The association between body mass index and varicocele: A meta-analysis

Guo Xiao-Bin Wu Fang-Lei Xia Hui Yang Cheng Cai Zhi-Xuan Huang Zhi-Peng Liu Cun-Dong Guo Wen-Bin About the authors

ABSTRACT

Objective:

Recently, several studies have found that obesity had a protective effect against varicocele, but no meta-analysis has confirmed this finding. Therefore, we conducted this meta-analysis to investigate the association between body mass index (BMI) and varicocele.

Material and Methods:

We searched for studies in PubMed, Science Direct and the Cochrane Library from inception until February 2018. The association between BMI and varicocele was assessed by pooling the odds ratios (ORs).

Results:

Eleven eligible studies with a total study population of 1.376.658 participants were included in our analysis. According to BMI, the subjects were defined as belonging to the obese, overweight and underweight groups. Our results showed that the obese group had a lower risk of varicocele when compared with the normal weight group (odds ratio [OR] 0.46, 95% confidence intervals [CIs] 0.37-0.58). Additionally, an overweight BMI had a protective effect against varicocele (OR 0.70, 95% CIs, 0.56-0.86). However, underweight patients had a more than 30% higher risk of varicocele (OR 1.31, 95% CI, 1.04-1.64). Furthermore, there was no publication bias in any of the analyses.

Conclusions:

Our study demonstrates that BMI is negatively associated with the presence of varicocele.

Keywords:
Varicocele; Meta-Analysis [Publication Type]; Body Mass Index

INTRODUCTION

Varicocele is present in approximately 15% of the general population. However, more than one-third of men consult doctors regarding infertility, and nearly 80% of secondary infertile men suffer from varicocele (11. Baazeem A, Belzile E, Ciampi A, Dohle G, Jarvi K, Salonia A, et al. Varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. Eur Urol. 2011;60:796-808.). Varicocele is caused by dilatation and tortuosity of the pampiniform plexus. When the valves within the veins along the spermatic cord do not work appropriately, leading to blood backflow, varicocele occurs. The backflow of blood into the pampiniform plexus increases vein pressure and hypoxia, which may damage testicular spermatogenesis (22. Naughton CK, Nangia AK, Agarwal A. Pathophysiology of varicoceles in male infertility. Hum Reprod Update. 2001;7:473-81.). It is well known that most patients have varicocele on the left side (33. Abdel-Meguid TA, Al-Sayyad A, Tayib A, Farsi HM. Does varicocele repair improve male infertility? An evidence-based perspective from a randomized, controlled trial. Eur Urol. 2011;59:455-61.). Left renal vein entrapment, defined as compression of the left renal vein between the aorta and the superior mesenteric artery, is common in varicocele patients (44. Lewis DS, Grimm LJ, Kim CY. Left renal vein compression as cause for varicocele: prevalence and associated findings on contrast-enhanced CT. Abdom Imaging. 2015;40:3147-51., 55. Sigmund G, Gall H, Bähren W. Stop-type and shunt-type varicoceles: venographic findings. Radiology. 1987;163:105-10.). There were studies that showed that body mass index (BMI) was lower in patients with renal-vein entrapment than in controls, with a regression of haematuria correlating with an increase in BMI (66. Vianello FA, Mazzoni MB, Peeters GG, Fossali EF, Camozzi P, Bianchetti MG, et al. Micro- and macroscopic hematuria caused by renal vein entrapment: systematic review of the literature. Pediatr Nephrol. 2016;31:175-84.). Therefore, the relationship between BMI and varicocele is worth further discussion.

The prevalence of overweight and obesity has become a global problem. Overweight and obese are assessed by the body mass index (BMI), which is calculated as the weight (kg) divided by the square of the height (m2). It was expected that there would be more than 700 million obese adults and 2.3 billion overweight adults worldwide by 2015 (77. Stothard KJ, Tennant PW, Bell R, Rankin J. Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA. 2009;301:636-50.). Recently, several studies (88. Najari BB, Katz MJ, Schulster ML, Lee DJ, Li PS, Goldstein M. Increased Body Mass Index in Men With Varicocele Is Associated With Larger Spermatic Vein Diameters When Supine. Urology. 2016;89:40-4.

9. Fazeli F, Shahraki M, Bazzaz MM, Fazeli K. Association between Body Mass Index and frequency and grade of varicocele in southeast Iran. J Med Life. 2015;8(Spec Iss 2):62-65.
-1010. Bae K, Shin HS, Jung HJ, Kang SH, Jin BS, Park JS. Adolescent varicocele: are somatometric parameters a cause? Korean J Urol. 2014;55:533-5.) have found that obesity has a protective effect against varicocele, but no meta-analysis has confirmed this finding. Previous research has discussed the association between varicocele and other factors, such as height, age, lifestyle habits and BMI (1111. Delaney DP, Carr MC, Kolon TF, Snyder HM 3rd, Zderic SA. The physical characteristics of young males with varicocele. BJU Int. 2004;94:624-6.

12. Handel LN, Shetty R, Sigman M. The relationship between varicoceles and obesity. J Urol. 2006;176:2138-40; discussion 2140.

13. May M, Taymoorian K, Beutner S, Helke C, Braun KP, Lein M, et al. Body size and weight as predisposing factors in varicocele. Scand J Urol Nephrol. 2006;40:45-8.

14. Nielsen ME, Zderic S, Freedland SJ, Jarow JP. Insight on pathogenesis of varicoceles: relationship of varicocele and body mass index. Urology. 2006;68:392-6.

15. Prabakaran S, Kumanov P, Tomova A, Hubaveshki S, Agarwal A. Adolescent varicocele: association with somatometric parameters. Urol Int. 2006;77:114-7.
-1616. Chen SS, Huang WJ. Differences in biochemical markers and body mass index between patients with and without varicocele. J Chin Med Assoc. 2010;73:194-8.). There are inconsistent results regarding the relationship between varicocele and BMI. Some research suggested that BMI was inversely associated with the prevalence of varicocele (1212. Handel LN, Shetty R, Sigman M. The relationship between varicoceles and obesity. J Urol. 2006;176:2138-40; discussion 2140.

13. May M, Taymoorian K, Beutner S, Helke C, Braun KP, Lein M, et al. Body size and weight as predisposing factors in varicocele. Scand J Urol Nephrol. 2006;40:45-8.
-1414. Nielsen ME, Zderic S, Freedland SJ, Jarow JP. Insight on pathogenesis of varicoceles: relationship of varicocele and body mass index. Urology. 2006;68:392-6.), whereas other studies found no such relationship (1010. Bae K, Shin HS, Jung HJ, Kang SH, Jin BS, Park JS. Adolescent varicocele: are somatometric parameters a cause? Korean J Urol. 2014;55:533-5., 1111. Delaney DP, Carr MC, Kolon TF, Snyder HM 3rd, Zderic SA. The physical characteristics of young males with varicocele. BJU Int. 2004;94:624-6., 1717. Oster J. Varicocele in children and adolescents. An investigation of the incidence among Danish school children. Scand J Urol Nephrol. 1971;5:27-32., 1818. Shafi H, Agajani Delavar M. Differences in body mass index and height factors between men with and without varicocele. Med Glas (Zenica). 2015;12:212-5.). With this background, we conducted this meta-analysis to elucidate the relationship between BMI and varicocele.

MATERIAL AND METHODS

Search strategy

A comprehensive computerized search in PubMed, Science Direct and the Cochrane Library was conducted from inception to February 2018. We used the following search strategy: varicocele AND (body mass index OR BMI or underweight or obese or overweight). Reference lists and conference proceedings were also searched manually to identify possible additional studies.

Study selection

The inclusion criteria were as follows: 1) the topic is varicocele; 2) odds ratios (ORs), relative risks (RRs), hazard ratios (HRs) and standardized incidence ratios with 95% confidence intervals (CIs) were provided or could be calculated; 3) randomized controlled trials or observational studies (case-control, cross-sectional or cohort studies) published as original studies to evaluate the association between BMI and varicocele; and 4) underweight, obese, overweight or BMI criteria were reported based on the definitions that were established by the Centers for Disease Control. Eligible studies were independently determined by two investigators (Guo Wenbin and Wu Fanglei). Differing decisions were resolved by mutual consensus.

Reviews, meeting abstracts, commentaries and editorials were excluded from our analysis. We also excluded the studies if they provided only an estimate of effect, with no means by which to calculate the standard error.

Data extraction

A standardized data collection form was used to extract the following information: last name of the first author, year of publication, country of origin, study design, sample size, BMI category, and adjusted effect estimates with 95% CI. Two investigators (Yang Cheng and Huang Zhipeng) independently performed the data extraction.

Statistical Analysis

The strength of the relationship between BMI and varicocele was assessed by ORs. ORs were extracted from individual studies and were combined with a fixed-effect model or a random-effect model. Multivariate ORs were used for statistical analysis in preference to the univariate ORs. If the ORs were not directly provided, case and control group numbers were obtained. We first translated the data to ORs for further combination. The ORs from individual studies were transformed to their log [ORs] to stabilize the variance and normalize the distribution before pooling the studies (1919. Walter SD, Cook RJ. A comparison of several point estimators of the odds ratio in a single 2 × 2 contingency table. Biometrics. 1991;47:795-811.). Pooled ORs <1 reflected a favourable outcome in obese patients compared with healthy subjects and indicated a lower morbidity rate.

For the meta-analysis, both the fixed-effects model (weighted with inverse variance) and the random-effects model were considered based on the level of heterogeneity. Pooled estimates of efficacy were calculated using the Mantel-Haenszel fixed-effects model first (2020. Wei M, Macera CA, Davis DR, Hornung CA, Nankin HR, Blair SN. Total cholesterol and high density lipoprotein cholesterol as important predictors of erectile dysfunction. Am J Epidemiol. 1994;140:930-7.). However, if there was heterogeneity, the following methods were used to explore the source of heterogeneity: 1) a subgroup analysis and 2) a sensitivity analysis excluding the trials that potentially biased the results. If heterogeneity still existed, the DerSimonian and Laird random-effects model was used.

For each meta-analysis, we assessed the between-study heterogeneity using the X2 test and I2 statistics, which assessed the appropriateness of pooling the individual study results (2121. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-60.). The value of I2 indicates the degree of heterogeneity, with 0-25% indicating insignificant heterogeneity, 26-50% indicating low heterogeneity, 51-75% indicating moderate heterogeneity and more than 75% indicating high heterogeneity.

The presence of publication bias was assessed by funnel plots of the logarithm of the odds ratios versus their standard errors. We used Begg's (2222. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088-101.) and Egger's (2323. Egger M, Smith GD. Bias in location and selection of studies. BMJ. 1998;316:61-6.) tests to evaluate the presence of publication bias in our primary end points; P <0.05 indicated bias, and P >0.05 indicated no publication bias. Stata 10.0 software was used for all the data analyses.

RESULTS

The search strategy generated 674 references: PubMed (N=103), ScienceDirect (N=556), and Cochrane Library (N=5). A total of thirty-six potentially eligible studies were identified by the literature search. Three articles were excluded because they were reviews, editorials and responses. We excluded twenty-two studies that did not report the outcome of varicocele or did not provide enough data to calculate the ORs. Finally, we identified eleven full-text articles (1212. Handel LN, Shetty R, Sigman M. The relationship between varicoceles and obesity. J Urol. 2006;176:2138-40; discussion 2140., 1414. Nielsen ME, Zderic S, Freedland SJ, Jarow JP. Insight on pathogenesis of varicoceles: relationship of varicocele and body mass index. Urology. 2006;68:392-6., 1818. Shafi H, Agajani Delavar M. Differences in body mass index and height factors between men with and without varicocele. Med Glas (Zenica). 2015;12:212-5., 2424. Baek M, Park SW, Moon KH, Chang YS, Jeong HJ, Lee SW, et al. Nationwide survey to evaluate the prevalence of varicoceles in South Korean middle school boys: a population based study. Int J Urol. 2011;18:55-60.

25. Chanc Walters R, Marguet CG, Crain DS. Lower prevalence of varicoceles in obese patients found on routine scrotal ultrasound. J Urol. 2012;187:599-601.

26. Soylemez H, Atar M, Ali Sancaktutar A, Bozkurt Y, Penbegul N. Varicocele among healthy young men in Turkey; prevalence and relationship with body mass index. Int Braz J Urol. 2012;38:116-21.

27. Gokce A, Demirtas A, Ozturk A, Sahin N, Ekmekcioglu O. Association of left varicocoele with height, body mass index and sperm counts in infertile men. Andrology. 2013;1:116-9.

28. Rais A, Zarka S, Derazne E, Tzur D, Calderon-Margalit R, Davidovitch N, et al. Varicocoele among 1.300.000 Israeli adolescent males: time trends and association with body mass index. Andrology. 2013;1:663-9.

29. Engin Do antekin, Sacit Nuri Görgel, Evren Şahin, Cengiz Girgin. elationship between varicocele and anthropometric indices in infertile population İnfertilite olgularında varikosel ve antropometrik index ili kisi. Dicle Medical Journal 2014;41:59-63.

30. Hadjkacem Loukil L, Hadjkacem H, Bahloul A, Ayadi H. Relation between male obesity and male infertility in a Tunisian population. Andrologia. 2015;47:282-5.
-3131. Liu J, Zhang S, Liu M, Wang Q, Shen H, Zhang Y, et al. Prevalence of varicocoele and its association with body mass index among 39,559 rural men in eastern China: a population-based cross-sectional study. Andrology. 2017;5:562-567.) that met the inclusion criteria. The search flow chart is shown in Figure-1, and the characteristics of the eleven included articles are summarized in Table-1. Of the eleven articles, eight were case-control studies (1212. Handel LN, Shetty R, Sigman M. The relationship between varicoceles and obesity. J Urol. 2006;176:2138-40; discussion 2140., 1414. Nielsen ME, Zderic S, Freedland SJ, Jarow JP. Insight on pathogenesis of varicoceles: relationship of varicocele and body mass index. Urology. 2006;68:392-6., 1818. Shafi H, Agajani Delavar M. Differences in body mass index and height factors between men with and without varicocele. Med Glas (Zenica). 2015;12:212-5., 2525. Chanc Walters R, Marguet CG, Crain DS. Lower prevalence of varicoceles in obese patients found on routine scrotal ultrasound. J Urol. 2012;187:599-601.

26. Soylemez H, Atar M, Ali Sancaktutar A, Bozkurt Y, Penbegul N. Varicocele among healthy young men in Turkey; prevalence and relationship with body mass index. Int Braz J Urol. 2012;38:116-21.

27. Gokce A, Demirtas A, Ozturk A, Sahin N, Ekmekcioglu O. Association of left varicocoele with height, body mass index and sperm counts in infertile men. Andrology. 2013;1:116-9.

28. Rais A, Zarka S, Derazne E, Tzur D, Calderon-Margalit R, Davidovitch N, et al. Varicocoele among 1.300.000 Israeli adolescent males: time trends and association with body mass index. Andrology. 2013;1:663-9.
-2929. Engin Do antekin, Sacit Nuri Görgel, Evren Şahin, Cengiz Girgin. elationship between varicocele and anthropometric indices in infertile population İnfertilite olgularında varikosel ve antropometrik index ili kisi. Dicle Medical Journal 2014;41:59-63., 2929. Engin Do antekin, Sacit Nuri Görgel, Evren Şahin, Cengiz Girgin. elationship between varicocele and anthropometric indices in infertile population İnfertilite olgularında varikosel ve antropometrik index ili kisi. Dicle Medical Journal 2014;41:59-63., 3030. Hadjkacem Loukil L, Hadjkacem H, Bahloul A, Ayadi H. Relation between male obesity and male infertility in a Tunisian population. Andrologia. 2015;47:282-5.), and three (2424. Baek M, Park SW, Moon KH, Chang YS, Jeong HJ, Lee SW, et al. Nationwide survey to evaluate the prevalence of varicoceles in South Korean middle school boys: a population based study. Int J Urol. 2011;18:55-60., 2828. Rais A, Zarka S, Derazne E, Tzur D, Calderon-Margalit R, Davidovitch N, et al. Varicocoele among 1.300.000 Israeli adolescent males: time trends and association with body mass index. Andrology. 2013;1:663-9., 3131. Liu J, Zhang S, Liu M, Wang Q, Shen H, Zhang Y, et al. Prevalence of varicocoele and its association with body mass index among 39,559 rural men in eastern China: a population-based cross-sectional study. Andrology. 2017;5:562-567.) were cross-sectional studies. Three (1212. Handel LN, Shetty R, Sigman M. The relationship between varicoceles and obesity. J Urol. 2006;176:2138-40; discussion 2140., 1414. Nielsen ME, Zderic S, Freedland SJ, Jarow JP. Insight on pathogenesis of varicoceles: relationship of varicocele and body mass index. Urology. 2006;68:392-6., 2525. Chanc Walters R, Marguet CG, Crain DS. Lower prevalence of varicoceles in obese patients found on routine scrotal ultrasound. J Urol. 2012;187:599-601.) were conducted in the US, four (2626. Soylemez H, Atar M, Ali Sancaktutar A, Bozkurt Y, Penbegul N. Varicocele among healthy young men in Turkey; prevalence and relationship with body mass index. Int Braz J Urol. 2012;38:116-21.

27. Gokce A, Demirtas A, Ozturk A, Sahin N, Ekmekcioglu O. Association of left varicocoele with height, body mass index and sperm counts in infertile men. Andrology. 2013;1:116-9.

28. Rais A, Zarka S, Derazne E, Tzur D, Calderon-Margalit R, Davidovitch N, et al. Varicocoele among 1.300.000 Israeli adolescent males: time trends and association with body mass index. Andrology. 2013;1:663-9.
-2929. Engin Do antekin, Sacit Nuri Görgel, Evren Şahin, Cengiz Girgin. elationship between varicocele and anthropometric indices in infertile population İnfertilite olgularında varikosel ve antropometrik index ili kisi. Dicle Medical Journal 2014;41:59-63.) in Europe, three (1818. Shafi H, Agajani Delavar M. Differences in body mass index and height factors between men with and without varicocele. Med Glas (Zenica). 2015;12:212-5., 2424. Baek M, Park SW, Moon KH, Chang YS, Jeong HJ, Lee SW, et al. Nationwide survey to evaluate the prevalence of varicoceles in South Korean middle school boys: a population based study. Int J Urol. 2011;18:55-60., 3131. Liu J, Zhang S, Liu M, Wang Q, Shen H, Zhang Y, et al. Prevalence of varicocoele and its association with body mass index among 39,559 rural men in eastern China: a population-based cross-sectional study. Andrology. 2017;5:562-567.) in Asia and one in Africa (3030. Hadjkacem Loukil L, Hadjkacem H, Bahloul A, Ayadi H. Relation between male obesity and male infertility in a Tunisian population. Andrologia. 2015;47:282-5.). The included studies were published between 2006 and 2017, with a total study population of 1.376.658 participants. The sample size of the studies varied from 98 (3030. Hadjkacem Loukil L, Hadjkacem H, Bahloul A, Ayadi H. Relation between male obesity and male infertility in a Tunisian population. Andrologia. 2015;47:282-5.) to 1.323.061 (2828. Rais A, Zarka S, Derazne E, Tzur D, Calderon-Margalit R, Davidovitch N, et al. Varicocoele among 1.300.000 Israeli adolescent males: time trends and association with body mass index. Andrology. 2013;1:663-9.). The Newcastle-Ottawa scale was applied for assessment of quality of included studies in Table-3. As show, overall quality score of included studies were 8 or 9. This shows that the findings of these articles are trustworthy.

Figure 1
Flow chart for the selection of articles.
Table 1
Characteriste of the included studies.

Overweight and risk of varicocele

The relationship between overweight and the risk of varicocele was explored in the eleven studies (1212. Handel LN, Shetty R, Sigman M. The relationship between varicoceles and obesity. J Urol. 2006;176:2138-40; discussion 2140., 1414. Nielsen ME, Zderic S, Freedland SJ, Jarow JP. Insight on pathogenesis of varicoceles: relationship of varicocele and body mass index. Urology. 2006;68:392-6., 1818. Shafi H, Agajani Delavar M. Differences in body mass index and height factors between men with and without varicocele. Med Glas (Zenica). 2015;12:212-5., 2424. Baek M, Park SW, Moon KH, Chang YS, Jeong HJ, Lee SW, et al. Nationwide survey to evaluate the prevalence of varicoceles in South Korean middle school boys: a population based study. Int J Urol. 2011;18:55-60.

25. Chanc Walters R, Marguet CG, Crain DS. Lower prevalence of varicoceles in obese patients found on routine scrotal ultrasound. J Urol. 2012;187:599-601.

26. Soylemez H, Atar M, Ali Sancaktutar A, Bozkurt Y, Penbegul N. Varicocele among healthy young men in Turkey; prevalence and relationship with body mass index. Int Braz J Urol. 2012;38:116-21.

27. Gokce A, Demirtas A, Ozturk A, Sahin N, Ekmekcioglu O. Association of left varicocoele with height, body mass index and sperm counts in infertile men. Andrology. 2013;1:116-9.

28. Rais A, Zarka S, Derazne E, Tzur D, Calderon-Margalit R, Davidovitch N, et al. Varicocoele among 1.300.000 Israeli adolescent males: time trends and association with body mass index. Andrology. 2013;1:663-9.

29. Engin Do antekin, Sacit Nuri Görgel, Evren Şahin, Cengiz Girgin. elationship between varicocele and anthropometric indices in infertile population İnfertilite olgularında varikosel ve antropometrik index ili kisi. Dicle Medical Journal 2014;41:59-63.

30. Hadjkacem Loukil L, Hadjkacem H, Bahloul A, Ayadi H. Relation between male obesity and male infertility in a Tunisian population. Andrologia. 2015;47:282-5.
-3131. Liu J, Zhang S, Liu M, Wang Q, Shen H, Zhang Y, et al. Prevalence of varicocoele and its association with body mass index among 39,559 rural men in eastern China: a population-based cross-sectional study. Andrology. 2017;5:562-567.). The ORs pooled by the random-effects model showed that overweight subjects had a lower overall risk of varicocele compared with healthy subjects (OR, 0.70; 95% CI, 0.56-0.86, P <0.001); Figure-2). There was significant heterogeneity in the pooled result (P for heterogeneity <0.001, I2=92.4%). In Rais's study, classification was carried out according to four groups: underweight (<5th percentile); normal weight (5th-84.9th percentile), overweight (85th-94.9th percentile) and obese (≥95th percentile), with normal weight as the reference group. An expanded analysis of the normal weight group included further classification into five percentile groups (5-9.9; 10-24.9; 25-49.9; 50-74.9 and 75-84.9), with 25-49.9 (the largest group) as the reference group. In the other studies, according to the National Institutes of Health definition, those patients with a BMI of less than 25kg/m2 were categorized as normal weight. Patients with a BMI of 25kg/m2 to less than 30kg/m2 were considered overweight, and those with a BMI greater than 30kg/m2 were categorized as obese.

Figure 2
Pooled OR of varicocele in subjects with and without overweight.

Obesity and risk of varicocele

Ten (1212. Handel LN, Shetty R, Sigman M. The relationship between varicoceles and obesity. J Urol. 2006;176:2138-40; discussion 2140., 1414. Nielsen ME, Zderic S, Freedland SJ, Jarow JP. Insight on pathogenesis of varicoceles: relationship of varicocele and body mass index. Urology. 2006;68:392-6., 1818. Shafi H, Agajani Delavar M. Differences in body mass index and height factors between men with and without varicocele. Med Glas (Zenica). 2015;12:212-5., 2525. Chanc Walters R, Marguet CG, Crain DS. Lower prevalence of varicoceles in obese patients found on routine scrotal ultrasound. J Urol. 2012;187:599-601.

26. Soylemez H, Atar M, Ali Sancaktutar A, Bozkurt Y, Penbegul N. Varicocele among healthy young men in Turkey; prevalence and relationship with body mass index. Int Braz J Urol. 2012;38:116-21.

27. Gokce A, Demirtas A, Ozturk A, Sahin N, Ekmekcioglu O. Association of left varicocoele with height, body mass index and sperm counts in infertile men. Andrology. 2013;1:116-9.

28. Rais A, Zarka S, Derazne E, Tzur D, Calderon-Margalit R, Davidovitch N, et al. Varicocoele among 1.300.000 Israeli adolescent males: time trends and association with body mass index. Andrology. 2013;1:663-9.

29. Engin Do antekin, Sacit Nuri Görgel, Evren Şahin, Cengiz Girgin. elationship between varicocele and anthropometric indices in infertile population İnfertilite olgularında varikosel ve antropometrik index ili kisi. Dicle Medical Journal 2014;41:59-63.

30. Hadjkacem Loukil L, Hadjkacem H, Bahloul A, Ayadi H. Relation between male obesity and male infertility in a Tunisian population. Andrologia. 2015;47:282-5.
-3131. Liu J, Zhang S, Liu M, Wang Q, Shen H, Zhang Y, et al. Prevalence of varicocoele and its association with body mass index among 39,559 rural men in eastern China: a population-based cross-sectional study. Andrology. 2017;5:562-567.) studies reported the relationship between obesity and the risk of varicocele. After pooling the data from these studies, the rate of varicocele was significantly lower in the obese group, and there was high heterogeneity among the studies (OR, 0.46; 95% CI, 0.37-0.58, P <0.001; P for heterogeneity=0.001, I2=80.3%; Figure-3).

Figure 3
Pooled OR of varicocele in subjects with and without obesity.

Underweight and risk of varicocele

Four (2424. Baek M, Park SW, Moon KH, Chang YS, Jeong HJ, Lee SW, et al. Nationwide survey to evaluate the prevalence of varicoceles in South Korean middle school boys: a population based study. Int J Urol. 2011;18:55-60., 2727. Gokce A, Demirtas A, Ozturk A, Sahin N, Ekmekcioglu O. Association of left varicocoele with height, body mass index and sperm counts in infertile men. Andrology. 2013;1:116-9., 2828. Rais A, Zarka S, Derazne E, Tzur D, Calderon-Margalit R, Davidovitch N, et al. Varicocoele among 1.300.000 Israeli adolescent males: time trends and association with body mass index. Andrology. 2013;1:663-9., 3131. Liu J, Zhang S, Liu M, Wang Q, Shen H, Zhang Y, et al. Prevalence of varicocoele and its association with body mass index among 39,559 rural men in eastern China: a population-based cross-sectional study. Andrology. 2017;5:562-567.) studies reported the relationship between underweight and the risk of varicocele. The combined OR showed that the risk of varicocele was significantly higher in the underweight group than in the control group. There was high heterogeneity among the studies (OR, 1.31; 95% CI, 1.04-1.64, P=0.0381; P for heterogeneity=0.001, I2=81.3%; Figure-4).

Figure 4
Pooled OR of varicocele in subjects with and without underweight.

A subgroup analysis was performed to investigate the source of heterogeneity in the overweight group according to study design and geographic location. Of the eleven studies, eight were case-control studies, and three used cross-sectional designs. The results derived from the subgroup analysis were consistent with the overall results, with ORs of 0.76 (95% CI, 0.69-0.84, P <0.001; P for heterogeneity=0.523, I2=0.0%) and 0.58 (95% CI, 0.37-0.93, P=0.024; P for heterogeneity=0.000, I2=97.5%), respectively, in the case-control and cross-sectional studies (Table-2).

Table 2
Summary of pooled ORs of BMI and risk of varicocele by subgroup analysis.
Table 3
Newcastle-Ottawa scale for assessment of quality of included studies.

According to the geographic location analysis, the estimated ORs of varicocele in the overweight group compared with the normal group were 0.79 (95% CI, 0.70-0.90; P<0.001; P for heterogeneity=0.185; I2=40.7%) in the US, 0.65 (95% CI, 0.50-1.64; P=0.001; P for heterogeneity <0.001; I2=84.3%) in Europe and 0.67 (95% CI, 0.44-1.03; P=.070; P for heterogeneity=0.024; I2=73.3%) in Asia (Table-2). Begg's funnel plot and Egger's test were performed to assess the publication bias. The shape of the funnel plots did not reveal any evidence of asymmetry. The statistical results still did not show any publication bias (Begg's test P=0.062; Egger's test P=0.067).

DISCUSSION

Obesity is associated with significant alterations in the hormonal milieu that can damage the reproductive system (3232. Schneider G, Kirschner MA, Berkowitz R, Ertel NH. Increased estrogen production in obese men. J Clin Endocrinol Metab. 1979;48:633-8., 3333. Giagulli VA, Kaufman JM, Vermeulen A. Pathogenesis of the decreased androgen levels in obese men. J Clin Endocrinol Metab. 1994;79:997-1000.). The relationship between obesity and fertility has received increased attention owing to the recent rapid increase in the prevalence of obesity worldwide, especially in developed countries (3434. Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan JP. The spread of the obesity epidemic in the United States, 1991-1998. JAMA. 1999;282:1519-22., 3535. Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002. JAMA. 2004;291:2847-50.). Recent studies (1313. May M, Taymoorian K, Beutner S, Helke C, Braun KP, Lein M, et al. Body size and weight as predisposing factors in varicocele. Scand J Urol Nephrol. 2006;40:45-8., 1414. Nielsen ME, Zderic S, Freedland SJ, Jarow JP. Insight on pathogenesis of varicoceles: relationship of varicocele and body mass index. Urology. 2006;68:392-6., 2424. Baek M, Park SW, Moon KH, Chang YS, Jeong HJ, Lee SW, et al. Nationwide survey to evaluate the prevalence of varicoceles in South Korean middle school boys: a population based study. Int J Urol. 2011;18:55-60., 2525. Chanc Walters R, Marguet CG, Crain DS. Lower prevalence of varicoceles in obese patients found on routine scrotal ultrasound. J Urol. 2012;187:599-601.) have found a lower prevalence of varicocele in obese patients. Consistent with most of these studies, our meta-analysis showed an inverse association between BMI and varicocele. With increasing BMI, the risk of varicocele decreases from 1.31 to 0.46 in individuals in the underweight and obese groups Our data showed that overweight people had a significantly lower incidence of varicocele, except for in the Asian population. Some previous studies in Asia found a similar phenomenon. In 2004, a study in Philadelphia (1111. Delaney DP, Carr MC, Kolon TF, Snyder HM 3rd, Zderic SA. The physical characteristics of young males with varicocele. BJU Int. 2004;94:624-6.) reported that patients with varicocele were significantly taller and heavier than those without varicocele, but there was no significant difference in BMI. In 2014, a Korean (1010. Bae K, Shin HS, Jung HJ, Kang SH, Jin BS, Park JS. Adolescent varicocele: are somatometric parameters a cause? Korean J Urol. 2014;55:533-5.) study showed that the varicocele group had a significantly lower BMI in adolescents, but the difference was not significant in adults according to logistic regression analysis. Therefore, more studies are still needed to confirm the protective effect of obesity against varicocele in Asian populations.

Furthermore, the pooled ORs seem to show that the source of the heterogeneity was the study by Rais (2828. Rais A, Zarka S, Derazne E, Tzur D, Calderon-Margalit R, Davidovitch N, et al. Varicocoele among 1.300.000 Israeli adolescent males: time trends and association with body mass index. Andrology. 2013;1:663-9.). When the study by Rais was omitted, the heterogeneity disappeared. The reason may be that the defined BMI categories in Rais's study were significantly different from those in other studies. In Rais's study, classification was carried out according to four groups: underweight (<5th percentile); normal weight (5th-84.9th percentile); overweight (85th-94.9th percentile) and obese (≥95th percentile), with normal weight as the reference group. An expanded analysis of the normal weight group included further classification into five percentile groups (5-9.9, 10-24.9, 25-49.9, 50-74.9 and 75-84.9), with 25-49.9 (the largest group) as the reference group. In the other studies, according to the National Institutes of Health definition, those patients with a BMI of less than 25kg/m2 were categorized as normal weight. Patients with a BMI of 25kg/m2 to less than 30kg/m2 were considered overweight, and those with a BMI greater than 30kg/m2 were categorized as obese.

Our meta-analysis showed an inverse association between BMI and varicocele. Two main theories have been postulated to clarify the inverse relationship between increasing BMI and decreasing occurrence of varicocele. One theory states that varicocele is caused by increased pressure in the left renal vein because it is compressed between the aorta and the superior mesenteric artery (3636. Al-Ali BM, Shamloul R, Pichler M, Augustin H, Pummer K. Clinical and laboratory profiles of a large cohort of patients with different grades of varicocele. Cent European J Urol. 2013;66:71-4.). Most researchers suggest that increased amounts of adipose tissue may decrease the compression of the left renal vein and provide a cushion, decreasing the nutcracker phenomenon in men with a higher BMI (1212. Handel LN, Shetty R, Sigman M. The relationship between varicoceles and obesity. J Urol. 2006;176:2138-40; discussion 2140., 1414. Nielsen ME, Zderic S, Freedland SJ, Jarow JP. Insight on pathogenesis of varicoceles: relationship of varicocele and body mass index. Urology. 2006;68:392-6., 3737. Tsao CW, Hsu CY, Chou YC, Wu ST, Sun GH, Yu DS, et al. The relationship between varicoceles and obesity in a young adult population. Int J Androl. 2009;32:385-90.). Another theory believes that the detection of varicocele is decreased in men with a higher BMI because of the difficulty of palpation on physical examination due to the presence of adipose tissue in the inguinal and scrotal areas (1414. Nielsen ME, Zderic S, Freedland SJ, Jarow JP. Insight on pathogenesis of varicoceles: relationship of varicocele and body mass index. Urology. 2006;68:392-6., 3636. Al-Ali BM, Shamloul R, Pichler M, Augustin H, Pummer K. Clinical and laboratory profiles of a large cohort of patients with different grades of varicocele. Cent European J Urol. 2013;66:71-4.). However, a recent study showed that obese patients had a lower prevalence of varicocele that was not due to difficulties with the physical examination caused by obesity. It is due to the decrease in the nutcracker phenomenon in men with a higher BMI (2525. Chanc Walters R, Marguet CG, Crain DS. Lower prevalence of varicoceles in obese patients found on routine scrotal ultrasound. J Urol. 2012;187:599-601.).

This is a meta-analysis of observational studies with the limitations inherent in the study design. Therefore, at best, it can demonstrate an association but not a causal relationship. First, most studies calculated the ORs based on data without adjusting for confounding factors. Second, no prospective study could be included in the analysis, which may have biased the results. Third, some of the included studies had different BMI categories, which may confound the pooled results. Furthermore, these studies may have been vulnerable to surveillance bias, as patients with comorbidities would have been more likely to have follow-up imaging studies, leading to the more frequent detection of varicocele than in patients without comorbidities. Future studies that minimize these confounders and biases are needed to confirm this potential causal relationship.

Studies have shown that BMI could be a risk factor for left renal vein entrapment. In addition, our meta-analysis showed an inverse association between BMI and varicocele. Thus, for varicocele patients, especially those with lower BMI, attention should be paid to left renal vein entrapment.

It is well known that obesity is harmful to human health. The global obesity epidemic parallels a decrease in male fertility. However, the association between BMI and sperm parameters remains controversial. A study found that overweight and obesity are associated with an increased risk of azoospermia and oligozoospermia, which suggests that excess body weight affects sperm production (3838. Sermondade N, Faure C, Fezeu L, Shayeb AG, Bonde JP, Jensen TK, et al. BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis. Hum Reprod Update. 2013;19:221-31.). The inverse association between obesity and varicocele found in our study indicates that the causal relationship between obesity and poor sperm quality may be even stronger if the elevated risk of varicocele among lean males is taken into account. The diagnosis of varicocele in obese patients should be thoroughly discussed. Colour Doppler ultrasound (CDU) has the ability to detect the size of the pampiniformis plexus and blood flow parameters of the spermatic vein and is widely used in the diagnosis of varicocele (3939. Liguori G, Trombetta C, Garaffa G, Bucci S, Gattuccio I, Salamè L, et al. Color Doppler ultrasound investigation of varicocele. World J Urol. 2004;22:378-81.). However, at present, there is a lack of completely standardized diagnostic criteria in obese men. We recommend using CDU to exclude nutcracker syndrome in patients with low BMI. It is of great value in the management of patients with different BMI varicocele, which can help find the cause of varicocele in some patients, so as to achieve better therapeutic result. Researchers have reported that ultrasound has a 95% sensitivity for the detection of a varicocele using a 2mm cut off for vein diameter (4040. Gonda RL Jr, Karo JJ, Forte RA, O’Donnell KT. Diagnosis of subclinical varicocele in infertility. AJR Am J Roentgenol. 1987;148:71-5.). Pilatz reported that clinical varicocele can be predicted with high accuracy based only on the diameter of the testicular veins using cut-off values of 2.45mm at rest or 2.95mm during the Valsalva manoeuvre in the supine position (4141. Pilatz A, Altinkilic B, Köhler E, Marconi M, Weidner W. Color Doppler ultrasound imaging in varicoceles: is the venous diameter sufficient for predicting clinical and subclinical varicocele? World J Urol. 2011;29:645-50.). It would be more accurate in terms of diagnosing varicocele if patients were evaluated for reflux pattern, pampiniform venous plexus diameter, and venous reflux time (4242. Bagheri 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.). A study indicated that there was a significant correlation between the reflux pattern and two parameters of semen analysis, namely, sperm count and motility (4242. Bagheri 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.). Future research should explore the relationships between BMI and sperm parameters, male fertility and varicocele. Our study shows a significantly decreased risk of varicocele with increased BMI. However, this potential benefit should not be overemphasized, as obesity itself is harmful to the reproductive system. Is there any difference (s) in the workup and management of varicocele patients with different BMI? There is still not a clear answer. Future research should explore it.

CONCLUSIONS

Our study shows a significantly decreased risk of varicocele with increased BMI. However, this potential benefit should not be overemphasized, as obesity itself is harmful to the reproductive system.

  • Funding
    This study was supported by Guangdong Provincial Science and Technology Programme (2017ZC0097)

ACKNOWLEDGEMENTS

Guo Xiao-Bin, Wu Fang-Lei and Xia Hui 1 contributed similarly as first author

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Publication Dates

  • Publication in this collection
    18 Nov 2020
  • Date of issue
    Jan-Feb 2021

History

  • Received
    09 Apr 2019
  • Accepted
    17 Nov 2019
  • Published
    10 Mar 2020
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