Obesity has been increasingly linked to impaired male reproductive function, yet the association between body mass index (BMI) and semen quality remains unclear, particularly in large Asian populations. In this retrospective cross-sectional study, we analyzed 11 154 men aged 18-50 years who underwent semen analysis at Nanjing Drum Tower Hospital (Nanjing, China), between January 2024 and January 2025. Semen parameters were assessed according to the World Health Organization Laboratory Manual (6th edition), and sperm kinematics were measured via computer-aided sperm analysis. BMI was modeled both as a continuous variable and as a categorical variable, and associations of BMI with sperm parameters were evaluated using multivariable linear regression, sensitivity analyses, restricted cubic splines, and locally estimated scatterplot smoothing (LOESS) curves. The mean BMI of the participants was 26.3 (standard deviation: 3.8) kg m-2. A higher BMI was associated with modest but consistent reductions in semen volume, total sperm count, sperm concentration, and selected sperm kinematic parameters. No U- or J-shaped associations were observed. The results of the restricted cubic spline analyses suggested only modest nonlinearity in the relationships of BMI with sperm concentration and total sperm count, whereas the associations with semen volume and kinematic parameters were largely linear. The results of the sensitivity analyses were consistent with the primary findings. In the subset analyses, obesity was associated with more severe sperm DNA fragmentation, whereas exploratory hormone analyses in men with obesity indicated that a higher BMI was associated with lower total testosterone levels, higher estradiol levels, and a lower total testosterone/estradiol (TT/E2) ratio, which were also related to a lower semen volume. Overall, a higher BMI was linearly and inversely associated with several semen parameters, although the effect sizes were modest.

Actin-like 9 (ACTL9) is a testis-specific actin-like protein located in the perinuclear theca of the sperm head and neck that plays a role in acrosome formation and sperm head shaping. Pathogenic mutations in ACTL9 have been reported to be associated with male infertility and fertilization failure after conventional in vitro fertilization (cIVF) and intracytoplasmic sperm injection (ICSI). In this study, we identified a homozygous chromosomal microdeletion within the ACTL9 gene in an infertile male characterized by polyspermy in cIVF and nearly total fertilization failure in ICSI. Transmission electron microscopy revealed that spermatozoa from the affected individual exhibited a ruffled acrosome, and the inner acrosomal membrane was detached from the nuclear envelope. Immunofluorescence staining revealed the absence of phospholipase C zeta 1 (PLCZ1) protein in mutant spermatozoa, which explains the characteristic multipronuclei observed in cIVF. ICSI and artificial oocyte activation treatment successfully rescued the cIVF polyspermic phenotype and resulted in a live birth. These findings expand the spectrum of ACTL9 mutations and could facilitate the diagnosis of sperm-borne polyspermy.

Onvansertib (ONV) is a selective inhibitor of polo-like kinase 1 (PLK1) and has promise in treating cancer. However, its potential effects on male reproductive function remain insufficiently characterized. In this study, male mice received clinically relevant doses of ONV by intragastric gavage for five consecutive days. Evaluations conducted on day 1, day 6, and day 35 after treatment revealed a marked increase in germ cell apoptosis accompanied by a significant reduction in epididymal sperm counts, whereas somatic cell architecture was preserved. Mechanistically, PLK1 inhibition by ONV led to a pronounced decrease in eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) phosphorylation. This disruption is likely linked to impaired meiotic centrosome maturation and aberrant spindle organization in germ cells. Collectively, these findings demonstrate that ONV preferentially induces apoptosis in germ cells via PLK1 suppression, thereby compromising spermatogenic capacity.

Male factor infertility accounts for approximately 50% of all infertility cases. Metabolomics has recently been applied to the assessment of sperm quality and male fertility. However, studies on the biological functions and clinical effects of sperm metabolites in relation to asthenozoospermia (AZS) remain limited. In this study, we analyzed the metabolomic profiles of seminal plasma from 20 men with AZS and compared them with those from 20 men with normal semen parameters (healthy controls) using a standardized untargeted high-performance liquid chromatography-tandem mass spectrometry approach. Metabolite levels differed significantly between the AZS and healthy control groups. A total of 177 potential biomarkers and multiple metabolic pathways were identified in men with AZS. Specifically, tyrosol levels were significantly reduced in the AZS group. Preincubation with tyrosol significantly increased the percentage of spermatozoa with progressive motility in men with AZS. Moreover, tyrosol supplementation improved progressive motility, DNA integrity, and acrosomal integrity in cryopreserved sperm samples from these individuals, as reflected by post-thaw sperm parameters. In conclusion, this study reveals the distinctive metabolic characteristics of seminal plasma and the dysregulation of the metabolite tyrosol, which is associated with AZS. Tyrosol notably enhanced sperm performance, suggesting its potential integration into clinical strategies for AZS management and fertility preservation.

The progressive decline in sperm motility is a major contributor to male infertility. The cation channel of sperm (CatSper) complex is a sperm-specific calcium (Ca2+) channel that plays a crucial role in regulating sperm motility. However, the molecular mechanisms governing CatSper regulation remain incompletely understood. This study found that the expression level of transmembrane protein 196 (TMEM196) positively influences human sperm quality and Ca2+ concentration. TMEM196-null male mice showed reduced fertility, characterized by fewer offspring and decreased sperm Ca2+ concentration. Sperm quality analysis revealed that TMEM196 deficiency led to reduced sperm concentration, impaired hyperactivation, and decreased motility in male mice. Further investigations demonstrated that the reduction in sperm motility in TMEM196-null mice was associated with decreased sperm Ca2+ concentration and was independent of hormone levels. Considering the essential role of CatSper in regulating sperm Ca2+ homeostasis, we examined the expression of CatSper subunits and observed significantly reduced protein levels of CatSper1-4 in the testes of TMEM196-null mice. In vitro, overexpression of TMEM196 in GC2 cells enhanced Ca2+ signaling and upregulated CatSper-related protein expression. Mechanistically, TMEM196 promoted the transcription of CatSper-related genes by enhancing the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Collectively, these results identify TMEM196 as a novel regulator of the sperm-specific CatSper Ca2+ channel and demonstrate its critical role in modulating sperm motility.

Simenafil, a newly developed oral phosphodiesterase type 5 (PDE5) inhibitor, substantially improves erectile function; however, its efficacy has not been evaluated via RigiScan monitoring. This study evaluated the efficacy and safety of simenafil in erectile dysfunction (ED) using audiovisual sexual stimulation. A randomized, double-blind, placebo-controlled, multicenter, two-cohort, three-way crossover study was conducted in 84 men aged 18-65 years with mild-to-moderate ED of ≥6 months. Each patient received placebo, simenafil 5.0 mg, and simenafil 2.5 mg (Cohort A, n = 42) or 10.0 mg (Cohort B, n = 42) administered in random order at least 5 days apart. RigiScan was used to assess the time to achieve and duration of ≥60% penile rigidity. In Cohort A, relative to placebo, 2.5 mg simenafil (single-dose) led to a least square mean (LSM) increase in the duration of ≥60% penile rigidity of 3.1 min (95% confidence interval [CI]: 0.5-5.7 min, P = 0.021) and 8.3 min (95% CI: 3.5-13.2 min, P = 0.001) at the tip and base, respectively; for the 5.0 mg, it was 3.7 min (95% CI: 1.0-6.4 min, P = 0.008) and 8.5 min (95% CI: 3.5-13.5 min, P = 0.001) at the tip and base, respectively. In Cohort B, the LSM duration of ≥60% rigidity of the penile base was significantly longer with 10.0 mg simenafil than with placebo by 5.9 min (95% CI: 0.8-10.9 min, P = 0.023). The 5.0 mg (tip and base) and 10.0 mg (tip) simenafil were not statistically significant compared with the placebo (all P > 0.05). The pharmacodynamic and safety profiles support simenafil as a suitable candidate for further investigation in ED.

Rhesus (Rh) family B glycoprotein (RHBG) is a conserved ammonium transporter of the Rhesus family with established roles in systemic acid-base regulation. Although Rh family members are expressed in the male reproductive tract, the physiological role of RHBG in spermatogenesis and sperm function remains unclear. To investigate its role in male reproduction, Rhbg-/- mice were generated using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated gene editing, and male fertility and reproductive phenotypes were assessed by breeding assays, histological analyses of the testes and epididymides, sperm morphology evaluation, computer-assisted sperm analysis during capacitation, and transmission electron microscopy of flagellar ultrastructure. Rhbg-/- male mice showed largely preserved fertility and produced offspring numbers comparable to those of wild-type controls, although a modest reduction in litter size was observed. Consistently, testicular architecture, spermatogenesis, and epididymal morphology were normal, and transmission electron microscopy confirmed intact flagellar ultrastructure. Computer-assisted sperm analysis further showed normal progressive motility under both basal and capacitating conditions. However, under hyperactivation-associated conditions, Rhbg-/- sperm exhibited a mild reduction in total motility, accompanied by subtle decreases in straight-line velocity and straightness. In addition, a slight increase in tail-coiling abnormalities was observed, whereas overall sperm morphology remained largely normal. Together, these findings indicate that Rhbg is not essential for spermatogenesis or male fertility in mice, but its absence causes minor, context-dependent alterations in sperm trajectory efficiency during capacitation without affecting core motility or ultrastructural integrity. Thus, RHBG may contribute to the fine regulation of sperm motility behavior rather than acting as a major determinant of reproductive capacity.

Androgens and the androgen receptor (AR) play a central role in the development and progression of prostate cancer. While biochanin A (BCA) has been reported to suppress androgen synthesis and overcome resistance to abiraterone and enzalutamide, its direct effects on AR, particularly mutant AR, remain unclear. In this study, we systematically investigated the binding affinity and functional impact of BCA on a panel of clinically relevant AR mutations to identify patient subgroups that may benefit from BCA treatment. Our results demonstrated that BCA exhibits high-binding affinity toward the ART877A and ARW741C mutants. Our findings reveal a previously unrecognized mechanism by which BCA directly targets specific AR mutants, in addition to inhibiting androgen biosynthesis. This study provides mechanistic insights into the mutation-selective activity of BCA and supports its potential clinical application in molecularly stratified prostate cancer.

This prospective cohort study investigated the association between dyslipidemia and prostate volume progression in middle-aged Chinese men. A total of 5607 men aged >40 years at The Second Xiangya Hospital of Central South University (Changsha, China), between January 2020 and January 2023, who did not have baseline benign prostatic hyperplasia, were followed for three years. Participants were categorized by their baseline lipid status according to Chinese guidelines. Prostate volume was measured annually, using transrectal ultrasound, with enlargement defined as a volume of ≥31 ml. The results showed that 48.0% of men with dyslipidemia developed prostatic enlargement, compared to 36.5% with normal lipid levels. Elevated ratios of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol and total cholesterol to high-density lipoprotein cholesterol were significantly associated with an increased risk in a dose-response manner. This association was independent of age, body mass index, and fasting glucose levels. High-density lipoprotein cholesterol demonstrated a protective effect. These findings suggest that dyslipidemia, particularly as reflected in specific lipid ratios, is an independent and modifiable risk factor for accelerated prostatic enlargement. This indicates that lipid assessment could be valuable for early risk stratification and prevention.

Paternal environmental factors can influence offspring health intergenerationally through alterations in sperm epigenetics. Exercise, as a key modifiable lifestyle factor, may similarly affect epigenetic inheritance. Emerging evidence from animal and human studies indicates that exercise modulates sperm DNA methylation and noncoding RNA expression. In animal models, paternal exercise has also been linked to changes in offspring phenotypes. However, inconsistencies exist across studies because of variations in exercise modalities and the specific epigenetic markers analyzed. More importantly, the mechanisms underlying the relationship between sperm epigenetic alterations and offspring phenotypes remain unclear. This review integrates evidence from January 2010 to December 2025 to summarize exercise-induced changes in sperm epigenetics and their associations with offspring metabolic and behavioral outcomes. It critically discusses major inconsistencies in the current literature and highlights underexplored areas, including exercise-induced changes in histone modifications and chromatin architecture in sperm, as well as a striking lack of human data on offspring health. We propose that future rigorous exercise standardization, multidimensional epigenetic profiling, well-designed human studies, and functional validation are essential to establish causality and translate findings into effective interventional strategies.

With global population aging, erectile dysfunction is becoming increasingly prevalent among middle-aged and older men, who frequently present with cardiometabolic comorbidities, such as hypertension and diabetes mellitus. Although these conditions are well-established risk factors for erectile dysfunction, their long-term pharmacological management may exert heterogeneous and adverse effects on erectile function, complicating clinical decision-making. This review synthesizes current evidence on the shared pathophysiological mechanisms linking erectile dysfunction with hypertension and diabetes mellitus, including endothelial dysfunction, oxidative stress, vascular remodeling, metabolic dysregulation, and neurovascular impairment. This review also critically evaluates the effects of commonly prescribed antihypertensive and antidiabetic drug classes on erectile function, highlighting both their beneficial and detrimental profiles. By integrating mechanistic insights with clinical evidence, this review highlights medication-associated sexual dysfunction in aging men. It emphasizes its recognition and management in clinical practice. The goal is to guide individualized treatment strategies that control cardiometabolic disease while preserving sexual health and quality of life.

Emerging evidence highlights a link between heavy metal exposure and semen quality, but discrepancies persist regarding the effects of metals like lead and cadmium across different biological matrices. This systematic review and meta-analysis aimed to explore the association between heavy metal exposure in blood, urine, and seminal plasma and male semen quality. A comprehensive search was conducted across four databases (PubMed, Embase, Scopus, and Cochrane Library), and a bibliometric analysis was performed using the Web of Science Core Collection. Based on this analysis, a systematic literature review and meta-analyses were conducted. Database searches were updated until November 2024. A total of 10 qualitative and 14 quantitative studies were included. Exposure to lead and cadmium in seminal plasma was significantly correlated with progressive sperm motility, with odds ratio (OR) of 2.27 (95% confidence interval [CI]: 1.18 to 4.34) for lead and of 2.55 (95% CI: 1.29 to 5.03) for cadmium. Arsenic exposure was significantly linked to total sperm motility (OR = 2.88, 95% CI: 1.35 to 6.17), while zinc deficiency in seminal plasma was associated with reduced total sperm motility (OR = 1.77, 95% CI: 1.17 to 2.66). Given the widespread exposure to heavy metals, assessing their impact on male reproductive health should be prioritized as a public health concern. This study highlights the reprotoxicity of heavy metals in seminal plasma, blood, and urine, with seminal plasma emerging as the most sensitive biomarker for reproductive risk.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent genitourinary disease that has gradually become recognized as a potential autoimmune disease. Our previous research revealed that a high-glucose diet exacerbated experimental autoimmune prostatitis (EAP), a widely used animal model of CP/CPPS. However, its effects on the metabolism of EAP mice remain unknown. Here, we applied non-targeted metabolomics analysis of feces and enzyme-linked immunosorbent assays to identify differential metabolites in EAP mice with and without high-glucose feeding. Metabolomics analysis demonstrated significant enrichment of the vitamin digestion and absorption pathway. Glucose-fed EAP mice exhibited increased fecal excretion and reduced absorption of 1,25-dihydroxyvitamin D3 (DHVD3) into the bloodstream, accompanied by decreased expression of the vitamin D receptor (VDR) in prostate tissue. In vitro experiments, proteomic sequencing, western blot, and flow cytometry analyses demonstrated that DHVD3 suppressed T helper 17 (Th17) cell differentiation by activating the VDR/extracellular signal-regulated kinase (ERK) pathway. DHVD3 supplementation ameliorated Th17 responses and EAP severity in glucose-fed mice, whereas the administration of the VDR antagonist MeTC7 reversed these effects. We concluded that high-glucose feeding aggravates EAP through DHVD3/VDR/ERK axis-mediated Th17 differentiation. VD3 supplementation may benefit CP/CPPS patients consuming a high-sugar diet.

Acephalic spermatozoa syndrome (ASS) is a rare cause of male infertility characterized by sperm tails lacking heads. Although zinc finger MYND-type containing 15 (ZMYND15) mutations are linked to male infertility, their role in ASS is unknown. In this study, whole-exome sequencing identified novel homozygous truncating mutations, c.292C>T (p.Arg98Ter) and c.337G>T (p.Glu113Ter), in ZMYND15 from two infertile patients. These mutations caused protein truncation and impaired function, leading to extremely low sperm counts, poor motility, and numerous acephalic spermatozoa. Electron microscopy and sperm immunofluorescence revealed abnormal sperm neck structures, missing mitochondrial sheaths, failure of acrosome formation, and a lack of central microtubules. Experiments showed reduced mutant protein expression and high rates of degradation. Coimmunoprecipitation experiments indicated a direct interaction between ZMYND15 and Sad1 and UNC84 domain containing 5 (SUN5), crucial for forming the sperm head-tail connection. One patient achieved a live birth via intracytoplasmic sperm injection (ICSI), whereas the other had an early miscarriage. This study links ZMYND15 mutations directly to ASS, highlighting its role in spermatogenesis and offering insights for clinical diagnosis and treatment.

Fertilization and early-cleavage failure are the major causes of assisted reproductive technology failure, but genotype-guided care is underused. We conducted whole-exome sequencing with Sanger confirmation in 20 men from couples with unexplained fertilization and cleavage failure after in vitro fertilization or intracytoplasmic sperm injection (ICSI). Then, further sperm transmission electron microscopy, immunofluorescence, and, where appropriate, embryo quantitative parental contamination test (qPCT) and kinship analysis were integrated in selected cases. Six novel variants were found in four families: two each in dynein axonemal heavy chain 10 (DNAH10) and dynein axonemal heavy chain 12 (DNAH12) and one in cilia and flagella associated protein 47 (CFAP47) and phospholipase C zeta 1 (PLCZ1), respectively. DNAH10/DNAH12 variants segregated with multiple morphological abnormalities of the sperm flagella and showed "9+2" axonemal disruption and reduced dynein signals. Hemizygous CFAP47 c.8006C>T is associated with cleavage failure and altered PLCZ1 localization. Homozygous PLCZ1 c.589C>T in a consanguineous pedigree coincided with multinuclear (≥3 pronuclei) zygotes, and qPCT/kinship indicated excess paternal contribution, consistent with suspected polyspermy in multinuclear zygotes. Management-matched genotype: ICSI restored fertilization in DNAH10/DNAH12 deficiency, whereas ICSI plus assisted oocyte activation (AOA) improved cleavage and yielded ongoing pregnancies in CFAP47/PLCZ1 deficiency. These findings outline potentially actionable clinical strategies-ICSI for axonemal dynein defects and ICSI plus AOA for activation pathway defects-and support targeted genetic testing plus embryo qPCT/kinship in selected cases.