Hagai Levine, Faculty of Medicine, Braun School of Public Health and Community Medicine, Hebrew University-Hadassah, P.O Box 12272, Kiryat Hadassah, Ein Kerem, Jerusalem 91120, Israel. E-mail: email@example.com
Scarce data are available on epidemiology of varicocoele, the most common surgically correctable cause of male infertility. The objectives of this study were to evaluate the association between body mass index (BMI) and varicocoele and to assess trends in prevalence over time. We conducted a nationwide population-based long-term (1967–2010) study among 1 323 061 Israeli adolescent males using data from mandatory medical examination. BMI was grouped into underweight, normal weight, overweight and obese categories by percentiles adjusted for age in months and by further classification to five categories within normal weight. Univariable and multivariable logistic regression models were constructed, adjusting for possible confounders. Varicocoele prevalence (N = 47 398) increased during the study period from 1.6% for the 1950–1954 birth cohort to 4.6% for the 1990–1993 birth cohort, with the steepest rise in the normal weight group. Varicocoele unadjusted rates were highest (4.1%) among underweight and lowest (1.6%) among obese. In a multivariable model, adjusted for birth cohort, height, age and socio-demographic factors, we found a decreased risk for varicocoele in the overweight group [odds ratio (OR) = 0.51, 95% confidence interval (CI): 0.49, 0.54] and the obese group (OR = 0.34, 95% CI: 0.32, 0.37), compared with the normal weight group. Within the normal weight group, a monotonic inverse association between BMI percentile and varicocoele was observed, most notable among 75–84.9 percentile compared to 25–49.9 percentile (OR = 0.65, 95% CI: 0.63, 0.68). In conclusion, varicocoele is common among adolescents in Israel, and its prevalence had increased in recent decades, providing clues to direct further andrological research on the role of modern lifestyle and environment in the aetiology of varicocoele. BMI, across percentiles, was found to be monotonically inversely associated with varicocoele, thus directing research and clinical efforts.
Male infertility is a major public health problem that has been increasing in recent decades, at least in Western countries (Carlsen et al., 1992; Swan et al., 2000). Varicocoele, an abnormal dilation of the veins of the pampiniform plexus of the spermatic cord, is the most common surgically correctable cause of male infertility (Dubin & Amelar, 1971; Sigman & Jarow, 2007; Serefoglu et al., 2013). It is a common entity among adolescents and young adults with prevalence rates ranging from 3 to 25% in the general population, varying by method of examination, population characteristics and age at examination (Oster, 1971; Steeno et al., 1976; Stavropoulos et al., 2002; Kumanov et al., 2008). Varicocoele is associated with orhchalgia and significant usage of medical services (Skoog et al., 1997). Varicocoele is commonly defined by physical examination, and ancillary diagnostic measures are not recommended in standard evaluation procedures (Dubin & Amelar, 1970; Jarow et al., 2002; Schneck & Bellinger, 2007). The prevalence of varicocoele is as high as 40% in patients attending infertility clinics and up to 80% in those with secondary infertility (WHO, 1992; Witt & Lipshultz, 1993; Gorelick & Goldstein, 1993; Jarow, 2001). Despite its frequency and importance, data on the epidemiology of varicocoele are scarce. There are limited data supporting an inverse association between obesity and varicocoele and a direct association between height and varicocoele (Nielsen et al., 2006; May et al., 2006; Handel et al., 2006; Prabakaran et al., 2006; Kumanov et al., 2008; Tsao et al., 2009; Chen & Huang, 2010; Baek et al., 2011; Gokce et al., 2013). Other studies did not find an association between body mass index (BMI) or weight and varicocoele (Oster, 1971; Delaney et al., 2004). There is lack of evidence regarding the association between BMI and varicocoele from population-based studies of healthy adolescents as most previous studies included small non-random samples of men attending infertility clinics or small samples of school boys. Most studies were unable to adjust for possible confounders. There is no data on long-term time trends or regarding the association between BMI and varicocoele within the normal range of BMI. Against this background, the objectives of this study were to assess trends in varicocoele prevalence over time and evaluate the association between BMI and varicocoele, controlling for possible confounders, such as birth cohort, height, age, and socio-demographic characteristics.
Materials and methods
Design, setting and participants
The study was designed as a nationwide, long-term, population-based repeated cross-sectional study. Israel is one of the few Western countries where military service is compulsory (for the Jewish population). Israeli adolescents are obligated to undergo a medical board examination, predominantly at age 17. Consequently, these data provide a generally representative sample of the male population at this age. Our study population included 1 323 061 Jewish adolescent males born during the period of 1950–1993 and examined between 1967 and 2010 at age 16.5–19.9. We excluded 29 subjects without testicles. Data were retrieved from the Israeli Defense Forces database and then re-identified. The study protocol was approved by the Ethics Committee of the IDF Medical Corps.
Body mass index and covariates
Socio-demographic and clinical data, height and weight, were measured and recorded during the obligatory medical board examination. Adolescents were measured barefoot wearing only a shirt and underwear. The measurements were performed by trained medical personnel using a beam balance and stadiometer. Values were recorded and rounded to the nearest 0.5 kg for weight and 1 cm for height. BMI was calculated as weight in kilograms divided by height in metres squared. Age-adjusted percentiles were coded according to the 2000 United States CDC BMI-for-age growth charts, which are internationally used for reference purposes (Kuczmarski et al., 2002). Classification was carried out according to four groups: underweight (<5th percentile); normal weight (5th–84.9th percentile); overweight (85th–94.9thpercentile) and obese (≥95th percentile), with normal weight as the reference group. An elaborated analysis of the normal weight group included further classification for five percentile groups (5–9.9; 10–24.9; 25–49.9; 50–74.9 and 75–84.9), with 25–49.9 (largest group) as reference group.
Height in centimetres was grouped into quintiles in our dataset (≤168; 169–172; 173–175; 176–179; and ≥180). All comparisons were to the lowest quintile. Birth cohorts (1950–1993) were divided into nine groups of 5 years, except the last cohort of 4 years. Birth cohort groups were almost equal in size. Age at examination (16.5–19.9) was grouped by half years; comparison was made to the largest group of 17.0–17.4 years. Socioeconomic status (SES) was based on the score of place of residence, according to a national classification of 10 clusters by geographical units (Israel Central Bureau of Statistics, 2006), which we categorized as low (1–4) [reference group], medium (5–7) and high (8–10). Place of residence was classified by size to urban (≥2000 residents) or rural (<2000 residents). Years of education were grouped into <11 years and ≥11 years. Country of birth was grouped into Western, that is, mainly Israel, Europe and America, or non-Western, referring to North Africa and Asia.
A routine examination of the testicles was conducted by a qualified physician as part of the general screening physical examination required to determine military fitness. The guidelines for the testicle examination were that it should be conducted under warm temperature in a private room, in both reclining and standing positions, with and without the Valsalva manoeuver. These examination guidelines and the criteria for varicocoele diagnosis or its significance for service were materially unchanged throughout the course of the study period. Following the examination, a specific code was given to adolescents diagnosed with varicocoele. Data on laterality and exact grade by Dubin/Amelar system (Dubin & Amelar, 1970) of the varicocoele were not recorded. Since 1997, the code also included hydrocele. The prevalence of hydrocele was at least 10 times lower than that of varicocoele, according to pre-1997 data.
The outcome variable was defined as the presence of varicocoele of any severity according to the physical examination or evidence of previous varicocoele correction. Thus, examinees that had undergone surgical correction for varicocoele in the past were assigned the same code.
All analyses were performed with IBM spss statistics for Windows, version 19 (Armonk, NY, USA). BMI and height means were compared between participants with varicocoele and those without varicocoele, using a two-sided T-test. Prevalence of varicocoele per 10 000 examinees was calculated overall and by each variable category, as well as for each birth cohort, stratified by the four BMI groups. Linear regression was used to test trends over time of varicocoele prevalence. Univariable (adjusted by 5-year birth cohorts, as birth cohort was strongly associated with varicocoele prevalence) logistic regressions were used to assess the associations between BMI or each of the other covariates and varicocoele. Two-sided p < 0.05 was considered as statistically significant. The association between BMI and varicocoele was then assessed by multivariable logistic regressions, introducing all other variables, as all were significant in the univariable model. The same models were analysed within normal weight group by five different percentile groups. Results for the logistic regression were presented as OR with 95% CI.
Varicocoele was diagnosed in 47 398 of the 1 323 061 adolescent males in the sample, for an overall prevalence of 358 per 10 000 (95% CI: 355, 361) participants. The mean age at examination was 17.5 (SD = 0.6), given that over 75% of our population were examined between the ages of 17.0–17.9. BMI distribution was comparable to the standard US young adult population, albeit leaner, as 56.1% were in the lower 50% percentiles. The mean BMI of individuals with varicocoele (20.98, SD = 2.8) was significantly lower than that of the other participants (21.66, SD = 3.3, p < 0.001). Moreover, the mean height of those with varicocoele (175.0 cm, SD = 6.8) was significantly higher than that of the other participants (173.6, SD = 6.8, p < 0.001). The sample socio-demographic, age and anthropometric characteristics, varicocoele prevalence by category and associations with varicocoele are shown in Table 1. Varicocoele prevalence was associated with all variables in the univariable (adjusted for birth cohort) models. All variables, except years of education, remained statistically significant after mutual adjustment in a multivariable model with correlates coefficients slightly attenuated (data not shown).
Table 1. Characteristics of 1 323 061 Israeli adolescent males examined between 1967 and 2010 and association with varicocoele (N = 47 398) in ‘univariable’ modelsa
Varicocoele prevalence was found to be strongly associated with birth cohort. The prevalence of varicocoele increased three to four times during the study period, from 1.6% for the birth cohort of 1950–1954 to 4.6% for the birth cohort of 1990–1993 (p for trend = 0.001), peaking for the 1975–1979 birth cohort and then stabilizing. Prevalence rates per 10 000 increased by 47 (95% CI: 26, 68) for each 5-year birth cohort. The increase was highest for normal weight (53, 95% CI: 33, 74), and the trend was significant for all BMI groups: underweight (49, 95% CI: 23, 74); overweight (33, 95% CI: 22, 44); and obese (24, 95% CI: 15, 33) (Fig. 1).
BMI was found to be strongly associated with varicocoele in the univariable model (Table 1). Adjusting for possible confounders did not substantially alter the association between BMI and varicocoele. In comparison to the normal weight group (5–84.9 percentiles), the adjusted OR of the association between BMI and varicocoele were lower in the overweight group (0.51, 95% CI: 0.49, 0.54, p < 0.001) and the obese group (0.34, 95% CI: 0.32, 0.37, p < 0.001), whereas higher in the underweight group (1.06, 95% CI: 1.02, 1.09, p = 0.001).
This association between BMI and varicocoele was further elaborated by stratification of the normal weight group to five age-specific percentile groups. The prevalence rates ranged monotonically within normal weight group (Table 2). A strong, monotonic inverse association was found between BMI and varicocoele within the normal weight range in univariable analysis, materially unchanged in the multivariable analysis (Table 2).
Table 2. Distribution by BMI age-specific percentilea of 1 056 574 normal weight Israeli adolescent males examined between 1967 and 2010 and association with varicocoele in a multivariable modelb
BMI: body mass index; CI, confidence interval; OR: odds ratio.
BMI percentiles within normal weight group, according to CDC 2000 growth charts (Kuczmarski et al., 2002).
Adjusted for birth cohort, height, age, socioeconomic status, urban/rural residence, country of birth and years of education, logistic regression model.
In this long-term, nationwide, population-based screening of over 1.3 million Israeli adolescents we found varicocoele to be common among males in Israel, and its prevalence had been increasing in recent decades. The entire range of BMI was found to be strongly, monotonically, inversely associated with varicocoele prevalence. These results were independent of potential confounders, such as birth cohort, height, age, SES, urban residence and country of origin. To the best of our knowledge, this is, by far, the largest study on varicocoele epidemiology, enabling elaboration of association with BMI, including, for the first time, within normal weight group. In addition, this is the first study to assess population-based long-term trends of varicocoele.
The present analysis has certain limitations. Our outcome measure of varicocoele was based on a one-time general screening medical examination, carried by different examiners, which may lead to under-diagnosis and under-reporting of the actual varicocoele rates. Nevertheless, even if this were the case, a non-differential information bias is anticipated with respect to BMI or time, which would only lead to attenuation of the association found, and not to a change in the direction of the association. Our study design was cross-sectional, so the interpretation of our results regarding causality should be carried out with great caution and should be investigated further by longitudinal and interventional studies.
A thorough literature review of studies conducted on the association between BMI and varicocoele underlines the uniqueness of this study (Table 3). Previous studies were of either case-control or cross-sectional designs. Most studies, conducted in the United States, Bulgaria, Germany, Taiwan, South Korea, Iran and Turkey, found an inverse association between BMI and varicocoele (Nielsen et al., 2006; May et al., 2006; Handel et al., 2006; Prabakaran et al.,2006; Kumanov et al., 2008; Tsao et al., 2009; Chen & Huang, 2010; Baek et al., 2011; Hassanzadeh et al., 2011; Soylemez et al., 2012; Yigitler et al., 2012). Differences between overweight and normal weight groups were not always significant (Nielsen et al., 2006; Soylemez et al., 2012). An association between BMI and varicocoele was not found in other small-scale studies of populations in various stages of puberty (Oster, 1971; Delaney et al., 2004). Recent studies found lower mean BMI among varicocoele cases compared with controls, both for young and elderly populations (Chen, 2012; Gokce et al., 2013). Most of the previous studies were not population-based, and many focused on infertile males rather than on the general population. None of the studies adjusted for all the various possible confounders controlled in our study (age, height, birth cohort, and socio-demographic variables), and none investigated the association between BMI and varicocoele within the normal weight group or time trend.
Table 3. Literature review of studies on association between BMI and Varicocoelea
Setting and participants
Age in years
BMI, body mass index; OR, odds ratio.
Review conducted by search in PubMed using keywords: ‘varicocoele and BMI’ or ‘varicocoele and body mass’ or ‘varicocoele and obesity’. In addition, all references in relevant articles were sought. Studies with a statistical analysis of the association between BMI and varicocoele prevalence are presented. 95% confidence interval is given in parenthesis, when available. Last updated on 12 April 2013.
Candidates for junior officer studentship in a military college from 2002 to 2009, Turkey
BMI inversely correlated with the prevalence of varicocoele (p = 0.0001)
Men presenting for infertility at a tertiary academic referral centre from 2000 to 2010, Turkey
BMI inversely correlated with the prevalence of varicocoele (p < 0.001)
Population-based Jewish men, mandatory medical examination at adolescence, Israel
1 323 061 (47 398 with varicocoele)
Age-specific BMI percentiles
OR = 0.51 (0.49–0.54) for overweight and OR = 0.34 (0.32–0.37) for obese compared with normal weight
The inverse association found in our study of BMI across percentiles and varicocoele prevalence is unlikely to be fortuitous or influenced by confounding or bias, as evidenced by the results. A genuine association between BMI and varicocoele is supported by the monotonicity and strength of the association found. Although it has been previously claimed that physical examination is less sensitive for the diagnosis of varicocoele among obese individuals because of increased scrotal adipose tissue, the association found here over the entire BMI range does not support this claim. Moreover, clinicians report no problem in identifying varicocoele among the obese population (Handel et al., 2006; Kumanov et al., 2007; Tsao et al., 2009). Indeed, a recent study, showing that obese men have a lower prevalence of ultrasound-detected varicocoele than normal weight men, concludes that a difficult physical examination should not be seen as the cause of the lower prevalence of varicocoeles in obese patients (Walters et al., 2012). A recent study demonstrated that BMI does not appear to affect varicocoele repair outcomes (Pham & Sandlow, 2010). In summary, the inverse association between BMI and varicocoele found in our study, together with previous reports further supports a real association.
According to the ‘nutcracker phenomenon’ theory, varicocoele is caused by a rise in blood pressure in the left renal vein as it is compressed between the aorta and the superior mesenteric artery. In this case, the increased adipose tissue could protect the left renal vein from compression (Handel et al., 2006; Kumanov et al., 2008). Although our results do support the claim that adiposity protects against varicocoele, the theory was not directly tested in our study. Further research of the association of BMI and varicocoele with measurements of skinfold body fat, waist and hip circumference, trajectory of BMI during adolescence and ultrasound of the left renal vein could support or refute this theory. In addition, further research is warranted to examine the diagnosis, prevention and treatment possibilities based on this suggested pathogenesis.
Obesity has been linked to many human illnesses. Obesity prevalence has increased in our population during the study period (Gross et al., 2009). The global obesity epidemic parallels a decrease in male fertility. Yet, the association between BMI and sperm parameters remains controversial. A recent meta-analysis found overweight and obesity to be associated with an increased risk of azoospermia or oligozoospermia, which suggests that excess body weight affects the sperm production (Sermondade et al., 2012). The strong inverse association between obesity and varicocoele found in this study suggests that the association between obesity and poor sperm quality may be even stronger, if the difference risk of varicocoele among lean and obese males is taken into account. Future research should explore the pathogenesis and the effect of obesity and weight reduction on sperm parameters, male fertility and varicocoele.
Height was found in our study to be strongly and monotonically associated with varicocoele. Such an association was found in most (Smith, 1957; Oster, 1971; Delaney et al., 2004; Prabakaran et al., 2006; May et al., 2006; Kumanov et al., 2008; Gokce et al., 2013), but not all previous studies (Nielsen et al., 2006; Baek et al., 2011). This association was previously explained by mechanical factors, as height may increase the ‘nutcracker phenomenon’. Another explanation could be other factors that affect both height and varicocoele risk. The highest risk found among lean as well as tall males, could direct clinicians to put special emphasis on this populations.
Varicocoele prevalence among Israelis has been increasing in all BMI groups, but even more so for normal weight groups. In addition, higher SES and Western country of origin are two of the socio-demographic characteristics found in our study to be associated with varicocoele. Kumanov previously postulated that Western lifestyle and/or environmental exposures related to modern industrialization may be a risk factor for varicocoele (Kumanov et al., 2008). Further investigation is warranted to ascertain whether the socio-demographic correlates and alarming increase in prevalence found in our study supports a possible association between varicocoele and factors related to modern lifestyle or environment, which may contribute to declining sperm density. This possibility was considered in some studies assessing sperm counts time trends, for example, in a recent study among students in Spain, which showed a non-significant decline in varicocoele prevalence over the last decade (Mendiola et al., 2013). However, these studies were not intended to assess varicocoele time trends, and this study is the first to assess population-based long-term trends of varicocoele. Interestingly, obesity prevalence has increased in our population during the study period (Gross et al., 2009). The inverse association found between varicocoele and obesity while both morbidities have increased over time points to different mechanism involved in obesity and varicocoele time trends.
The strengths of our study include its population-based design, the routine standard screening examination for varicocoele at a similar age, the large sample size, the completeness of data, the timing of the examination at the end of adolescence and the ability to adjust for possible confounders. The actual measurement of weight and height by trained medical personnel in the same manner and the correction for age in months provided us with a valid BMI measurement. Given that varicocoele is considered to be accurately detected by clinical examination, our outcome measure has high validity. The large sample size enabled us, for the first time, to refine the study of the association between BMI and varicocoele within the normal weight group. The mandatory health screening of our population served to increase the representativeness of the study sample and to protect against selection bias. As the data were collected by the same methods for more than 40 years, we were able to assess varicocoele secular trends and the association of BMI with varicocoele over time. Finally, the timing of the examination at the end of adolescence allowed us to avoid possible confounding related to various stages of puberty.
In conclusion, varicocoele is common among adolescents in Israel, and its prevalence had increased in recent decades, providing clues to direct further research on the role of modern lifestyle and environment in the aetiology of varicocoele. BMI, along its full range, was inversely and independently associated with varicocoele prevalence, thus directing research and clinical efforts.
H.L. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, and was also involved in study concept and design. A.R., S.Z., E.D., D.T., N.D., A.A., R.C., and H.L. were involved in acquisition of data; A.R., S.Z., E.D., D.T., R.C.-M., N.D., A.A., R.C., and H.L. were involved in analysis and interpretation of data, and critical revision of the manuscript for important intellectual content; H.L. and A.R. drafted the manuscript; E.D. and H.L. performed the statistical analysis; S.Z., D.T., N.D., A.A., and R.C. provided administrative, technical, or material support; H.L., S.Z., and R.C. supervised the study.
Access to the anonymized databases was provided by the Israel Defense Force (IDF) Medical Corps. The IDF Medical Corps was not involved in the design and conduct of the study; the collection, management, analysis and interpretation of the data; or the preparation, review or approval of the manuscript.