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PURPOSE: Varicocele is a condition known to cause damage to seminal parameters and sperm function. Furthermore, it has been hypothesized that the varicocele effect on fertility is time-dependent; however, little is known about the consequences of its establishment time on reproductive organs and/or sperm function. This study aimed to evaluate the effect of the duration of experimental varicocele on reproductive organs, sperm parameters, and sperm function. MATERIALS AND METHODS: Varicocele induction surgeries were performed in Wistar rats aged 40 or 100 days old. At 160-day-old, analyses were performed, including biometry of reproductive organs (prostate, seminal vesicles, epididymis, and testis), sperm parameters (vitality, morphology, and motility), and sperm function tests (nuclear DNA integrity, acrosome integrity, and mitochondrial activity). RESULTS: The analysis of the biometry of reproductive organs showed no differences between distinct ages in which varicocele was induced. The total abnormal sperm morphology was bigger in animals with varicocele induced to 100 days old than in animals with varicocele induced to 40 days old. Regarding nuclear DNA integrity, animals of varicocele induced to 100 days old showed worse results compared to animals of varicocele induced to 40 days old. Other parameters analyzed showed no differences between varicocele groups. CONCLUSION: In this study conducted on rats, we conclude that varicocele adversely affects sperm, particularly its function. However, we did not observe a negative progressive effect on sperm.

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OBJECTIVE: To evaluate the effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation (SDF) rates in infertile men with clinical varicocele. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Infertile men with clinical varicocele subjected to varicocelectomy. INTERVENTION(S): Systematic search using PubMed/Medline, EMBASE, Cochrane's central database, Scielo, and Google Scholar to identify relevant studies published from inception until January 2021. We included studies comparing SDF rates before and after varicocelectomy in infertile men with clinical varicocele. MAIN OUTCOME MEASURE(S): The primary outcome was the difference between the SDF rates before and after varicocelectomy. A meta-analysis of weighted data using random-effects models was performed. Results were reported as weighted mean differences (WMD) with 95% confidence intervals (CIs). Subgroup analyses were performed on the basis of the SDF assay, varicocelectomy technique, preoperative SDF levels, varicocele grade, follow-up time, and study design. RESULT(S): Nineteen studies involving 1,070 patients provided SDF data. Varicocelectomy was associated with reduced postoperative SDF rates (WMD -7.23%; 95% CI: -8.86 to -5.59; I2 = 91%). The treatment effect size was moderate (Cohen's d = 0.68; 95% CI: 0.77 to 0.60). The pooled results were consistent for studies using sperm chromatin structure assay, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, sperm chromatin dispersion test, and microsurgical varicocele repair. Subgroup analyses showed that the treatment effect was more pronounced in men with elevated vs. normal preoperative SDF levels, but the impact of varicocele grade remained equivocal. Meta-regression analysis demonstrated that SDF decreased after varicocelectomy as a function of preoperative SDF levels (coefficient: 0.23; 95% CI: 0.07 to 0.39). CONCLUSION(S): We concluded that pooled results from studies including infertile men with clinical varicocele indicated that varicocelectomy reduced the SDF rates. The treatment effect was greater in men with elevated (vs. normal) preoperative SDF levels. Further research is required to determine the full clinical implications of SDF reduction for these men.

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PURPOSE: "Omics" techniques have been used to understand and to identify biomarkers of male infertility. We report on the first metabonomics models created to diagnose varicocele and infertility among men with varicocele. METHODS: We recruited 35 infertile men with varicocele (VI group), 21 fertile men with varicocele (VF group) and 24 fertile men without varicocele (C group). All men underwent standard semen analysis, scrotal duplex ultrasonography, and sexual hormone level measurement. Hydrogen-1 nuclear magnetic resonance (1H NMR) spectra of seminal plasma were used to create metabonomics models to discriminate between men with and without varicocele, and between fertile and infertile men with varicocele. RESULTS: Using the statistical formalisms partial least square discriminants analysis and genetic algorithm-based linear discriminant analysis (GA-LDA), we created two models that discriminated the three groups from each other with accuracy of 92.17%. We also created metabonomics models using orthogonal partial least square discriminants analysis and GA-LDA that discriminated VF group from VI group, with an accuracy of 94.64% and 100% respectively. We identified 19 metabolites that were important in group segregation: caprate, 2-hydroxy-3-methylvalerate, leucine, valine, 3-hydroxybutyrate, lactate, alanine, 4-aminobutyrate, isoleucine, citrate, methanol, glucose, glycosides, glycerol-3-phosphocoline, n-acetyltyrosine, glutamine, tyrosine, arginine, and uridine. CONCLUSIONS: 1HNMR-based metabonomics of seminal plasma can be used to create metabonomics models to discriminate between men with varicocele from those without varicocele, and between fertile men with varicocele from those infertile with varicocele. Furthermore, the most important metabolites for group segregation are involved in the oxidative stress caused by varicocele.

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BACKGROUND: Treatment of palpable varicocele in infertile men with abnormal semen parameters is widely accepted, and physical examination (PE) remains a cornerstone for recommending varicocele repair. However, identification of clinical varicocele during PE can be challenging for both urology residents and consultants. OBJECTIVE: To compare the diagnostic accuracy of PE to color Doppler ultrasonography (CDU) for the diagnosis of varicocele in experienced and non-experienced examiners. MATERIALS AND METHODS: Diagnostic accuracy study involving 78 patients attending a university-based infertility unit. Patients underwent scrotal PE by both experienced (over 10 years experience in male infertility) and non-experienced urologists (senior residents), and were subjected to CDU. varicocele diagnosis and varicocele grading were compared between examiner groups and to CDU. Accuracy measures were evaluated, and interobserver agreement was estimated using unweighted kappa statistics. A subgroup analysis for normal and high body mass index (BMI) was also performed for the same variables. RESULTS: Accuracy of PE for varicocele diagnosis was 63.5% with a positive predictive value (PPV) of 75.5%. The specificity and PPV of PE were higher among experienced than non-experienced urologists (82.0% CI: 74.27-88.26 and 81.1% CI: 74.39-86.44% vs 67.2% CI: 58.33-75.22 and 70.6% CI: 64.52-76.08, respectively). Agreements on varicocele diagnosis (k: 0.625 vs 0.517) and grading (k: 0.548 vs 0.418) by PE were higher among experienced than non-experienced urologists. Differences between eutrophic and overweight/obese patients were also suggested. DISCUSSION AND CONCLUSIONS: PE performed by infertility specialists identify patients with varicocele more precisely than non-specialists. However, PE alone has suboptimal accuracy for varicocele diagnosis. Our results indicate that PE should be followed by CDU to decrease the number of false positives and increase the diagnostic accuracy of varicocele diagnosis.

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Varicocelectomy is associated to improved semen quality and sperm functional quality, but individual response is highly variable. Thus, a prospective study was performed including 25 men who collected a semen sample before and 12 months after subinguinal microsurgical varicocelectomy. Semen analysis, sperm functional analysis, and seminal plasma proteomic analysis was performed before and 12 months after varicocelectomy, and according to improvement or not of semen quality (positive and negative outcome). Varicocelectomy led to an increase in semen volume and sperm count, morphology, and mitochondrial activity. In the pre- vs. post-samples, 698 proteins were quantified - 91 differentially expressed after varicocelectomy. In the positive vs. negative outcome analysis, 647 proteins were identified - 151 differentially expressed in the negative outcome group and 30 differentially expressed in the positive outcome group. Tripeptidyl peptidase-1 offered a predictive value for outcome, with an area under a ROC curve of 84.5%. It seems TPP1 is an outcome predictor for varicocelectomy in adults. More importantly, this study demonstrates that the seminal plasma proteome is different in men with varicocele when compared to post-treatment samples from the same individuals. Understanding and monitoring the molecular mechanisms of semen may further establish therapeutic options for these men. SIGNIFICANCE: Although several large-scale studies have demonstrated varicocele is unequivocally associated to male infertility, these same studies have also demonstrated that varicocele is not a determinant of male infertility. We have yet to answer the question of why don't all men with varicocele present with infertility. Varicocele treatment improves semen quality, but its results are variable, and one cannot know who will and who will not benefit from surgical treatment. Results from this study strongly advance a concept that our previous studies have shown: that men with varicocele present an inflammatory semen profile. We have further demonstrated that men operated for varicocele present a decrease in this inflammatory profile, and that when they do not, semen quality remains unaltered. Trypeptidil peptidase-1, a seminal protein, was 3-fold higher in men with a positive outcome after the procedure, when compared to men with a negative outcome. Therefore, inflammation seems to be a central point to varicocele-derived male infertility.

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BACKGROUND: Cysteine-rich secretory protein (CRISP-3), a protein involved in inflammatory response, is highly increased in seminal plasma of adolescents with varicocoele and altered semen analysis, but not in adolescents with varicocoele and normal semen. It is not known, however, whether this increased seminal concentration occurs as an acute marker during the initial stages of varicocoele or whether this persists as an altered protein pathway. OBJECTIVE: The purpose of this study, thus, was to test the hypothesis that this inflammatory state persists through adulthood and the correction of varicocoele could correct this state, by identifying the levels of CRISP-3 in seminal plasma. MATERIALS AND METHODS: This study was carried out in two substudies: (i) to verify the effect of varicocoele and (ii) to verify the effect of varicocelectomy on seminal plasma CRISP-3 levels. Seminal plasma CRISP-3 levels (29 and 31 kDa isoforms) were assessed for each provided sample using standard Western blotting. RESULTS: The varicocoele group presented higher seminal levels of CRISP-3 when compared to controls, with a 67.5-fold increase in the unglycosylated isoform (29 kDa) and a 5.2-fold increase in the glycosylated isoform (31 kDa). In contrast, CRISP-3 levels decreased following varicocelectomy, both in the unglycosylated (5.6-fold decrease) and in the glycosylated (4.3-fold decrease) isoforms. DISCUSSION: CRISP-3, a protein involved in inflammation, is increased in seminal plasma of men with varicocoele and this is partially reversed by varicocelectomy. Monitoring its seminal levels may be useful for assessing inflammation-related alterations to fertility in men with varicocoele. CONCLUSION: We conclude that, in the presence of varicocoele, there is a marked increase in seminal CRISP-3 levels. Surgical intervention (varicocelectomy) decreases CRISP-3 levels and improves semen quality.

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ABSTRACT Introduction: We evaluated the relationship between total testicular volume (TTV) and testicular volume differential (TVD) in adolescent males with varicocele. Both low TTV and high TVD have been independently associated with higher incidences of infertility later in life, but a predictive relationship between TTV and TVD directly has yet to be described. Materials and Methods: We retrospectively analyzed a database of Tanner 5 boys ages 16-21 who presented with varicocele at a single institution between 2009 and 2017. All patients had a scrotal sonogram prior to surgical intervention. TTV and TVD were calculated for each individual and four non-exclusive groupings of patients were created for statistical analysis. We chose 30 cc as a cut off value for low TTV based on prior studies. Results: 209 patients met our inclusion criteria. Mean age was 18.3 years (16-21, SD 1.7) with a mean total testicular volume of 36 cc (13.5-78.2, SD 11.1). Cut off points of TVD of 20% and TTV of 30 cc were used to separate patients. There were 65 boys (31%) with TTV < 30 cc and 58 boys (28%) with TVD ≥ 20%. Among males with TTV < 30 cc, 23 (35%) had a TVD ≥ 20%. Among males with TTV ≥ 30 cc, 35 (24%) had a TVD ≥ 20%. The relationship between TVD and TTV was found to be non-significant (p > 0.05). Discussion: Adolescent varicoceles continue to pose a challenge to pediatric urologists. The dilemma of over-aggressive treatment has proven difficult to balance with the risk of infertility. We hoped that elucidating the relationship between TTV and TVD could be useful in identifying patients who are at greater risk for infertility while decreasing the need for more intrusive testing, such as semen analysis, in an adolescent population. We looked at the direct relationship between low TTV and high TVD. In our population, there was a non-significant relationship between TTV < 30 cc and TVD ≥ 20% (p > 0.05) indicating that in adolescents with varicocele, TTV and TVD are independent variables. Our study limitations include the inherent user dependent bias of ultrasound measurements and data collection at a single institution with high ethnic diversity, possibly not comparable to all patient populations. Conclusions: Low TTV (< 30 cc) itself is not predictive of high TVD (≥ 20%) in adolescent boys with varicocele, despite their reported independent associations with impaired fertility in other studies.

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INTRODUCTION: We evaluated the relationship between total testicular volume (TTV) and testicular volume differential (TVD) in adolescent males with varicocele. Both low TTV and high TVD have been independently associated with higher incidences of infertility later in life, but a predictive relationship between TTV and TVD directly has yet to be described. MATERIALS AND METHODS: We retrospectively analyzed a database of Tanner 5 boys ages 16-21 who presented with varicocele at a single institution between 2009 and 2017. All patients had a scrotal sonogram prior to surgical intervention. TTV and TVD were calculated for each individual and four non-exclusive groupings of patients were created for statistical analysis. We chose 30 cc as a cut off value for low TTV based on prior studies. RESULTS: 209 patients met our inclusion criteria. Mean age was 18.3 years (16-21, SD 1.7) with a mean total testicular volume of 36 cc (13.5-78.2, SD 11.1). Cut off points of TVD of 20% and TTV of 30 cc were used to separate patients. There were 65 boys (31%) with TTV < 30 cc and 58 boys (28%) with TVD ≥ 20%. Among males with TTV < 30 cc, 23 (35%) had a TVD ≥ 20%. Among males with TTV ≥ 30 cc, 35 (24%) had a TVD ≥ 20%. The relationship between TVD and TTV was found to be non-significant (p > 0.05). DISCUSSION: Adolescent varicoceles continue to pose a challenge to pediatric urologists. The dilemma of over-aggressive treatment has proven difficult to balance with the risk of infertility. We hoped that elucidating the relationship between TTV and TVD could be useful in identifying patients who are at greater risk for infertility while decreasing the need for more intrusive testing, such as semen analysis, in an adolescent population. We looked at the direct relationship between low TTV and high TVD. In our population, there was a non-significant relationship between TTV < 30 cc and TVD ≥ 20% (p > 0.05) indicating that in adolescents with varicocele, TTV and TVD are independent variables. Our study limitations include the inherent user dependent bias of ultrasound measurements and data collection at a single institution with high ethnic diversity, possibly not comparable to all patient populations. CONCLUSIONS: Low TTV (< 30 cc) itself is not predictive of high TVD (≥ 20%) in adolescent boys with varicocele, despite their reported independent associations with impaired fertility in other studies.

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Chronic epididymitis and varicocele are frequently observed genital disorders in men consulting for couple infertility, but their impact on semen characteristics at the time of infertility consultation is still a matter of debate. We investigated 652 male partners of couples who had their first infertility consultation between 1999 and 2015 in Argentina. Men with chronic epididymitis (n = 253), Grade III varicocele (n = 106), and both conditions (n = 125) were compared with a control group (n = 168) composed of men without these disorders or any other recognized causes of male infertility. We showed that men who presented isolated chronic epididymitis were more likely to have high percentages of low sperm motility and abnormal sperm morphology as well as a high number of white blood cells. Men with isolated Grade III varicocele had low sperm production and motility and an increased percentage of abnormal sperm morphology. Finally, men who simultaneously presented chronic epididymitis with Grade III varicocele had a low sperm motility and increased percentage of abnormal sperm morphology as well as a high number of white blood cells. Physical examination of the genital organs may identify common disorders, potentially involved as causal factors of patient's infertility. These disorders are associated with specific seminal profiles that should help in identifying the best treatment from the available therapeutic options, effectiveness, safety, and allowing as much as possible natural conception.

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