genes that were differentially expressed at the translational level only (MEIOB, MEI1, and SMC1B) were mainly involved in meiosis. A total of 4,236 genes with different translation efficiencies (TEs) were identified, and the TEs of most of the genes gradually decreased as the mRNA expression level increased. Further research revealed that genes with higher TE had a shorter coding sequence (CDS) length, lower GC content, and higher normalized minimum free energy in the testes of yaks, but this characteristic was not found in cattle–yaks. We also identified upstream open reading frames (uORFs) in yak and cattle–yak testes, and the sequence characteristics of translated uORFs and untranslated uORFs were markedly different. In addition, we identified several short polypeptides that may play potential roles in spermatogenesis. In summary, our study uncovers distinct translational dysregulations in cattle–yak testes, particularly affecting meiosis, which provides novel insights into the mechanisms of spermatogenesis and male infertility in hybrids. Full article

Lycopene, a carotenoid found in tomatoes and watermelon, has been investigated for its potential to improve male fertility through its antioxidant and anti-inflammatory mechanisms. However, evidence of its effectiveness remains inconsistent. We conducted a systematic review and meta-analysis of studies published until February 2025 in the PubMed, Scopus, Web of Science, and Medline databases. Clinical studies evaluating lycopene supplementation in relation to male fertility outcomes were included in this review. Standardized mean differences (SMDs) were calculated for the key outcomes. Four clinical studies involving 151 participants were included. Lycopene supplementation significantly improved sperm concentration (SMD 0.33, 95% CI [0.02–0.65], p = 0.037) and nonprogressive motility (SMD 0.45, 95% CI [0.04–0.87], p = 0.032). No statistically significant effects were observed on total motility, progressive motility, normal or abnormal morphology, semen volume, or DNA damage. Sensitivity analyses showed that the findings were generally robust, although publication bias and methodological heterogeneity were noted. Lycopene supplementation may offer modest benefits in improving sperm concentration and nonprogressive motility in men. However, evidence for other fertility-related outcomes is inconclusive. Larger, high-quality randomized trials are needed to confirm these findings and clarify the role of lycopene in male reproductive health. Full article

Sperm flagellum defects are tightly associated with male infertility. Centriolar satellites are small multiprotein complexes that recruit satellite proteins to the centrosome and play an essential role in sperm flagellum biogenesis, but the precise mechanisms underlying this role remain unclear. Serologically defined colon cancer autoantigen protein 8 (SDCCAG8), which encodes a protein containing eight coiled-coil (CC) domains, has been associated with syndromic ciliopathies and male infertility. However, its exact role in male infertility remains undefined. Here, we used an Sdccag8 mutant mouse carrying a CC domains 5–8 truncated mutation (c.1351–1352insG p.E451GfsX467) that models the mutation causing Senior–Løken syndrome (c.1339–1340insG p.E447GfsX463) in humans. The homozygous Sdccag8 mutant mice exhibit male infertility characterized by multiple morphological abnormalities of the flagella (MMAF) and dysmorphic structures in the sperm manchette. A mechanistic study revealed that the SDCCAG8 protein is localized to the manchette and centrosomal region and interacts with PCM1, the scaffold protein of centriolar satellites, through its CC domains 5–7. The absence of the CC domains 5–7 in mutant spermatids destabilizes PCM1, which fails to recruit satellite components such as Bardet–Biedl syndrome 4 (BBS4) and centrosomal protein of 131 kDa (CEP131) to satellites, resulting in defective sperm flagellum biogenesis, as BBS4 and CEP131 are essential to flagellum biogenesis. In conclusion, this study reveals the central role of SDCCAG8 in maintaining centriolar satellite integrity during sperm flagellum biogenesis. Full article

Male infertility is a pathological condition that affects many subjects and for which a progressive increase in cases has been observed in recent years. The mechanisms underlying male reproductive system dysfunction are not fully understood and the specific drugs use has not produced optimal results. Therefore, the focus on developing new therapeutic options to prevent or treat this dysfunction is continuously growing. Defective sperm function has been associated with oxidative stress (OS) due to reactive oxygen species (ROS) excessive production. OS is related to mitochondrial dysfunction, lipid peroxidation, DNA damage and fragmentation, and ultimately sperm cell death. Many defense mechanisms to protect from ROS injuries have been developed; natural antioxidants, such as vitamin C and E are able to interact with oxidizing radicals, neutralizing them. Interestingly, resveratrol (RSV), a natural polyphenol with proven health-promoting actions, has been found to be an effective free radical scavenger in several in vitro and in vivo models, providing protection against OS. In this review, we discussed mechanisms related to the modulation of redox homeostasis in the testis and how the alteration of these processes can determine a damage in testicular function; particularly, we focused on the antioxidant properties of RSV that could give beneficial effects in preserving male fertility. Full article