Inflatable penile prosthesis (IPP) is the gold standard for refractory erectile dysfunction, yet long-term outcomes in the Veterans Affairs (VA) health care population remain incompletely characterized. Using the Satisfaction Survey for Inflatable Penile Implant (SSIPI)-a recently validated, English-language, IPP-specific instrument (16 items; 1-5 Likert scale; total score 16-80)-we conducted a retrospective chart review and telephone-administered survey as an Institutional Review Board-approved quality improvement project at our regional VA medical center. All men undergoing primary IPP implantation from 1993 to 2021 were identified. Of 114 patients (82 living, 32 deceased at census date), 52 of 82 living patients (63.4%) completed the SSIPI. Median follow-up was 129.4 months (IQR 46.9-203.0), and median age at first surgery was 62 years (IQR 58-67). Median total SSIPI score was 67.5/80 (IQR 58.0-76.0); 67.3% of respondents were satisfied or somewhat satisfied. Smokers reported significantly lower satisfaction with post-implant penile length than non-smokers (SSIPI item #8: median 3.0 vs. 4.5; Mann-Whitney U, p = 0.032), and 48.1% of all respondents scored ≤3 on this domain regardless of smoking status, highlighting the importance of preoperative counseling on length expectations. Patients with lower comorbidity burden (ASA ≤ 2) reported higher overall satisfaction than those with ASA ≥ 3 (mean 70.36 vs. 61.13; p = 0.028). Older age at surgery was positively correlated with overall satisfaction (Spearman ρ = 0.463, p < 0.001), supporting IPP as appropriate management in older patients. No significant differences in overall SSIPI score were observed by diabetes status or BMI. Long-term IPP satisfaction in this VA cohort was favorable overall. Smoking history and higher comorbidity burden identify patients warranting enhanced preoperative counseling. The SSIPI demonstrates utility as a long-term quality improvement outcome measure for IPP in a real-world VA setting.
BACKGROUND:The brain plays a critical role in premature ejaculation (PE), but the specific regions involved remain unclear. This study aimed to identify functional brain network alterations in PE-like rats and investigate the modulatory effects of electroacupuncture (EA) at SP6. METHODS:Sixteen male Sprague-Dawley rats were divided into PE-like (n = 8) and control (n = 8) groups based on ejaculation frequency (EF). Copulatory behavior (EF, ejaculation latency [EL]), resting-state fMRI, and plasma norepinephrine (NE) were assessed at baseline and after 4 weeks of daily EA at SP6. Functional brain networks were constructed using graph theory, and nodal measures were compared between groups. RESULTS:PE-like rats exhibited significantly shortened EL and elevated plasma NE. Global network measures did not differ between groups. However, PE-like rats showed: (1) decreased nodal strength and betweenness centrality in hypothalamus; (2) decreased betweenness centrality in retrosplenial granular cortex zone a/postsubiculum; (3) increased clustering coefficient and global efficiency in RSD/RSGa; (4) decreased local efficiency in primary somatosensory and dorsal thalamic nucleus. EF and NE were negatively associated with dorsal thalamic nucleus local efficiency, while EL was negatively associated with hypothalamus strength and betweenness centrality. EA treatment significantly reduced EF and NE, prolonged EL, and normalized most nodal abnormalities; the improvement in dorsal thalamic nucleus local efficiency survived FDR correction. CONCLUSION:PE-like behavior in rats is associated with specific nodal alterations in hypothalamus, thalamus, and somatosensory cortex, alongside elevated NE. EA at SP6 was associated with partial normalization of these abnormalities, suggesting potential neuromodulatory mechanisms for PE, though causal relationships require further investigation.
BACKGROUND:Nonorganic erectile dysfunction (nonorganic ED) is a common subtype of ED characterized by impaired erectile function in the absence of identifiable organic causes. Although ED is increasingly recognized as a multidimensional condition involving interacting biological, psychological, relational, and sociocultural factors, how these influences are integrated within central neural systems in nonorganic ED remains incompletely understood. Objective neurobiological markers are therefore still lacking. OBJECTIVES:To investigate whether patients with nonorganic ED exhibit abnormalities in local intrinsic brain activity and to examine the association between these alterations and erectile function. MATERIALS AND METHODS:Resting-state functional magnetic resonance imaging data were acquired from 29 patients with nonorganic ED and 29 age-matched healthy controls. Regional homogeneity (ReHo) was used to assess local synchronization of spontaneous neural activity across the whole brain. Between-group differences were evaluated using voxel-wise analysis. Correlation analyses were performed to assess associations between altered ReHo and erectile function as measured by the International Index of Erectile Function (IIEF). RESULTS:Compared with healthy controls, patients with nonorganic ED exhibited significantly decreased ReHo in the right anterior insula (family-wise error corrected). Furthermore, reduced ReHo in this region was significantly associated with greater ED severity. DISCUSSION:These findings indicate that nonorganic ED is associated with disrupted local functional coherence in the anterior insula, a key region involved in integrating interoceptive, emotional, cognitive, and autonomic processes. The observed association with erectile function suggests that impaired integration of these processes may contribute to the central neural mechanisms underlying nonorganic ED. CONCLUSION:Patients with nonorganic ED exhibit reduced local functional coherence in the anterior insula, which is associated with ED severity. These findings provide preliminary evidence linking central neural dysfunction to clinical symptoms and support the further evaluation of resting-state fMRI metrics as candidate neurobiological markers for nonorganic ED.
BACKGROUND:Male accessory gland inflammation (MAGI) comprises a heterogeneous group of inflammatory conditions that may differentially affect the seminal microenvironment and sperm function. However, whether transrectal ultrasound (TRUS)-defined MAGI phenotypes correspond to distinct biological profiles remains insufficiently characterized. OBJECTIVE:To evaluate whether TRUS-defined phenotypes of MAGI can be discriminated using seminal inflammatory and oxidative stress biomarkers and sperm proteomic profiles, and to assess their potential clinical relevance for disease stratification. MATERIALS AND METHODS:In this case-control study, 20 men with MAGI and 10 healthy controls were enrolled. Patients were classified by TRUS as hypertrophic-congestive (acute) or fibro-sclerotic (chronic) phenotypes. Semen analysis, seminal plasma antioxidant capacity, and sperm lipid peroxidation were assessed. Seminal inflammatory biomarkers were quantified and evaluated by receiver operating characteristic analysis. Proteomic profiling of purified spermatozoa was performed with multivariate and differential expression analyses, followed by functional enrichment and immunofluorescence validation. RESULTS:Both MAGI phenotypes showed reduced sperm concentration and motility compared with controls, whereas abnormal morphology was more pronounced in the fibro-sclerotic phenotype. Antioxidant capacity was reduced, and lipid peroxidation increased in both groups, with greater oxidative imbalance in the hypertrophic-congestive phenotype. SuPAR discriminated MAGI patients from controls with high specificity, whereas sST2 accurately differentiated acute and chronic phenotypes. Proteomic analysis identified distinct, nonoverlapping molecular signatures across groups. Pathway analysis showed downregulation of proteins involved in sperm function and fertilization, with additional impairment of motility-related processes in the chronic phenotype. Immunofluorescence confirmed reduced expression of a key flagellar structural protein, most markedly in fibro-sclerotic MAGI. DISCUSSION AND CONCLUSION:TRUS-defined MAGI phenotypes are associated with distinct biomarker and proteomic profiles, consistent with different inflammatory states and patterns of sperm molecular injury. These findings support a biomarker-assisted approach to phenotype stratification and provide mechanistic insight into inflammation-driven male reproductive dysfunction.
BACKGROUND:Klinefelter syndrome (KS) is the most common genetic cause of male infertility and is associated with nonobstructive azoospermia. Advances in surgical sperm retrieval techniques have enabled biological fatherhood in a subset of men with KS. Limited data exist concerning the presence of spermatozoa in the ejaculate of adolescent patients with KS. The question remains, on how to discuss fertility preservation with adolescents with KS, and to what extent attempts to obtain ejaculated spermatozoa should be encouraged, knowing that the chances of sperm retrieval are limited. OBJECTIVES:To evaluate the prevalence of spermatozoa in ejaculate samples from adolescents with KS followed at a single tertiary center in Copenhagen, Denmark. MATERIALS AND METHODS:This retrospective study included 48 patients with KS who had delivered a semen sample before the age of 21 years. Data on semen quality and serum concentrations of reproductive hormones were obtained from patient files. RESULTS:Spermatozoa were detected in the ejaculate from seven (14.6%) patients, including one with mosaic karyotype and six with non-mosaic KS. Six of the patients with spermatozoa in the ejaculate and 41 of the patients without were on testosterone replacement therapy at the time of semen sampling. No difference in biochemical or clinical parameters between patients with and without spermatozoa in the ejaculate was found. DISCUSSION:Our findings align with prior reports finding spermatozoa in the ejaculate of 3.4%-8.5% of patients with KS. Similar to other studies, neither biochemical nor clinical parameters explained the presence of spermatozoa in the ejaculate. This highlights the need for age-appropriate fertility counseling that balances emotional readiness with realistic expectations. CONCLUSION:We found spermatozoa in the ejaculate of seven of 48 (14.6%) adolescents with KS, although the majority were treated with testosterone.
BACKGROUND:Vasectomy is the most common non-diagnostic procedure performed by urologists and the only permanent form of sterilization routinely offered to men. Though vasal fluid has been estimated to represent less than 10% of seminal volume, studies describing the effect of vasectomy on semen volume remain limited. OBJECTIVE:To describe the effect of vasectomy on semen volume compared to controls independent of changes with time/aging. MATERIALS AND METHODS:Men undergoing vasectomy between January 2015 and December 2024, who underwent a pre-vasectomy semen analysis (SA) with volume ≥ 1.5 mL and sperm concentration ≥ 15.0 M/mL, and post-vasectomy SA, were identified and included in this single-center retrospective case-control study. Non-vasectomized men with normal semen parameters and two SAs were identified as controls. Cases were matched to controls in a 1:2 ratio regarding patient age at the time of initial SA. RESULTS:A total of 957 patients were included in the analysis cohort, including 319 vasectomized men and 638 controls. Mean age (33.3 ± 5.1 vs. 33.4 ± 5.0 years, p = 0.80) and sperm concentration on initial SA (69.2 ± 50.5 vs. 75.5 ± 54.7 M/mL, p = 0.08) did not differ between cases and controls, nor did mean volume on initial (3.51 ± 1.51 vs. 3.51 ± 1.51 mL, p = 0.98) or subsequent SA (3.07 ± 1.42 vs. 3.19 ± 1.60 mL, p = 0.22). Semen volume decreased slightly in both groups between measurements (cases: -0.44 mL; controls: -0.32 mL; both p < 0.0001), but the between-group difference was not statistically significant (p = 0.19). Vasectomy status was not associated with volume change in the univariate (β = 0.06 mL, p = 0.19) or multivariable models (β = 0.04 mL, p = 0.50) adjusted for time between SAs. A sensitivity analysis among matched groups from whom initial and subsequent SA volumes ≥1.5 mL echoed these findings. DISCUSSION AND CONCLUSION:Vasectomy does not result in a significant change in semen volume when SA parameters are compared between cases and controls. Patients should be counseled that vasectomy itself does not change semen volume, but that volume might subtly decrease with aging.
Klinefelter syndrome (KS) is typically diagnosed in young adults, but advances in prenatal testing have led to its recognition at a much earlier age. Conversely, diagnosis in late adulthood remains uncommon, but still occurs. Independently from the age at diagnosis, KS individuals now receive more accurate and tailored care management than in the past, thanks to advances in disease knowledge, improvements in health care systems, and greater awareness among both physicians and patients. Thus, individuals with KS are often placed under structured follow-up care, ensuring long-term monitoring that extends into older age. This review focuses on the pathophysiology and the management of osteopenia and osteoporosis in KS. Besides, aging with KS moves the physician's attention from reproductive function in the youth to comorbidities, cognitive changes and biological markers of aging and in the long run. From this perspective, chronic cardiovascular and metabolic diseases along with bone health become a priority in older individuals with KS. In particular, osteoporosis and osteoporotic fractures should be screened and treated with compensation of hypogonadism and eventual bone active therapy, since osteoporosis might be present already in young adults but worsens with advancing age. The extent to which these comorbidities, that are associated with KS in literature, occur more frequently in KS individuals (especially in older KS) compared to the general population remains to be established with certainty. In clinical practice, the management of older men with KS should include several assessments beyond hormone assays and hypogonadism treatment, aiming to address the health of individuals with KS in a holistic manner.
BACKGROUND:SUMO proteins are highly expressed in testicular cells, including spermatocytes and Sertoli, where they modify numerous proteins. Nonetheless, the role of SUMO proteins in spermatogenesis in vivo has remained unconfirmed. OBJECTIVES:To confirm the requirement for sumoylation in the mouse in vivo during meiosis and in testicular Sertoli cells. MATERIALS AND METHODS:To inactivate sumoylation, we targeted the UBA2 gene, a subunit of the only known SUMO-activating enzyme. Stra8-Cre, Amh-Cre, and Uba2fx/fl mice were used to produce Uba2fl/fl-Cre mice with the conditional deletion of Uba2 in either early meiotic or Sertoli cells. RESULTS:Both mouse models have exhibited complete male infertility, a significant decrease in testicular weight, and spermatogenic arrest. Inactivation of sumoylation in spermatocytes led to meiotic arrest and misregulated expression of many genes involved in meiotic completion and spermatid differentiation. Inactivation of sumoylation in Sertoli cells leads to loss of germ cells, progressive testicular degeneration, and misregulated expression of genes that control Sertoli cell function, including those involved in germ cell adhesion and junctional complex formation. Transcription factor WT1 may be an important target of sumoylation in Sertoli cells. DISCUSSION:Sumoylation may provide a dual-layer regulatory mechanism through direct binding to proteins required for meiosis and Sertoli cell functions, and indirect control of transcriptional events through regulation of transcription factors and chromatin modifiers. Future studies will address the mechanisms by which sumoylation controls transcription and other events in testicular cells. CONCLUSION:UBA2-mediated sumoylation is required for both spermatocyte and Sertoli cell functions.
The recently published World Health Organization (WHO) infertility guideline introduces a global approach to infertility care with significant implications for male reproductive health. This review examines the male infertility components of the WHO guideline and compares them with those from the American Urological Association/American Society for Reproductive Medicine (AUA/ASRM), European Association of Urology (EAU), European Society of Human Reproduction and Embryology (ESHRE) and National Institute for Health and Care Excellence (NICE). The WHO guideline adopts a public health perspective, emphasizing infertility prevention, standardized diagnostic algorithms, and the central role of semen analysis, while prioritizing feasibility across diverse healthcare settings. In contrast, AUA/ASRM and EAU guidelines offer comprehensive, specialist-oriented recommendations, including endocrine evaluation, genetic testing, and a wide range of therapeutic interventions, whereas ESHRE and NICE follow a couple-centered approach with limited focus on male-specific pathways. The WHO guideline provides a more selective approach to management, with a neutral stance on antioxidant therapy and specific recommendations for varicocele, highlighting it as a key, potentially treatable condition. Across guidelines, there is broad consensus on core diagnostic principles, but differences remain in scope, depth, and implementation strategies. These variations reflect not only differences in target populations and healthcare contexts but also notable gaps in the evidence base. Strengthening evidence for commonly used interventions, including antioxidants, hormonal therapies, and advanced diagnostics, and promoting greater harmonization across guidelines are essential to advancing male infertility care.
BACKGROUND:Previous studies have found no significant difference in birth weight between donor sperm and partner sperm, and some studies have found that donor sperm is more likely to lead to small for gestational age (SGA). OBJECTIVE:Does the use of donor sperm affect the birth weight of the offspring? MATERIALS AND METHODS:This study was a retrospective cohort study, including patients who achieved a singleton using in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) in fresh embryo transfer cycles in Peking University Third Hospital from January 2012 to December 2022. Birth weight and complete maternal baseline data were collected. A total of 3360 cycles were included in the study, of which 611 cycles used donor sperm and 2749 cycles used partner sperm from males with oligoasthenozoospermia. Multiple linear regression analysis and logistic regression analysis were performed to evaluate the possible relationship between donor sperm use and the birth weight of the offspring and the occurrence rates of large for gestational age (LGA), SGA, high birth weight (HBW), and low birth weight (LBW) in offspring. RESULTS:Comparing 611 cycles in which donor sperm was used with 2749 cycles in which partner sperm was used, baseline data did not differ significantly between the two groups in terms of female age, BMI, parity, and cause of infertility. Offspring born in the donor group had higher birth weight (p < 0.01) and Z score (p < 0.01) than those in the partner sperm. There were no differences in the incidence of LGA, SGA, HBW, LBW, preterm birth, and the proportion of offspring gender between the two groups. CONCLUSION:This study found that the babies born in the donor sperm cycles have higher birth weights than the use of partner sperm from males with oligoasthenozoospermia in fresh embryo transfer cycles, but there were no significant differences in LGA, SGA, HBW, and LBW. The research results suggest that we should pay attention to the safety issues of donor sperm. It is necessary to conduct further research to determine whether the cause of the increased birth weight is the sperm freezing technology or the factors of the male donors who provided the sperm.
BACKGROUND:Little is known about the relative contribution of genetic and environmental factors on male reproductive function. OBJECTIVES:We studied in a cross-sectional setting, whether testicular function and genital size correlate in father-son pairs. The study included young men from a prospective Finnish-Danish Boy cohort study and their fathers. MATERIALS AND METHODS:We collected data on young men born between 1997 and 2002 at Turku University Hospital, Finland, and at the University Hospital of Copenhagen, Denmark. These young men were invited for an adult follow-up visit at 18-23 years together with their fathers. Altogether 38 Finnish and 79 Danish father-son pairs participated in the study. The study visits included analysis of a semen sample, measurement of serum reproductive hormones and genital size (testes, penis, anogenital distance [AGD]). Intraclass correlation coefficients (ICCs) were used to evaluate familial resemblance between fathers and sons. RESULTS:In the adjusted analyses, weak significant positive correlations between fathers and sons were observed in testicular volume measured by ultrasonography (ICC 0.30), concentrations of inhibin B (ICC 0.25), FSH (ICC 0.24), LH (ICC 0.22), and SHBG (ICC 0.26), sperm concentration (ICC 0.21), and anopenile distance (ICC 0.19). Penile width (ICC 0.23) showed significant father-son correlation, but it was of borderline statistical significance when pairs with cryptorchidism that had required surgical correction (n = 5) were excluded. Father-son correlation for testicular size based on orchidometer (ICC 0.16) was statistically significant only when excluding pairs with a history of cryptorchidism (ICC 0.18). CONCLUSION:In conclusion, while genetics contributes to reproductive health, the studied reproductive variables showed rather weak correlations between fathers and sons.
BACKGROUND:Erectile dysfunction (ED) is a prevalent male health disorder and a recognized sentinel marker for cardiovascular disease. Current diagnostic reliance on subjective questionnaires or invasive examinations limits early screening. AIM:We aimed to develop and validate a machine learning model based on routine blood test data to predict ED risk to facilitate its early clinical screening. METHODS:Data from 4116 men in the NHANES database (2001-2004) formed the training/internal validation sets. An independent external validation set comprised 489 clinical patients with NPTR-confirmed ED. From 49 initial demographic and blood-based indicators, feature selection via univariate logistic, multivariate logistic, and LASSO regression identified nine key predictors. Seven machine learning models were constructed, optimized via grid search with fivefold cross-validation, and evaluated using ROC analysis, calibration curves, and decision curve analysis (DCA). The optimal model was interpreted via SHAP. RESULTS:The random forest model achieved superior performance, with an external validation AUC of 0.934, accuracy of 0.918, and specificity of 0.986, significantly outperforming logistic regression (AUC = 0.743). SHAP analysis identified age, sex hormone-binding globulin (SHBG), testosterone, glucose, cholesterol, and creatinine as the most influential predictors. DISCUSSION:The study established a concise, nine-feature blood test panel and validated a high-performing predictive model in an independent clinical cohort, demonstrating significant clinical net benefit. Meanwhile, this model provides an economical, non-invasive, and scalable screening tool suitable for health check-ups, facilitating early ED identification. CONCLUSION:A machine learning model based on routine blood tests can effectively evaluate ED risk, offering a novel foundation for early screening and precision management.
BACKGROUND:Direct comparison of robot-assisted peritoneal flap (PF) to penile inversion (PI) vaginoplasty for gender affirming surgery is absent. OBJECTIVES:We sought to compare these two techniques to aid patient decision-making. MATERIALS AND METHODS:A retrospective case-control study of patients who underwent primary PI (N = 40) or PF (N = 40) vaginoplasty by one of two surgeons at a single center from 2020 to 2023 was conducted. RESULTS:PF yielded greater vaginal depth at 1 month (18 cm [13-20] vs. 15 cm [4.0-23], p < 0.01) and 6 months (18 cm [11-20] vs. 15 cm [2.5-19], p < 0.01) compared to PI, despite shorter preoperative phallic skin length. No rectal injuries occurred with PF versus three with PI. PF had less estimated blood loss than PI (p < 0.01). Length of stay, operative time, vaginal stenosis, vault granulation tissue, and transfusion rates were similar among groups. DISCUSSION:This early institutional experience demonstrated that primary PF yielded longer perioperative vaginal depth compared to PI with short-term stability at 6 months, despite shorter preoperative phallic skin length. Complication rates were similar among techniques. CONCLUSION:Both PF and PI are safe options for gender affirming vaginoplasty with low risk of complications that warrant ongoing use and future study.
BACKGROUND:Lower testosterone concentrations in older men are associated with poorer health outcomes. OBJECTIVE:We examined whether, on a background of lifestyle intervention, testosterone treatment modulates leucocyte telomere length, a postulated marker of biological ageing, in overweight men with impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetes (T2D). PARTICIPANTS AND METHODS:We conducted a secondary analysis of a randomised, placebo-controlled trial in 50- to 74-year-old men with waist circumference ≥ 95 cm and dysglycaemia (ACTRN12612000287831). All men received a background lifestyle program, and were randomised to 2 years treatment with intramuscular testosterone undecanoate (1000 mg) every 3 months or placebo. Leucocyte telomere length was assayed by multiplex quantitative polymerase chain reaction and expressed as relative telomere length (rTL), a ratio of telomeric DNA to β-globin, a single-copy control gene (T/S ratio). RESULTS:There were 720 participants, aged 60 ± 6 years (mean ± SD), 38% had BMI 30-34.99 kg/m2 and 44% ≥ 35 kg/m2. Mean rTL at baseline was 1.63 ± 0.27 in testosterone-treated men (N = 375) and 1.61 ± 0.28 in placebo-treated men (N = 345). At 2 years, mean rTL was 1.61 ± 0.28 and 1.58 ± 0.29, respectively. Change in rTL after 2 years treatment was -0.02 ± 0.15 in testosterone-treated and -0.03 ± 0.12 in placebo-treated men. Adjusting for baseline values there was no effect of testosterone treatment on rTL at 2 years (mean difference 0.01 [95% CI, -0.01 to 0.03], p = 0.24). Results were similar for rTL change at 2 years from baseline. CONCLUSIONS:There was no effect of testosterone treatment on telomere length in this group of men. Larger studies with longer treatment durations are merited.
BACKGROUND AND OBJECTIVES:While in vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI) bypasses abnormalities in sperm concentration, motility, and morphology, it still has a significant failure rate. We report our experience on the effect of varicocele embolization (VE) on couples with varicocele related primary male factor infertility in whom IVF/ICSI failed to result in a live birth (LB). MATERIAL AND METHODS:This single center retrospective cohort study documents 42 couples who had failed to have a LB after single or multiple IVF/ICSI cycles and in whom the male partner subsequently had left or bilateral varicoceles treated by transcatheter embolization. Other inclusion criteria were maternal age of 35 or less at the time of VE and at least 24 months follow up after embolization. The end point was LB by natural conception or by IVF-ICSI. Pre-procedure data was documented at the time of referral for varicocele embolization. Images of the procedures were reviewed, and post VE data was collected by telephone questionnaire from one of the partners. RESULTS:Prior to varicocele embolization, the 42 couples had undergone 151 oocyte retrievals (median 2, range 1-21) and 200 embryo transfers (median 3, range 1-26) with no LB. During a median follow up period of 54 months (range 25-111) following VE, there were 60 LB (65 children) amongst 36 of the 42 couples (86%). Thirty-four couples underwent a total of 119 oocyte retrievals and 149 embryo transfer procedures with 28 achieving 36 LB (41 children). Fifteen couples had 23 LB (23 children) from natural conceptions. One couple had an LB after intrauterine insemination. CONCLUSION:VE in this challenging patient population may treat varicocele associated sperm function problems not addressed by ICSI and could be beneficial before assisted reproductive techniques in varicocele related male factor infertility.
BACKGROUND:As the only approved oral medication for premature ejaculation (PE), dapoxetine faces a high discontinuation rate, primarily due to lower than expected efficacy. The impact of serum metabolites on PE treatment remains undetermined; therefore, we aimed to identify metabolites associated with dapoxetine efficacy. METHODS:Clinical data and blood samples were collected from 116 patients with lifelong PE before 8 weeks of dapoxetine treatment. Serum was analyzed by untargeted metabolomics profiling. Efficacy was assessed with the Clinical Global Impression of Change (CGIC) scale: scores ≥ 1 were classified as the effective group and ≤ 0 as the ineffective group. Differential serum metabolites between the two groups were identified using the Mann-Whitney U test. Enrichment analysis determined metabolic pathways significantly associated with efficacy. RESULTS:Compared to the ineffective group, indoleacrylic acid and (-)-riboflavin were significantly upregulated in the effective group, while 15-keto-13,14-dihydroprostaglandin A2, dienestrol, hippuric acid, and PC (16:0/16:0) were downregulated. The six metabolites showed a discriminatory ability of 0.646, 0.667, 0.633, 0.645, 0.651, and 0.635, respectively. Incorporating them significantly improved the accuracy of the model predicting efficacy (0.892 vs. 0.738, p = 0.001), suggesting that modulating these specific metabolites may be a novel strategy for PE treatment. Moreover, differential metabolic ions between the two groups were mostly enriched in the arachidonic acid metabolism pathway, indicating that this pathway may represent an additional route associated with dapoxetine response. CONCLUSIONS:This study revealed serum metabolites correlated with dapoxetine efficacy, paving the way for future research into novel therapeutic targets and personalized treatment strategies.
BACKGROUND:Varicocele (VC) grading has long relied on qualitative assessments of venous diameter and reflux signals, lacking standardization. OBJECTIVES:This study aimed to explore the value of spermatic vein reflux time (SVRT) as a quantitative indicator for VC grading and to enhance diagnostic accuracy using machine learning (ML) models. MATERIALS AND METHODS:A total of 3855 VC patients were enrolled, with color Doppler ultrasound used to measure SVRT, venous diameter, and testicular hemodynamic parameters (peak systolic velocity [PSV], end-diastolic velocity [EDV], and resistance index [RI]). VC grades were defined using an institutional clinical grading protocol based on a dual-index grading standard (venous diameter + SVRT). Statistical analyses included one-way ANOVA, Spearman correlation, and receiver operating characteristic (ROC) curve analysis. Three ML models (Random Forest, XGBoost, and Logistic Regression) were developed using clinical and ultrasound features; two XGBoost versions (with/without SVRT) were designed to rule out circular reasoning. SHAP analysis was applied to interpret feature contributions. RESULTS:SVRT increased significantly with VC grade (left side: Grade I, 2.85 ± 1.12 s; Grade II, 5.28 ± 0.92 s; Grade III, 7.61 ± 1.32 s; all p < 0.001) and showed significant correlations with venous diameter (r = 0.389-0.426) and reflux velocity (r = 0.478-0.512, all p < 0.001). ROC analysis demonstrated SVRT's diagnostic efficacy (AUC = 0.826-0.935) and derived grade-specific cutoffs (Grade I: 2.30 s; Grade II: 4.50 s; Grade III: 6.20 s). XGBoost (with SVRT) achieved the highest performance: overall accuracy 89.2% (95% CI: 0.881-0.903), Macro-F1 0.882, and AUC = 0.941 (95% CI: 0.925-0.957) for Grade III, outperforming the traditional SVRT-based ROC (AUC = 0.935, 95% CI: 0.922-0.948; DeLong test: Z = 2.13, p = 0.03) and the SVRT-excluded model (accuracy 80.4%, 95% CI: 0.783-0.825; Grade III AUC = 0.872, 95% CI: 0.844-0.899). SHAP analysis identified left SVRT (mean absolute SHAP value = 0.23), left venous diameter (0.19), and left EDV (0.15) as key predictive features. For SVRT regression, the Random Forest model showed high accuracy (R2 = 0.820, 95% CI: 0.802-0.838; RMSE = 0.76 ± 0.12 s; MAE = 0.58 ± 0.09 s), with minimal error for severe VC cases (SVRT > 6.2 s, MAE = 0.41 ± 0.07 s). DISCUSSION AND CONCLUSION:These findings support SVRT as a quantitative reference for VC severity grading, and the developed ML models may assist in standardizing VC grading by integrating multidimensional features, with the potential to reduce inter-observer variability and borderline case misclassification. However, the absence of clinical outcome data means these tools have been validated only against grading criteria, not against patient-relevant endpoints; prospective studies with outcome data are needed before clinical adoption.
