A new approach for hemodynamics of varicoceles: Perfusion patterns based on contrast- enhanced ultrasound

A new approach for hemodynamics of varicoceles: Perfusion patterns based on contrast- enhanced ultrasound | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A new approach for hemodynamics of varicoceles: Perfusion patterns based on contrast- enhanced ultrasound Penglin Zou, Gaoxiang Fan, Zheng Li, Yuchen Tao, Chao Jia, Hongmei Liang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5209676/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Jan, 2025 Read the published version in Basic and Clinical Andrology → Version 1 posted 11 You are reading this latest preprint version Abstract Background Hemodynamic alterations in the spermatic vein are implicated in infertility among patients with varicocele (VC). Contrast-enhanced ultrasound (CEUS), a powerful tool for hemodynamic analysis, remains unexplored for VC. This study aimed to demonstrate the feasibility of using CEUS to evaluate spermatic vein hemodynamics in patients with VC and establish a clear correlation between specific hemodynamic patterns and impaired semen parameters. This study included 165 patients with left-sided VC and 50 healthy volunteers. All participants underwent CEUS of the spermatic veins, along with maximum venous diameter and testicular volume measurements and serum sex hormone levels and routine semen analyses. The sperm DNA fragmentation index was measured in 146 patients with VC and 37 healthy controls. Results The analyses revealed four distinct perfusion patterns ofthe spermatic vein: steady flow, intermittent stasis, intermittent reflux, and filling defect. In healthy spermatic veins, the predominant perfusion patterns included steady flow and intermittent stasis. Spermatic veins with VC exhibited a significant increase in the intermittent reflux and filling defect patterns, with the proportion rising as the clinical grade increased. The four patterns were further grouped into the “steady flow & intermittent stasis” and “intermittent reflux & filling defect” patterns for logistic regression analyses; the intermittent reflux & filling defect pattern was revealed as an independent risk factor for impaired sperm concentration, total sperm counts, progressive motility, morphology, and DNA fragmentation index. Conclusions This study validated the feasibility of CEUS for assessing the hemodynamics of the spermatic vein and established the intermittent reflux & filling defect pattern as an independent predictor of impaired semen parameters. male infertility varicocele contrast-enhanced ultrasound hemodynamics Figures Figure 1 Figure 2 Figure 3 Background Varicocele (VC) is defined as an abnormal dilatation of the pampiniform plexus of veins in the spermatic cord. 1 – 5 VC causes venous stasis and retrograde flow, leading to several pathophysiological changes, such as scrotal hyperthermia, oxidative stress, and apoptosis. These changes contribute to ipsilateral progressive testicular atrophy, deterioration of sperm parameters, and sperm DNA damage. 6 – 8 Researchers have suggested that insights into the hemodynamic characteristics of the spermatic veins could aid in clinical decision-making for VC. 9 – 11 However, a reliable clinical method for assessing the hemodynamics of the spermatic veins is currently lacking. Venography, a technique for accurately assessing venous hemodynamics, is considered to be the most sensitive test for VC. 12 , 13 However, its invasive nature and ionizing radiation limit its use as an independent diagnostic method. 14 Ultrasound is the preferred imaging modality for VC, with Doppler ultrasound capable of detecting hemodynamic parameters such as reflux time. Numerous ultrasound-based diagnostic and grading systems have been proposed. 3 However, these systems are difficult to use, operator-dependent, obsolete, and contradictory. 10 The European Urological Association recommends basing surgical decisions on clinical staging rather than ultrasound, 10 possibly due to ultrasound’s inability to reflect the pathophysiological mechanisms of VC, specifically the hemodynamics, in the same manner as venography. Contrast-enhanced ultrasound (CEUS) is the first-line modality for evaluating vascular pathology. 15 , 16 The application of CEUS has been documented in various veins, 17 – 19 showcasing its potential in venous disease diagnostics. Although Caretta et al . 20 and Cao et al . 21 used CEUS to assess testicular microcirculation in patients with VC, no relevant research has reported the CEUS assessment of spermatic veins. In this study, CEUS was used to evaluate the spermatic veins of healthy volunteers and patients with VC. This study aimed to explore the feasibility of this technique for noninvasive detection of spermatic vein hemodynamics and identify new methods for the diagnosis and assessment of VC. Methods Study participants The study was conducted from October 2020 to July 2024. A total of 165 patients with left-side VC were included in the VC group. The inclusion criteria comprised left-sided VC based on physical examination following the Dubin and Amelar grading system. 9 The exclusion criteria included (a) right-sided or bilateral VC, (b) previous urogenital surgery, such as orchiopexy, hydrocelectomy, or inguinal hernia repair, (c) other conditions affecting fertility, such as orchitis, epididymitis, chronic prostatitis, and vas deferens obstruction, (d) severe oligospermia, cryptozoospermia, obstructive and non-obstructive azoospermia, and multiple morphological abnormalities of the sperm flagella, and (e) poor quality of ultrasound images. Additionally, 50 healthy volunteers were recruited as controls during the same period. The inclusion criteria for the control group were (a) the absence of VC detected during physical examination and (b) normal routine semen analysis parameters. The exclusion criteria for the control group were identical to those for the VC group. Ultrasound examination and image analysis The ultrasound device used was the Aplio 900 (Toshiba, Beijing, China), equipped with a linear probe frequency of 4.0–18.2 MHz, center frequency of 12 MHz, mechanical index of 0.07, and dynamic range of 50–55 dB. The contrast agent used was SonoVue microbubbles (Bracco, Milan, Italy). Participants were positioned supine with the perineum fully exposed at a temperature of 20–24℃. Initially, the three dimensions of the left testicle were measured using gray-scale ultrasound, and testicular volume (TV) was calculated using Lambert’s formula (TV = length × width × height × 0.71). 3 Subsequently, the maximum venous diameter (MVD) of the left spermatic vein was measured three times, and the average value was recorded. After that, the CEUS examination was performed using the same scanning plane. The contrast agent suspension (2.4 mL in total) was injected via the antecubital vein of the left arm, followed by 5 mL of saline solution. CEUS images were recorded for 3 min. The right side was examined similarly, with a 15-min interval between the two contrast injections, which allowed for the complete elimination of the contrast agent through respiration. CEUS images were analyzed frame-by-frame by two radiologists with over 10 years of experience in urogenital ultrasound. They evaluated the perfusion pattern of the spermatic vein and calculated the corresponding temporal parameters. Serum sex hormone levels, routine semen analysis, and DNA fragmentation index (DFI) testing Levels of serum sex hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (T), prolactin (PRL), and estradiol (E2), were measured using an electrochemiluminescence immunoassay (COBAS 6000; Roche Diagnostics GmbH, Basel, Switzerland). Routine semen analysis was performed according to the fifth edition of the World Health Organization Laboratory Manual for the Examination and Processing of Human Semen. 22 Normal semen parameters were defined based on the reference values provided in the manual: sperm concentration ≥ 15 × 10 6 /mL, total sperm counts ≥ 39 × 10 6 /mL, progressive motility ≥ 32%, and normal morphology ≥ 4%. Parameters below the reference values were considered impaired. The DFI test was performed on 146 participants in the VC group and 37 participants in the control group, as the other participants declined to undergo this examination. A sperm chromatin structure assay was used for DFI testing. The reference values for the DFI in our laboratory are: ≤15% indicates good DNA integrity, 15–30% indicates general DNA integrity, and ≥ 30% indicates poor DNA integrity. In this study, a DFI > 15% was defined as impaired DNA integrity. Statistical analysis Continuous variables are expressed as means ± standard deviations, and categorical variables are expressed as frequencies (percentages). The unweighted kappa statistic was used to evaluate the agreement between observers in the perfusion pattern. Intra-class correlation (ICC) under a two-way random model with absolute agreement was employed to evaluate the agreement of the observers in CEUS quantitative parameters. One-way analysis of variance was utilized to compare differences between quantitative data, and post-hoc multiple pairwise comparisons were performed using the Bonferroni test. Categorical variables were compared using the chi-square test. Univariate and multivariate analyses were performed using binary logistic regression. Statistical analyses were performed using SPSS version 25.0 (IBM, Armonk, NY, USA), and p < 0.05 was considered statistically significant. Results Baseline characteristics of the study population In this study, 50 healthy volunteers and 165 patients were enrolled. Among the patients, 71 were categorized into the VC grade 1 group, whereas 94 were categorized into the VC grades 2 & 3 group. The baseline characteristics of the three groups are presented in Table 1 . There were significant differences in the left MVD, total sperm counts, progressive motility, and DFI among the three groups (all p <0.05). As the clinical grade increased, the left MVD (1.8±0.4 mm, 2.5±0.2 mm, and 3.2±0.6 mm, respectively) and DFI (14.9±6.0%, 19.7±12.7%, and 21.5±13.1%, respectively) showed a gradual increase. The total sperm counts (263.6±219.0×10 6 , 199.0±143.7×10 6 , and 166.2±143.1×10 6 , respectively) and progressive motility (50.0±11.4%, 44.0±16.1%, and 40.5±15.4%, respectively) gradually decreased. Post-hoc multiple pairwise comparisons are depicted in Figure 1 . The left MVDs of all three groups were statistically different in pairwise comparisons (all p <0.001). The total sperm counts, progressive motility, and DFI of the VC grades 2 & 3 group were significantly higher than those of the control group (all p 0.05). CEUS characteristics of the spermatic veins In this study, CEUS was performed on the bilateral spermatic veins of 215 participants, and all were completed safely with no significant adverse events. CEUS images are shown in Figure 2 . Based on the dynamics of microbubbles, the perfusion patterns of the spermatic vein can be classified into the following four types: Steady flow: The microbubbles flow forward steadily in the spermatic vein without obvious pause or reflux. An additional movie file shows this in more detail (see Additional file 1). Intermittent stasis: The microbubbles flow forward with intermittent transient pauses (see Additional file 2). Intermittent reflux: The microbubbles flow forward with intermittent transient reflux, after which the flow returns to the forward direction (see Additional file 3). Filling defect: No contrast agent was found to enter the spermatic vein during the examination (see Additional file 4). For the perfusion patterns of the control group, VC grade 1, and VC grades 2 & 3 groups, the kappa coefficients of the two observers were 0.809, 0.819, and 0.839, respectively, indicating almost perfect agreement. For the intermittent stasis pattern, the pause times assessed by the two observers were 1.3±0.5 s (range, 0.4–2.1 s) and 1.4±0.4 s (range, 0.4–2.7 s), respectively, with an ICC value of 0.387, indicating poor agreement. For the intermittent reflux pattern, the reflux times assessed by the two observers were 1.2±0.6 s (range, 0.4–2.1 s) and 1.3±0.5 s (range, 0.4–2.5 s), respectively, with an ICC value of 0.634, indicating moderate agreement. Distribution of perfusion patterns The distribution of perfusion patterns in the bilateral spermatic veins of the study population is illustrated in Figure 3 . The chi-square test results showed no significant differences in the distribution of perfusion patterns of the spermatic veins without VC, including the bilateral sides of the control group, the right side of the VC grade 1 group, and the right side of the VC grade 2 & 3 group. However, pairwise comparison with the left side of the VC grade 1 group and the left side of the VC grades 2 & 3 group showed significant differences (both p <0.05). The proportion of cases with intermittent reflux pattern was greater in the spermatic veins with higher clinical grades than in those with low clinical grades (VC grades 2 & 3: 32% vs. VC grade 1: 23% vs. no VC: 0–4%), and the proportion of cases with filling defect pattern was greater than in those with low clinical grade (VC grades 2 & 3: 12% vs. VC grade 1: 7% vs. no VC: 0–1%). Baseline characteristics of patients with VC with different perfusion patterns Based on the perfusion pattern of the left spermatic vein, the VC group was divided into four subgroups with baseline characteristics presented in Table 2 . A significant difference was observed in progressive motility among the four groups ( p 0.05), and the rest of the pairwise comparisons were statistically different (all p <0.05). Association of perfusion patterns with impaired semen parameters Based on the results stated above, the perfusion patterns of the left spermatic vein were dichotomized into “steady flow & intermittent stasis” and “intermittent reflux & filling defect,” and logistic regression analysis was performed with other baseline parameters to identify risk factors for impaired semen parameters. Other baseline parameters included age, body mass index (BMI), left MVD, left TV, FSH, LH, T, PRL, and E2. Univariate analysis revealed that the intermittent reflux & filling defect pattern was a risk factor for impaired sperm concentration, total sperm counts, progressive motility, morphology, and DFI (all p <0.05, Table 3 ). The sensitivity of the intermittent reflux & filling defect pattern in predicting impaired sperm concentration was 66.7%, specificity was 64.7%, negative predictive value (NPV) was 96.1%, and positive predictive value (PPV) was 12.9%. The sensitivity of the intermittent reflux & filling defect pattern in predicting impaired total sperm counts was 73.3%, the specificity was 66.0%, the NPV was 96.1%, and the PPV was 17.7%. The sensitivity of the intermittent reflux & filling defect pattern in predicting impaired progressive motility was 79.5%, the specificity was 77.7%, the NPV was 91.3%, and the PPV was 56.5%. The sensitivity of the intermittent reflux & filling defect pattern in predicting impaired morphology was 72.4%, the specificity was 69.9%, the NPV was 92.2%, and the PPV was 33.9%. The sensitivity of the intermittent reflux & filling defect pattern in predicting an impaired DFI was 47.1%, the specificity was 74.6%, the NPV was 48.9%, and the PPV was 73.2%. Among the baseline parameters, the left MVD was statistically correlated with impaired total sperm counts (OR=2.246, 95% CI=1.046–4.820, p =0.038). Multivariate analyses were performed to estimate the predictive value of the intermittent reflux & filling defect pattern for impaired semen parameters. After adjusting for all the above baseline factors, the association of the intermittent reflux & filling defect pattern with impaired sperm concentration, impaired total sperm counts, impaired progressive motility, impaired morphology, and an impaired DFI was sustained ( Table 3 ). The associations between impaired semen parameters with baseline parameters were not statistically significant (data not shown). Discussion This study introduces a novel, noninvasive approach to assess the hemodynamics of spermatic veins. We identified four distinct perfusion patterns of the spermatic vein: steady flow, intermittent stasis, intermittent reflux, and filling defect. Healthy spermatic veins predominantly exhibit steady flow and intermittent stasis patterns, and the other two patterns are more prevalent in spermatic veins with VC. Additionally, after further categorization for logistic regression analyses, the intermittent reflux & filling defect pattern was revealed as an independent predictor of impaired semen parameters. Dysfunction of the spermatic vein is a significant contributor to VC-induced semen parameters impairment. Exploring the hemodynamics of VC is crucial to improving the clinical diagnosis and treatment of VC. 9–11 However, it is challenging to study the hemodynamics of spermatic veins because of the complex and diverse structure of the pampiniform plexus. This study offers CEUS as a new method to assess the hemodynamics of the spermatic vein. The principle of this method is similar to that of venography, 12,13 as it records and analyzes the spatiotemporal characteristics of the contrast agent in the blood vessel to obtain hemodynamic information. The CEUS technique utilizes microbubbles — small, inert gas-filled spheres encapsulated in a phospholipid shell with a size of 2–8 μm — to enhance image clarity and contrast. Microbubbles possess several key characteristics. 15 The safety profile of microbubbles is well established, with no evidence of cardiac, hepatic, thyroid, or renal toxicity, and no obvious adverse reactions occurred during this study. Microbubbles can oscillate non-linearly in the diagnostic ultrasound field, generate harmonic frequencies, and produce stable and clear contrast images. Additionally, since microbubbles are similar in size to red blood cells, they remain strictly intravascular and do not pass through the vascular endothelium, unlike contrast media in CT and MRI, which may affect image quality. Finally, microbubbles have good blood traceability, meaning their dynamic characteristics align closely with blood flow. These advantages ensure the safety and accuracy of CEUS, making it the first-line modality for evaluating vascular lesions. 15–19 CEUS offers unique advantages over venography and Doppler ultrasound, which are classical methods for detecting hemodynamics. CEUS is noninvasive and does not produce ionizing radiation, facilitating a greater possibility of clinical application than venography. Although venography has been used to study the perfusion pattern of VC, 12,13 it only shows the blood reflux from the testicular vein to the renal vein at a macroscopic scale. CEUS, on the other hand, provides detailed information on the blood flow in the spermatic vein around the testis and epididymis, which is theoretically more directly related to testicular function. Doppler ultrasound is currently the first-line method to detect the blood flow of the spermatic vein. The commonly used parameters are reflux time, 23 maximum reflux velocity, 24 and reflux pattern 9 – 11 during the Valsalva maneuver. However, owing to challenges in fully calibrating the incidence angle of ultrasound and variations in the participants’ understanding and execution of the Valsalva maneuver, Doppler ultrasound systems are associated with operational difficulties, significant inter-operator differences, and contradictory results. 10 CEUS can make up for the inherent limitations of Doppler ultrasound, including a lower signal-to-noise ratio, lower sensitivity for slow flow, and technical artifacts, thus significantly improving blood flow visualization. 15 Four perfusion patterns of the spermatic vein were summarized in this study. The flow of blood in the spermatic vein, including advancement, pause, and reflux, is mainly affected by the pressure gradient and venous valve function. 25 The venous pressure of the normal spermatic vein is higher than that of the left renal vein, allowing blood to return to the left renal vein when blood flow exhibits a steady flow pattern. Peripheral venous pressure fluctuates within the normal range as influenced by physiological activities such as heartbeat and respiration. 26 When the peripheral venous pressure is at a high value, the left renal vein pressure exceeds the spermatic vein pressure, and the blood in the spermatic vein tends to reflux. If the valve is functioning normally or is minimally damaged, it can block reflux and pause blood flow, at which point perfusion exhibits an intermittent stasis pattern. If the degree of valve function damage is high and the blood breaks through the valve and backflows, the perfusion pattern shows intermittent reflux. After a brief pause or reflux, the left renal vein pressure falls back below the spermatic vein pressure, and blood resumes an antegrade flow. A small portion of testicular blood returns via the cremasteric and differential veins, which have small anastomotic branches with the spermatic vein and are normally not opened. 11 When the anastomotic branch opens pathologically, blood will enter the cremasteric and differential veins through the anastomotic branch. Currently, although the spermatic vein proximal to the anastomotic branch is markedly dilated, no contrast agent can be observed, resulting in a filling defect pattern. The above pathophysiological mechanisms may explain the distribution of perfusion patterns in this study: intermittent reflux and filling defect patterns were almost exclusively found in the diseased spermatic vein, and the proportion increased with an increase in the clinical grade. In this study, we analyzed the correlation between the perfusion pattern of the left spermatic vein and semen parameters in the VC group. The progressive motility of the intermittent reflux group (33.1±16.1%) and filling defect group (31.8±14.2%) was significantly lower than that of the steady flow group (48.8±12.0%) and intermittent stasis group (45.2±14.7%), but there were no significant differences in semen parameters between the steady flow group and intermittent stasis group or between the intermittent reflux group and filling defect group. Theoretically, the lesion severity in the filling defect group was higher than that in the intermittent reflux group, 11 but the difference in semen parameters between the two groups was not significant, which may be attributable to the small sample size of this study. For this reason, logistic regression analysis was performed after dichotomizing the perfusion patterns. The intermittent reflux & filling defect pattern was an independent risk factor for impaired semen parameters with high sensitivity (66.7%, 73.3%, 79.5%, and 72.4%, respectively) and specificity (64.7%, 66.0%, 77.7%, and 69.9%, respectively) in predicting impaired sperm concentration, total sperm counts, progressive motility, and morphology. Conversely, it had high specificity (74.6%) but low sensitivity (47.1%) in predicting an impaired DFI. These findings are consistent with the pathophysiological mechanisms of spermatogenic dysfunction previously described. 4 – 6 This study has the following major limitations. First, the sample size for the filling defect pattern was small; therefore, we simplified the perfusion pattern to a binary category in the logistic regression analysis. Second, this study was performed at rest without the Valsalva maneuver because the subjectivity of the Valsalva maneuver can reduce accuracy. Moreover, Cavallini et al . 10 found that continuous hemodynamic abnormalities can affect spermatogenesis, whereas temporary reflux (mainly during the Valsalva maneuver) has little effect on testicular function. Finally, further analysis of quantitative parameters was not performed due to significant inter-observer variability in reflux and pause times. The current clinical application of CEUS mainly relies on subjective and qualitative evaluation and interpretation by the physician performing the examination 15 ; thus, the results of this study still have potential value for clinical application. Conclusions This study revealed that the perfusion patterns of the spermatic vein can be classified into four types. Further categorization for logistic regression identified the intermittent reflux & filling defect pattern as an independent risk factor for impaired sperm concentration, total sperm counts, progressive motility, morphology, and DFI. These results demonstrate that CEUS is a reliable and non-invasive approach for evaluating the hemodynamics of the spermatic veins. In future studies, we will use CEUS to comprehensively and systematically explore various aspects of VC, including its natural course, surgical indications, and postoperative outcomes. Abbreviations Varicocele (VC); Contrast-enhanced ultrasound (CEUS); DNA fragmentation index (DFI); Intra-class correlation (ICC); Follicle-stimulating hormone (FSH); Luteinizing hormone (LH); Total testosterone (T); Prolactin (PRL); Estradiol (E2). Declarations Ethics approval and consent to participate The present study protocol was reviewed and approved by the Institutional Ethical Review Committee of Shanghai General Hospital (ID: 2020KY139 and [2022]115). All patients provided written informed consent. The trial was registered with the Chinese Clinical Trial Registry (ID: ChiCTR2000036241). Consent of publication Not applicable. Availability of data and materials Not applicable. Competing interests The authors declare that they have no competing interests. Funding This work was supported by the National Key Research and Development Program of China (No. 2022YFC2702700) and the Clinical Research Plan of SHDC (No. SHDC2020CR2071B). Authors’ contributions PLZ drafted the manuscript. PLZ and GXF analyzed the data. PLZ, GXF, YCT, CJ, and HML performed the clinical trial. RHT and ZL were in charge of technical support. QSS, JLH, and RW were in charge of study design and supervision. All authors read and approved the final manuscript. Acknowledgments Not applicable. References Sasson DC, Kashanian JA. Varicoceles. JAMA. 2020;323:2210. Fallara G, Capogrosso P, Pozzi E, Belladelli F, Corsini C, Boeri L, et al. The effect of varicocele treatment on fertility in adults: a systematic review and meta-analysis of published prospective trials. Eur Urol Focus. 2023;9:154–61. 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Contrast-enhanced ultrasound for the characterization of portal vein thrombosis vs tumor-in-vein in HCC patients: a systematic review and meta-analysis. Eur Radiol. 2020;30:2871–80. Li Q, Wang Z, Ma X, Tang J, Luo Y. Diagnostic accuracy of contrast-enhanced ultrasound for detecting bland thrombus from inferior vena cava tumor thrombus in patients with renal cell carcinoma. Int Braz J Urol. 2020;46:92–100. Caretta N, Palego P, Schipilliti M, Torino M, Ferlin A, Pati M, et al. Testicular contrast harmonic imaging to evaluate intratesticular perfusion alterations in patients with varicocele. J Urol. 2010;183:263–9. Cao W, Han H, Guan X, Lyu C, Zhou Q, Tian L, et al. Elastography and contrast-enhanced ultrasound to assess the effect of varicocelectomy: a case-controlled study. Andrologia. 2022;54:e14586. World Health Organization. WHO laboratory manual for the examination and processing of human semen, 5th ed. Geneva: WHO Press; 2010. Patil V, Shetty SM, Das SK. Redefining the criteria for grading varicoceles based on reflux times: a clinicoradiological correlation. Ultrasound Q . 2016;32:82–5. Van Batavia JP, Badalato G, Fast A, Glassberg KI. Adolescent varicocele-is the 20/38 harbinger a durable predictor of testicular asymmetry? J Urol. 2013;189:1897–901. Recek C. The venous reflux. Angiology. 2004;55:541–8. Chang D, Leisy PJ, Sobey JH, Reddy SK, Brophy C, Alvis BD, et al. Physiology and clinical utility of the peripheral venous waveform. JRSM Cardiovasc Dis. 2020;9:2048004020970038. Tables Table 1. The baseline characteristics of the study population Control group VC group p Grade 1 Grade 2&3 Number 50 71 94 – Age (years) 30.5±4.9 (21–44) 32.1±4.2 (24–43) 31.7±5.8 (18–57) 0.219 BMI (kg/m 2 ) 24.5±4.3 (18.0–32.7) 25.4±3.6 (18.3–32.3) 25.7±3.6 (18.3–36.1) 0.156 Gray-scale ultrasound parameters Left MVD (mm) 1.8±0.4 (0.8–2.2) 2.5±0.2 (2.0–2.9) 3.2±0.6 (2.4–5.4) <0.001 * Right MVD (mm) 1.6±0.4 (0.8–2.5) 1.5±0.4 (0.7–2.2) 1.5±0.3 (0.8–2.2) 0.081 Left TV (mL) 15.2±4.4 (8.4–27.7) 13.5±4.3 (8.2–29.0) 14.0±3.9 (8.2–23.6) 0.065 Right TV (mL) 16.2±4.0 (9.2–24.5) 14.5±4.4 (8.0–29.9) 15.6±4.2 (8.1–25.1) 0.084 Reproductive hormone level FSH (mIU/mL) 4.4±1.6 (1.5–9.1) 5.2±3.0 (1.3–17.1) 4.5±1.9 (1.9–13.2) 0.077 LH (mIU/mL) 4.3±1.5 (2.2–8.7) 4.3±1.8 (1.6–8.1) 4.4±1.8 (1.3–10.5) 0.909 T (ng/mL) 5.2±2.4 (2.5–12.4) 5.0±2.6 (1.4–14.6) 5.3±2.5 (1.2–14.3) 0.667 PRL (ng/mL) 12.0±6.7 (1.1–45.1) 11.6±9.1 (2.1–47.7) 11.9±9.4 (2.1–75.8) 0.964 E2 (Pmol/L) 148.3±82.6 (58.5–368.7) 130.1±65.4 (39.4–304.8) 148.2±88.0 (34.7–384.7) 0.297 Semen parameters Volume (mL) 3.0±1.1 (0.7–6.0) 2.8±1.1 (0.8–7.0) 2.7±1.1 (0.2–7.0) 0.174 Concentration (×10 6 /mL) 80.2±51.8 (16.3–219.2) 72.4±45.8 (8.0–216.0) 62.2±45.3 (7.0–214.1) 0.080 Total sperm counts (×10 6 ) 263.6±219.0 (45.0–824.0) 199.0±143.7 (14.0–618.0) 166.2±143.1 (10.8–748.4) 0.004 * Progressive motility (%) 50.0±11.4 (32.0–86.0) 44.0±16.1 (11.0–75.1) 40.5±15.4 (13.0–70.0) 0.002 * Normal morphology (%) 7.8±3.0 (4.0–16.0) 7.4±4.4 (2.0–25.0) 6.7±4.1 (1.0–21.0) 0.233 DFI (%) a 14.9±6.0 (4.4–24.7) 19.7±12.7 (2.2–54.2) 21.5±13.1 (3.4–67.0) 0.022 * BMI: body mass index; MVD: maximum venous diameter; TV: testicular volume; FSH: follicle-stimulating hormone; LH: luteinizing hormone; T: total testosterone; PRL: prolactin; E2: estradiol; DFI: DNA fragmentation index. a The number of DFI tests performed in the three groups was 37, 66, and 80, respectively. * Asterisks indicate significant differences ( p <0.05). Table 2. The baseline characteristics of VC groups with different perfusion patterns of the left spermatic vein Steady flow Intermittent stasis Intermittent reflux Filling defect p Number 68 35 46 16 – Age (years) 31.1±4.0 (21–41) 32.0±5.4 (18–44) 33.0±6.4 (24–57) 31.6±5.1 (22–41) 0.293 BMI (kg/m 2 ) 26.0±3.3 (18.3–32.3) 25.7±4.1 (18.5–36.1) 25.3±3.7 (18.3–32.2) 24.2±3.5 (19.9–32.2) 0.265 Gray-scale ultrasound parameters Left MVD (mm) 2.8±0.6 (2.3–5.4) 2.9±0.5 (2.3–4.7) 2.9±0.6 (2.0–4.8) 2.9±0.5 (2.4–4.3) 0.737 Right MVD (mm) 1.4±0.4 (0.7–2.2) 1.5±0.4 (0.9–2.2) 1.4±0.3 (0.8–2.2) 1.6±0.4 (1.0–2.2) 0.129 Left TV (mL) 14.0±4.3 (8.2–29.0) 13.5±3.9 (8.3–22.2) 13.1±3.7 (8.2–23.6) 15.4±3.9 (9.1–23.2) 0.250 Right TV (mL) 15.5±4.6 (8.1–29.9) 14.4±3.9 (8.2–22.0) 14.7±4.1 (8.0–24.6) 16.7±4.0 (12.7–25.0) 0.261 Reproductive hormone level FSH (mIU/mL) 5.1±2.9 (1.6–17.1) 4.6±1.9 (1.5–9.3) 4.7±2.4 (1.3–13.2) 4.4±1.7 (1.8–7.7) 0.661 LH (mIU/mL) 4.5±2.0 (1.3–9.9) 4.2±1.8 (2.3–10.5) 4.4±1.6 (1.9–8.1) 4.0±1.4 (2.1–7.2) 0.755 T (ng/mL) 5.1±2.6 (1.6–14.3) 5.2±2.6 (1.4–12.3) 5.3±2.6 (2.0–14.6) 4.9±2.5 (1.2–11.0) 0.919 PRL (ng/mL) 12.5±11.1 (2.1–75.8) 13.4±10.0 (2.8–43.6) 9.6±5.8 (2.1–27.2) 11.9±6.0 (2.9–25.6) 0.271 E2 (Pmol/L) 133.8±76.1 (34.7–321.5) 143.8±78.7 (44.6–371.6) 156.6±86.2 (48.6–384.7) 115.0±70.3 (48.2–248.3) 0.253 Semen parameters Volume (mL) 2.7±1.1 (1.1–7.0) 2.5±0.9 (0.8–4.2) 2.9±1.4 (0.2–7.0) 2.7±0.9 (1.3–4.4) 0.492 Concentration (×10 6 /mL) 72.6±45.6 (10.0–216.0) 67.1±48.8 (8.0–209.1) 57.2±44.8 (7.0–213.5) 67.0±40.4 (9.0–149.8) 0.377 Total sperm counts (×10 6 ) 190.7±131.1 (15.4–642.3) 170.4±147.5 (20.0–748.4) 165.1±158.0 (10.8–566.4) 201.3±152.9 (11.7–485.8) 0.714 Progressive motility (%) 48.8±12.0 (20.0–74.5) 45.2±14.7 (15.0–75.1) 33.1±16.1 (11.0–65.3) 31.8±14.2 (13.0–61.3) <0.001 * Normal morphology (%) 7.6±4.0 (3.0–25.0) 7.9±4.8 (2.0–21.0) 5.7±3.8 (1.0–18.0) 6.2±4.5 (2.0–20.0) 0.059 DFI (%) a 18.7±12.0 (2.6–48.1) 20.4±15.3 (2.2–67.0) 23.8±13.4 (3.4–52.6) 20.7±7.8 (5.7–40.9) 0.288 BMI: body mass index; MVD: maximum venous diameter; TV: testicular volume; FSH: follicle-stimulating hormone; LH: luteinizing hormone; T: total testosterone; PRL: prolactin; E2: estradiol; DFI: DNA fragmentation index. a The number of DFI tests performed in the four groups was 58, 32, 41, and 15, respectively. * Asterisks indicate significant differences ( p <0.05). Table 3. Binary logistic regression analysis to confirm reflux and filling defect patterns as independent risk factors for impaired semen parameters (n=165) Without adjustment With adjustment a OR (95% CI) p OR (95% CI) p Impaired sperm concentration 3.667 (1.056–12.737) 0.041 * 3.998 (1.059–15.095) 0.041 * Impaired total sperm counts 5.338 (1.619–17.604) 0.006 * 5.443 (1.493–19.840) 0.010 * Impaired progressive motility 13.539 (5.796–31.626) <0.001 * 14.694 (5.910–36.534) <0.001 * Impaired morphology 6.082 (2.491–14.854) <0.001 * 7.807 (2.906–20.975) <0.001 * Impaired DFI b 2.614 (1.271–5.380) 0.009 * 2.893 (1.336–6.266) 0.007 * CI: confidence interval; DFI: DNA fragmentation index. a Adjusted for age, BMI, left MVD, left TV, FSH, LH, T, PRL, and E2. b The number of DFI tests performed was 146. Additional Declarations No competing interests reported. Supplementary Files Additionalfile1.mp4 Additional file 1. Example of the steady flow pattern Additionalfile2.mp4 Additional file 2. Example of the intermittent stasis pattern Additionalfile3.mp4 Additional file 3. Example of the intermittent reflux pattern Additionalfile4.mp4 Additional file 4. Example of the filling defect pattern Cite Share Download PDF Status: Published Journal Publication published 23 Jan, 2025 Read the published version in Basic and Clinical Andrology → Version 1 posted Editorial decision: Revision requested 25 Nov, 2024 Reviews received at journal 24 Nov, 2024 Reviews received at journal 17 Nov, 2024 Reviewers agreed at journal 11 Nov, 2024 Reviews received at journal 06 Nov, 2024 Reviewers agreed at journal 04 Nov, 2024 Reviewers agreed at journal 21 Oct, 2024 Reviewers invited by journal 08 Oct, 2024 Editor assigned by journal 07 Oct, 2024 Submission checks completed at journal 07 Oct, 2024 First submitted to journal 05 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5209676","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":382311016,"identity":"c7f8aa18-1ac8-44be-8187-a7c13c558d21","order_by":0,"name":"Penglin Zou","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Penglin","middleName":"","lastName":"Zou","suffix":""},{"id":382311018,"identity":"12dfed6c-eacd-4a10-b0a3-8e59d1555a35","order_by":1,"name":"Gaoxiang Fan","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Gaoxiang","middleName":"","lastName":"Fan","suffix":""},{"id":382311026,"identity":"965f2463-3c57-4e12-b677-20875ceaefbf","order_by":2,"name":"Zheng Li","email":"","orcid":"","institution":"Urologic Medical Center, Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Zheng","middleName":"","lastName":"Li","suffix":""},{"id":382311028,"identity":"3d1c982f-ca3f-47ae-860b-4c193bbbf5f0","order_by":3,"name":"Yuchen Tao","email":"","orcid":"","institution":"Huadong Hospital of Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Yuchen","middleName":"","lastName":"Tao","suffix":""},{"id":382311030,"identity":"28bb69b0-1951-4e0b-bfab-4f80407b1daf","order_by":4,"name":"Chao Jia","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chao","middleName":"","lastName":"Jia","suffix":""},{"id":382311031,"identity":"633caac3-ac1b-4241-a311-57cbc3e33e56","order_by":5,"name":"Hongmei Liang","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hongmei","middleName":"","lastName":"Liang","suffix":""},{"id":382311032,"identity":"dbd3b765-591c-46c8-9702-93c5d6a14e47","order_by":6,"name":"Ruhui Tian","email":"","orcid":"","institution":"Urologic Medical Center, Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Ruhui","middleName":"","lastName":"Tian","suffix":""},{"id":382311033,"identity":"49fa5acf-e0e1-40a3-9d64-275540461f5a","order_by":7,"name":"Qiusheng Shi","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Qiusheng","middleName":"","lastName":"Shi","suffix":""},{"id":382311034,"identity":"89562243-b460-407e-807d-8a766606c435","order_by":8,"name":"Jianlin Hu","email":"","orcid":"","institution":"Urologic Medical Center, Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Jianlin","middleName":"","lastName":"Hu","suffix":""},{"id":382311035,"identity":"c3e97430-6dc8-4d37-8c6d-a4cffc6fcf89","order_by":9,"name":"Rong Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIiWNgGAWjYPCC/zxszMwHDnz4QbwWZhk+drbEgzN7SNBiI8fPY3yYg40ItQY3ch8+LvjFBnQYz4fDDDwM8vxiBwhpSTc2ntnHA9TCu+FwgQWD4czZCfi1mN1IY5Pm7ZGAaJnBw5BgcJs4LQYghz04zMNGrBaeHwkgLQzEabE/84zZmLfhAFALmwEwkCUI+0WyPY3xMc+fA/by/Ycff/jww0aeX5qAFjBgbIMzJYhQDgZ/iFU4CkbBKBgFIxIAACHkPDbjvWePAAAAAElFTkSuQmCC","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Rong","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2024-10-05 15:53:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5209676/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5209676/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12610-024-00249-8","type":"published","date":"2025-01-23T15:57:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71478630,"identity":"6c5a2d2a-7915-4c1e-a62e-3fa7c23094b2","added_by":"auto","created_at":"2024-12-16 05:36:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":209309,"visible":true,"origin":"","legend":"\u003cp\u003eBonferroni’s post-hoc test for the left MVD, total sperm counts, progressive motility, and DFI\u003c/p\u003e\n\u003cp\u003eMVD, maximum venous diameter; DFI, DNA fragmentation index\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5209676/v1/a8a0c68988dd1c03de8ed609.png"},{"id":71478637,"identity":"620fadd4-4ced-47d3-9b29-3d93fb692378","added_by":"auto","created_at":"2024-12-16 05:37:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3865969,"visible":true,"origin":"","legend":"\u003cp\u003eExample of CEUS images. (\u003cstrong\u003ea\u003c/strong\u003e) No microbubbles appeared in the spermatic vein before contrast injection. (\u003cstrong\u003eb\u003c/strong\u003e) Microbubbles began to enter the spermatic vein after contrast injection. The number of microbubbles entering the spermatic vein gradually increased to the peak (\u003cstrong\u003ec\u003c/strong\u003e), then gradually decreased (\u003cstrong\u003ed\u003c/strong\u003e), and finally disappeared. The red circles and red arrows indicate the spermatic vein.\u003c/p\u003e\n\u003cp\u003eCEUS, Contrast-enhanced ultrasound\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5209676/v1/5dd5d0c11ca13da87728bf82.png"},{"id":71481166,"identity":"3831db3d-3223-463f-8272-cf4ed26008a0","added_by":"auto","created_at":"2024-12-16 06:00:59","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":311137,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of perfusion patterns in the study population\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5209676/v1/a5cae2bf89e7cfba94641dda.png"},{"id":74858580,"identity":"8a296984-bd90-445c-ae2f-01b93bb3e1b7","added_by":"auto","created_at":"2025-01-27 16:11:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5170810,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5209676/v1/b71b1fbf-283a-46f7-969c-8e787678fef9.pdf"},{"id":71478632,"identity":"36f42592-5acc-49a9-89b2-1a896fd0215b","added_by":"auto","created_at":"2024-12-16 05:36:59","extension":"mp4","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":3046189,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 1. Example of the steady flow pattern\u003c/p\u003e","description":"","filename":"Additionalfile1.mp4","url":"https://assets-eu.researchsquare.com/files/rs-5209676/v1/d0568f05185630b9201bf4f8.mp4"},{"id":71478635,"identity":"6356d0ea-6766-4186-9bee-60698dad7c88","added_by":"auto","created_at":"2024-12-16 05:37:00","extension":"mp4","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":3888270,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 2. Example of the intermittent stasis pattern\u003c/p\u003e","description":"","filename":"Additionalfile2.mp4","url":"https://assets-eu.researchsquare.com/files/rs-5209676/v1/4ec8d4311416993d34faa6cb.mp4"},{"id":71478636,"identity":"315e8793-1423-4947-8499-ceb6d2dbd9ca","added_by":"auto","created_at":"2024-12-16 05:37:00","extension":"mp4","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":3781847,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 3. Example of the intermittent reflux pattern\u003c/p\u003e","description":"","filename":"Additionalfile3.mp4","url":"https://assets-eu.researchsquare.com/files/rs-5209676/v1/37679e1dc4244b139a3b8100.mp4"},{"id":71478634,"identity":"744cbc10-141f-4b3d-8967-09d918ee68b5","added_by":"auto","created_at":"2024-12-16 05:36:59","extension":"mp4","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":2518261,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 4. Example of the filling defect pattern\u003c/p\u003e","description":"","filename":"Additionalfile4.mp4","url":"https://assets-eu.researchsquare.com/files/rs-5209676/v1/e3b24f89a528a130423e2158.mp4"}],"financialInterests":"No competing interests reported.","formattedTitle":"A new approach for hemodynamics of varicoceles: Perfusion patterns based on contrast- enhanced ultrasound","fulltext":[{"header":"Background","content":"\u003cp\u003eVaricocele (VC) is defined as an abnormal dilatation of the pampiniform plexus of veins in the spermatic cord.\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e VC causes venous stasis and retrograde flow, leading to several pathophysiological changes, such as scrotal hyperthermia, oxidative stress, and apoptosis. These changes contribute to ipsilateral progressive testicular atrophy, deterioration of sperm parameters, and sperm DNA damage.\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Researchers have suggested that insights into the hemodynamic characteristics of the spermatic veins could aid in clinical decision-making for VC.\u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e However, a reliable clinical method for assessing the hemodynamics of the spermatic veins is currently lacking.\u003c/p\u003e \u003cp\u003eVenography, a technique for accurately assessing venous hemodynamics, is considered to be the most sensitive test for VC.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e However, its invasive nature and ionizing radiation limit its use as an independent diagnostic method.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eUltrasound is the preferred imaging modality for VC, with Doppler ultrasound capable of detecting hemodynamic parameters such as reflux time. Numerous ultrasound-based diagnostic and grading systems have been proposed.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e However, these systems are difficult to use, operator-dependent, obsolete, and contradictory.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e The European Urological Association recommends basing surgical decisions on clinical staging rather than ultrasound,\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e possibly due to ultrasound\u0026rsquo;s inability to reflect the pathophysiological mechanisms of VC, specifically the hemodynamics, in the same manner as venography.\u003c/p\u003e \u003cp\u003eContrast-enhanced ultrasound (CEUS) is the first-line modality for evaluating vascular pathology.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e The application of CEUS has been documented in various veins,\u003csup\u003e\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e showcasing its potential in venous disease diagnostics. Although Caretta \u003cem\u003eet al\u003c/em\u003e.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e and Cao \u003cem\u003eet al\u003c/em\u003e.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e used CEUS to assess testicular microcirculation in patients with VC, no relevant research has reported the CEUS assessment of spermatic veins.\u003c/p\u003e \u003cp\u003eIn this study, CEUS was used to evaluate the spermatic veins of healthy volunteers and patients with VC. This study aimed to explore the feasibility of this technique for noninvasive detection of spermatic vein hemodynamics and identify new methods for the diagnosis and assessment of VC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy participants\u003c/h2\u003e \u003cp\u003eThe study was conducted from October 2020 to July 2024. A total of 165 patients with left-side VC were included in the VC group. The inclusion criteria comprised left-sided VC based on physical examination following the Dubin and Amelar grading system.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e The exclusion criteria included (a) right-sided or bilateral VC, (b) previous urogenital surgery, such as orchiopexy, hydrocelectomy, or inguinal hernia repair, (c) other conditions affecting fertility, such as orchitis, epididymitis, chronic prostatitis, and vas deferens obstruction, (d) severe oligospermia, cryptozoospermia, obstructive and non-obstructive azoospermia, and multiple morphological abnormalities of the sperm flagella, and (e) poor quality of ultrasound images.\u003c/p\u003e \u003cp\u003eAdditionally, 50 healthy volunteers were recruited as controls during the same period. The inclusion criteria for the control group were (a) the absence of VC detected during physical examination and (b) normal routine semen analysis parameters. The exclusion criteria for the control group were identical to those for the VC group.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eUltrasound examination and image analysis\u003c/h3\u003e\n\u003cp\u003eThe ultrasound device used was the Aplio 900 (Toshiba, Beijing, China), equipped with a linear probe frequency of 4.0\u0026ndash;18.2 MHz, center frequency of 12 MHz, mechanical index of 0.07, and dynamic range of 50\u0026ndash;55 dB. The contrast agent used was SonoVue microbubbles (Bracco, Milan, Italy).\u003c/p\u003e \u003cp\u003e Participants were positioned supine with the perineum fully exposed at a temperature of 20\u0026ndash;24℃. Initially, the three dimensions of the left testicle were measured using gray-scale ultrasound, and testicular volume (TV) was calculated using Lambert\u0026rsquo;s formula (TV\u0026thinsp;=\u0026thinsp;length \u0026times; width \u0026times; height \u0026times; 0.71).\u003csup\u003e3\u003c/sup\u003e Subsequently, the maximum venous diameter (MVD) of the left spermatic vein was measured three times, and the average value was recorded. After that, the CEUS examination was performed using the same scanning plane. The contrast agent suspension (2.4 mL in total) was injected via the antecubital vein of the left arm, followed by 5 mL of saline solution. CEUS images were recorded for 3 min. The right side was examined similarly, with a 15-min interval between the two contrast injections, which allowed for the complete elimination of the contrast agent through respiration.\u003c/p\u003e \u003cp\u003eCEUS images were analyzed frame-by-frame by two radiologists with over 10 years of experience in urogenital ultrasound. They evaluated the perfusion pattern of the spermatic vein and calculated the corresponding temporal parameters.\u003c/p\u003e\n\u003ch3\u003eSerum sex hormone levels, routine semen analysis, and DNA fragmentation index (DFI) testing\u003c/h3\u003e\n\u003cp\u003eLevels of serum sex hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (T), prolactin (PRL), and estradiol (E2), were measured using an electrochemiluminescence immunoassay (COBAS 6000; Roche Diagnostics GmbH, Basel, Switzerland).\u003c/p\u003e \u003cp\u003eRoutine semen analysis was performed according to the fifth edition of the World Health Organization Laboratory Manual for the Examination and Processing of Human Semen.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Normal semen parameters were defined based on the reference values provided in the manual: sperm concentration\u0026thinsp;\u0026ge;\u0026thinsp;15 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e/mL, total sperm counts\u0026thinsp;\u0026ge;\u0026thinsp;39 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e/mL, progressive motility\u0026thinsp;\u0026ge;\u0026thinsp;32%, and normal morphology\u0026thinsp;\u0026ge;\u0026thinsp;4%. Parameters below the reference values were considered impaired.\u003c/p\u003e \u003cp\u003eThe DFI test was performed on 146 participants in the VC group and 37 participants in the control group, as the other participants declined to undergo this examination. A sperm chromatin structure assay was used for DFI testing. The reference values for the DFI in our laboratory are: \u0026le;15% indicates good DNA integrity, 15\u0026ndash;30% indicates general DNA integrity, and \u0026ge;\u0026thinsp;30% indicates poor DNA integrity. In this study, a DFI\u0026thinsp;\u0026gt;\u0026thinsp;15% was defined as impaired DNA integrity.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables are expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations, and categorical variables are expressed as frequencies (percentages). The unweighted kappa statistic was used to evaluate the agreement between observers in the perfusion pattern. Intra-class correlation (ICC) under a two-way random model with absolute agreement was employed to evaluate the agreement of the observers in CEUS quantitative parameters. One-way analysis of variance was utilized to compare differences between quantitative data, and post-hoc multiple pairwise comparisons were performed using the Bonferroni test. Categorical variables were compared using the chi-square test. Univariate and multivariate analyses were performed using binary logistic regression. Statistical analyses were performed using SPSS version 25.0 (IBM, Armonk, NY, USA), and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics of the study population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, 50 healthy volunteers and 165 patients were enrolled. Among the patients, 71 were categorized into the VC grade 1 group, whereas 94 were categorized into the VC grades 2 \u0026amp; 3 group. The baseline characteristics of the three groups are presented in \u003cstrong\u003eTable 1\u003c/strong\u003e. There were significant differences in the left MVD, total sperm counts, progressive motility, and DFI among the three groups (all \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05). As the clinical grade increased, the left MVD (1.8±0.4 mm, 2.5±0.2 mm, and 3.2±0.6 mm, respectively) and DFI (14.9±6.0%, 19.7±12.7%, and 21.5±13.1%, respectively) showed a gradual increase. The total sperm counts (263.6±219.0×10\u003csup\u003e6\u003c/sup\u003e, 199.0±143.7×10\u003csup\u003e6\u003c/sup\u003e, and 166.2±143.1×10\u003csup\u003e6\u003c/sup\u003e, respectively) and progressive motility (50.0±11.4%, 44.0±16.1%, and 40.5±15.4%, respectively) gradually decreased.\u003c/p\u003e\n\u003cp\u003ePost-hoc multiple pairwise comparisons are depicted in \u003cstrong\u003eFigure 1\u003c/strong\u003e. The left MVDs of all three groups were statistically different in pairwise comparisons (all \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001). The total sperm counts, progressive motility, and DFI of the VC grades 2 \u0026amp; 3 group were significantly higher than those of the control group (all \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05), and there were no significant differences in other pairwise comparisons (all \u003cem\u003ep\u003c/em\u003e\u0026gt;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCEUS characteristics of the spermatic veins\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, CEUS was performed on the bilateral spermatic veins of 215 participants, and all were completed safely with no significant adverse events. CEUS images are shown in \u003cstrong\u003eFigure 2\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBased on the dynamics of microbubbles, the perfusion patterns of the spermatic vein can be classified into the following four types:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eSteady flow: The microbubbles flow forward steadily in the spermatic vein without obvious pause or reflux. An additional movie file shows this in more detail (see Additional file 1).\u003c/li\u003e\n \u003cli\u003eIntermittent stasis: The microbubbles flow forward with intermittent transient pauses (see Additional file 2).\u003c/li\u003e\n \u003cli\u003eIntermittent reflux: The microbubbles flow forward with intermittent transient reflux, after which the flow returns to the forward direction (see Additional file 3).\u003c/li\u003e\n \u003cli\u003eFilling defect: No contrast agent was found to enter the spermatic vein during the examination (see Additional file 4).\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eFor the perfusion patterns of the control group, VC grade 1, and VC grades 2 \u0026amp; 3 groups, the kappa coefficients of the two observers were 0.809, 0.819, and 0.839, respectively, indicating almost perfect agreement. For the intermittent stasis pattern, the pause times assessed by the two observers were 1.3±0.5 s (range, 0.4–2.1 s) and 1.4±0.4 s (range, 0.4–2.7 s), respectively, with an ICC value of 0.387, indicating poor agreement. For the intermittent reflux pattern, the reflux times assessed by the two observers were 1.2±0.6 s (range, 0.4–2.1 s) and 1.3±0.5 s (range, 0.4–2.5 s), respectively, with an ICC value of 0.634, indicating moderate agreement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDistribution of perfusion patterns\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe distribution of perfusion patterns in the bilateral spermatic veins of the study population is illustrated in \u003cstrong\u003eFigure 3\u003c/strong\u003e. The chi-square test results showed no significant differences in the distribution of perfusion patterns of the spermatic veins without VC, including the bilateral sides of the control group, the right side of the VC grade 1 group, and the right side of the VC grade 2 \u0026amp; 3 group. However, pairwise comparison with the left side of the VC grade 1 group and the left side of the VC grades 2 \u0026amp; 3 group showed significant differences (both \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05). The proportion of cases with intermittent reflux pattern was greater in the spermatic veins with higher clinical grades than in those with low clinical grades (VC grades 2 \u0026amp; 3: 32% vs. VC grade 1: 23% vs. no VC: 0–4%), and the proportion of cases with filling defect pattern was greater than in those with low clinical grade (VC grades 2 \u0026amp; 3: 12% vs. VC grade 1: 7% vs. no VC: 0–1%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline characteristics of patients with VC with different perfusion patterns\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the perfusion pattern of the left spermatic vein, the VC group was divided into four subgroups with baseline characteristics presented in \u003cstrong\u003eTable 2\u003c/strong\u003e. A significant difference was observed in progressive motility among the four groups (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.001). There was no significant difference in the progressive motility between the steady flow and intermittent stasis groups, the intermittent reflux and filling defect groups (both \u003cem\u003ep\u003c/em\u003e\u0026gt;0.05), and the rest of the pairwise comparisons were statistically different (all \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssociation of perfusion patterns with impaired semen parameters\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the results stated above, the perfusion patterns of the left spermatic vein were dichotomized into “steady flow \u0026amp; intermittent stasis” and “intermittent reflux \u0026amp; filling defect,” and logistic regression analysis was performed with other baseline parameters to identify risk factors for impaired semen parameters. Other baseline parameters included age, body mass index (BMI), left MVD, left TV, FSH, LH, T, PRL, and E2.\u003c/p\u003e\n\u003cp\u003eUnivariate analysis revealed that the intermittent reflux \u0026amp; filling defect pattern was a risk factor for impaired sperm concentration, total sperm counts, progressive motility, morphology, and DFI (all \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05, \u003cstrong\u003eTable 3\u003c/strong\u003e). The sensitivity of the intermittent reflux \u0026amp; filling defect pattern in predicting impaired sperm concentration was 66.7%, specificity was 64.7%, negative predictive value (NPV) was 96.1%, and positive predictive value (PPV) was 12.9%. The sensitivity of the intermittent reflux \u0026amp; filling defect pattern in predicting impaired total sperm counts was 73.3%, the specificity was 66.0%, the NPV was 96.1%, and the PPV was 17.7%. The sensitivity of the intermittent reflux \u0026amp; filling defect pattern in predicting impaired progressive motility was 79.5%, the specificity was 77.7%, the NPV was 91.3%, and the PPV was 56.5%. The sensitivity of the intermittent reflux \u0026amp; filling defect pattern in predicting impaired morphology was 72.4%, the specificity was 69.9%, the NPV was 92.2%, and the PPV was 33.9%. The sensitivity of the intermittent reflux \u0026amp; filling defect pattern in predicting an impaired DFI was 47.1%, the specificity was 74.6%, the NPV was 48.9%, and the PPV was 73.2%. Among the baseline parameters, the left MVD was statistically correlated with impaired total sperm counts (OR=2.246, 95% CI=1.046–4.820, \u003cem\u003ep\u003c/em\u003e=0.038).\u003c/p\u003e\n\u003cp\u003eMultivariate analyses were performed to estimate the predictive value of the intermittent reflux \u0026amp; filling defect pattern for impaired semen parameters. After adjusting for all the above baseline factors, the association of the intermittent reflux \u0026amp; filling defect pattern with impaired sperm concentration, impaired total sperm counts, impaired progressive motility, impaired morphology, and an impaired DFI was sustained (\u003cstrong\u003eTable 3\u003c/strong\u003e). The associations between impaired semen parameters with baseline parameters were not statistically significant (data not shown).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study introduces a novel, noninvasive approach to assess the hemodynamics of spermatic veins. We identified four distinct perfusion patterns of the spermatic vein: steady flow, intermittent stasis, intermittent reflux, and filling defect. Healthy spermatic veins predominantly exhibit steady flow and intermittent stasis patterns, and the other two patterns are more prevalent in spermatic veins with VC. Additionally, after further categorization for logistic regression analyses, the intermittent reflux \u0026amp; filling defect pattern was revealed as an independent predictor of impaired semen parameters.\u003c/p\u003e\n\u003cp\u003eDysfunction of the spermatic vein is a significant contributor to VC-induced semen parameters impairment. Exploring the hemodynamics of VC is crucial to improving the clinical diagnosis and treatment of VC.\u003csup\u003e9–11\u003c/sup\u003e However, it is challenging to study the hemodynamics of spermatic veins because of the complex and diverse structure of the pampiniform plexus. This study offers CEUS as a new method to assess the hemodynamics of the spermatic vein. The principle of this method is similar to that of venography,\u003csup\u003e12,13\u003c/sup\u003e as it records and analyzes the spatiotemporal characteristics of the contrast agent in the blood vessel to obtain hemodynamic information. The CEUS technique utilizes microbubbles — small, inert gas-filled spheres encapsulated in a phospholipid shell with a size of 2–8 μm — to enhance image clarity and contrast. Microbubbles possess several key characteristics.\u003csup\u003e15\u003c/sup\u003e The safety profile of microbubbles is well established, with no evidence of cardiac, hepatic, thyroid, or renal toxicity, and no obvious adverse reactions occurred during this study. Microbubbles can oscillate non-linearly in the diagnostic ultrasound field, generate harmonic frequencies, and produce stable and clear contrast images. Additionally, since microbubbles are similar in size to red blood cells, they remain strictly intravascular and do not pass through the vascular endothelium, unlike contrast media in CT and MRI, which may affect image quality. Finally, microbubbles have good blood traceability, meaning their dynamic characteristics align closely with blood flow. These advantages ensure the safety and accuracy of CEUS, making it the first-line modality for evaluating vascular lesions.\u003csup\u003e15–19\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eCEUS offers unique advantages over venography and Doppler ultrasound, which are classical methods for detecting hemodynamics. CEUS is noninvasive and does not produce ionizing radiation, facilitating a greater possibility of clinical application than venography. Although venography has been used to study the perfusion pattern of VC,\u003csup\u003e12,13\u003c/sup\u003e it only shows the blood reflux from the testicular vein to the renal vein at a macroscopic scale. CEUS, on the other hand, provides detailed information on the blood flow in the spermatic vein around the testis and epididymis, which is theoretically more directly related to testicular function. Doppler ultrasound is currently the first-line method to detect the blood flow of the spermatic vein. The commonly used parameters are reflux time,\u003csup\u003e23\u003c/sup\u003e maximum reflux velocity,\u003csup\u003e24\u003c/sup\u003e and reflux pattern\u003csup\u003e9\u003c/sup\u003e\u003csup\u003e–\u003c/sup\u003e\u003csup\u003e11\u003c/sup\u003e during the Valsalva maneuver. However, owing to challenges in fully calibrating the incidence angle of ultrasound and variations in the participants’ understanding and execution of the Valsalva maneuver, Doppler ultrasound systems are associated with operational difficulties, significant inter-operator differences, and contradictory results.\u003csup\u003e10\u003c/sup\u003e CEUS can make up for the inherent limitations of Doppler ultrasound, including a lower signal-to-noise ratio, lower sensitivity for slow flow, and technical artifacts, thus significantly improving blood flow visualization.\u003csup\u003e15\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eFour perfusion patterns of the spermatic vein were summarized in this study. The flow of blood in the spermatic vein, including advancement, pause, and reflux, is mainly affected by the pressure gradient and venous valve function.\u003csup\u003e25\u003c/sup\u003e The venous pressure of the normal spermatic vein is higher than that of the left renal vein, allowing blood to return to the left renal vein when blood flow exhibits a steady flow pattern. Peripheral venous pressure fluctuates within the normal range as influenced by physiological activities such as heartbeat and respiration.\u003csup\u003e26\u003c/sup\u003e When the peripheral venous pressure is at a high value, the left renal vein pressure exceeds the spermatic vein pressure, and the blood in the spermatic vein tends to reflux. If the valve is functioning normally or is minimally damaged, it can block reflux and pause blood flow, at which point perfusion exhibits an intermittent stasis pattern. If the degree of valve function damage is high and the blood breaks through the valve and backflows, the perfusion pattern shows intermittent reflux. After a brief pause or reflux, the left renal vein pressure falls back below the spermatic vein pressure, and blood resumes an antegrade flow. A small portion of testicular blood returns via the cremasteric and differential veins, which have small anastomotic branches with the spermatic vein and are normally not opened.\u003csup\u003e11\u003c/sup\u003e When the anastomotic branch opens pathologically, blood will enter the cremasteric and differential veins through the anastomotic branch. Currently, although the spermatic vein proximal to the anastomotic branch is markedly dilated, no contrast agent can be observed, resulting in a filling defect pattern. The above pathophysiological mechanisms may explain the distribution of perfusion patterns in this study: intermittent reflux and filling defect patterns were almost exclusively found in the diseased spermatic vein, and the proportion increased with an increase in the clinical grade.\u003c/p\u003e\n\u003cp\u003eIn this study, we analyzed the correlation between the perfusion pattern of the left spermatic vein and semen parameters in the VC group. The progressive motility of the intermittent reflux group (33.1±16.1%) and filling defect group (31.8±14.2%) was significantly lower than that of the steady flow group (48.8±12.0%) and intermittent stasis group (45.2±14.7%), but there were no significant differences in semen parameters between the steady flow group and intermittent stasis group or between the intermittent reflux group and filling defect group. Theoretically, the lesion severity in the filling defect group was higher than that in the intermittent reflux group,\u003csup\u003e11\u003c/sup\u003e but the difference in semen parameters between the two groups was not significant, which may be attributable to the small sample size of this study. For this reason, logistic regression analysis was performed after dichotomizing the perfusion patterns. The intermittent reflux \u0026amp; filling defect pattern was an independent risk factor for impaired semen parameters with high sensitivity (66.7%, 73.3%, 79.5%, and 72.4%, respectively) and specificity (64.7%, 66.0%, 77.7%, and 69.9%, respectively) in predicting impaired sperm concentration, total sperm counts, progressive motility, and morphology. Conversely, it had high specificity (74.6%) but low sensitivity (47.1%) in predicting an impaired DFI. These findings are consistent with the pathophysiological mechanisms of spermatogenic dysfunction previously described.\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e–\u003c/sup\u003e\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThis study has the following major limitations. First, the sample size for the filling defect pattern was small; therefore, we simplified the perfusion pattern to a binary category in the logistic regression analysis. Second, this study was performed at rest without the Valsalva maneuver because the subjectivity of the Valsalva maneuver can reduce accuracy. Moreover, Cavallini \u003cem\u003eet al\u003c/em\u003e.\u003csup\u003e10\u003c/sup\u003e found that continuous hemodynamic abnormalities can affect spermatogenesis, whereas temporary reflux (mainly during the Valsalva maneuver) has little effect on testicular function. Finally, further analysis of quantitative parameters was not performed due to significant inter-observer variability in reflux and pause times. The current clinical application of CEUS mainly relies on subjective and qualitative evaluation and interpretation by the physician performing the examination\u003csup\u003e15\u003c/sup\u003e; thus, the results of this study still have potential value for clinical application.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study revealed that the perfusion patterns of the spermatic vein can be classified into four types. Further categorization for logistic regression identified the intermittent reflux \u0026amp; filling defect pattern as an independent risk factor for impaired sperm concentration, total sperm counts, progressive motility, morphology, and DFI. These results demonstrate that CEUS is a reliable and non-invasive approach for evaluating the hemodynamics of the spermatic veins. In future studies, we will use CEUS to comprehensively and systematically explore various aspects of VC, including its natural course, surgical indications, and postoperative outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eVaricocele (VC); Contrast-enhanced ultrasound (CEUS); DNA fragmentation index (DFI); Intra-class correlation (ICC); Follicle-stimulating hormone (FSH); Luteinizing hormone (LH); Total testosterone (T); Prolactin (PRL); Estradiol (E2).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present study protocol was reviewed and approved by the Institutional Ethical Review Committee of Shanghai General Hospital (ID: 2020KY139 and [2022]115). All patients provided written informed consent. The trial was registered with the Chinese Clinical Trial Registry (ID: ChiCTR2000036241).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent of publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Key Research and Development Program of China (No. 2022YFC2702700) and the Clinical Research Plan of SHDC (No. SHDC2020CR2071B).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePLZ drafted the manuscript. PLZ and GXF analyzed the data. PLZ, GXF, YCT, CJ, and HML performed the clinical trial. RHT and ZL were in charge of technical support. QSS, JLH, and RW were in charge of study design and supervision. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSasson DC, Kashanian JA. Varicoceles. JAMA. 2020;323:2210.\u003c/li\u003e\n \u003cli\u003eFallara G, Capogrosso P, Pozzi E, Belladelli F, Corsini C, Boeri L, et al. The effect of varicocele treatment on fertility in adults: a systematic review and meta-analysis of published prospective trials. Eur Urol Focus. 2023;9:154\u0026ndash;61.\u003c/li\u003e\n \u003cli\u003eFreeman S, Bertolotto M, Richenberg J, Belfield J, Dogra V, Huang DY, et al. Ultrasound evaluation of varicoceles: guidelines and recommendations of the European Society of Urogenital Radiology Scrotal and Penile Imaging Working Group (ESUR-SPIWG) for detection, classification, and grading. Eur Radiol. 2020;30:11\u0026ndash;25.\u003c/li\u003e\n \u003cli\u003eSchlegel PN, Sigman M, Collura B, De Jonge CJ, Eisenberg ML, Lamb DJ, et al. Diagnosis and treatment of infertility in men: AUA/ASRM Guideline PART II. J Urol. 2021;205:44\u0026ndash;51.\u003c/li\u003e\n \u003cli\u003eMinhas S, Bettocchi C, Boeri L, Capogrosso P, Carvalho J, Cilesiz NC, et al. European Association of Urology Guidelines on Male Sexual and Reproductive Health: 2021 Update on Male Infertility. Eur Urol. 2021;80:603\u0026ndash;20.\u003c/li\u003e\n \u003cli\u003eFinelli R, Leisegang K, Kandil H, Agarwal A. Oxidative stress: a comprehensive review of biochemical, molecular, and genetic aspects in the pathogenesis and management of varicocele. World J Mens Health. 2022;40:87\u0026ndash;103.\u003c/li\u003e\n \u003cli\u003eFang Y, Su Y, Xu J, Hu Z, Zhao K, Liu C, et al. Varicocele-mediated male infertility: from the perspective of testicular immunity and inflammation. Front Immunol\u003cem\u003e.\u003c/em\u003e 2021;12:729539.\u003c/li\u003e\n \u003cli\u003eJeremias JT, Belardin LB, Okada FK, Antoniassi MP, Fraietta R, Bertolla RP, et al. Oxidative origin of sperm DNA fragmentation in the adult varicocele. Int Braz J Urol. 2021;47:275\u0026ndash;83.\u003c/li\u003e\n \u003cli\u003eYou K, Chen BB, Wang P, Bu RG, Xu XW. Intense venous reflux, quantified by a new software to analyze presurgical ultrasound, is associated with unfavorable outcomes of microsurgical varicocelectomy. Asian J Androl. 2023;25:119\u0026ndash;25.\u003c/li\u003e\n \u003cli\u003eCavallini G, Scroppo FI, Colpi GM. The clinical usefulness of a novel grading system for varicoceles using duplex Doppler ultrasound examination based on postsurgical modifications of seminal parameters. Andrology. 2019;7:62\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eBagheri SM, Khajehasani F, Iraji H, Fatemi I. A novel method for investigating the role of reflux pattern in color doppler ultrasound for grading of varicocele. Sci Rep. 2018;8:6517.\u003c/li\u003e\n \u003cli\u003eSigmund G, Gall H, B\u0026auml;hren W. Stop-type and shunt-type varicoceles: venographic findings. Radiology. 1987;163:105\u0026ndash;10.\u003c/li\u003e\n \u003cli\u003eSigmund G, B\u0026auml;hren W, Gall H, Lenz M, Thon W. Idiopathic varicoceles: feasibility of percutaneous sclerotherapy. Radiology\u003cem\u003e.\u003c/em\u003e 1987;164:161\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eBelay RE, Huang GO, Shen JK, Ko EY. Diagnosis of clinical and subclinical varicocele: how has it evolved? Asian J Androl. 2016;18:182\u0026ndash;5.\u003c/li\u003e\n \u003cli\u003eRafailidis V, Huang DY, Yusuf GT, Sidhu PS. General principles and overview of vascular contrast-enhanced ultrasonography. Ultrasonography. 2020;39:22\u0026ndash;42.\u003c/li\u003e\n \u003cli\u003eGolemati S, Cokkinos DD. Recent advances in vascular ultrasound imaging technology and their clinical implications. Ultrasonics. 2022;119:106599.\u003c/li\u003e\n \u003cli\u003eHayashi M, Matsuda M, Yamadera Y, Nakamura J, Fujita M, Abe K, et al. Isolated small bowel varices diagnosed by contrast-enhanced ultrasound. Am J Gastroenterol. 2023;118:931.\u003c/li\u003e\n \u003cli\u003eChen J, Zhu J, Zhang C, Song Y, Huang P. Contrast-enhanced ultrasound for the characterization of portal vein thrombosis vs tumor-in-vein in HCC patients: a systematic review and meta-analysis. Eur Radiol. 2020;30:2871\u0026ndash;80.\u003c/li\u003e\n \u003cli\u003eLi Q, Wang Z, Ma X, Tang J, Luo Y. Diagnostic accuracy of contrast-enhanced ultrasound for detecting bland thrombus from inferior vena cava tumor thrombus in patients with renal cell carcinoma. Int Braz J Urol. 2020;46:92\u0026ndash;100.\u003c/li\u003e\n \u003cli\u003eCaretta N, Palego P, Schipilliti M, Torino M, Ferlin A, Pati M, et al. Testicular contrast harmonic imaging to evaluate intratesticular perfusion alterations in patients with varicocele. J Urol. 2010;183:263\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eCao W, Han H, Guan X, Lyu C, Zhou Q, Tian L, et al. Elastography and contrast-enhanced ultrasound to assess the effect of varicocelectomy: a case-controlled study. Andrologia. 2022;54:e14586.\u003c/li\u003e\n \u003cli\u003eWorld Health Organization. WHO laboratory manual for the examination and processing of human semen, 5th ed. Geneva: WHO Press; 2010.\u003c/li\u003e\n \u003cli\u003ePatil V, Shetty SM, Das SK. Redefining the criteria for grading varicoceles based on reflux times: a clinicoradiological correlation. Ultrasound Q\u003cem\u003e.\u003c/em\u003e 2016;32:82\u0026ndash;5.\u003c/li\u003e\n \u003cli\u003eVan Batavia JP, Badalato G, Fast A, Glassberg KI. Adolescent varicocele-is the 20/38 harbinger a durable predictor of testicular asymmetry? J Urol. 2013;189:1897\u0026ndash;901.\u003c/li\u003e\n \u003cli\u003eRecek C. The venous reflux. Angiology. 2004;55:541\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eChang D, Leisy PJ, Sobey JH, Reddy SK, Brophy C, Alvis BD, et al. Physiology and clinical utility of the peripheral venous waveform. JRSM Cardiovasc Dis. 2020;9:2048004020970038.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. The baseline characteristics of the study population\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 109px;\"\u003e\n \u003cp\u003eControl group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 219px;\"\u003e\n \u003cp\u003eVC group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003eGrade 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003eGrade 2\u0026amp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eNumber\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e30.5\u0026plusmn;4.9 (21\u0026ndash;44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e32.1\u0026plusmn;4.2 (24\u0026ndash;43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e31.7\u0026plusmn;5.8 (18\u0026ndash;57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.219\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e24.5\u0026plusmn;4.3 (18.0\u0026ndash;32.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e25.4\u0026plusmn;3.6 (18.3\u0026ndash;32.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e25.7\u0026plusmn;3.6 (18.3\u0026ndash;36.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.156\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eGray-scale ultrasound parameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eLeft MVD (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e1.8\u0026plusmn;0.4 (0.8\u0026ndash;2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e2.5\u0026plusmn;0.2 (2.0\u0026ndash;2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e3.2\u0026plusmn;0.6 (2.4\u0026ndash;5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eRight MVD (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e1.6\u0026plusmn;0.4 (0.8\u0026ndash;2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e1.5\u0026plusmn;0.4 (0.7\u0026ndash;2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e1.5\u0026plusmn;0.3 (0.8\u0026ndash;2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.081\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eLeft TV (mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e15.2\u0026plusmn;4.4 (8.4\u0026ndash;27.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e13.5\u0026plusmn;4.3 (8.2\u0026ndash;29.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e14.0\u0026plusmn;3.9 (8.2\u0026ndash;23.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eRight TV (mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e16.2\u0026plusmn;4.0 (9.2\u0026ndash;24.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e14.5\u0026plusmn;4.4 (8.0\u0026ndash;29.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e15.6\u0026plusmn;4.2 (8.1\u0026ndash;25.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.084\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eReproductive hormone level\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eFSH (mIU/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e4.4\u0026plusmn;1.6 (1.5\u0026ndash;9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e5.2\u0026plusmn;3.0 (1.3\u0026ndash;17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e4.5\u0026plusmn;1.9 (1.9\u0026ndash;13.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.077\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eLH (mIU/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e4.3\u0026plusmn;1.5 (2.2\u0026ndash;8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e4.3\u0026plusmn;1.8 (1.6\u0026ndash;8.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e4.4\u0026plusmn;1.8 (1.3\u0026ndash;10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.909\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eT (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e5.2\u0026plusmn;2.4 (2.5\u0026ndash;12.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e5.0\u0026plusmn;2.6 (1.4\u0026ndash;14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e5.3\u0026plusmn;2.5 (1.2\u0026ndash;14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.667\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003ePRL (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e12.0\u0026plusmn;6.7 (1.1\u0026ndash;45.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e11.6\u0026plusmn;9.1 (2.1\u0026ndash;47.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e11.9\u0026plusmn;9.4 (2.1\u0026ndash;75.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.964\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eE2 (Pmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e148.3\u0026plusmn;82.6 (58.5\u0026ndash;368.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e130.1\u0026plusmn;65.4 (39.4\u0026ndash;304.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e148.2\u0026plusmn;88.0 (34.7\u0026ndash;384.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.297\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eSemen parameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eVolume (mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e3.0\u0026plusmn;1.1 (0.7\u0026ndash;6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e2.8\u0026plusmn;1.1 (0.8\u0026ndash;7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e2.7\u0026plusmn;1.1 (0.2\u0026ndash;7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.174\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eConcentration (\u0026times;10\u003csup\u003e6\u003c/sup\u003e/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e80.2\u0026plusmn;51.8 (16.3\u0026ndash;219.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e72.4\u0026plusmn;45.8 (8.0\u0026ndash;216.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e62.2\u0026plusmn;45.3 (7.0\u0026ndash;214.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.080\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eTotal sperm counts (\u0026times;10\u003csup\u003e6\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e263.6\u0026plusmn;219.0 (45.0\u0026ndash;824.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e199.0\u0026plusmn;143.7 (14.0\u0026ndash;618.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e166.2\u0026plusmn;143.1 (10.8\u0026ndash;748.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.004\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eProgressive motility (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e50.0\u0026plusmn;11.4 (32.0\u0026ndash;86.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e44.0\u0026plusmn;16.1 (11.0\u0026ndash;75.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e40.5\u0026plusmn;15.4 (13.0\u0026ndash;70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.002\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eNormal morphology (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e7.8\u0026plusmn;3.0 (4.0\u0026ndash;16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e7.4\u0026plusmn;4.4 (2.0\u0026ndash;25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e6.7\u0026plusmn;4.1 (1.0\u0026ndash;21.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.233\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eDFI (%)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e14.9\u0026plusmn;6.0 (4.4\u0026ndash;24.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e19.7\u0026plusmn;12.7 (2.2\u0026ndash;54.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e21.5\u0026plusmn;13.1 (3.4\u0026ndash;67.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.022\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eBMI: body mass index; MVD: maximum venous diameter; TV: testicular volume; FSH: follicle-stimulating hormone; LH: luteinizing hormone; T: total testosterone; PRL: prolactin; E2: estradiol; DFI: DNA fragmentation index.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e The number of DFI tests performed in the three groups was 37, 66, and 80, respectively.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003eAsterisks indicate significant differences (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05).\u003c/p\u003e\n\u003cp\u003eTable 2. The baseline characteristics of VC groups with different perfusion patterns of the left spermatic vein\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eSteady flow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eIntermittent stasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eIntermittent reflux\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eFilling defect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eNumber\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e31.1\u0026plusmn;4.0 (21\u0026ndash;41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e32.0\u0026plusmn;5.4 (18\u0026ndash;44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e33.0\u0026plusmn;6.4 (24\u0026ndash;57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e31.6\u0026plusmn;5.1 (22\u0026ndash;41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.293\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e26.0\u0026plusmn;3.3 (18.3\u0026ndash;32.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e25.7\u0026plusmn;4.1 (18.5\u0026ndash;36.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e25.3\u0026plusmn;3.7 (18.3\u0026ndash;32.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e24.2\u0026plusmn;3.5 (19.9\u0026ndash;32.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.265\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eGray-scale ultrasound parameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eLeft MVD (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e2.8\u0026plusmn;0.6 (2.3\u0026ndash;5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e2.9\u0026plusmn;0.5 (2.3\u0026ndash;4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e2.9\u0026plusmn;0.6 (2.0\u0026ndash;4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e2.9\u0026plusmn;0.5 (2.4\u0026ndash;4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.737\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eRight MVD (mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.4\u0026plusmn;0.4 (0.7\u0026ndash;2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.5\u0026plusmn;0.4 (0.9\u0026ndash;2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.4\u0026plusmn;0.3 (0.8\u0026ndash;2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e1.6\u0026plusmn;0.4 (1.0\u0026ndash;2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.129\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eLeft TV (mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e14.0\u0026plusmn;4.3 (8.2\u0026ndash;29.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e13.5\u0026plusmn;3.9 (8.3\u0026ndash;22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e13.1\u0026plusmn;3.7 (8.2\u0026ndash;23.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e15.4\u0026plusmn;3.9 (9.1\u0026ndash;23.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.250\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eRight TV (mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e15.5\u0026plusmn;4.6 (8.1\u0026ndash;29.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e14.4\u0026plusmn;3.9 (8.2\u0026ndash;22.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e14.7\u0026plusmn;4.1 (8.0\u0026ndash;24.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e16.7\u0026plusmn;4.0 (12.7\u0026ndash;25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.261\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eReproductive hormone level\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eFSH (mIU/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e5.1\u0026plusmn;2.9 (1.6\u0026ndash;17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e4.6\u0026plusmn;1.9 (1.5\u0026ndash;9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e4.7\u0026plusmn;2.4 (1.3\u0026ndash;13.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e4.4\u0026plusmn;1.7 (1.8\u0026ndash;7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.661\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eLH (mIU/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e4.5\u0026plusmn;2.0 (1.3\u0026ndash;9.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e4.2\u0026plusmn;1.8 (2.3\u0026ndash;10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e4.4\u0026plusmn;1.6 (1.9\u0026ndash;8.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e4.0\u0026plusmn;1.4 (2.1\u0026ndash;7.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.755\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eT (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e5.1\u0026plusmn;2.6 (1.6\u0026ndash;14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e5.2\u0026plusmn;2.6 (1.4\u0026ndash;12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e5.3\u0026plusmn;2.6 (2.0\u0026ndash;14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e4.9\u0026plusmn;2.5 (1.2\u0026ndash;11.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.919\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003ePRL (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e12.5\u0026plusmn;11.1 (2.1\u0026ndash;75.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e13.4\u0026plusmn;10.0 (2.8\u0026ndash;43.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e9.6\u0026plusmn;5.8 (2.1\u0026ndash;27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e11.9\u0026plusmn;6.0 (2.9\u0026ndash;25.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.271\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eE2 (Pmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e133.8\u0026plusmn;76.1 (34.7\u0026ndash;321.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e143.8\u0026plusmn;78.7 (44.6\u0026ndash;371.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e156.6\u0026plusmn;86.2 (48.6\u0026ndash;384.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e115.0\u0026plusmn;70.3 (48.2\u0026ndash;248.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.253\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eSemen parameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eVolume (mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e2.7\u0026plusmn;1.1 (1.1\u0026ndash;7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e2.5\u0026plusmn;0.9 (0.8\u0026ndash;4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e2.9\u0026plusmn;1.4 (0.2\u0026ndash;7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e2.7\u0026plusmn;0.9 (1.3\u0026ndash;4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.492\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eConcentration (\u0026times;10\u003csup\u003e6\u003c/sup\u003e/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e72.6\u0026plusmn;45.6 (10.0\u0026ndash;216.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e67.1\u0026plusmn;48.8 (8.0\u0026ndash;209.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e57.2\u0026plusmn;44.8 (7.0\u0026ndash;213.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e67.0\u0026plusmn;40.4 (9.0\u0026ndash;149.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.377\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eTotal sperm counts (\u0026times;10\u003csup\u003e6\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e190.7\u0026plusmn;131.1 (15.4\u0026ndash;642.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e170.4\u0026plusmn;147.5 (20.0\u0026ndash;748.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e165.1\u0026plusmn;158.0 (10.8\u0026ndash;566.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e201.3\u0026plusmn;152.9 (11.7\u0026ndash;485.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.714\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eProgressive motility (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e48.8\u0026plusmn;12.0 (20.0\u0026ndash;74.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e45.2\u0026plusmn;14.7 (15.0\u0026ndash;75.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e33.1\u0026plusmn;16.1 (11.0\u0026ndash;65.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e31.8\u0026plusmn;14.2 (13.0\u0026ndash;61.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eNormal morphology (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e7.6\u0026plusmn;4.0 (3.0\u0026ndash;25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e7.9\u0026plusmn;4.8 (2.0\u0026ndash;21.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e5.7\u0026plusmn;3.8 (1.0\u0026ndash;18.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e6.2\u0026plusmn;4.5 (2.0\u0026ndash;20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003eDFI (%)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e18.7\u0026plusmn;12.0 (2.6\u0026ndash;48.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e20.4\u0026plusmn;15.3 (2.2\u0026ndash;67.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e23.8\u0026plusmn;13.4 (3.4\u0026ndash;52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e20.7\u0026plusmn;7.8 (5.7\u0026ndash;40.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.288\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eBMI: body mass index; MVD: maximum venous diameter; TV: testicular volume; FSH: follicle-stimulating hormone; LH: luteinizing hormone; T: total testosterone; PRL: prolactin; E2: estradiol; DFI: DNA fragmentation index.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e The number of DFI tests performed in the four groups was 58, 32, 41, and 15, respectively.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003eAsterisks indicate significant differences (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05).\u003c/p\u003e\n\u003cp\u003eTable 3. Binary logistic regression analysis to\u0026nbsp;confirm reflux and filling defect patterns as independent risk factors for impaired semen parameters (n=165)\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"607\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 216px;\"\u003e\n \u003cp\u003eWithout adjustment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 217px;\"\u003e\n \u003cp\u003eWith adjustment\u003csup\u003e\u0026nbsp;a\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003eImpaired sperm concentration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003e3.667 (1.056\u0026ndash;12.737)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.041\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e3.998 (1.059\u0026ndash;15.095)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.041\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003eImpaired total sperm counts\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003e5.338 (1.619\u0026ndash;17.604)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.006\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e5.443 (1.493\u0026ndash;19.840)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.010\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003eImpaired progressive motility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003e13.539 (5.796\u0026ndash;31.626)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e14.694 (5.910\u0026ndash;36.534)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003eImpaired morphology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003e6.082 (2.491\u0026ndash;14.854)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e7.807 (2.906\u0026ndash;20.975)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003eImpaired DFI\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003e2.614 (1.271\u0026ndash;5.380)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.009\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 130px;\"\u003e\n \u003cp\u003e2.893 (1.336\u0026ndash;6.266)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 87px;\"\u003e\n \u003cp\u003e0.007\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eCI: confidence interval; DFI: DNA fragmentation index.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Adjusted for age, BMI, left MVD, left TV, FSH, LH, T, PRL, and E2.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e The number of DFI tests performed was 146.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"basic-and-clinical-andrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"andr","sideBox":"Learn more about [Basic and Clinical Andrology](https://bacandrology.biomedcentral.com/)","snPcode":"12610","submissionUrl":"https://submission.nature.com/new-submission/12610/3","title":"Basic and Clinical Andrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"male infertility, varicocele, contrast-enhanced ultrasound, hemodynamics","lastPublishedDoi":"10.21203/rs.3.rs-5209676/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5209676/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHemodynamic alterations in the spermatic vein are implicated in infertility among patients with varicocele (VC). Contrast-enhanced ultrasound (CEUS), a powerful tool for hemodynamic analysis, remains unexplored for VC. This study aimed to demonstrate the feasibility of using CEUS to evaluate spermatic vein hemodynamics in patients with VC and establish a clear correlation between specific hemodynamic patterns and impaired semen parameters. This study included 165 patients with left-sided VC and 50 healthy volunteers. All participants underwent CEUS of the spermatic veins, along with maximum venous diameter and testicular volume measurements and serum sex hormone levels and routine semen analyses. The sperm DNA fragmentation index was measured in 146 patients with VC and 37 healthy controls.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe analyses revealed four distinct perfusion patterns ofthe spermatic vein: steady flow, intermittent stasis, intermittent reflux, and filling defect. In healthy spermatic veins, the predominant perfusion patterns included steady flow and intermittent stasis. Spermatic veins with VC exhibited a significant increase in the intermittent reflux and filling defect patterns, with the proportion rising as the clinical grade increased. The four patterns were further grouped into the “steady flow \u0026amp; intermittent stasis” and “intermittent reflux \u0026amp; filling defect” patterns for logistic regression analyses; the intermittent reflux \u0026amp; filling defect pattern was revealed as an independent risk factor for impaired sperm concentration, total sperm counts, progressive motility, morphology, and DNA fragmentation index.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study validated the feasibility of CEUS for assessing the hemodynamics of the spermatic vein and established the intermittent reflux \u0026amp; filling defect pattern as an independent predictor of impaired semen parameters.\u003c/p\u003e","manuscriptTitle":"A new approach for hemodynamics of varicoceles: Perfusion patterns based on contrast- enhanced ultrasound","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-16 05:36:54","doi":"10.21203/rs.3.rs-5209676/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-25T11:48:58+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-24T18:58:39+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-18T02:43:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"186163855912111531936043443245352240650","date":"2024-11-11T17:05:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-06T10:59:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"302808795417119144222710678088031372167","date":"2024-11-04T07:30:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"175449800098177616713454735522094576884","date":"2024-10-21T07:27:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-08T09:34:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-07T14:54:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-07T14:51:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"Basic and Clinical Andrology","date":"2024-10-05T15:39:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"basic-and-clinical-andrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"andr","sideBox":"Learn more about [Basic and Clinical Andrology](https://bacandrology.biomedcentral.com/)","snPcode":"12610","submissionUrl":"https://submission.nature.com/new-submission/12610/3","title":"Basic and Clinical Andrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8b866fc1-8867-4b2d-acf6-186e50611df9","owner":[],"postedDate":"December 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-27T16:05:44+00:00","versionOfRecord":{"articleIdentity":"rs-5209676","link":"https://doi.org/10.1186/s12610-024-00249-8","journal":{"identity":"basic-and-clinical-andrology","isVorOnly":false,"title":"Basic and Clinical Andrology"},"publishedOn":"2025-01-23 15:57:21","publishedOnDateReadable":"January 23rd, 2025"},"versionCreatedAt":"2024-12-16 05:36:54","video":"","vorDoi":"10.1186/s12610-024-00249-8","vorDoiUrl":"https://doi.org/10.1186/s12610-024-00249-8","workflowStages":[]},"version":"v1","identity":"rs-5209676","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5209676","identity":"rs-5209676","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}