Search Results (517)

Background/Objectives: Dynein axonemal heavy chain (DNAH) genes, including DNAH6, are implicated in male infertility, particularly multiple morphological abnormalities of the spermatozoa flagellum (MMAF). However, an underlying mechanism is unclear. Methods: This in silico study analyzed 19 previously reported DNAH6 mutations to elucidate their effects on the structural, mechanical, and microstructural aspects and axonemal assembly of flagellum and how these changes impact reproductive health, correlating with pathogenicity scores, ATP binding capacity, and protein interactions. Results: DNAH mutations were associated with CDGP (52.63%), male infertility (36.84%), and primary ovarian insufficiency (10.53%). MMAF-linked mutations exhibited higher SNAP2 scores (57.25 ± 5.68 vs. −32.58 ± 44.85, p = 0.002), reduced ATP binding affinity (−6.27 ± 4.20 vs. −8.92 ± 0.23 kcal/mol, p = 0.05), and smaller catalytic cavity size (17,646 ± 13,005 vs. 27190 ± 3485 ų, p = 0.04). These mutations showed reduced DNAH6-CLIP4 binding affinity (−303.90 ± 5.23 vs. −313.60 ± 4.28 kcal/mol, p = 0.002). Literature-based semen analysis revealed correlations between Phred scores and absent flagella (r = 0.952, p = 0.012) and inverse correlations between ATP binding capacity and absent flagella (r = −0.902, p = 0.036) or irregular width (r = −0.949, p = 0.014). A mathematical model of ATP binding kinetics predicted reduced flagellar motility in MMAF mutants due to impaired dynein function. Ultrastructural analyses indicated that high pathogenicity scores and reduced ATP binding correlate with absent inner dynein arms and radial spokes, while impaired DNAH6-CLIP4 interactions disrupt axonemal assembly. Conclusions: In silico analyses, integrated with microstructural, axonemal, and mathematical modeling data, demonstrate that DNAH6 mutations cause MMAF by impairing ATP binding, protein interactions, and axonemal assembly, leading to severe flagellar dysfunction and thereby negatively affecting reproductive health. Full article

Male infertility is increasingly recognized as a complex, multifactorial disorder that extends beyond abnormalities in conventional semen parameters. A growing body of evidence highlights oxidative stress, sperm DNA fragmentation (SDF), and epigenetic alterations as tightly interconnected mechanisms contributing to sperm dysfunction and impaired fertility. Reactive oxygen species, though vital for sperm maturation and signaling, can inflict extensive genomic and chromatin damage when their levels exceed the antioxidant capacity of the testis and seminal plasma. These redox-driven lesions not only compromise fertilization potential but may also influence embryonic development and offspring health. Clinical studies and meta-analyses consistently report that elevated SDF and redox imbalance are associated with reduced pregnancy and live birth rates, particularly in assisted reproductive technologies (ARTs). The use of testicular sperm in men with high ejaculated SDF appears to improve ART outcomes, although long-term safety data remain limited. Advances in redox and genomic diagnostics, including assays for oxidation–reduction potential, SDF, and sperm epigenetic profiling, have opened new avenues for precision-based andrology, enabling targeted antioxidant, metabolic, and surgical interventions. Nonetheless, methodological variability, lack of assay standardization, and insufficient longitudinal follow-up constrain the full clinical translation of these findings. This review synthesizes evidence linking OS, SDF, and epigenetic alterations, highlighting their mechanistic crosstalk and translational relevance in the personalized management of male infertility. Full article

Reproductive performance in livestock and poultry is a core determinant of economic efficiency in the animal industry. While traditional research has primarily focused on genetics, endocrinology, and immune regulation, emerging microbiome studies reveal that commensal microbiota within the gut and reproductive tracts play an underestimated yet pivotal role in host reproductive health. This review systematically synthesizes recent advances regarding the relationship between the microbiome and reproductive functions in major livestock species (cattle, pigs, sheep, and chickens). We first delineate the theoretical basis and mechanisms of the “gut-reproductive axis,” highlighting cross-system communication mediated by microbial metabolites, including short-chain fatty acids (SCFAs), indoles, and bile acids. Subsequently, we provide an in-depth comparative analysis of the microecological features of both female (vagina/uterus) and male (semen/epididymis) reproductive systems, examining their impacts on fertility, sperm quality, and pregnancy outcomes. Furthermore, we explore the molecular and systemic mechanisms governing microbial regulation of reproduction, encompassing the modulation of the hypothalamic-pituitary-gonadal (HPG) axis, the balance of local mucosal immunity and inflammation, and epigenetic regulation. Finally, we address current challenges—such as causal validation and the scarcity of multi-species databases—and propose future directions, including spatial multi-omics, AI-integrated analysis, and microbial intervention strategies. Ultimately, this review aims to offer a theoretical foundation and translational insights for elucidating reproductive regulatory networks and developing microbiome-driven precision strategies to enhance reproductive performance. Full article

Background/Objectives: Energy availability (EA), defined as the dietary energy remaining after exercise energy expenditure (EEE), is a central determinant of both health and performance in athletes. Chronic insufficient EA leads to low energy availability (LEA), which is an underlying mechanism of Relative Energy Deficiency in Sport (REDs). This narrative review critically explores the conceptual evolution of EA and LEA, summarizes current physiological evidence, and discusses methodological and practical challenges in their assessment and application in free-living athletes. Methods: Evidence from experimental and observational studies was reviewed to describe the hormonal, metabolic, and performance outcomes associated with LEA. Screening tools, including the Low Energy Availability in Females Questionnaire (LEAF-Q) and the Low Energy Availability in Males Questionnaire (LEAM-Q), were also evaluated for their validity and applicability in different sports contexts. Results: LEA is associated with alterations in thyroid and reproductive hormones, which, in turn, contribute to reduced resting metabolic rate, lower bone mineral density, and delayed recovery. While screening questionnaires can help identify athletes at risk, their accuracy varies by sport and individual characteristics. Incorporating hormonal and metabolic biomarkers provides a more direct and sensitive method for detecting physiological stress. Measuring dietary intake, EEE, endocrine balance and body composition in real-world settings remains a major methodological challenge. Combining hormonal, metabolic, and behavioral indicators may improve the identification of athletes experiencing LEA. Conclusions: EA plays a central role in the interaction between nutrition, exercise, and athlete health, but methodological limitations in its assessment may compromise accurate diagnosis. Improving measurement techniques and adopting integrated monitoring strategies are essential to improve early detection, guide individualized nutrition, and prevent RED-related health and performance impairments. Full article

Conventional semen analysis fails to capture the molecular determinants underlying impaired reproductive function. Emerging evidence positions seminal plasma (SP) and extracellular vesicles (EVs) as dynamic regulators of sperm physiology, rather than passive transport components. SP, enriched with proteins, metabolites, hormones, and antioxidants, modulates sperm motility, capacitation, acrosome reaction, and immune tolerance. Complementarily, EVs, including prostasomes, epididymosomes, and testicular vesicles, deliver proteins, lipids, and small RNAs that remodel sperm membranes, protect against oxidative insults, and influence fertilization success. A critical dimension of the SP-EV axis is its role in balancing oxidative stress (OS) and endocrine signaling. Hormones and metabolic regulators within SP, together with EV-mediated transfer of receptors and regulatory RNAs, further integrate systemic metabolic health with local reproductive outcomes. Dysregulation of these networks, particularly in conditions such as varicocele, obesity, diabetes, and idiopathic infertility, compromises sperm function and reduces assisted reproductive technology (ART) success. This evidence-based review synthesizes current evidence on SP and EVs as ‘molecular gatekeepers’ in male infertility, emphasizing OS regulation, endocrine crosstalk, and their potential as biomarker reservoirs. By integrating proteomic, metabolomic, and transcriptomic insights, the translational opportunities for biomarker-informed diagnostics, prognostication, and therapeutic interventions are highlighted. Full article

This paper presents a semi-autonomous AI-based platform designed for the efficient management and quantitative analysis of human spermatozoa. Addressing the limitations of manual semen analysis, this system integrates advanced image processing and analytical techniques to offer a high-throughput diagnostic solution. During operation, the proposed system autonomously performs a precise quantitative assessment of sperm concentration, accurately tracks individual sperm motility patterns, and systematically classifies morphological abnormalities. The result is a comprehensive sperm analysis report, meticulously generated according to the latest established World Health Organization (WHO) guidelines for concentration, motility, and morphology. A distinguishing feature of this system is the ability to yield reliable preliminary results even with minimally pre-processed clinical samples, thereby enhancing diagnostic objectivity, efficiency, and reliability in male reproductive health assessments. Full article

Melamine, a nitrogen-rich industrial chemical, has raised increasing concern as an emerging environmental contaminant with potential reproductive toxicity. While its nephrotoxic effects are well established, the direct impact of melamine on human sperm remains poorly defined. In this study, we investigated the in vitro effects of melamine on human sperm, under both capacitating and non-capacitating conditions. Functional analyses revealed that the exposure to 0.8 mM melamine, the highest non-cytotoxic concentration in vitro, significantly compromised sperm motility and disrupted key capacitation processes, including tyrosine phosphorylation patterns, cholesterol efflux, and the acrosome reaction. Molecular assessments demonstrated melamine-induced mitochondrial dysfunction, characterized by COX4I1 downregulation, reduced mitochondrial membrane potential, and altered reactive oxygen species production. In parallel, gene expression analyses revealed the activation of apoptotic pathways, with the upregulation of BAX and downregulation of BCL2, changes that were more pronounced during capacitation. Furthermore, melamine exposure significantly increased sperm DNA fragmentation and denaturation, indicating genotoxic stress. Collectively, these findings demonstrate that even low, non-cytotoxic concentrations of melamine compromise sperm function by disrupting capacitation, mitochondrial activity, and genomic integrity. This study identifies capacitation as a critical window of vulnerability and underscores the need to consider melamine as a potential environmental risk factor for male reproductive health. Full article

Declining Leydig cell steroidogenesis contributes to late-onset hypogonadism and to age-associated impairment of male reproductive health. Determinants of dysfunction extend beyond chronological aging. This review synthesizes recent experimental and translational evidence on cellular and molecular processes that compromise Leydig cell endocrine output and the interstitial niche that supports spermatogenesis. Evidence spanning environmental endocrine-disrupting chemicals (EDCs), obesity and metabolic dysfunction, and testicular aging is integrated with emphasis on oxidative stress, endoplasmic reticulum stress, mitochondrial dysregulation, apoptosis, disrupted autophagy and mitophagy, and senescence-associated remodeling. Across model systems, toxicant exposure and metabolic stress converge on impaired organelle quality control and altered redox signaling, with downstream loss of steroidogenic capacity and, in some settings, premature senescence within the Leydig compartment. Aging further reshapes the testicular microenvironment through inflammatory shifts and biomechanical remodeling and may erode stem and progenitor Leydig cell homeostasis, thereby constraining regenerative potential. Single-cell transcriptomic atlases advance the field by resolving Leydig cell heterogeneity, nominating subsets that appear more vulnerable to stress and aging, and mapping age-dependent rewiring of interstitial cell-to-cell communication with Sertoli cells, peritubular myoid cells, vascular cells, and immune cells. Many mechanistic insights derive from rodent in vivo studies and in vitro platforms that include immortalized Leydig cell lines, and validation in human tissue and human clinical cohorts remains uneven. Together, these findings frame mechanistically informed opportunities to preserve endogenous androgen production and fertility through exposure mitigation, metabolic optimization, fertility-preserving endocrine stimulation, and strategies that target inflammation, senescence, and regenerative capacity. Full article

Chronic stress (CS) contributes to male infertility, reduced testosterone levels, and impaired semen quality. CS models induced by glucocorticoids, such as dexamethasone (DEX), negatively affect sperm parameters and testicular health, notably by promoting testicular apoptosis. While individual plant extracts have been studied for their ability to mitigate stress-induced reproductive dysfunction, the preventive effect of the Tri Garn Pis (TGP) polyherbal extract in DEX-induced CS (DexCS) has not previously been investigated. This study evaluated the effects of TGP extract on testicular function, sexual behavior, and sperm quality in DexCS male mice. Seventy-two ICR mice were randomly divided into six groups: control, DexCS, TGP (50, 100, and 200) + DexCS, and TGP200. Mice received TGP (50, 100, 200 mg/kgBW) for 14 days before DEX co-treatment for 28 days. Behavioral and reproductive assessments included depression-like behavior tests, sexual behavior, sperm quality, testicular histopathology, steroidogenesis proteins (AR, CYP11A1, StAR), and apoptosis markers (Hsp70, caspase-3, caspase-9). TGP extract—which is rich in phenolics and flavonoids with antioxidant activity—improved depressive behavior, sexual performance, testicular histology, and low sperm quality. TGP also upregulated testicular StAR expression while reducing caspase-3 and caspase-9 levels. TGP prevents testicular apoptosis, sexual dysfunction, and poor sperm motility induced by DexCS. Full article

Neonicotinoids are synthetic nicotine-like compounds extensively used globally as insecticides for agricultural and urban purposes. Neonicotinoid-contaminated produce is a major public health concern worldwide. Limited epidemiological studies have shown an association of neonicotinoid exposure with abnormal semen analysis. This study aimed to elucidate the potential disruption of the androgen receptor (AR) by eight common neonicotinoids, including imidacloprid (IMI), acetamiprid, clothianidin, thiamethoxam, dinotefuran, thiacloprid (THI), nitenpyram, and nithiazine using docking and molecular dynamics (MD) simulation. The results showed good binding strength of all compounds (except THI) with AR, as indicated by high binding energy, high binding affinity, and number of bonding interactions. The results of MD simulation supported the conformational stability and structural dynamic behavior of the AR-IMI (receptor-neonicotinoid) complex upon binding. This was indicated by root mean square deviation showing stability of the complex; the root mean square fluctuation showing minimized residual fluctuations upon binding; the radius of gyration showing greater compactness of the protein structure; the solvent-accessible surface area showing no changes upon binding; and the Gibbs funnel energy of the landscape showing a stable conformation state with minimum energy and slight change in size and position of the sampled energy basin of the AR, with a stable equilibrium. Taken together, the structural dynamics results showed that neonicotinoids are bound stably in the same ligand-binding domain of the AR as the native ligand testosterone. This may perturb the natural binding of testosterone with the AR and potentially disrupt downstream signaling and biological pathways, leading to male reproductive dysfunction. Full article

Testosterone is a key regulator of male and female physiology, influencing reproductive function, muscle and bone anabolism, metabolic homeostasis, and psychological well-being. Growing evidence indicates a secular, age-independent decline in testosterone levels across populations, a trend associated with reduced fertility, metabolic and cardiovascular dysfunction, mood disturbances, and impaired quality of life. While aging and genetic factors play a role, a wide range of modifiable influences—including obesity, physical inactivity, unhealthy dietary patterns, chronic stress, poor sleep, and exposure to endocrine-disrupting chemicals or other environmental stressors—appear to contribute substantially to this phenomenon. This narrative review synthesizes the evidence on testosterone’s physiological significance, the causes and consequences of its secular decline, and evaluates potential interventions, emphasizing lifestyle and environmental strategies (physical activity, nutrition, weight management, sleep, stress reduction, sunlight exposure) as well as pharmacological and nutraceutical options. Overall, the contemporary testosterone decline represents a complex, multifactorial public health issue requiring integrated approaches to preserve hormonal and systemic health. Full article

Infertility affects thousands of couples internationally, leaving a profound effect on their families and communities. According to the World Health Organization (WHO), approximately one out of six individuals of reproductive age worldwide experiences infertility in their life span. Approximately 35% of infertile couples are affected by male factor infertility, in which semen analysis is the gold standard diagnostic procedure. Oxidative stress (OS) is considered to play a pivotal role in the pathogenesis of male infertility. A thorough literature search was conducted in PubMed/MEDLINE, Scopus and Google Scholar databases, using MeSH terms and free-text keywords, to retrieve eligible articles published in the last decade, focusing on the potential beneficial role of oral antioxidants in male infertility. Antioxidant supplementation appears to improve the majority of sperm parameters. Therefore, antioxidant therapy is emerging as a promising aid in addressing male infertility. The purpose of this comprehensive literature review is to evaluate the significance of antioxidant supplementation in improving sperm parameters. Most of the included randomized controlled trials demonstrated the positive effects of oral antioxidants in various parameters, such as sperm concentration, total sperm count, motility and progressive motility. Consequently, pregnancy outcomes were evaluated, and increased pregnancy rates were reported in the majority of the included studies. Full article

Male infertility is a prevalent global health issue, with urological disorders representing some of the most common and correctable causes. Key conditions such as varicocele, obstructive azoospermia, erectile dysfunction and Peyronie’s disease impair fertility through distinct pathophysiological mechanisms, including disrupted spermatogenesis, reproductive tract obstruction and failed sperm delivery. The effective management of these conditions hinges on a systematic diagnostic evaluation, which integrates clinical history, physical examination, semen analysis and specialized imaging. Modern management follows a logical progression, beginning with foundational lifestyle modifications, advancing to targeted medical or surgical interventions, and culminating, when necessary, in assisted reproductive technologies. Treatment strategies are therefore highly targeted, ranging from medical management and surgical correction—such as varicocelectomy or microsurgical reconstruction—to sperm retrieval techniques. Furthermore, evidence-based lifestyle modifications and a multidisciplinary clinical approach are fundamental to optimizing reproductive outcomes for affected couples. A comprehensive understanding of these urological etiologies is therefore essential for guiding appropriate intervention and improving the prospects of achieving pregnancy. Full article

Background/Objectives: The hypothalamic-pituitary-testis axis is known to be dysregulated in patients with hematological malignancies. However, data on the association between the type of hematological malignancies and semen quality are discordant. In the era of personalized medicine, identifying disease-specific patterns of reproductive impairment is crucial to optimize fertility preservation strategies. While patients with leukemia often show a clear deterioration in semen quality, studies on Hodgkin and non-Hodgkin lymphomas have shown that spermatogenesis is not always compromised. Indeed, some patients may present normospermia before treatment. This study aimed to assess semen parameters in males affected by hematological malignancies compared with a non-cancer population and to explore implications for individualized fertility preservation counseling. Methods: We performed a retrospective monocentric study including all patients affected by hematological malignancies who underwent fertility preservation at the Maternal and Child Department, Gynecology and Obstetrics, Oncofertility Unit, Federico II of Naples, from January 2017 through December 2024. In total, 247 patients with hematological malignancies and 63 non-cancer males undergoing in vitro fertilization for female tubal factor, selected as a control group, were included in the analysis. Sperm parameters (semen volume, sperm concentration, motility, and morphology) were first compared between the hematological malignancy group and the control group, and then among hematological malignancies classified as Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and leukemia (L). Results: Overall, according to World Health Organization (WHO, 2021) criteria, semen parameters of patients with hematological malignancies were at the 25th percentile, except for motility, which was below the 5th percentile. Significant differences were observed in sperm concentration/mL, total sperm number, and percentage of total sperm motility between the hematological malignancy group and the control group (p = 0.0004; p = 0.0003; p < 0.0001). Based on disease classification, 158 patients had Hodgkin lymphoma, 54 had non-Hodgkin lymphoma, and 35 had leukemia. Significant differences in concentration/mL and total sperm number were found between the Hodgkin lymphoma group and the control group (p = 0.003; p = 0.001). The percentage of total sperm motility was significantly decreased in all subtypes of hematological malignancies compared with controls, especially in the leukemia group (HL p = 0.001; NHL p = 0.004; L p < 0.001). Conclusions: These findings highlight significant impairment of semen quality, particularly motility, reinforcing the role of personalized medicine in tailoring fertility preservation strategies according to malignancy subtype and baseline reproductive risk. Full article

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental endocrine disruptors (EDCs) that enter the human body through respiratory, digestive, and dermal exposure. Prolonged exposure has been associated with adverse health outcomes, including carcinogenicity, mutagenicity, and reproductive toxicity. However, whether genetic variation in apoptosis-related pathways modifies the reproductive effects of PAH exposure remains unclear. To investigate gene-environment interactions between urinary PAH metabolites and polymorphisms in apoptosis-related genes in relation to sperm apoptosis, we conducted a cross-sectional study involving 176 male participants from an infertility clinic in Wuhan, China, who completed structured questionnaires and provided biological samples. Ten OH-PAH metabolites in repeated urine samples were measured, along with genotyping of single-nucleotide polymorphisms (SNPs) at apoptosis-related genes (Fas, FasL, and caspase-3) in whole blood DNA, and sperm apoptosis. Multivariable linear regression evaluated the interaction between urinary OH-PAH levels and apoptotic gene SNPs on apoptotic sperm, with genotype-stratified analyses. PAH exposure appeared to interact with SNPs in FasL rs763110, Fas rs2234767, and caspase-3 rs12108497 to jointly influence sperm cell apoptosis. Specifically, for the FasL rs763110, higher 9-OHFlu was associated with fewer viable sperm and more apoptotic sperm, and this association was more pronounced among CC genotype homozygotes. For the caspase-3 rs12108497, higher 2-OHFlu was associated with more dead sperm, and this association was significant among TC and TC/CC genotypes. These findings suggest that genetic variation in apoptosis-related genes may modify susceptibility to PAH-induced sperm apoptosis, highlighting the importance of gene–environment interactions in male reproductive toxicity. Full article