Abstract
Purpose
Despite the significant role of varicocele in the pathogenesis of male infertility, its association with anti-sperm antibodies (ASA) remains controversial. This systematic review and meta-analysis (SRMA) aims to investigate the frequency of ASA positivity in men with varicocele.
Materials and Methods
This SRMA is conducted in accordance with the Meta-analysis of Observational Studies in Epidemiology guidelines. We investigated the frequency of ASA positivity in ejaculates or serum of men with varicocele as compared to men without varicocele (controls). A literature search was performed using the Scopus and PubMed databases following the Population Exposure Comparison Outcome, Study Design model. Data extracted from eligible studies were meta-analyzed and expressed as odds ratios (ORs) and confidence intervals (CIs).
Results
Out of 151 abstracts identified during the initial screening, 6 articles met the inclusion criteria and were included in the meta-analysis. Using mixed antiglobulin reaction (MAR) assay, 61 out of the 153 (39.8%) patients with varicocele tested positive for ASA in their ejaculates as compared to 22 out of the 129 control subjects (17%, OR=4.34 [95% CI: 1.09–17.28]; p=0.04). Using direct or indirect immunobead test, 30 out of 60 cases diagnosed with varicocele (50%) had shown ASA positivity in their ejaculates as compared to 16 out of 104 controls (15.4%, OR=3.57 [95% CI: 0.81–15.68]; p=0.09). Using enzyme-linked immunosorbent assay (ELISA), out of 89 varicocele patients, 33 (37.1%) tested positive for serum ASA as compared to 9 out of 57 participants in the control group (15.8%, OR=7.87 [95% CI: 2.39–25.89]; p<0.01).
Conclusions
This SRMA indicates that ASA positivity is significantly higher among men with varicocele when tested by direct method (MAR) or indirect method (ELISA). This data suggests an immunological pathology in infertile men with varicocele and may have implications for the management of these patients.
Keywords: Antisperm antibodies, Enzyme-linked immunosorbent assay, Immunoglobulins, Infertility, Varicocele
INTRODUCTION
The prevalence of varicocele is variable, subject to the method of varicocele identification, age, and fertility status of these individuals [1,2]. Varicocele is reported in up to 45% of men presenting with primary infertility and up to 80% of males with secondary infertility [3].
The correlation between male infertility and varicocele has been a subject of thorough investigation over time. Although the impact of varicocele on male fertility remains incompletely understood [4], several potential mechanisms have been proposed. These include oxidative stress, testicular hypoperfusion, blood stasis leading to toxin accumulation, temperature dysregulation, and hormonal imbalances [5]. Yet, none of these individual mechanisms alone offer a comprehensive explanation for the adverse effects of varicocele on testicular function [6].
It is widely accepted that the blood-testis barrier shields the spermatozoa from the immune system. However, the immune system may produce anti-sperm antibodies (ASA) in instances of injury or inflammation [7]. ASA have been correlated with urogenital infections, vasectomy, and varicocele [8,9,10]. The production of these antibodies has been linked to immunological infertility, although their relevance remains controversial [11]. The methods of ASA detection directly in semen include the mixed antiglobulin reaction (MAR) and the immunobead test (IBT). However, a clinically relevant reference range based on the proportion of bound spermatozoa has not been unanimously established. The latest World Health Organization (WHO) guidelines recommend individual laboratories to determine their own reference range by testing healthy, fertile men [12]. Indirect methods for ASA detection in sperm-free fluids (seminal plasma or serum) include IBT and enzyme-linked immunosorbent assay (ELISA).
The current literature lacks evidence on the impact of varicocele on the levels of ASA. Therefore, the aim of the current systematic review and meta-analysis (SRMA) was to investigate the potential for ASA positivity among men with varicocele as compared to men without varicocele.
MATERIALS AND METHODS
1. Protocol and registration
This SRMA was performed following the Meta-Analysis and Systematic Reviews of Observational Studies guidelines [13]. The PROSPERO database registration number of this SRMA is CRD42023430030. This study was approved by the Global Andrology Forum Internal Review Board (IR-IR-02-23-106).
2. Study eligibility
This SRMA included human observational studies investigating the presence of ASA in ejaculates or sera of men with varicocele as compared to men without varicocele. A specific population (P), exposure (E), comparator (C), outcome (O) and study design (S) framework was used to define study eligibility. Studies were considered eligible for inclusion if they investigated ASAs in men with varicocele as compared to men without varicocele.
3. Study outcomes
The primary outcome of the study was the percentage of ASA positivity using direct methods (MAR and direct IBT) or indirect methods (indirect IBT or ELISA). Secondary outcomes included basic semen parameters (semen volume, sperm concentration, total sperm motility, progressive sperm motility, sperm morphology, sperm vitality, sperm agglutination, and seminal leukocyte count).
4. Exclusion criteria
Articles published as abstracts, conference papers, case reports, case series, reviews, and book chapters, and animal studies were excluded. Studies on varicocele in men with azoospermia were also excluded.
5. Search strategy
A comprehensive systematic search was conducted using the Scopus and PubMed databases using a combination of Medical Subject Heading (MeSH) terms and free words.
An initial keyword string was created on Scopus “TITLE-ABS-KEY ( varicocel* AND antisperm AND antibod* ) AND ( LIMIT-TO ( DOCTYPE , “ar”) )” and PubMed “varicocel*”[All Fields] AND “antisperm”[All Fields] AND (“antibodie”[All Fields] OR “antibodies”[MeSH Terms] OR “antibodies”[All Fields] OR “antibody s”[All Fields] OR “antibodys”[All Fields] OR “immunoglobulins”[MeSH Terms] OR “immunoglobulins”[All Fields] OR “antibody”[All Fields])”. The databases were searched for studies published until October 2023. All English and non-English articles were included in the search. The search was filtered for males and humans.
After the removal of duplicates, investigators (VK, JFS, TM, MDD, RB, BK) independently screened the titles and abstracts of identified records for eligibility. The full texts of all potentially eligible records were then screened by 2 independent investigators. Any disagreement was resolved by discussion or by consulting a third investigator (MF).
6. Data extraction
Data were extracted by two independent investigators. Any disagreement was resolved by discussion or by consulting a third investigator. In case of missing data, the authors of the original study were contacted. Extracted data included the first author’s last name, year of publication, journal, study design, clinical characteristics of participants (volume of right and left testes, grade of varicocele, laterality of varicocele, and fertility status), the numbers of participants in both experimental and control groups, frequency of ASA positivity in semen using MAR or direct IBT or in sperm-free fluids using indirect IBT or ELISA, and basic semen parameters (semen volume [mL], sperm concentration [×106/mL], total sperm count [×106] total sperm motility [%], progressive sperm motility [%], sperm vitality [%], normal sperm forms [%], and sperm agglutination [%], seminal leukocytes [×106/mL]).
7. Assessment of quality of included studies
The quality of included studies was assessed using the Cambridge quality checklistsof observational studies [14]. The quality scores of each study were assessed by 2 independent investigators (KB, HK). Any disagreement was resolved by discussion or by consulting a 3rd investigator (MF).
8. Statistical analysis
The results of the studies evaluating the level of ASA in men with varicocele versus men without varicocele were pooled by meta-analysis. Odds ratio (OR) and confidence interval (IC) were used to estimate the differences in ASA positivity between the two study groups while mean difference (MD) was used to estimate the differences in basic semen parameters between groups. The in-between study heterogeneity was evaluated using the I2 statistic and the Cochrane Q test. Moderate heterogeneity was considered if the I2 was >40% and a p-value of <0.1 was considered significant heterogeneity. The random and fixed effect models were used for high and low heterogeneity. The Der-Simonian-Laird estimator [15] was used to calculate the in-between study variance and the Mantel-Haenszel method was used to pool the effect size. Publication bias was assessed using the funnel plot. Sensitivity analysis was done by excluding one study at a time and observing the changes in the pooled effect size. A study was considered sensitive when it significantly changed the pooled effect size when removed. The statistical analysis was performed using the R programming language (https://www.r-project.org/) and a p-value of <0.05 was considered statistically significant for the overall difference between groups.
RESULTS
1. Results of the literature search
Using the defined search strategy mentioned above, 179 abstracts were identified. After removing the duplicate records, 151 abstracts remained and were reviewed. Based on screening the title and abstract content, 126 of the abstracts were excluded as they were narrative reviews, commentaries, SRMAs, or letters to the editor. Among the remaining 25 articles that were initially considered eligible, 19 were excluded due to non-extractable data, inappropriate study population, and the unavailability of full texts. Eventually, 6 studies [16,17,18,19,20,21] met the inclusion criteria and were included in the meta-analysis. The Preferred Reporting Items of Systematic Reviews and Meta-analysis flowchart summarizing the literature research and article selection is shown in Fig. 1.
Fig. 1. PRISMA flowchart summarizing the literature research and article selection.
2. Quality of included studies
Two studies scored 10/15 [16,17], whereas four studies scored ≤5 points [18,19,20,21]. The summary of the outcomes of the Cambridge Quality Checklists is shown in Table 1.
Table 1. Quality of included studies assessed using the Cambridge Quality Checklist.
3. Patients’ features and basic semen parameters
Table 2 summarizes the extracted data. Generally, most of the patients’ basic features and semen parameters were found sporadic and inconsistent among the studies. The only meta-analyzable data was sperm concentration and total motility which was recorded in 2 studies [16,20]. The meta-analysis included 110 and 109 in the varicocele and no varicocele groups, respectively. The pooled estimate was not significantly different between the compared groups (MD: -16, 95% CI: -36 to 4.59).
Table 2. Summary of patients’ features and basic semen parameters of included studies.
| Reference | Study design | Patients (n) | Right testis volume (cc) | Left testis volume (cc) | Semen volume (mL) | Sperm concentration (M sperm/mL) | Sperm count (M sperm) | Total motility, n (%) | Normal sperm forms | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | Cases | Controls | ||
| Djaladat et al [16] | Case-control | 81 | 27 | NA | NA | NA | NA | NA | NA | 22.6 (1.9) | 28 (6.4) | NA | NA | 30.8 (16.8) | 30.7 (12) | NA | NA |
| Isitmangil et al [17] | Case-control | 30 | 30 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Gubin et al [18] | Case-control | 10 | 50 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Golomb et al [19] | Cross sectional | 32 | 22 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
| Oshinsky et al [20] | Case-control | 29 | 82 | NA | NA | NA | NA | 2.9 (0.26) | 3.4 (0.18) | 37.9 (1.26) | 64.2 (4.4) | NA | NA | 34.9 (3.7) | 58.3 (2.6) | NA | NA |
| Fichorova et al [21] | Cross sectional | 57 | 35 | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
NA: not applicable.
4. Anti-sperm antibodies detection using mixed antiglobulin reaction test
Using direct MAR assay, 4 studies evaluated ASA positivity in the ejaculates of varicocele patients and controls [16,17,18,19]. Antiserum bead combination for IgA, antiserum bead combination for IgG, or both monoclonal antihuman anti-immunoglobulins were used for direct MAR assay in the included studies. The reference value for a positive ASA test in semen varied from 25% to 50% for both IgG and IgA. Out of the pooled sample of 153 men diagnosed with varicocele, 61 (39.8%) were tested positive for seminal ASA versus 22/129 control subjects (17%, OR=4.34 [95% CI: 1.09–17.28]; p=0.04), with a significant inter-study heterogeneity (I2=63%) (Fig. 2).
Fig. 2. Forest plot of the ASA positivity using the MAR test in men with varicocele compared to men without varicocele. ASA: anti-sperm antibodies, MAR: mixed antiglobulin reaction, OR: odds ratio, CI: confidence interval.
At the leave-one-out sensitivity analysis, 3 studies [16,17,19] were found to be sensitive enough to impact the outcome (Fig. 3). The publication bias is shown in the funnel plot, Fig. 4.
Fig. 3. The forest plot of the ASA positivity using the MAR test in men with varicocele compared to men without varicocele: leave-one-out sensitivity analysis. ASA: anti-sperm antibodies, MAR: mixed antiglobulin reaction, OR: odds ratio, CI: confidence interval.
Fig. 4. Funnel plot (sensitivity analysis) of the ASA positivity using the MAR test in men with varicocele compared to men without varicocele. ASA: anti-sperm antibodies, MAR: mixed antiglobulin reaction.
5. Anti-sperm antibodies detection using immunobead test
Oshinsky et al [20] used direct IBT in the ejaculate, whereas Golomb et al [19] applied indirect IBT assay on both seminal plasma and serum. Anti-IgA and anti-IgG bead combination was used for IBT assay in these studies. The reference value for the ASA positivity ranged from 20%–25% for both immunoglobulins. Among the 60 patients diagnosed with varicocele, 30 cases (50%) were shown to be ASA-positive, whereas 16 out of 104 controls (15.4%) exhibited ASA positivity, a difference that was not found significant (OR=3.57 [95% CI: 0.81–15.68]; p=0.09) (Fig. 5). No significant interstudy heterogeneity was found in this analysis (I2=67%).
Fig. 5. Forest plot of the ASA positivity using IBT in men with varicocele compared to men without varicocele. ASA: anti-sperm antibodies, IBT: immunobead test, OR: odds ratio, CI: confidence interval.
6. Serum anti-sperm antibodies detection using enzyme-linked immunosorbent assay
In 2 studies including 89 cases and 57 controls, the detection of ASA positivity in serum was evaluated using ELISA assay [19,21]. However, these 2 studies did not determine exact plasma values for ASA positivity. Out of the of 89 varicocele patients, 33 (37.1%) individuals tested positive for serum ASA. On the other hand, 9 (15.8%) participants from the control group showed ASA positivity in their sera. The ASA-positivity rate in the sera of men with varicocele was significantly higher than the controls (OR=7.87 [95% CI: 2.39–25.89]; p<0.01) (Fig. 6), with the absence of significant interstudy heterogeneity (I2=2%).
Fig. 6. Forest plot of the ASA positivity in serum using ELISA in men with varicocele as compared to men without varicocele. ASA: anti-sperm antibodies, ELISA: enzyme-linked immunosorbent assay, OR: odds ratio, CI: confidence interval.
DISCUSSION
The findings of this SRMA indicate a significant increase in the prevalence of ASAs among men with varicocele as compared to those without varicocele. This observation was evident when MAR and ELISA tests were used for ASA assessment in ejaculates and sera, respectively, while ASA assessment by IBT failed to show a statistically significant difference between the 2 study groups.
Considering the potential effects of ASAs on both sperm quality and function, these findings may explain, at least in part, the impairment of sperm parameters and infertility in varicocele patients [22].
ASA refer to immunoglobulins that target antigens found on the surface of the sperm [23]. Antibodies directed against sperm can be detected in seminal plasma as well as in serum. These antibodies may be present either in a free form or attached to the surface of the sperm cell [24]. Immunoglobulins that specifically target sperm cells are predominantly categorized as IgG or IgA [25]. Regulatory T cells and B cells secreting IgG and IgA protect the testicular environment and spermatogenesis from damage normally induced by viral or bacterial infection [26,27].
Semen contains high levels of antigens, and immunological infertility may develop secondary to ASA formation [28]. Self-tolerance to sperm surface antigens does not develop in men during immunologic maturation. This is because spermatogenesis beginsatpuberty, when tolerance to self-antigens has already been established [28]. Typically, the locations responsible for sperm production, semen creation, and semen transportation are immune-privileged. However, when there is a disruption to the anatomical or immune barriers, it could lead to the formation of ASAs [29]. The impact of ASAs on male fertility is complex and directly related to sperm autoimmunity and the antigen specificity of ASAs. ASA can negatively affect sperm function by interfering with their motility, acrosome reaction, capacitation, and fertilization abilities [30]. Immune responses directed against sperm can lead to decreased sperm function and quality, as well as an increase in DNA breaks [31,32].
Studies conducted by Pan et al [33] and Raĭtsina et al [34] revealed a significant impairment in the blood-testis barrier in animal models with experimentally-induced varicocele. Furthermore, Raĭtsina et al [34] reported the presence of sensitized lymphocytes to spermatozoa antigens in the lymphatic organs of rats with varicocele. Soares et al [35] have indicated that the activation of the C kinase 1 receptor, due to varicocele, may have a significant impact on the phosphorylation of focal adhesion kinase. This was thought to disrupt the function of the blood-testis barrier and apical ectoplasmic specialization.
The lack of basic semen analysis data in human studies included in this meta-analysis precluded us from exploring the potential impact of ASA positivity on semen parameters. However, studies on animal models provide evidence that ASA may significantly impair sperm function in patients with varicocele [36]. Additionally, it has been stated that ASA-positive varicocele patients have lower sperm concentration, progressive motility, and normal morphology compared to ASA-negative patients with varicocele [37]. Similarly, the level of reactive oxygen species in varicocele patients who tested positive for ASA was 2.8 and 3.5 times higher than ASA-negative patients [38]. Further, Bozhemov et al [37] suggested that varicocele is a synergistic factor that increases the risk of ASA production during the sperm autoimmune response and leads to immune infertility. In other words, varicocele may be a cofactor for ASA production but not directly the main cause of ASA production.
To date, it is unclear when ASA testing should be conducted in varicocele patients. The WHO manual (6th edition) mentioned testing for antibody coating of spermatozoa in the extended semen examination section [12]. This guide states that if spermatozoa demonstrate abnormally high agglutination, the presence of ASA may be investigated. However, the manual states that ASAs can be present in the absence of sperm agglutination; and that factors other than ASAs can cause agglutination. In addition, the guideline highlights that detecting the presence of ASAs alone is insufficient for diagnosing sperm autoimmunity. The American Society for Reproductive Medicine, the American Urological Association, and the European Association of Urology do not recommend the use of the ASA test in the primary evaluation of male infertility. These guidelines have not made specific recommendations regarding ASA testing in patients suffering from clinical varicocele [39,40,41].
In a recent publication, Gupta et al [42] presented findings from a global survey that examined clinical practices regarding ASA testing. The latter study revealed that several reproductive health professionals consider sperm agglutination, asthenozoospermia, and failed assisted reproduction as indications to perform the ASA test in infertile men.
Despite the interesting findings of this systematic review, a few limitations are noted (Fig. 7). First, the number of studies testing ASAs in men with varicocele is relatively small. Second, the studies included in this SRMA exhibited some heterogeneity related to subjects’ characteristics, assay methods for ASA detection, and varicocele classification. These factors could have influenced the results and should be considered when interpreting the findings. Third, we were unable to correlate the results of ASA testing with semen parameters due to the paucity of studies reporting the two outcomes. Fourth, the quality of included studies was found to be low in four studies and moderate in two studies, thus precluding our ability to draw a firm conclusion about the relationship between varicocele and ASA.
Fig. 7. SWOT analysis. SRMA: systematic review and meta-analysis, ASA: anti-sperm antibodies.
CONCLUSIONS
The findings of this SRMA suggest that ASA positivity is more likely in men with varicocele as compared to men without varicocele. This result is in line with the immunological role of varicocele in the pathogenesis of male infertility. However, interpretation of these results should be done with caution due to factors such as the small number of studies on the topic, the low quality of most studies included in the analysis, bias related to the inclusion of heterogenous populations (fertile men and infertile men) and wide variability of the results. New research is warranted to address the above-mentioned limitations and to explore the relationship of ASA with semen quality and fertility potential among men with clinical varicocele.
Acknowledgements
The authors extend their gratitude to Taha Hamoda, MD (Saudi Arabia and Egypt), Tuncay Toprak, MD (Turkey), Taymour Moustafa, MD (Egypt) for their valuable review and feedback on this article. Special thanks to Damayanthi Durairajanayagam, PhD (Malaysia) for her assistance in reviewing and editing this manuscript. Additionally, the authors appreciate the contributions of Daniela Delgadillo, BSc for enhancing the illustrations and helping with the manuscript's submission.
Footnotes
Conflict of Interest: The authors have nothing to disclose.
Funding: None.
- Conceptualization: MF, RS, AA, RS.
- Writing – original draft preparation: MF, KB, HK, JFSV, RB, TM, MDD, VK, PM, AMH.
- Writing – review & editing: all authors.
- Statistical analysis: AMH.
- Supervision: MF, RS, AA.
- All authors have read and agreed to the published version of the manuscript.
References
- 1.Lomboy JR, Coward RM. The varicocele: clinical presentation, evaluation, and surgical management. Semin Intervent Radiol. 2016;33:163–169. doi: 10.1055/s-0036-1586143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Besiroglu H, Otunctemur A, Dursun M, Ozbek E. The prevalence and severity of varicocele in adult population over the age of forty years old: a cross-sectional study. Aging Male. 2019;22:207–213. doi: 10.1080/13685538.2018.1465913. [DOI] [PubMed] [Google Scholar]
- 3.Clavijo RI, Carrasquillo R, Ramasamy R. Varicoceles: prevalence and pathogenesis in adult men. Fertil Steril. 2017;108:364–369. doi: 10.1016/j.fertnstert.2017.06.036. [DOI] [PubMed] [Google Scholar]
- 4.Jensen CFS, Østergren P, Dupree JM, Ohl DA, Sønksen J, Fode M. Varicocele and male infertility. Nat Rev Urol. 2017;14:523–533. doi: 10.1038/nrurol.2017.98. [DOI] [PubMed] [Google Scholar]
- 5.Arya D, Balasinor N, Singh D. Varicocoele-associated male infertility: cellular and molecular perspectives of pathophysiology. Andrology. 2022;10:1463–1483. doi: 10.1111/andr.13278. [DOI] [PubMed] [Google Scholar]
- 6.Kang C, Punjani N, Lee RK, Li PS, Goldstein M. Effect of varicoceles on spermatogenesis. Semin Cell Dev Biol. 2022;121:114–124. doi: 10.1016/j.semcdb.2021.04.005. [DOI] [PubMed] [Google Scholar]
- 7.Kaur G, Thompson LA, Dufour JM. Sertoli cells--immunological sentinels of spermatogenesis. Semin Cell Dev Biol. 2014;30:36–44. doi: 10.1016/j.semcdb.2014.02.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Parslow JM, Royle MG, Kingscott MM, Wallace DM, Hendry WF. The effects of sperm antibodies on fertility after vasectomy reversal. Am J Reprod Immunol (1980) 1983;3:28–31. doi: 10.1111/j.1600-0897.1983.tb00208.x. [DOI] [PubMed] [Google Scholar]
- 9.Bonyadi MR, Madaen SK, Saghafi M. Effects of varicocelectomy on anti-sperm antibody in patients with varicocele. J Reprod Infertil. 2013;14:73–78. [PMC free article] [PubMed] [Google Scholar]
- 10.Jiang Y, Cui D, Du Y, Lu J, Yang L, Li J, et al. Association of anti-sperm antibodies with chronic prostatitis: A systematic review and meta-analysis. J Reprod Immunol. 2016;118:85–91. doi: 10.1016/j.jri.2016.09.004. [DOI] [PubMed] [Google Scholar]
- 11.Barbonetti A, Castellini C, D'Andrea S, Cordeschi G, Santucci R, Francavilla S, et al. Prevalence of anti-sperm antibodies and relationship of degree of sperm auto-immunization to semen parameters and post-coital test outcome: a retrospective analysis of over 10 000 men. Hum Reprod. 2019;34:834–841. doi: 10.1093/humrep/dez030. [DOI] [PubMed] [Google Scholar]
- 12.World Health Organization (WHO) WHO laboratory manual for the examination and processing of human semen. 6th ed. WHO; 2021. [Google Scholar]
- 13.Brooke BS, Schwartz TA, Pawlik TM. MOOSE reporting guidelines for meta-analyses of observational studies. JAMA Surg. 2021;156:787–788. doi: 10.1001/jamasurg.2021.0522. [DOI] [PubMed] [Google Scholar]
- 14.Murray J, Farrington DP, Eisner MP. Drawing conclusions about causes from systematic reviews of risk factors: the Cambridge Quality Checklists. J Exp Criminol. 2009;5:1–23. [Google Scholar]
- 15.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. doi: 10.1016/0197-2456(86)90046-2. [DOI] [PubMed] [Google Scholar]
- 16.Djaladat H, Mehrsai A, Rezazade M, Djaladat Y, Pourmand G. Varicocele and antisperm antibody: fact or fiction? South Med J. 2006;99:44–47. doi: 10.1097/01.smj.0000197036.08282.70. [DOI] [PubMed] [Google Scholar]
- 17.Isitmangil G, Yildirim S, Orhan I, Kadioglu A, Akinci M. A comparison of the sperm mixed-agglutination reaction test with the peroxidase-labelled protein A test for detecting antisperm antibodies in infertile men with varicocele. BJU Int. 1999;84:835–838. doi: 10.1046/j.1464-410x.1999.00283.x. [DOI] [PubMed] [Google Scholar]
- 18.Gubin DA, Dmochowski R, Kutteh WH. Multivariant analysis of men from infertile couples with and without antisperm antibodies. Am J Reprod Immunol. 1998;39:157–160. doi: 10.1111/j.1600-0897.1998.tb00348.x. [DOI] [PubMed] [Google Scholar]
- 19.Golomb J, Vardinon N, Homonnai ZT, Braf Z, Yust I. Demonstration of antispermatozoal antibodies in varicocele-related infertility with an enzyme-linked immunosorbent assay (ELISA) Fertil Steril. 1986;45:397–402. doi: 10.1016/s0015-0282(16)49224-1. [DOI] [PubMed] [Google Scholar]
- 20.Oshinsky GS, Rodriguez MV, Mellinger BC. Varicocele-related infertility is not associated with increased sperm-bound antibody. J Urol. 1993;150:871–873. doi: 10.1016/s0022-5347(17)35636-7. [DOI] [PubMed] [Google Scholar]
- 21.Fichorova RN, Dimitrova E, Nakov L, Tzvetkov D, Penkov R, Taskov H. Detection of antibodies toward epididymal sperm antigens--an obligatory step in evaluation of human immunologic infertility? Am J Reprod Immunol. 1995;33:341–349. doi: 10.1111/j.1600-0897.1995.tb00902.x. [DOI] [PubMed] [Google Scholar]
- 22.Verón GL, Molina RI, Tissera AD, Estofan GM, Marín-Briggiler CI, Vazquez-Levin MH. Incidence of sperm surface autoantibodies and relationship with routine semen parameters and sperm kinematics. Am J Reprod Immunol. 2016;76:59–69. doi: 10.1111/aji.12519. [DOI] [PubMed] [Google Scholar]
- 23.Restrepo B, Cardona-Maya W. Antisperm antibodies and fertility association. Actas Urol Esp. 2013;37:571–578. doi: 10.1016/j.acuro.2012.11.003. [DOI] [PubMed] [Google Scholar]
- 24.Cui D, Han G, Shang Y, Liu C, Xia L, Li L, et al. Antisperm antibodies in infertile men and their effect on semen parameters: a systematic review and meta-analysis. Clin Chim Acta. 2015;444:29–36. doi: 10.1016/j.cca.2015.01.033. [DOI] [PubMed] [Google Scholar]
- 25.Tung KS. Human sperm antigens and antisperm antibodies I. Studies on vasectomy patients. Clin Exp Immunol. 1975;20:93–104. [PMC free article] [PubMed] [Google Scholar]
- 26.Schroeder HW, Jr, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S41–S52. doi: 10.1016/j.jaci.2009.09.046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Bryan ER, Trim LK, Sadowski P, Paramasivan S, Kim JJ, Gough K, et al. Prophylactic and therapeutic vaccination protects sperm health from Chlamydia muridarum-induced abnormalities. Biol Reprod. 2023;108:758–777. doi: 10.1093/biolre/ioad021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Leathersich S, Hart RJ. Immune infertility in men. Fertil Steril. 2022;117:1121–1131. doi: 10.1016/j.fertnstert.2022.02.010. [DOI] [PubMed] [Google Scholar]
- 29.Chereshnev VA, Pichugova SV, Beikin YB, Chereshneva MV, Iukhta AI, Stroev YI, et al. Pathogenesis of autoimmune male infertility: juxtacrine, paracrine, and endocrine dysregulation. Pathophysiology. 2021;28:471–488. doi: 10.3390/pathophysiology28040030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Archana SS, Selvaraju S, Arangasamy A, Binsila B, Swathi D, Ramya L, et al. Seminal antigenicity affects mitochondrial membrane potential and acrosome reaction ability of the spermatozoa during cryopreservation. Theriogenology. 2021;159:132–139. doi: 10.1016/j.theriogenology.2020.10.025. [DOI] [PubMed] [Google Scholar]
- 31.Kaltsas A. Oxidative stress and male infertility: the protective role of antioxidants. Medicina (Kaunas) 2023;59:1769. doi: 10.3390/medicina59101769. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Dada R. Sperm DNA damage diagnostics: when and why. Transl Androl Urol. 2017;6(Suppl 4):S691–S694. doi: 10.21037/tau.2017.05.26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Pan J, Zhu Z, Xu G, Niu L, Yu L, Luo Z, et al. Expression of claudin-11 in a rat model of varicocele and its effects on the blood-testis barrier. Mol Med Rep. 2018;18:5647–5651. doi: 10.3892/mmr.2018.9603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Raĭtsina SS, Kurnosov AV, Iarovaia IM, Gladkova NS, Davydova AI. [Autoimmune nature of spermatogenesis disorders in varicocele models in rats] Biull Eksp Biol Med. 1979;87:44–48. Russian. [PubMed] [Google Scholar]
- 35.Soares TS, Fernandes SA, Lima ML, Stumpp T, Schoorlemmer GH, Lazari MF, et al. Experimental varicocoele in rats affects mechanisms that control expression and function of the androgen receptor. Andrology. 2013;1:670–681. doi: 10.1111/j.2047-2927.2013.00103.x. [DOI] [PubMed] [Google Scholar]
- 36.Fang 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. 2021;12:729539. doi: 10.3389/fimmu.2021.729539. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Bozhedomov VA, Lipatova NA, Rokhlikov IM, Alexeev RA, Ushakova IV, Sukhikh GT. Male fertility and varicocoele: role of immune factors. Andrology. 2014;2:51–58. doi: 10.1111/j.2047-2927.2013.00160.x. [DOI] [PubMed] [Google Scholar]
- 38.Eisenberg ML, Lipshultz LI. Varicocele-induced infertility: newer insights into its pathophysiology. Indian J Urol. 2011;27:58–64. doi: 10.4103/0970-1591.78428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Minhas S, Bettocchi C, Boeri L, Capogrosso P, Carvalho J, Cilesiz NC, et al. EAU Working Group on Male Sexual and Reproductive Health. European Association of Urology guidelines on male sexual and reproductive health: 2021 update on male infertility. Eur Urol. 2021;80:603–620. doi: 10.1016/j.eururo.2021.08.014. [DOI] [PubMed] [Google Scholar]
- 40.Schlegel 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 I. J Urol. 2021;205:36–43. doi: 10.1097/JU.0000000000001521. [DOI] [PubMed] [Google Scholar]
- 41.Schlegel 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. Fertil Steril. 2021;115:62–69. doi: 10.1016/j.fertnstert.2020.11.016. [DOI] [PubMed] [Google Scholar]
- 42.Gupta S, Sharma R, Agarwal A, Boitrelle F, Finelli R, Farkouh A, et al. Antisperm antibody testing: a comprehensive review of its role in the management of immunological male infertility and results of a global survey of clinical practices. World J Mens Health. 2022;40:380–398. doi: 10.5534/wjmh.210164. [DOI] [PMC free article] [PubMed] [Google Scholar]