Introduction. Original Article: Clinical Investigation

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1 bs_bs_banner International Journal of Urology (2014) 21, doi: /iju Original Article: Clinical Investigation Is the presence of varicocele associated with static and dynamic components of benign prostatic hyperplasia/lower urinary tract Alper Otunctemur, 1 Emin Ozbek, 2 Huseyin Besiroglu, 1 Murat Dursun, 3 Suleyman Sahin, 4 Ismail Koklu, 1 Mustafa Erkoc, 1 Eyyup Danis, 1 Muammer Bozkurt 1 and Ahmet Gurbuz 1 1 Department of Urology, Okmeydani Training and Research Hospital, Istanbul, 2 Department of Urology, Katip Celebi University Atatürk Training and Research Hospital, Izmir, 3 Department of Urology, Bahcelievler State Hospital, Istanbul, and 4 Department of Urology, Bilecik State Hospital, Bilecik, Turkey Abbreviations & Acronyms BMI = body mass index BPH = benign prostatic hyperplasia CV = coefficient of variability IPSS = International Prostate Symptom Score LUTS = lower urinary tract symptoms PSA = prostate-specific antigen PV = prostate volume Qmax = maximum flow rate t-psa = total prostate-specific antigen t-testosterone = total testosterone Correspondence: Huseyin Besiroglu M.D., Department of Urology, Okmeydani Training and Research Hospital, Sisli, Istanbul 34384, Turkey. drhuseyin1985@hotmail.com Received 7 February 2014; accepted 30 June Online publication 23 July 2014 Objectives: To evaluate the relationship between varicocele and benign prostatic hyperplasia/lower urinary tract symptoms in patients over the age of 40 years. Methods: A total of 1040 patients with benign prostatic hyperplasia/lower urinary tract symptoms were evaluated for prostate volume, testicular volume, testicular consistency, total testosterone, total prostate-specific antigen and body mass index. A questionnaire including International Prostate Symptom Score and a uroflow test were also carried out. The presence and grade of varicocele was determined in each patient by physical examination. Results: Varicocele was found bilaterally in 22.3% and unilaterally in 25.7% of the patients. There was no difference in terms of age and body mass index distribution between subgroups. When grouping patients for varicocele laterality, total testosterone (P = 0.04), prostate volume (P = 0.009) and total prostate-specific antigen (P = 0.02) level were significantly different. Similarly, these parameters were significant between patients with grade 1, 2 and 3 varicocele. Total testosterone level (P = 0.02) and prostate volume (P = 0.035) were found to be significantly different when patients were grouped according to testicular size. A positive correlation was found between testosterone level and prostate volume (P = 0.004; r 2 = 0.084). Conclusions: Bilateral and/or higher-grade varicocele is associated with lower prostate volume and testosterone levels, as well as lower prostate-specific antigen levels. However, it is not associated with dynamic components of benign prostatic hyperplasia/lower urinary tract symptoms in patients over the age of 40 years. Key words: benign prostatic hyperplasia/lower urinary tract symptoms, prostate volume, prostate-specific antigen, total testosterone, varicocele. Introduction Varicocele is an abnormal dilatation of internal spermatic veins within the pampiniform plexus. Varicoceles are a frequent scrotal finding in normal males. Although its pathogenesis and natural history remain controversial, varicocele is thought to contribute to the risk of infertility in males. Furthermore, two population-based studies showed that 85% of men with varicoceles have fathered children, suggesting that its effect on paternity is less clear. 1,2 The underlying pathological process is not well known, but varicoceles have been associated with turbulent venous flow related to the right angle insertion of the left testicular vein into the left renal vein, which could be an explanation why left-sided varicoceles are observed more frequently. Additionally, the nutcracker phenomenon, defined as the compression of the left renal vein between the superior mesenteric artery and aorta could contribute to the pathogenesis of varicoceles. 3,4 The absence of valves within the left internal spermatic vein in cadavers with varicoceles, and the presence of numerous valves within the internal spermatic vein in cadavers without varicoceles might contribute to the pathology associated with varicoceles. Additionally, the absence of valves is less common in the right internal spermatic vein. 5,6 The leading theory regarding the effect of varicoceles on testicular cells is based on the knowledge that the testicular process is quite temperature dependent. 7 Venous pooling resulting from varicoceles leads to an increase in intrascrotal temperature resulting in reductions in testosterone production by Leydig cells, injury to germinal cells and reduced Sertoli cell The Japanese Urological Association

2 Varicoceles and BPH/LUTS in elderly men function. Furthermore, varicocele ligation has been shown to be associated with decreases in intrascrotal temperature. 8 The other proposed mechanisms that result in alteration to the microenvironment of testicular cells include free reflux of adrenal and renal metabolites from the left renal vein. It has also been shown that the level of seminal oxidative stress correlates with varicocele grade, and improves with the treatment of varicoceles. 9 BPH is a pathological process that contributes to, but is not the sole cause of, LUTS in aging men. The development of BPH/LUTS is a complex process by which androgens, estrogens, stromal epithelial interactions, growth factors and neurotransmitters might play a role, either singly or in combination. Androgens have a critical role for normal cell proliferation and differentiation in the prostate by actively inhibiting cell death, and regulating many growth factors and their receptors. In light of this, testosterone level, which might be affected by varicocele presence, could be associated with static and dynamic components of BPH. Another interesting possible mechanism that could represent an explanation for the relationship of varicocele to BPH/LUTS is venous blood reflux from the high-pressure testicular venous drainage system to the lowpressure prostatic drainage system. Gat et al. showed that the selective occlusion of impaired venous drainage in the male reproductive system was associated with a reduction in PV and BPH-related symptoms. 10 The prevalence of varicoceles has been widely studied in adolescents and young adults, and is stated to be approximately 15%, but ranges from 3% to 43% in some studies To the best of our knowledge, there is no clinical study investigating the association between varicoceles with the lower urinary tract in an elderly population. In the present study patients aged over 40 years presenting with LUTS were evaluated. We have chosen 40 years-of-age, as the cut-off age, as many men older than the age of 40 years will develop histological hyperplasia. As varicocele is a chronic process, older patients might be affected more, and the static and dynamic components of BPH might be related to the varicocele, and its effects on testis volume, consistency and testosterone level. We have investigated whether the existence and grade of varicoceles is associated with LUTS, prostate size, PSA and testosterone level through the wellknown effects of varicoceles on Leydig cells. Methods A total of 1040 patients who presented to the Department of Urology, Okmeydani Training and Research Hospital, Istanbul, Turkey, with the complaint of LUTS were included in the study. Institutional review board approval was obtained before the start of the study. All participants signed an informed consent before being enrolled in the study. Patients with hydroceles, epididymitis, orchitis, testicular trauma and tumor; and those who previously had scrotal interventions, such as inguinal herniorrhaphy, orchiectomy or hydrocelectomy, were excluded from the study. As testosterone and PSA levels alter with outside interference, patients receiving anti-androgen therapy for prostate cancer or those who were taking testosterone preparations for androgen deficiency and 5-α reductase inhibitors for benign prostate hyperplasia were also excluded from the study. All organic and psychogenic causes related to BPH/LUTS and hypogonadism, except varicoceles and lower testosterone levels, were excluded based on clinical and laboratory investigations. To evaluate LUTS, a questionnaire including IPSS and a uroflow test measuring the peak urinary flow rate were carried out to appreciate the complaints of the patients objectively. Digital rectal examination was carried out to establish the approximate PV, and patients with suspicious findings were assessed for transrectal ultrasound-guided biopsy. PV was measured according to the prostate ellipsoid formula, multiplying the largest anteroposterior (height), transverse (width) and cephalocaudal (length) prostate diameters as (height width length π/6) by using transrectal ultrasound. Testicular size was analyzed with a Prader orchidometer, which is a chain of 12 solid wooden ellipsoids with volumes of 1 through 6, 8, 10, 12, 15, 20 and 25 ml that are visually compared with the size of each testis. We grouped the participants by whether their testicular volume was greater than 20 ml or not. Although the orchidometer overestimated the testicular size, it correlated closely with the measurements by ultrasonography. 14 It was dominantly left testis size, in just six patients with right unilateral varicoceles was right testis size measured. We evaluated the testicular consistency by palpation. The consistency was subjectively graded as either soft or normal. T-testosterone and PSA levels were measured from a morning time blood draw. Plasma testosterone levels for each participant were measured by automated chemiluminescent microparticle immunoassay; the intra-assay CV was 4.4% and interassay CV was 5.2%. In order to detect varicoceles, the patients were examined in a warm room in the supine and standing position. The spermatic cord was palpated at rest and during Valsalva maneuver. Each side was evaluated using the following standard grading system: grade 1, palpable only with Valsalva; grade 2, easily palpable, but not visible; and grade 3, easily visible. To prevent interobserver bias, the same experienced physician carried out all examinations. Scrotal ultrasound was not carried out to detect varicoceles; only physical examination was applied. Varicocelectomy was not carried out in any patients. Statistical analysis All statistical analysis was carried out using SPSS version 15.0 (SPSS, Chicago, IL, USA). Patients were divided into three groups. The parameters were compared with ANOVA and Kruskal Wallis tests. To evaluate the subgroups, Student s t-test and Mann Whitney U-test were carried out. The Spearman s correlation analysis was carried out to evaluate the relationship between testosterone level and clinical parameters. In all comparisons of parameters, a P-value of less than 0.05 was considered to be statistically significant. All P-values reported in the present study are two-tailed unless stated otherwise. Results A total of 1040 participants were included in the study. Of these, 500 patients were found to have varicoceles with 48% prevalence; 25.7% were unilateral and 22.3% were bilateral The Japanese Urological Association 1269

3 A OTUNCTEMUR ET AL. Table 1 Demographic and clinical features of patients stratified by varicocele laterality Parameters Bilateral varicocele (n = 232) Unilateral varicocele (n = 268) No varicocele (n = 540) P-value Mean age (years) BMI (kg/m 2 ) T-testosterone (ng/ml) 3.09 ± ± ± * IPSS score (average) ± ± ± PSA (ng/ml) 1.48 ± ± ± * Mean PV (ml) ± ± ± * Uroflowmetry (Qmax) ± ± ± Testicular size <20 ml (%) Soft testis (%) *Statistically significant. BMI, kg/m 2. Table 2 Demographic and clinical features of the three groups stratified by varicocele grade Parameters Grade 1 varicocele (n = 141) Grade 2 varicocele (n = 220) Grade 3 varicocele (n = 139) P-value Mean age (years) BMI (kg/m 2 ) T-testosterone (ng/ml) 3.43 ± ± ± * IPSS (average) PSA (ng/ml) 2.1 ± ± ± * Mean PV (ml) 41 ± ± ± * Uroflowmetry (Qmax) Testicular size <20 ml (%) Soft testis (%) *Statistically significant. BMI, kg/m 2. Grade 2 varicocele was the most common pattern with a percentage of 21%; grade 1 and grade 3 varicocele prevalence was 13.6% and 13.3%, respectively. There was no significant difference between the distribution of age and BMI in the three groups. The percentage of the patients with testicular volume <20 ml was 35% in patients with bilateral varicoceles and 21% in those with unilateral varicoceles. The percentage of soft testis in patients with bilateral and unilateral varicocele was 78% and 70%, respectively. The details about demographic and clinical properties are shown in Table 1. T-testosterone levels were discovered to be 3.09 ± 1.64 in patients with bilateral varicoceles, 3.32 ± 1.15 in those with unilateral varicoceles and 3.75 ± 1.29 in those without varicoceles. Similarly, when patients were stratified by varicocele grade; t-testosterone levels were 3.43 ± 1.09; 3.22 ± 1.7 and 2.94 ± 1.4, respectively, in patients with grade 1, grade 2 and grade 3 varicoceles, and statistical analysis was significant (P = 0.015). The mean IPSS scores in patients with bilateral varicoceles were ± 3.54, whereas in patients with unilateral varicoceles they were ± 3.59, and in those without varicoceles it was ± No statistically significant difference was noted. Similarly, no statistical difference was found in terms of IPSS score when patients were stratified by varicocele grade. Qmax levels were ± 7.46, ± 8.34 and ± 5.64, respectively, and no statistically significant difference was observed. Qmax levels of the patients with grade 1, grade 2, and grade 3 varicocele were 16.41, and 15.12, respectively, and the statistical analysis showed no significance. Mean t-psa levels were 1.48 ± 1.23, 2.02 ± 4.15 and 2.21 ± 2.59, respectively, and there was a significant difference with a P-value of 0.02 between three groups. When patients were grouped for varicocele grade, the results of t-psa levels were 2.1 ± 1.38; 1.95 ± 1.54 and 1.65 ± 1.26, respectively, and statistical analysis showed a significant difference (P = 0.034). Mean PV in patients with bilateral, unilateral, and no varicoceles was ± 13.85, ± and ± 15.06, respectively, and statistical analysis was significant (P = 0.009). When patients were grouped for varicocele grade, the results of mean PV were 41 ± 14.25, 36 ± and 33 ± 13.65, respectively, and statistical analysis showed a significant difference (P = 0.026). The details regarding varicocele laterality, grade, and clinical parameters are shown in Tables 1 and 2. The patients were grouped according to testicular volume, and clinical parameters were evaluated. Mean PV and testosterone level were significant, whereas the other parameters were not. The details are shown in Table 3. Spearman s correlation analysis was carried out between t-testosterone, PV and IPSS score. A positive correlation was found between t-testosterone level and PV (P = 0.004; r 2 = 0.084), whereas no correlation was found between t-testosterone level and IPSS score (not shown). Discussion In the present study, we aimed to evaluate the presence of varicoceles and its effect on the low urinary tract in elderly patients. Although there are many studies in the literature The Japanese Urological Association

4 Varicoceles and BPH/LUTS in elderly men Table 3 Parameters Clinical parameters of patients stratified by testicular volume Testicular volume >20 ml Testicular volume <20 ml P-value T-testosterone (ng/ml) 3.63 ± ± * IPSS (average) PSA (ng/ml) 2.07 ± ± Mean PV (ml) 42.8 ± ± * Uroflowmetry (Qmax) *Statistically significant. regarding the prevalence and the clinical results of varicoceles in a young population, the association between varicoceles and LUTS/BPH has not been specifically examined yet. Androgens are well-known factors contributing to BPH/ LUTS, but the relationship between sex hormones on the regulation of prostatic growth and BPH/LUTS is quite complex, and is still not thoroughly understood. 15,16 Consequently, androgens, estrogens, stromal epithelial interactions, growth factors and neurotransmitters could play a role, either singly or in combination, in the etiology of the hyperplastic process. Varicoceles seem to be an important factor altering the microenviroment of testicular cells, resulting in a decrease in testosterone production. Testicular histology findings in patients with varicoceles have been evaluated in some studies, and altered Leydig cell numbers were observed in some cases. 17,18 Varicoceles also result in testicular hypotrophy, which could be another reason for the lower degree of testosterone levels in elderly patients, especially those with high-grade varicoceles. We observed that both varicocele laterality and grade have an effect on testosterone level; also, patients with lower testicular size having lower testosterone levels. PV was measured in the present study to assess the effect of varicoceles on prostatic growth, and we found a positive correlation between prostate size and varicocele existence and grade. Both varicocele laterality and grade have an effect on PV; also, patients with lower testicular size having lower PV. Similar to the etiology of LUTS, prostate size etiology is a well-known subject of confusion in the literature, but developmental studies of the prostate have established that ductal morphogenesis, epithelial cytodifferentiation and proliferation/apoptosis are regulated by androgens. 19 Kim et al. found that prostate size correlates with fasting blood glucose in non-diabetic benign prostatic hyperplasia patients with normal testosterone levels, indicating other unknown factors affecting prostate growth through other mechanisms distinct from testosterone; obesity or abnormal glucose homeostasis. 20 There are not many studies in the literature investigating the relationship between prostate enlargement and varicocele presence. Although many findings in numerous studies suggest a more complex relationship between sex steroids and prostate volume in older men than simple independent effects, in the present study the presence of either bilateral or high-grade varicoceles could be an indicative factor to assess PV. PSA levels were lower in patients with bilateral varicocele compared with unilateral varicocele. A similar association was observed when patients were grouped according to varicocele grade. Patients with higher-grade varicoceles have lower PSA levels. However, testicular size was not correlated with PSA level, showing that other parameters could affect PSA levels. We also investigated the dynamic component of BPH through IPSS and uroflowmetry, and no statistically significant difference was found between subgroups, showing that the clinical features of BPH/LUTS depend on multifactors, and there are complex associations between etiological factors. The present study had some limitations. First, the analysis was carried out in an elderly population, and there might be different factors affecting testosterone levels other than varicoceles in this group. Additionally, BPH is a hyperplastic process in which many factors other than testosterone make contributions, and also it is not the sole cause of LUTS in aging men. The lower testicular volume might be associated with lower fertility potential, and we did not examine the patients for hormonal parameters, such as follicle-stimulating hormone and luteinizing hormone. This could be another investigation issue in an older population. In summary, to the best of our knowledge, this is the first study regarding varicocele presence, grade and BPH/LUTS, and we have discovered that either bilateral or high-grade varicocele presence is correlated with lower prostate size, PSA and testosterone levels. These findings are correlated with the wellknown knowledge about the effects of varicoceles on Leydig cells. However, no correlation was found between dynamic components of BPH/LUTS and varicoceles. Further studies are required to confirm these findings. Conflict of interest None declared. References 1 Pinto KJ, Kroovand RL, Jarow JP. Varicocele related testicular atrophy and its predictive effect upon fertility. J. Urol. 1994; 152: Safarinejad MR. Infertility among couples in a population-based study in Iran. Prevalence and associated risk factors. Int. J. Androl. 2008; 31: Coolsaet BL. The varicocele syndrome. Venography determining the optimal level for surgical management. J. Urol. 1980; 124: Kim WS, Cheon JE, Kim IO et al. Hemodynamic investigation of the left renal vein in pediatric varicocele. Doppler US, venography, and pressure measurements. Radiology 2006; 241: Takihara H, Sakatoku J, Cockett AT. The pathophysiology of varicocele in male infertility. Fertil. Steril. 1991; 55: Sofikitis N, Dritsas K, Miyagawa I, Koutselinis A. Anatomical characteristics of the left testicular venous system in man. Arch. Androl. 1993; 30: Khera M, Lipshultz LI. Evolving approach to the varicocele. Urol. Clin. North Am. 2008; 35: Wright EJ, Young GP, Goldstein M. Reduction in testicular temperature after varicocelectomy in infertile men. Urology 1997; 50: The Japanese Urological Association 1271

5 bs_bs_banner A OTUNCTEMUR ET AL. 9 Allamaneni SS, Naughton CK, Sharma RK, Thomas AJ Jr, Agarwal A. Increased seminal reactive oxygen species levels in patients with varicoceles correlate with varicocele grade but not with testis size. Fertil. Steril. 2004; 82: Gat Y, Gornish M, Heiblum M, Joshua S. Reversal of benign prostate hyperplasia by selective occlusion of impaired venous drainage in the male reproductive system: novel mechanism, new treatment. Andrologia 2008; 40: Kumanov P, Robeva RN, Tomova A. Adolescent varicocele: who is at risk? Pediatrics 2008; 121: Zampieri N, Cervellione RM. Varicocele in adolescents: a 6-year longitudinal and follow up observational study. J. Urol. 2008; 180: Stavropoulos NE, Mihailidis I, Hastazeris K et al. Varicocele in schoolboys. Arch. Androl. 2002; 48: Sakamoto H, Saito K, Ogawa Y, Yoshida H. Testicular volume measurements using Prader orchidometer versus ultrasonography in patients with infertility. Urology 2007; 69: Ansari MA, Begum D, Islam F. Serum sex steroids, gonadotrophins and sex hormone-binding globulin in prostatic hyperplasia. Ann. Saudi Med. 2008; 28: Roberts RO, Jacobson DJ, Rhodes T, Klee GG, Leiber MM, Jacobsen SJ. Serum sex hormones and measures of benign prostatic hyperplasia. Prostate 2004; 61: Hienz HA, Voggenthaler J, Weissbach L. Histological findings in testes with varicocele during childhood and their therapeutic consequences. Eur. J. Pediatr. 1980; 133: Hadziselimovic F, Herzog B, Jenny P. The chance for fertility in adolescent boys after corrective surgery for varicocele. J. Urol. 1995; 154: Wu CT, Altuwaijri S, Ricke WA. Increased prostate cell proliferation and loss of cell differentiation in mice lacking prostate epithelial androgen receptor. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: Kim WT, Yun SJ, Choi YD et al. Prostate size correlates with fasting blood glucose in non-diabetic benign prostatic hyperplasia patients with normal testosterone levels. J. Korean Med. Sci. 2011; 26: Editorial Comment Editorial Comment from Dr Li to Is the presence of varicocele associated with static and dynamic components of benign prostatic hyperplasia/lower urinary tract Varicocele is well known as the common cause of male infertility. One of the possible mechanisms is that varicocele can affect testicular Leydig cells function and result in a reduction of testosterone production. 1 Benign prostatic hyperplasia is a major disease among aging men, and its etiology is not clear. 2 In this interesting study, Otunctemur et al. investigated the association between varicoceles and benign prostatic hyperplasia/ lower urinary tract symptoms in patients over the age of 40 years. 3 These data are of clinical use, as they show that bilateral and/or higher-grade varicocele is associated with lower prostate volume, prostate-specific antigen and testosterone levels, but not correlated with benign prostatic hyperplasia/lower urinary tract symptoms. Conflict of interest None declared. References 1 Tanrikut C, Goldstein M. Varicocele repair for treatment of androgen deficiency. Curr. Opin. Urol. 2010; 20: Gat Y, Gornish M, Heiblum M, Joshua S. Reversal of benign prostate hyperplasia by selective occlusion of impaired venous drainage in the male reproductive system: novel mechanism, new treatment. Andrologia 2008; 40: Otunctemur A, Ozbek E, Besiroglu H et al. Is the presence of varicocele associated with static and dynamic components of benign prostatic hyperplasia/lower urinary tract Int. J. Urol. 2014; 21: Fuping Li Ph.D. Human Sperm Bank, West China Second University Hospital of Sichuan University, Chengdu, China lfpsnake@hotmail.com DOI: /iju Editorial Comment Editorial Comment from Dr Zampieri to Is the presence of varicocele associated with static and dynamic components of benign prostatic hyperplasia/lower urinary tract I read with interest these results; from an andrological point of view, clinical examinations should be carried out focusing on testicular volume, presence of varicocele, presence of penile malformation (i.e. curvature, tight frenulum, hypospadias) and prostatic volume with digital rectal examination (DRE). 1 DRE of the prostate provides useful information on the state of prostate growth and on the presence of suspected peripheral nodules. The results of this article report some information about the correlation between total testosterone (TT) levels, prostatic volume, presence of varicocele, prostate-specific antigen levels and the presence of benign prostatic hyperplasia/ lower urinary tract symptoms. The authors conclusions are that The Japanese Urological Association