Cardiovascular evaluation of young patients with varicocele

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1 MALE FACTOR Cardiovascular evaluation of young patients with varicocele Süleyman Kılıç, M.D., a Yüksel Aksoy, M.D., b İsa Sincer, M.D., b Fatih Oğuz, M.D., a Nevzat Erdil, M.D., c and Ertan Yetkin, M.D. b a Department of Urology, b Department of Cardiology, and c Department of Cardiovascular Surgery, Inonu University School of Medicine, Malatya, Turkey Objective: To evaluate cardiovascular risk factors and demographic parameters in patients with varicocele. Design: Although some pathophysiologic hypotheses have been suggested to explain the etiology of varicocele, the exact mechanism underlying varicocele is not yet known. The coexistence of arterial and venous system pathologic conditions has been reported recently, including varicosities of the coronary venous system and leg veins. Cardiovascular risk factors have not been evaluated previously in patients with varicocele. In addition to the presence of cardiovascular risk factors and demographic parameters, we assessed the prevalence of peripheral varicose veins in patients with and without varicocele. Patient(s): Study groups consisted of 52 patients with varicocele and 100 patients without varicocele younger than 50 years old. Result(s): There were no statistically significant differences between the two groups with respect to presence of hypertension, diabetes mellitus, hyperlipidemia, family history of coronary artery disease, body mass index, age, and height. The weight and presence of peripheral varicose veins in the patients with varicocele were significantly higher than in those without varicocele. It was found that presence of peripheral varicose veins was independently and positively associated with varicocele. Conclusion(s): We have demonstrated that varicocele is not associated with cardiovascular risk factors or demographic parameters. However, the presence of peripheral varicose veins is positively associated with varicocele, suggesting a possible common pathologic step. (Fertil Steril 2007;88: by American Society for Reproductive Medicine.) Key Words: Varicocele, peripheral varicose vein, venous system pathology A varicocele is a dilation of the scrotal portion of the pampiniform plexus/internal spermatic venous system that drains the testicle; 75% to 90% of varicoceles are left sided and may result in part from increased pressure to the internal spermatic vein (1). Varicocele has been found in 7% to 20% of healthy adolescents and young men (2 6). Although some pathophysiologic hypotheses have been suggested to explain the etiology of varicocele, the exact mechanism underlying varicocele is not yet known. The coexistence of arterial and venous system pathologic conditions has been demonstrated in previous reports, including varicosities of the coronary venous tree and of the leg veins (7, 8). Recently, an increased prevalence of varicocele has been reported in patients with coronary artery ectasia compared with patients with coronary artery disease (9). Furthermore, Received May 25, 2006; revised November 21, 2006; accepted November 27, Reprint requests: Süleyman Kılıç, M.D., İnönü Üniversitesi Tıp Fakültesi, Turgut Özal Tıp Merkezi, Üroloji AD, 44315, Malatya, Turkey (FAX: ; skilic@inonu.edu.tr; drskilic@hotmail.com; drskilic70@yahoo.com). an association between coronary artery ectasia and peripheral varicose veins has been reported (10). Additionally, decreased intima-media thickness of the carotid artery has been shown in patients with coronary artery ectasia compared with those with coronary artery disease, suggesting that the mechanism underlying vascular dilatation might be a systemic vascular abnormality (11). As an indirect relation, inflammatory pathogenesis has been reported to play a role in both coronary artery ectasia and peripheral varicose veins (12 14). Although several previous studies have explored the relationship between peripheral varicose veins and risk of cardiovascular disease with inconsistent results (15 19), cardiovascular risk factors have never before been evaluated in patients with varicocele. In addition to the presence of cardiovascular risk factors and demographic parameters, we assessed the prevalence of peripheral varicose veins in patients with and without varicocele. MATERIALS AND METHODS Study groups consisted of 52 patients younger than 50 years old with varicocele. One hundred male patients aged be /07/$32.00 Fertility and Sterility Vol. 88, No. 2, August 2007 doi: /j.fertnstert Copyright 2007 American Society for Reproductive Medicine, Published by Elsevier Inc. 369

2 TABLE 1 Clinical and demographical characteristics of patients with and without varicocele. Patients without varicocele (n 100) Patients with varicocele (n 52) P value a Mean age (y) Hypertension 12% (12/100) 17% (9/52).56 Hypercholesterolemia 32% (32/100) 28% (16/52).61 (cholesterol 200 mg/dl) Smoking 29% (29/100) 23% (12/52).43 Diabetes mellitus 5% (5/100) 6% (3/52).78 Weight (kg) Height (cm) BMI Intima-media thickness (mm) Peripheral varicose vein 4% (4/100) 17% (9/52).005 a Patients with versus patients without varicocele. Kılıç. Risk factors for varicocele. Fertil Steril tween 14 and 50 years who were admitted to the outpatient department of a urology clinic with any urologic symptom other than varicocele-associated symptoms and whose physical examinations did not reveal any finding of varicocele were involved in the control group. Patients who underwent scrotal color Doppler ultrasonography because of scrotal problems and whose spermatic veins were found to be normal during these examinations also were enrolled in the control group. Patients with known collagen vascular disease and malignancy were not included in the study. All the patients were examined for the presence of varicocele during physical examination by a specialist urologist (S.K.). Patients were examined in a warm room after standing for 5 minutes. The scrotal contents were examined with palpation for the determination of volume, position, and consistency of the testes and epididymis. Each spermatic cord was palpated with the patient in the supine and upright positions with and without the Valsalva maneuver. The varicocele was graded according to the system of Dubin and Amelar as follows (20): grade 1, varicocele palpable only during the Valsalva maneuver; grade 2, varicocele palpable in standing position; and grade 3, varicocele detectable by visual scrutiny alone. The patients whose physical examinations had inconclusive results were examined with scrotal color Doppler ultrasonography. Patients having undergone surgical or another treatment modality for varicose veins were thought to have varicocele. All study patients were evaluated for demographic parameters and cardiovascular risk factors for coronary artery disease. The following clinical and demographic parameters were recorded: age, body mass index (BMI), weight, height, hypertension (known hypertension treated with antihypertensive drugs, two or more blood pressure recordings greater than 140/90 mm Hg), diabetes mellitus (known diabetes treated with diet or drugs or both, or a fasting serum glucose level of more than 126 mg/dl), history of coronary artery disease (angiographically proved coronary lesions 50% or documented myocardial infarction, angina pectoris, previous percutaneous coronary intervention, or coronary artery bypass grafting), and hypercholesterolemia (known treated hypercholesterolemia or fasting or nonfasting serum cholesterol concentrations higher than 200 mg/dl). Current cigarette smoking was defined as active smoking within the past 12 months. The patients were then examined clinically by two physicians for the presence of primary varicose veins. Both physicians had to confirm the presence of varicose veins for the subject to be characterized as having varicose veins. Primary varicose veins in the lower limbs were defined as clearly visible, dilated, elongated, or tortuous veins caused by valvular incompetence and venous hypertension according to chronic venous insufficiency guidelines (CEAP [clinic, etiologic, anatomic, pathologic] classification) (21). Patients with small subcutaneous reticular varicosities or intradermal telangiectasias of small venules (spider veins) and patients with a history of deep-vein thrombosis, congenital heart disease, connective tissue disease, previous coronary angioplasty, or cardiac surgery were not included in the study. Patients who had previously undergone surgical or other treatment for varicose veins were classified as having varicose veins. Statistical Analysis Numerical variables are expressed as mean SD, and categorical variables are expressed as percentages. Unpaired t-test, 2 test, and Fisher s exact test, where appropriate, were used to compare the baseline characteristics of the study groups. Logistic regression analysis was performed to detect possible significant associations between presence of 370 Kılıç et al. Risk factors for varicocele Vol. 88, No. 2, August 2007

3 TABLE 2 Association of varicocele with height, weight, and presence of peripheral varicose vein. Odds ratio 95% Confidence interval P value Weight Height Peripheral varicose vein Kılıç. Risk factors for varicocele. Fertil Steril varicocele and a number of independent variables (height, weight, and presence of peripheral varicose veins). All tests of statistical significance were two-tailed and were considered to be significant at a.05 level of statistical significance. Statistical analyses were performed with SPSS statistical software (version 11.5; SPSS, Chicago, IL). RESULTS The baseline characteristics of the study population are presented in Table 1. Severity of varicoceles was grade 1 in 13 patients (25%), grade 2 in 30 patients (57.7%), and grade 3 in 9 patients (17.3%). Varicoceles were left-sided in 43 patients (82.7%), bilateral in six patients (11.5%), and rightsided in three patients (5.8%). There were no statistically significant differences between the two groups with respect to presence of hypertension, diabetes mellitus, hyperlipidemia, family history of coronary artery disease, BMI, age, and height. The weight of the patients with varicocele was significantly higher than those without varicocele. Prevalence of peripheral varicose veins was significantly higher in patients with varicocele than in those without varicocele (Table 1). Presence of peripheral varicose veins, height, and weight of the patients were included in regression analysis. Binominal regression analysis did not reveal any significant association between these variables and varicocele except the presence of peripheral varicose veins (Table 2). It was found that presence of peripheral varicose veins independently and positively associated with varicocele (odds ratio: 4.8, 95% confidence interval: , P.019). DISCUSSION Theories about the cause of varicocele range from the increased length of the left side for drainage into the inferior vena cava, possible compression of the left renal vein between the superior mesenteric artery and aorta (the nutcracker phenomenon), to absent or malfunctioning venous valves (22, 23). However, the main cause of varicocele is not yet known. The main finding of our study is that presence of cardiovascular risk factors and demographic variables of the patients with varicocele is not different from that of patients without varicocele. However, the prevalence of peripheral varicose veins in patients with varicocele, which also is an abnormality of the venous system, is significantly higher than in those without varicocele and is found to be independently and positively associated with varicocele. Because dilatation of the pampiniform plexus is a vascular abnormality, it is reasonable to expect some association with other vascular disorders or their risk factors. Such an association has been reported recently: the prevalence of varicocele was found to be higher in patients with coronary artery ectasia, which is aneurysmal dilatation of the coronary artery (9). Although it was not a pathologic study, it raised the possibility that the mechanism underlying coronary artery ectasia might increase further the prevalence of varicocele. On the other hand, relatively younger patients compared with the patients in the literature who had coronary artery disease might mask the possible differences in our study population with respect to these parameters. Several previous studies have explored whether an association exists between heart disease and varicose veins, but results have been inconsistent. Komsuoglu et al. reported a lower prevalence of angina in elderly individuals with varicose veins (15). The Kaiser-Permanente Epidemiologic Study of Myocardial Infarction also reported that coronary heart disease is less frequent in subjects with either varicose veins or hemorrhoids (16). To the contrary, increased risk for coronary artery disease was reported by the Framingham Heart Study and the Paris Prospective (17, 18). Scott et al. showed that varicose veins are associated with a 36% decrease in risk of symptomatic coronary heart disease, even after adjusting for many other common cardiovascular risk factors (19). Recently Androulakis et al. showed increased prevalence of varicose veins in patients with coronary artery ectasia compared with those with coronary artery disease and normal coronary arteries (10). The prevalence of varicose veins is significantly higher among patients with coronary artery ectasia compared with age-matched patients with coronary artery disease but without coronary artery ectasia and randomly selected subjects from the general population. Furthermore, in multivariate analysis, coronary artery ectasia is found to be significantly and independently associated with peripheral varicose veins (10). Varicoceles are presumably an evolutionary consequence of human beings upright posture (24). Although several anatomically based theories have been proposed to explain Fertility and Sterility 371

4 the genesis of varicoceles, no single model is uniformly accepted. Through cadaveric and venographic studies, several characteristic features of pampiniform plexus venous drainage patterns have been identified that explain how varicoceles arise and why there appears to be a predisposition to left-sided lesions (25, 26). It is generally agreed that these anatomic findings contribute to an increase in either venous hydrostatic pressure, venous reflux of blood within the pampiniform plexus, or both in patients with varicocele and result in abnormal venous dilatation and tortuosity (27). Delaney et al. (28) reported that patients with varicocele are taller and heavier than the age-matched controls, although the BMI is not different; these results may be interpreted in several ways. Several other studies of the literature also reported data similar to this finding (29 31). The data may imply that taller individuals are perhaps more susceptible to increased hydrostatic pressure because of the increased length required for drainage of the left spermatic vein. In our study, although height tended to be higher in patients with varicocele, the weight was significantly higher compared with those without varicocele. However, interestingly, multivariate analysis did not reveal any association between the varicocele and body habitus. Our finding is in accordance with that from a recent study from Greece (32) in which no significant difference in mean height was found between the schoolboys with and without varicocele. The discrepancy in the varicocele-height connection between the white European males and the Mediterranean males may be a result of genetic or environmental differences. An alternative explanation is that body height contributes to the pathogenesis of varicocele in white (tall) European populations but not in the shorter (Mediterranean) populations. Therefore, this topic remains to be elucidated. The increased prevalence of peripheral varicose veins in patients with varicocele highlights the possible association of these two venous system abnormalities. This finding raises the possibility that the two abnormalities might share common pathologic mechanisms. A survey of the prevalence of venous disease in the United States estimated that the prevalence of varicose veins among individuals younger than 30 years was less than 1% for men and less than 10% for women. However, in men and women aged 70 years and older the estimates increased substantially to 57% and 77%, respectively (17). We have demonstrated a high prevalence of peripheral varicose veins in patients with varicocele, compared with the Framingham study regarding a relatively similar age population. Although no studies have examined the prevalence in an elderly population, we have recently reported a relatively high prevalence of varicocele in patients with coronary artery ectasia and coronary artery disease (9). Because increasing age is known to be a risk factor for the development of varicosities (33), we can speculate that the association between peripheral varicose veins and varicocele might be stronger with increasing age. It would be a valuable approach to consider this association not only in young adults but also in elderly patients. Although the main mechanism is not known yet, most experts agree that valve reflux is the principal determinant of varicose veins. However, there is no consensus as to whether primary valve incompetence is the initiating event in the pathogenesis of venous disease or the incompetence is secondary to vein wall dilatation (14, 34 37). Altered collagen composition and elastin content in the vessel wall have been supposed to be responsible for the weakening of the vessel wall (38, 39). An additional contributing mechanism may be due to chronic inflammation and the release of cytokines (14). Cooper et al. reported that primary varicose veins are a result of primary wall abnormality predisposing to venous dilatation, as a precursor to later valvular incompetence and finally reflux (40). Because this incompetence predominates in areas that would not be anticipated to suffer the greatest pressures, a more complex interaction between luminal forces, and perhaps an unidentified molecular signal for vessels to dilate, may be fundamental to the genesis of varicose veins. 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