Systematic Review of the Impact of Varicocele Grade on Response to Surgical Management
Abstract
Purpose:
We evaluated the impact of varicocele grade on the response to varicocelectomy or spermatic vein embolization.
Materials and Methods:
We systematically reviewed the published English language literature to identify studies on changes in semen quality and pregnancy outcomes after varicocele treatment, stratified by varicocele grade. Descriptive statistics and continuous random effects models were used to study the impact of varicocele grade and the surgical approach on the response to treatment. Result heterogeneity among studies was analyzed using the I2 statistic. Quality assessment of nonrandomized studies was done with the Newcastle-Ottawa Scale. Publication bias was analyzed using funnel plots and the Egger test.
Results:
We identified 20 studies describing the outcome of varicocele treatment stratified by varicocele grade in a total of 2,001 infertile men with varicocele. A microsurgical approach (inguinal, subinguinal and/or Palomo) was used in 11 of the 20 studies (55%). Varicocele treatment was associated with improvements in sperm concentration and overall motility in patients with all grades of varicocele. Semen quality improvements were directly related to varicocele grade. The mean sperm concentration improvement in men with grades 1, 2, 2-3 and 3 varicoceles were 5.5, 8.9, 12.7 and 16.0 million sperm per ml, respectively. The mean improvement in the percent of overall motility in men with grades 1, 2, 2-3 and 3 varicoceles was 9.6%, 10.6%, 10.8% and 17.7%, respectively. Pregnancy outcomes were assessed but could not be analyzed systematically due to the lack of adequate published data.
Conclusions:
Mean improvements in the sperm concentration and the percent of overall motility after treatment of grade 1 varicocele were statistically significant but small in magnitude. In contrast, mean improvements in the sperm concentration and the percent of overall motility after treatment of grade 2-3 varicoceles were greater and highly likely to be clinically significant. Incorporating varicocele grade into shared decision making discussions with affected couples may improve the ability to select patients who are the best candidates for treatment.
| ART |
assisted reproductive technology |
| ASRM |
American Society for Reproductive Medicine |
| AUA |
American Urological Association |
| IVF |
in vitro fertilization |
| NOS |
Newcastle-Ottawa Scale |
Varicocele, the most commonly identified correctable cause of male infertility, is found in up to 35% to 50% of men with primary infertility and 69% to 81% with secondary infertility.1,2 Varicocelectomy in properly selected patients improves semen quality and increases the probability of natural conception.3–5 However, it has been shown that about 85% of adolescents with uncorrected varicocele go on to achieve paternity with potential improvement in semen parameters if followed with time.6,7
The AUA and the ASRM recommend considering varicocelectomy in men with documented infertility, abnormal semen quality and minimal/no identified female factor.8 However, couples affected by associated male factor subfertility due to varicocele may elect to defer varicocele surgery and instead select treatment with ARTs such as intrauterine insemination or IVF. Kirby et al called the published AUA and ASRM guidelines into question, having found that varicocelectomy also improves ART.9 This has led to the growing significance of varicocele management in infertility care.
Treatment selection of varicocelectomy or ART in this extremely common clinical scenario is best accomplished through shared, individualized decision making between the affected couple and the physician. Such a discussion should include counseling about the risks, costs, benefits and efficacy of each approach. Factors often considered in this decision process include the number of children desired by the couple, the surgical risk profile of the affected male, the age and medical status of the female partner, the personal feelings of each couple about ART and resource availability. Varicocelectomy may offer a permanent solution to male factor infertility and it is considerably more cost-effective than ART.10 However, ART circumvents the need to correct abnormal semen parameters and it can be associated with shorter time to pregnancy.
Dubin and Amelar introduced the varicocele grading system in 1970 when they evaluated whether preoperative varicocele size was related to semen parameter changes.11 The grading system classifies grade 1 varicocele as varicocele palpable only by the Valsalva maneuver, grade 2 as palpable at rest but not visible and grade 3 as easily visible.
The AUA and ASRM guidelines group all clinical varicoceles together and do not distinguish by grade.3–5,8 However, it is intuitive that the degree of testicular impairment resulting from a varicocele might be influenced by the grade of the varicocele. Our objective was to systematically study the relationships of varicocele grade to baseline semen quality and the response to varicocelectomy using the 2010 WHO standards for the lower limit of normal for the sperm concentration as 15 million/ml and 40% for sperm motility. In so doing we wanted to explore varicocele grade as a possible factor which could be used to counsel affected couples about treatment options for varicocele associated subfertility.
Materials and Methods
This study was initially performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic reviews.12 However, due to the methodological and clinical heterogeneity of the included studies a meta-analysis was inappropriate and so a systematic review was pursued.
Search Strategy
We searched the literature to identify randomized clinical trials, cohort and case-control studies of the impact of varicocele grade on the response to varicocele treatment. We used certain databases, including PubMed® (1966 to December 7, 2016), Embase® (1966 to December 7, 2016) and MEDLINE® (1946 to December 7, 2016) with combinations of the terms “varicocele” AND “male infertility” AND “grade” or “size” AND “varicocelectomy OR varicocele ligation or varicocele repair.” The Cochrane CENTRAL (Central Register of Controlled Trials) database was searched and yielded 1 study, which was also obtained in a prior search. We also searched references of included studies to identify additional, potentially relevant studies.
Two of us (CJ and CMD) independently performed identical literature searches with no discordance. The searches were limited to human and adult studies. Unpublished studies were not sought and only English language articles were included. If multiple studies were identified with overlapping patients, only the most recent study was selected for inclusion.
Study Selection
The described search strategy was used to obtain titles and abstracts potentially relevant to the review. Studies were screened based on titles and abstracts. All duplicates were removed at this point and the full text of the articles was obtained. The citations of these full text articles were used to find additional studies which may have been missed by the initial search.
Studies were included in analysis if they met all of certain criteria, including 1) infertile men with at least a unilateral varicocele who underwent varicocelectomy or embolization, 2) the men were stratified by varicocele grade and 3) the effects of varicocelectomy on fertility or semen parameters were evaluated by grade. Studies were excluded if they met any of certain criteria, including 1) they did not provide data stratified by individual grade or a grouping of grades 2-3, excluding grade 1, 2) the majority of the study population consisted of middle and late adolescents, typically ages 15 to 21 years, or 3) fertility was not described by the pregnancy rate or at least 1 standard semen analysis parameter. Studies were excluded if varicocele repair was performed for indications other than fertility purposes.
Data Extraction
Extracted data included baseline semen parameters stratified by grade, posttreatment semen parameters stratified by grade, pregnancy rates stratified by grade and the surgical approach. Surgical approaches included microsurgical (inguinal, subinguinal and Palomo) vs all other varicocelectomy approaches (inguinal, subinguinal, scrotal and Palomo). The first author, number of participants, study design, study participants and followup duration were also extracted. Some studies referred to grade 1, 2 and 3 varicoceles as small, medium and large, respectively. These studies described the classification methodologies, which were identical or similar to the varicocele grading system. Therefore, for the purpose of this analysis small, medium and large varicoceles were considered grade 1, 2 and 3, respectively.
The primary outcomes were associations of varicocele grade with posttreatment improvement in semen parameters and the posttreatment pregnancy rate. Data were collected from the study text and tables. Authors were not contacted about missing data.
Quality Assessment
Nonrandomized studies were qualitatively assessed with the NOS. The NOS evaluates 3 categories, including selection, comparability and outcome, using a star system in which yes answers to the scale criteria yield a star. Selection, which has a maximum of 4 stars, is an evaluation of how appropriate the study and control populations are for evaluating the study hypothesis. Comparability with a maximum of 2 stars evaluates the comparability of the control and study groups. Outcome with a maximum of 3 stars assesses the time and methods of how outcomes were gathered.13 A score of 7 or greater is considered to indicate a high quality study.
Many studies examined different questions, including other questions than in this systematic review. The 1 randomized control trial included in study was analyzed with the 7-item Cochrane Collaboration tool to detect the risk of bias.14
Data Synthesis
Attempts were made to perform a meta-analysis but the heterogeneity of reported study populations was high, limiting the statistical conclusions of a meta-analysis. Due to the methodological and clinical heterogeneity of the included studies a meta-analysis was inappropriate. A narrative synthesis of the data was performed and ranges are provided for data as applicable.
Semen quality and pregnancy outcomes were stratified by grade for analysis. Because of different reporting strategies in the included studies, we included a grade 2-3 cohort in addition to the grades 1, 2 and 3 cohorts. Patients were grouped into the grade 2-3 cohort when it was not possible to determine whether they had grade 2 or 3 varicocele according to the relevant publication. The grade 2-3 cohort did not overlap with the grade 2 and 3 cohorts.
Posttreatment and pretreatment semen parameters were compared. The mean differences in sperm concentration and percent total motility were analyzed using a continuous random effects model. Heterogeneity of results among studies was analyzed using I2 statistics. Low, mid and high level heterogeneity was considered I2 less than 25%, 25% to 75% and greater than 75%, respectively.15 A meta-analysis was performed using R (https://www.r-project.org/foundation/) to create forest plots of each outcome. To evaluate publication bias, we produced a funnel plot for each corresponding forest plot. Additionally, we applied the Egger test to test the asymmetry/bias of each funnel plot. Publication bias analysis was determined with R.
Changes in sperm morphology after treatment could not be systematically analyzed due to high levels of variation in the classification systems used to report sperm morphology in the included studies and inconsistent reporting of changes in sperm morphology after treatment.
Results
Search Results
The initial database search identified 569 studies, including 190 from MEDLINE, 245 from Embase and 134 from PubMed. After screening and then excluding duplicate studies 264 articles met the criteria for further review. An additional 5 studies were added after manually searching relevant references. At that point 1 study was excluded because an updated version had been published which included many of the same patients from the prior study. Therefore, 269 articles were assessed for study eligibility, of which 247 were excluded after reading the full text. The 20 studies which met the criteria were included in the review (fig. 1).
Figure 1. Flowchart of screened, excluded and analyzed publications
Study Characteristics
The supplementary table (https://www.jurology.com) shows characteristics of the included studies. All 20 studies were published, full text articles, 17 were cohort studies evaluating semen parameters before and after surgery and 3 compared pregnancy rates by grade before and after surgery. The 20 selected studies evaluated a total of 2,001 infertile men with varicocele. Mean age of the pooled study populations varied from 26.4 to 38 years (range 16 to 63). In 11 studies only the microsurgical approach (inguinal and subinguinal) was used. The remaining 9 studies consisted of various surgical approaches, including Palomo (retroperitoneal), inguinal, subinguinal, scrotal and embolization.
The supplementary table (https://www.jurology.com) shows the post-procedure semen analysis time points also obtained for each study. Postintervention followup was most often done between 3 and 6 months but in 1 study followup ranged from 3 to about 77 months.
Quality Assessment
Nine of the 19 nonrandomized studies were high quality and none had a score below 5 (see table). Factors contributing most to poor quality assessment were the lack of a good comparison cohort (whether it was a nonsurgery group for pregnancy data or a grade 1 vs 2/3 varicocele group) and inadequate followup. One randomized study was at high risk of performance and detection bias since participants and personnel were not blinded. The study was also at high risk for attrition bias in that incomplete data were not disclosed. However, the study was at low risk for reporting bias in that there was no selective reporting. It had an uncertain risk of selection bias in that it did not state how the random sequence was generated or describe allocation concealment.
| Selection* | Comparability† | Outcome‡ | ||||||||
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | Score | |
| Baker et al: BMJ 1985; 291: 1678 | Yes | No | Yes | Yes | Yes | No | Yes | No | No | 5 |
| Vermeulen et al: J Androl 1986; 7: 147 | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | 8 |
| Steckel et al16 | Yes | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | 8 |
| Scherr et al24 | Yes | No | Yes | Yes | No | No | Yes | No | Yes | 5 |
| Jungwirth et al17 | Yes | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | 8 |
| Onozawa et al18 | Yes | Yes | Yes | Yes | Yes | No | No | No | Yes | 6 |
| Ishikawa and Fujisawa19 | Yes | No | Yes | Yes | No | No | Yes | Yes | Yes | 6 |
| Ortapamuk et al20 | No | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | 7 |
| Pasqualotto et al25 | Yes | No | Yes | Yes | No | No | Yes | Yes | Yes | 6 |
| Mohamid21 | Yes | Yes | Yes | Yes | Yes | No | Yes | Yes | No | 7 |
| Ozturk et al26 | Yes | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | 8 |
| Tavalaee et al32 | Yes | No | Yes | Yes | No | No | Yes | No | Yes | 5 |
| Leung et al27 | Yes | No | Yes | Yes | No | No | Yes | No | Yes | 5 |
| Grasso et al30 | Yes | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | 8 |
| Hosseinifar et al22 | Yes | No | Yes | Yes | No | No | Yes | Yes | Yes | 6 |
| Lehtihet et al31 | Yes | No | Yes | Yes | No | No | Yes | No | Yes | 5 |
| Guo et al29 | Yes | No | Yes | Yes | No | No | Yes | Yes | Yes | 6 |
| Tavalaee et al28 | Yes | No | Yes | Yes | No | No | Yes | No | No | 7 |
| Ni et al23 | Yes | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | 8 |
Varicocele Grade Prevalence among Treated Men
In the studies for this systematic review, which included 1,299 men representing all 3 clinical varicocele grades, 417 (32.1%) were evaluated for clinical varicocele grade 1. The remaining 846 men (67.9%) had grade 2 or 3 varicocele. As stated, studies were included if they provided data stratified by individual grade or a group of grades 2-3, excluding grade 1.
Associations
Varicocele Grade and Baseline Semen Parameters
Baseline sperm concentration was directly related to varicocele grade. Nine studies in a total of 294 men with grade 3 varicoceles showed a mean baseline concentration of 32.79 million sperm per ml (95% CI 15.75–49.83, I2 = 73.7%).16–23 Seven studies in a total of 381 men with grade 2-3 varicocele showed a mean baseline of 20.3 million sperm per ml (95% CI 7.18–33.34, I2 = 30.8 %).21,24–29 Seven studies in a total of 213 men with grade 2 varicocele showed a mean baseline concentration of 27.6 million sperm per ml (95% CI 10.52–44.73, I2 = 82.4%).16–21,23 Eight studies in a total of 211 men with grade 1 varicocele showed a mean baseline of 30.1 million sperm per ml (95% CI 18.55–41.59, I2 = 85.6%)16–21,23,30 The generally high I2 values further confirmed heterogeneity across all studies in our analyses.
Mean baseline total motility was also directly related to varicocele grade. Nine studies in a total of 156 men with grade 3 varicocele reported a mean baseline motility of 30.8% (95% CI 13.37–48.17, I2 = 60.0%)16,19–23,31 Nine studies in a total of 445 men with grade 2/3 varicocele showed a mean baseline motility of 29.4% (95% CI 19.33–39.39, I2 = 0%).21,24–29,32 Five studies in a total of 131 men with grade 2 varicocele had a mean baseline of 33.5% (95% CI 15.50–51.45, I2 = 72.05 %).16,19–21,23,33 Seven studies in a total of 101 men with grade 1 varicocele showed a mean of 35.3% (95% CI 28.47–42.13, I2 = 0%).16,19–21,23,33 There was low heterogeneity among patients with grade 1 and 2/3 varicoceles in terms of baseline sperm motility. This had implications in the observed outcomes of this parameter in the respective groups.
Varicocele Grade and Improved Semen Quality after Varicocelectomy
Systematic review demonstrated statistically significant improvements in the mean sperm concentration after varicocelectomy in men with all grades of varicocele (fig. 2). The magnitude of improvement was directly related to varicocele grade. The mean improvement in the sperm concentration in men with grade 1, 2, 2-3 and 3 varicocele was 5.5, 8.9, 12.7 and 16.0 million sperm per ml, respectively. High heterogeneity was observed among studies included in sperm concentration analyses for men with grade 1, 2 and 3 varicocele (I2=92.6%, 82.9% and 96.7%, respectively). Mid level heterogeneity was observed among included studies on sperm concentration analysis in men with grade 2-3 varicoceles (I2=69.2%). The Egger test performed for comparisons showed no evidence of publication bias as no p value was statistically significant (fig. 2).
Figure 2. Forest plots of mean sperm concentration before vs after varicocelectomy in men with varicocele. A, grade 3.16-23B, grade 2 or 3.12,24-29b/l, bilateral varicocele group. Uni, unilateral varicocele group. MV, standard microsurgical varicocelectomy group. IVDU, intraoperative Doppler group. C, grade 2.16,21,23D, grade 1.16-21,23,30
Systematic review also revealed statistically significant improvement in the overall percent of sperm motility after varicocelectomy in men with all varicocele grades (fig. 3).34 The magnitude of improvement was also directly related to varicocele grade. Mean improvement in the percent of total motility in men with grade 1, 2, 2-3 and 3 varicocele was 9.6%, 10.6%, 10.8% and 17.7%, respectively. High heterogeneity was observed among studies included in sperm concentration analysis in men with grade 1, 2-3 and 3 varicocele (I2=76.2%, 92.4% and 96.0%, respectively). Mid level heterogeneity was observed among included studies on sperm concentration analysis in men with grade 2 varicocele (I2=71.4%).
Figure 3. Forest plots of mean percent total motility before vs after varicocelectomy in men with varicocele. A, grade 3.16,19-23,31,34B, grade 2 or 3. b/l, bilateral varicocele group. Uni, unilateral varicocele group. MV, standard microsurgical varicocelectomy group. IVDU, intraoperative Doppler group.21,24-29,32C, grade 2.16,19-21,23D, grade 1.16,19-21,23,34
Overall our findings showed some degree of publication bias in 2 subgroup analyses. This bias included a change in motility after varicocelectomy of grade 1 varicocele (Egger p <0.001) and after varicocelectomy in the grade 2 or 3 group (Egger p=0.048).
Improved Semen Quality after Varicocelectomy by Surgical Approach
In 11 studies a microsurgical approach (inguinal, subinguinal and Palomo) was used for varicocele repair. The remaining 9 studies described a combination of Palomo, inguinal, subinguinal and scrotal approaches. Comparative subanalysis was done to assess differences in semen concentration and overall sperm motility based on surgical approach (microsurgical vs all others) stratified by varicocele grade. There was no statistically significant improvement in semen concentration or overall sperm motility for any varicocele grade when comparing a microsurgical approach to all other approaches (Palomo, inguinal, subinguinal, scrotal and embolization).
Varicocele Grade and Pregnancy Outcomes after Varicocelectomy
There were insufficient pregnancy data to stratify by grade for comparison in this study.
Discussion
The key findings of this study show improvement in semen concentration and motility after varicocelectomy with greater improvement in patients with higher grade varicocele. This has major implications for the management of infertility.
Despite some persistent controversy, the efficacy of varicocelectomy as a treatment of varicocele associated infertility is well established and supported by high quality clinical studies. Current AUA and ASRM guidelines recommend treatment in infertile men with a palpable varicocele, abnormal semen analysis and a fertile partner.3–5,8 Nonetheless, many men who meet the recommended criteria for varicocelectomy choose to defer treatment and continue attempts at natural conception or pursue reproduction via ART.
The underuse of varicocelectomy as a treatment strategy is likely multifactorial. Some possible explanations include a lack of knowledge among reproductive endocrinologists and patients about the demonstrated efficacy of varicocelectomy in properly selected patients, financial incentives which may bias reproductive endocrinologists toward performing ART and reluctance of male patients to undergo what they view as testicular surgery. In addition, the somewhat unpredictable and quantitatively modest impact of varicocelectomy on semen quality and the pregnancy rate may also drive clinical care away from varicocelectomy. This latter potential driver of the underuse of varicocelectomy could be reduced by efforts to refine patient selection to restrict treatment to those most likely to derive substantive clinical benefit from surgery.
Incorporating more specific clinical factors beyond palpable varicocele and abnormal semen parameters into shared decision making about varicocelectomy has already begun. The most recent guidelines of the ASRM have for the first time qualified the treatment recommendation by suggesting that men who meet criteria for treatment but have isolated teratozoospermia may be less likely to benefit from varicocelectomy than men with oligozoospermia and/or asthenozoospermia.8 This qualifying amendment to the overall recommendation is an acknowledgement of recent research demonstrating a minimal morphology improvement after varicocelectomy in patients with isolated teratozoospermia.35,36
There has been a recent focus in reproductive medicine on the role of varicocele repair in the era of ART and its significant clinical benefits in terms of sperm parameters. Varicocele repairs may obviate the need to proceed with IVF or other forms of ART. In a retrospective review by Samplaski et al 373 men who underwent varicocele repair via a microscopic subinguinal approach had statistically significant improvement in the total motile sperm count with the largest improvement in the lowest baseline total motile sperm count group of less than 5 million.37 More notably, in that study almost 60% of men who were initial IVF candidates were upgraded to be candidates for natural conception or intrauterine insemination. This has significant psychosocial and financial implications, given the emotional investment and direct cost of ART. In a meta-analysis by Kirby et al varicocele repair was associated with improved live birth and pregnancy rates with IVF or intracytoplasmic sperm injection in men with oligozoospermia or azoospermia.9 Furthermore, men with persistent azoospermia after varicocele repair who required testicular sperm extraction had an improved sperm retrieval rate.
The current analysis was done to determine whether varicocele grade could be incorporated into shared decision making with patients considering varicocelectomy. In particular, this analysis was performed to further inform decision making in patients with grade 1 varicocele, who comprise a large subset of the population with varicocele. Epidemiological data suggest that grade 1 varicocele accounts for 34.6% to 76.6% of varicoceles in subfertile men.38-40 In this study patients with grade 1 varicocele accounted for 33.9% of men who underwent varicocele treatment.
Men with grade 1 varicocele may be at lower risk for varicocele related testicular dysfunction than men with larger varicoceles due to the less severe physiological alterations which would be expected to result from milder venous dilatation and congestion. In some of these patients small varicoceles could be incidental findings which occur in the setting of infertility resulting from a different or an idiopathic etiology. Recent data on a large, multinational, population based study of semen quality in healthy European men supports the notion that the testicular injury resulting from varicocele does indeed depend on varicocele grade.41 In that study the proportion of men with low semen quality among those with grade 1 varicocele did not differ from that of men without varicocele (35.1% vs 31.4%). However, the proportion of men with grade 2 and 3 varicocele who had low semen quality was significantly higher than in men without varicocele (40.4% and 54.9%, respectively vs 31.4%).
Our study is consistent with recently published, population based data from Europe. It suggests that men with larger varicoceles have a lower baseline sperm concentration and a lower percent of overall motility than men with smaller varicoceles. Additionally, our data demonstrate that the magnitude of the treatment response to varicocelectomy is higher among men with grade 2-3 than grade 1 varicocele.
There are several limitations to our analysis. The first is that we found significant heterogeneity in the systematic review with all forest plots revealing an I2 of 69% or higher. However, it should be noted that the I2 statistic was biased to provide exaggerated heterogeneity in our systematic review due to the small number of studies included in each forest plot and to the reporting style of the studies.42 The studies provide a mean parameter before and after surgery with the SD but not a SD on the mean improvement itself. Therefore, we structured the systematic review to analyze the mean before and after surgery as if there were 2 independent groups. Since the groups were not independent but rather included the same patients, the variance was again overestimated.
The retrospective nature of several of these studies is also a limitation in this review. Another limitation involves the subjectivity of varicocele grading and accuracy among different physicians. A final limitation is the limited number of randomized controlled trials. Most varicocele studies have been self-controlled with pre-intervention and postintervention parameters in the same patient. Therefore, the dominance of cohort study types could have limited significant findings.
Publication bias occurs when the outcome of a research study influences the decision to publish research findings. This can skew the available original data to include only information with major results and possibly eliminate null findings. Evaluating for publication bias is important in the setting of any literature review because generated conclusions can be biased if the original literature is contaminated by this bias. Overall our findings showed some degree of publication bias on subgroup analyses, including the change in motility after varicocelectomy for grade 1 varicocele (Egger p <0.001) and the change in motility after varicocelectomy in the grade 2 or 3 group (Egger p=0.048). This lends some confidence to the conclusions of our study.
Furthermore, many studies are outdated, small and nonrandomized, and only 1 included study was a randomized controlled trial. We could not include data from the highest quality randomized, controlled trial of varicocelectomy because that study did not stratify the treatment response by varicocele grade.5 There was also significant heterogeneity in regard to surgical approaches and techniques whether the patient populations were restricted to unilateral or bilateral varicocele and whether they were screened for at least 1 abnormal semen analysis parameter.
Despite the limitations of this study, to our knowledge the current analysis is the largest one reported to date in which the treatment response to varicocelectomy stratified by varicocele grade was evaluated. Our analyses offer definitive and robust support that men with larger varicoceles benefit more from treatment than men with smaller varicoceles. This has been posited for many years but it has not been definitively demonstrated until now.
Conclusions
The improvement in semen quality which occurs after varicocele treatment is directly related to varicocele grade. Mean reported improvements in sperm concentration and the percent of overall motility after treatment of grade 1 varicocele are statistically significant but small. In contrast, mean reported improvements in the sperm concentration and the percent of overall motility after treatment of grade 2-3 varicocele are larger and highly likely to be clinically significant. Incorporating varicocele grade into shared decision making discussions with affected couples may improve our ability to select patients for varicocelectomy who are most likely to benefit from surgery.
References
- 1. : Loss of fertility in men with varicocele. Fertil Steril 1993; 59: 613. Crossref, Medline, Google Scholar
- 2. : Varicocele: a progressive or static lesion?Urology 1993; 42: 541. Google Scholar
- 3. : Surgery or embolization for varicoceles in subfertile men. Cochrane Database Syst Rev 2012; 10: CD000479. Google Scholar
- 4. : Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis. Fertil Steril 2007; 88: 639. Google Scholar
- 5. : Does varicocele repair improve male infertility? An evidence-based perspective from a randomized, controlled trial. Eur Urol 2011; 59: 455. Google Scholar
- 6. : Pubertal screening and treatment for varicocele do not improve chance of paternity as adult. J Urol 2013; 189: 2298. Link, Google Scholar
- 7. : The natural history of semen parameters in untreated asymptomatic adolescent varicocele patients: a retrospective cohort study. J Pediatr Urol 2017; 13: 77. Google Scholar
- 8. Report on varicocele and infertility: a committee opinion. Practice Committee of the American Society for Reproductive Medicine and Society for Male Reproduction and Urology. Fertil Steril 2014; 102: 1556. Google Scholar
- 9. : Undergoing varicocele repair before assisted reproduction improves pregnancy rate and live birth rate in azoospermic and oligospermic men with a varicocele: a systematic review and meta-analysis. Fertil Steril 2016; 106: 1338. Google Scholar
- 10. : The cost-effectiveness of treatment for varicocele related infertility. J Urol 2002; 168: 2490. Link, Google Scholar
- 11. : Varicocele size and results of varicocelectomy in selected subfertile men with varicocele. Fertil Steril 1970; 21: 606. Crossref, Google Scholar
- 12. : Evaluation of the endorsement of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement on the quality of published systematic review and meta-analyses. PLoS One 2013; 8: e83138. Google Scholar
- 13. : Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25: 603. Google Scholar
- 14. : The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928. Crossref, Medline, Google Scholar
- 15. : Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557. Google Scholar
- 16. : Relationship between varicocele size and response to varicocelectomy. J Urol 1993; 149: 769. Link, Google Scholar
- 17. : Clinical outcome of microsurgical subinguinal varicocelectomy in infertile men. Andrologia 2001; 33: 71. Google Scholar
- 18. : Clinical study of varicocele: statistical analysis and the results of long-term follow-up. Int J Urol 2002; 9: 455. Google Scholar
- 19. : Effect of age and grade on surgery for patients with varicocele. Urology 2005; 65: 768. Google Scholar
- 20. : Hemodynamic evaluation of varicocele: the role of scrotal scintigraphy and Doppler ultrasonography in the prediction of postoperative seminal improvement. Ann Nucl Med 2005; 19: 529. Google Scholar
- 21. : The effect of magnified bilateral varicocele ligation on semen quality and the natural paternity rate in subfertile men, based on the sum of varicocele grading. Arab J Urol 2012; 10: 434. Google Scholar
- 22. : Study of the effect of varicocelectomy on sperm proteins expression in patients with varicocele and poor sperm quality by using two-dimensional gel electrophoresis. J Assist Reprod Genet 2014; 31: 725. Google Scholar
- 23. : A comprehensive investigation of sperm DNA damage and oxidative stress injury in infertile patients with subclinical, normozoospermic, and astheno/oligozoospermic clinical varicocoele. Andrology 2016; 4: 816. Google Scholar
- 24. : Comparison of bilateral versus unilateral varicocelectomy in men with palpable bilateral varicoceles. J Urol 1999; 162: 85. Link, Google Scholar
- 25. : Is it worthwhile to operate on subclinical right varicocele in patients with grade II-III varicocele in the left testicle?J Assist Reprod Genet 2005; 22: 227. Google Scholar
- 26. : Effect of spermatic vein ligation on seminal total antioxidant capacity in terms of varicocele grading. Andrologia 2012; 44: 199. Google Scholar
- 27. : Subinguinal microsurgical varicocelectomy for male factor subfertility: ten-year experience. Hong Kong Med J 2013; 19: 334. Google Scholar
- 28. : Effect of varicocelectomy on sperm functional characteristics and DNA methylation. Andrologia 2015; 47: 904. Google Scholar
- 29. : Outcomes of microscopic subinguinal varicocelectomy with and without the assistance of Doppler ultrasound: a randomized clinical trial. Urology 2015; 86: 922. Google Scholar
- 30. : Low-grade left varicocele in patients over 30 years old: the effect of spermatic vein ligation on fertility. BJU Int 2000; 85: 305. Google Scholar
- 31. : Left-sided grade 3 varicocele may affect the biological function of the epididymis. Scand J Urol 2014; 48: 284. Google Scholar
- 32. : Semen parameters and chromatin packaging in microsurgical varicocelectomy patients. Int J Fertil Steril 2012; 6: 165. Google Scholar
- 33. : Relationship between grade of varicocele and the response to varicocelectomy. Int J Urol 1996; 3: 282. Google Scholar
- 34. : Factors related to semen improvement and fertility after varicocele operation. Fertil Steril 1984; 41: 404. Crossref, Google Scholar
- 35. : Is varicocelectomy indicated in subfertile men with clinical varicoceles who have asthenospermia or teratospermia and normal sperm density?Int J Urol 2007; 14: 729. Google Scholar
- 36. : Results of varicocelectomy in patients with isolated teratozoospermia. Urol Int 2008; 80: 172. Google Scholar
- 37. : Varicocelectomy to “upgrade” semen quality to allow couples to use less invasive forms of assisted reproductive technology. Fertil Steril 2017; 108: 609. Google Scholar
- 38. The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. World Health Organization. Fertil Steril 1992; 57: 1289. Google Scholar
- 39. : Varicocele among healthy young men in Turkey; prevalence and relationship with body mass index. Int Braz J Urol 2012; 38: 116. Google Scholar
- 40. : Male fertility and varicocoele: role of immune factors. Andrology 2014; 2: 51. Google Scholar
- 41. : Varicocele is associated with impaired semen quality and reproductive hormone levels: a study of 7035 healthy young men from six European countries. Eur Urol 2016; 70: 1019. Google Scholar
- 42. : The heterogeneity statistic I2 can be biased in small meta-analyses. BMC Med Res Methodol 2015; 15: 35. Google Scholar
The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number.
No direct or indirect commercial, personal, academic, political, religious or ethical incentive is associated with publishing this article.
