Jun Guo

Varicocele (VC) is a common correctable factor in male infertility, yet its effect on fertility and response to repair vary markedly among patients. This narrative review examines whether mitochondrial injury links the hemodynamic lesion to oxidative stress, sterile inflammation, and persistent spermatogenic damage. Venous stasis, hyperthermia, hypoxia, and metabolic disturbance can impair mitochondrial respiration, membrane potential, ATP production, and quality control. These changes increase mitochondrial reactive oxygen species and favor mitochondrial DNA (mtDNA) oxidation and release. Oxidized mtDNA can engage cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling in nucleated testicular cells, but the evidence is uneven. Human studies mainly document sperm mitochondrial dysfunction, oxidative injury, DNA fragmentation, and altered inflammasome-related factors in seminal plasma. The integrated mtDNA-cGAS-STING-NLRP3 sequence is supported chiefly by animal and non-VC mechanistic models and has not been causally demonstrated in human VC. Anatomical and temporal context is therefore critical. Events in testicular somatic, germ, and immune cells during spermatogenesis cannot be inferred from epididymal, ejaculated-sperm, seminal-plasma, or female-tract findings. Endoplasmic reticulum stress and autophagy or mitophagy may modify mitochondrial injury, whereas programmed cell death, blood-testis barrier disruption, and epigenetic alterations may extend its consequences. Most of these links still require cell-resolved and longitudinal validation. Guideline-directed varicocele repair remains the clinical foundation. Sperm DNA fragmentation and other mechanism-related markers are useful research tools but lack source specificity or validated treatment thresholds, and pathway-directed therapies remain preclinical. The distinctive contribution of this review is a compartment-resolved and evidence-graded model that separates demonstrated findings from plausible links. It also defines the experiments needed to determine whether residual mitochondrial-inflammatory injury predicts reproductive outcomes or response to safe adjunctive treatment.

Background: As the problem of obesity‑induced reduction in male fertility is attracting growing concern, we conducted this network meta-analysis to assess the effects of different high-fat diet (HFD) interventions on male fertility in obese mouse models, aiming to identify the most suitable modeling approach for obesity-related male infertility research. Methods: Sixty-three studies were included. Interventions were categorized based on fat proportion and duration into four HFD groups and compared to a normal diet (ND) group. Network meta-analysis assessed outcomes including body weight, relative testes mass and sperm parameters. Results: The network meta-analysis demonstrated that HFD interventions exerted distinct effects on obesity and reproductive indicators in male mice. HFD4, characterized by high dietary fat content and prolonged feeding duration, induced the most significant weight gain and fertility potential loss. Conclusions: Elevated dietary fat content and prolonged HFD intervention are two indispensable synergistic factors for establishing stable mouse models of obesity with reproductive impairment. HFD-induced obesity primarily triggers oligozoospermia and asthenospermia, with negligible impacts on sperm morphology. Given the inherent heterogeneity and incomplete methodological reporting of preclinical animal studies, the present bias assessment and result interpretation remain preliminary. Standardized unified HFD formulations and rigorous, well-designed animal experiments are required in future studies to further validate relevant findings and optimize obese reproductive injury modeling protocols.

To evaluate the efficacy and safety of Linggui Yangyuan Paste (LG) in treating male infertility caused by asthenozoospermia (AZS) and oligoasthenozoospermia (OAZS) associated with the Chinese medicine (CM) pattern of Shen (Kidney) deficiency and blood stasis. This randomized, double-blind, double-dummy, parallel-group, multicenter clinical trial enrolled 162 male infertility patients at 5 hospitals in China from June 2023 to February 2024. Using block randomization within strata, participants were assigned (1:1) to LG + Wuzi Yanzong Oral Solution (WZ) placebo or WZ + LG placebo for 12 weeks (each LG 1 sachet and WZ 1 vial, twice daily), with a 12-week follow-up. The primary outcome was the change in total progressive motile sperm count (TPMSC) from baseline to week 12. Secondary outcomes included pregnancy rate, CM symptom score (CMSS), and semen parameters including semen volume (SV), sperm concentration (SC), total sperm count (TSC), progressive motility (PR), and PR + non-progressive motility (NP). Prespecified subgroup analyses on cumulative pregnancy rate and semen parameters were performed for participants with AZS and OAZS. Safety was monitored throughout the trial. Of 162 randomized participants, 145 completed the trial (75 in the LG group and 70 in the WZ group) and were included in the per-protocol analysis. At week 12, the LG group showed significantly greater improvement in TPMSC compared to the WZ group, with an adjusted between-group difference of 8.81 × 10⁶ sperm (P<0.05, 95% confidence interval 2.75-14.87). The cumulative pregnancy rate at week 24 was significantly higher in the LG group than the WZ group [24.0% (18/75) vs. 10.0% (7/70), P<0.05)]. CMSS decreased significantly in both groups, with greater reduction in the LG group (P<0.05). Subgroup analysis showed that cumulative pregnancy rates were higher in the LG group than in the WZ group in the AZS subgroup at both weeks 12 and 24 (both P<0.05). In the AZS subgroup analysis, PR and PR+NP showed significantly greater improvements in the LG group (P<0.05). In the OAZS subgroup, SV, SC, TSC, PR, and PR+NP all showed greater improvements in the LG group (P<0.05). No adverse events or adverse drug reactions were reported in either group. LG demonstrates significant efficacy and safety in treating male infertility associated with Shen deficiency and blood stasis syndrome, supporting its clinical application as an integrative therapy for male infertility. (Registration No. ITMCTR2023000009).

Background: Asthenospermia is one of the most common causes of male infertility. In recent years, with changes in dietary habits, the number of obese patients with asthenospermia has been increasing, leading to a decline in male fertility. However, there remains a lack of safe and effective treatments for this condition. Objective: This study aims to confirm the efficacy and safety of acupuncture in obese patients with asthenospermia. Methods: In our randomized controlled trial, 72 patients will be randomly assigned (1:1) to receive either acupuncture treatment or sham acupuncture treatment. Each group will receive treatment two times weekly for twelve weeks with another twelve weeks for follow-up. The primary outcome is the progressive sperm motility (PR). And the secondary outcomes include PR plus non-progressive sperm motility, sperm concentration, semen volume, sperm morphology, body mass index, waist-to-hip ratio, and body fat percentage. We will also evaluate adverse events that occur during the acupuncture process. Results: This study is expected to demonstrate whether acupuncture is effective and safe in the treatment of asthenospermia in obese men. Conclusion: The research findings will firstly provide new therapeutic evidence in treating asthenospermia of obese men and offer an alternative treatment options for improving the fertility of obese men. Study protocol registration: https://itmctr.ccebtcm.org.cn , identifier ITMCTR2025002025.

The monocyte-to-high-density lipoprotein cholesterol ratio (MHR), an indicator of inflammation and lipid metabolism, has demonstrated significant clinical potential. The study aims to investigate the association between the MHR and total testosterone (TT) levels, as well as testosterone deficiency (TD) risk, utilizing data from the NHANES. We analyzed data from 6,194 adult men from NHANES 2011-2016. Multivariate linear and logistic regression analyses were conducted to evaluate associations of MHR with TT levels and TD risk, respectively. Restricted cubic spline (RCS) analyses and subgroup analyses further assessed the robustness of our findings. In the fully adjusted model, each unit increase in log-transformed MHR was associated with a decrease in TT (β = -47.91, 95% CI: -62.39, -33.43, P < 0.001) and an increase in TD risk (OR = 1.81, 95% CI: 1.46, 2.24, P < 0.001). RCS analysis confirmed a linear relationship, and the findings were consistent across subgroup analyses. This study showed that in the United States (US) adult men, a high MHR is linked to low TT levels and a higher TD risk. These findings suggest MHR could be a useful marker for early detection of low testosterone and TD risk, warranting further prospective research for confirmation.

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Background: Lycii Fructus (dried goji berry), the dried ripe fruit of Lycium barbarum L., has long been used in traditional Chinese medicine for its functions of tonifying the kidney, nourishing essence, soothing the liver, and improving vision. It has been widely applied to enhance male reproductive function. In recent years, modern pharmacological studies have revealed that Lycii Fructus is rich in various bioactive metabolites, particularly Lycium barbarum polysaccharides, betaine, carotenoids, and flavonoids, which exhibit antioxidant, anti-apoptotic, and hormone-regulating effects. This review aims to systematically summarize existing clinical and mechanistic studies on the protective effects of Lycii Fructus and its key metabolites on male infertility.Methods: A literature survey was conducted on studies reporting the effects of Lycii Fructus and its bioactive metabolites on male reproductive parameters, including spermatogenesis, hormone regulation, testicular structure, and molecular signaling pathways.Results: Evidence suggests that Lycii Fructus and its metabolites can improve male reproductive function and sperm quality by modulating the hypothalamic–pituitary–gonadal axis, alleviating oxidative stress, inhibiting testicular cell apoptosis, suppressing pro-inflammatory factors, reducing testicular fibrosis, and regulating autophagy. Animal studies have shown that these effects may be mediated through key signaling pathways such as PI3K/Akt, SIRT1/Nrf2, and AMPK/PGC-1α, thereby enhancing testicular steroidogenesis and antioxidant capacity, among other benefits, and mitigating reproductive damage induced by diabetes, obesity, radiation, and environmental toxins. Although clinical evidence supporting the use of Lycii Fructus alone to improve male infertility is still lacking, traditional Chinese medicine compound formulas containing Lycii Fructus have demonstrated good efficacy and safety in treating oligoasthenozoospermia. Given the increasing attention to the safety and preventive health potential of natural botanical medicines, Lycii Fructus is emerging as a promising natural therapeutic agent for the treatment of male infertility.Conclusion: Lycii Fructus and its metabolites show promising therapeutic potential for male infertility by improving sperm quality, protecting testicular structure and function, and mitigating damage induced by various stressors.

Metabolic syndrome (MetS) causes vascular structural abnormalities, nerve damage, hormonal level changes and other lesions, which promote the occurrence and development of erectile dysfunction (ED). Penile vascular endothelial dysfunction is an important pathological feature of MetS-associated ED, and has received increasing attention in recent years. MetS negatively affects penile cavernous vascular function through the synergistic effects of insulin resistance, dyslipidemia, hypertension and obesity. The multiple pathological process may lead to impaired endothelium-dependent vasodilation, progressive fibrosis and reduced penile vascular blood flow reserve. This review summarized several common mechanisms of penile vascular endothelial dysfunction in MetS-associated ED, deeply discussed the roles of common pathological manifestations of MetS such as glucose metabolism disorder, hypertension, dyslipidemia and obesity on penile vascular endothelium, and explored treatments targeting these mechanisms in order to provide potential therapeutic targets and strategies in patients with MetS-associated ED.

Background: Benign prostatic hyperplasia (BPH), as a cause of various lower urinary tract symptoms (LUTS), can improve patients’ quality of life when effectively controlled. To elaborate on the effect of dietary calcium intake on BPH, we investigated the association between dietary calcium intake and the risk of BPH using data from the National Health and Nutrition Examination Survey (NHANES). Methods: Data from the NHANES conducted from 2003 to 2008 were utilized. BPH was identified through self-reported questionnaires, and dietary calcium intake was calculated based on the mean of two 24-hour dietary recall interviews. Multivariable logistic regression analyses were performed to assess the association, supplemented by restricted cubic spline analysis and subgroup analyses. Results: A total of 590 males aged 40 years and older were included in the study, of whom 138 had BPH. After adjusting for all covariates, a higher dietary calcium intake was associated with an increased risk of BPH [odds ratio (OR), 1.05; 95% confidence interval (CI): 1.01–1.09; P=0.04], and those without hypertension. Conclusions: The study found a positive association between dietary calcium intake and the risk of BPH among U.S. men aged 40 years and older. High calcium intake may be associated with the occurrence of BPH, particularly in older individuals. These findings underscore the importance of monitoring dietary calcium intake as part of BPH prevention strategies.