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Body Size and Testicular Cancer Olof Akre, Anders Ekbom, Pär Sparén, Steinar Tretli The incidence of testicular cancer has been increasing markedly among many populations worldwide for as long as cancer occurrence has been assessed (1,2). The cause of this increase, however, remains unknown. Sex hormones are instrumental in the growth and in the development of the testicle, both prenatally and postnatally, and have, therefore, frequently been the focus of etiologic research. Obesity often reflects increased levels of estradiol and estrone Journal of the National Cancer Institute, Vol. 92, No. 13, July 5, 2000 (3). We have performed a study of a cohort of approximately 500 000 Norwegian men to investigate the relation between body size, measured by height and body mass index (BMI), and testicular cancer. Between 1963 and 1975, the National Mass Radiography Service in Norway conducted a tuberculosis screening program. The program included all inhabitants who were more than 15 years of age in 17 of the 19 counties of Norway. In connection with the examination, height and weight were measured and recorded together with the individually unique, 11-digit identification number assigned to all inhabitants of Norway. Approximately 600 000 men went through the screening. This corresponded to 70.3% of those who were invited. We restricted our study population to men between 20 and 54 years of age at the time of examination, for a total of 476 912 individuals. Follow-up for occurrence of testicular cancer (4) was made by linkage to the Cancer Registry in Norway, in which all newly diagnosed cases of cancer in Norway are registered. Patients are entered in the Cancer Registry by use of their individual identification number. The Registry was started in 1952, and the completeness of registration of testicular cancer is almost 100% (3). The histologic classification and coding are done according to the Manual of Tumor Nomenclature of Pathology, 1968 (5). Only patients with tumors of germ cell origin were included in the analyses. We categorized the cases into the two major histopathologic subgroups: seminomas and nonseminomas. Those case patients with a histologic code indicating a pure seminoma type were classified as having seminomas, whereas those with the codes for embryonal carcinomas, endodermal sinus tumors, teratomas, choriocarcinomas, or germ cell Affiliations of authors: O. Akre, A. Ekbom, Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden; P. Sparén, Stockholm Centre on Health of Societies in Transition, Södertörns Högskola, Huddinge, Sweden; S. Tretli, The Norwegian Cancer Registry, Montebello, Oslo, Norway. Correspondence to: Olof Akre, M.D., Ph.D., Department of Medical Epidemiology, Karolinska Institute, Box 281, S-171 77, Stockholm, Sweden (e-mail: [email protected]) See “Notes” following “References.” © Oxford University Press BRIEF COMMUNICATIONS 1093 tumors of mixed morphology were classified as having nonseminomas. A latent period of 1 year was applied to preclude influence of disease on body weight. During the follow-up time, i.e., between 1964 and 1990, 553 cases of testicular cancer, including 363 seminomas and 190 nonseminomas, were diagnosed before the age of 60 years. The mean age at entry in the cohort (i.e., age at measurement) was 37.9 years (range ⳱ 20–54 years; median ⳱ 39 years), which is during the age peak of seminoma incidence but 10 years after the age peak of nonseminomas. This explains the relatively low number of the latter tumor subtype. The mean followup time among case patients was 9 years (range ⳱ 1–25 years; median ⳱ 9 years). Censoring among the cohort subjects occurred at death, at the subjects’ 60th birthday, or at the end of follow-up, i.e., January 1, 1990, whichever came first. Information about vital status was obtained from the Death Registry, again using the individual identification number. Fewer than 500 cohort members were lost to follow-up because of emigration. Mean follow-up time was 16 years (range ⳱ 1–27 years; median ⳱ 18 years). Thus, the total follow-up time was 7 264 736 person-years. BMI (weight [in kilograms] divided by height [in meters] squared) was calculated for each subject and categorized into slim (BMI <20.0 kg/m2), normal weight (BMI ⳱ 20.0–24.9 kg/m2), overweight (BMI ⳱ 25.0–29.9 kg/m2), and obese (BMI 艌30.0 kg/m2). Height was categorized into quintiles on the basis of the distribution among the entire study cohort. Age at measurement and year of birth were classified into 5- and 10-year groups, respectively. Person-years were calculated by use of the Datab package from Hirosoft International Corporation, Seattle, WA (www.hirosoft.com:). Calculation of incidence rates and statistical analysis were performed by use of a SAS® statistical package (SAS Institute, Inc., Cary, NC). The multivariate analysis was initially based on a Poissonregression model, including the following independent variables: height, BMI, age at measurement, birth cohort, and county of residence. The final models included only variables that were independent determinants and/or substantial confounders in the analysis of testicular cancer rates. Incidence rate ratios were 1094 BRIEF COMMUNICATIONS used as measures of relative risks. Tests for trend were performed by use of the categorized variables. All P values were derived from two-tailed tests. P for homogeneity of odds ratios was tested with the use of the likelihood ratio test of inclusion of a term for the product of histologic category and the exposure variable. Univariate characteristics of the cohort and rates of testicular cancer are shown in Table 1. Cross-tabulations of the exposure variables (data not shown) illustrate that BMI is higher in older age groups, that taller men are more often slim, and that height decreases with age. In the multivariate analysis, BMI was inversely associated and height was positively associated with risk of testicular cancer (Table 2). Height and BMI were only weakly associated and did not mutually confound each other. There were no statistically significant differences in the risk patterns of the two histologic types of testicular cancer; P for homogeneity was .14 for BMI and .99 for height. We also analyzed BMI categorized into quintiles, and the results were, in essence, the same. Since the study subjects were measured at different ages and age may modify the effect of our study variables, we performed analyses restricted to those measured in their 20s. Barring the instability of the estimates, the results from these analyses were similar. Restriction of follow-up to 10 years led to similar results. Finally, follow-up time was tested in the models with unchanged results. The results of this study indicate that testicular cancer is inversely associated with BMI and positively associated with height. The latter association was independent of BMI. The study was a large cohort study using an internal comparison group. In such studies, exposed and nonexposed subjects are followed-up identically, thus minimizing the risk of false-positive results due to bias. The age at measurement of weight may, however, be too high to accommodate the most relevant time window of exposure. Body size is primarily determined by hereditary, nutritional, and hormonal factors. The hormonal determinants can roughly be divided into growth hormones and sex hormones. Most previous studies on postnatal risk factors for testicular cancer have focused on endogenous sex hormones. Obesity is inversely associated with both total testosterone and sex hormone-binding globulin, but it is not fully understood what the implications of this are for the amount of biologically active testosterone (3,6,7). Furthermore, obese men have increased levels of both estradiol and estrone coming mostly from extraglandular conversion of androgen precursors, and the overall sex-hormonal profile thus seems to be shifted to a less Table 1. Testicular cancer rates and rate ratios (RRs) from univariate analysis No. of case patients No. of subjects No. of person-years Incidence rate, per 105 person-years Univariate RR (95% confidence interval) Age at measurement, y 20–24 25–29 30–34 35–39 40–44 45–49 50–54 130 123 104 75 63 38 20 61 122 65 594 60 051 63 682 72 778 74 597 79 088 1 161 689 1 230 352 1 132 795 1 184 830 1 164 867 852 827 537 375 11.19 10.00 9.18 6.33 5.41 4.46 3.72 1.00* 0.89 (0.70–1.14) 0.82 (0.63–1.06) 0.57 (0.43–0.75) 0.48 (0.36–0.65) 0.40 (0.28–0.57) 0.33 (0.21–0.53) Body mass index, kg/m2 <20.0 (slim) 20.0–24.9 (normal weight) 25.0–29.9 (overweight) 艌30.0 (obese) 39 347 155 12 19 875 272 846 164 882 18 992 324 783 4 321 542 2 367 036 251 374 12.01 8.03 6.55 4.77 1.50 (1.07–2.08) 1.00* 0.82 (0.67–0.99) 0.59 (0.33–1.06) Height, cm 艋171 172–175 176–178 179–182 艌183 89 115 100 130 119 107 526 109 437 87 959 95 150 76 663 1 504 937 1 628 788 1 356 567 1 512 759 1 261 685 5.91 7.06 7.37 8.59 9.43 1.00* 1.19 (0.91–1.57) 1.25 (0.94–1.66) 1.45 (1.11–1.90) 1.60 (1.21–2.10) *Referent category. For age and body mass index, where categories differed substantially in numbers, the category with the highest number of case patients was chosen to maximize statistical stability. For height, where numbers were approximately equal, the lowest category was chosen as reference for readability concerns. Journal of the National Cancer Institute, Vol. 92, No. 13, July 5, 2000 Table 2. Adjusted rate ratios (RRs) of all testicular cancers, testicular seminomas, and testicular nonseminomas in association with age and body size as determined by multivariate analysis Adjusted* RRs (95% confidence interval) Age at measurement, y 20–24 25–29 30–34 35–39 40–44 45–49 50–54 Body mass index, kg/m2 <20.0 (slim) 20.0–24.9 (normal weight) 25.0–29.9 (overweight) 艌30.0 (obese) Height, cm 艋171 172–175 176–178 179–182 艌183 All testicular cancer Seminoma Nonseminoma 1.00† 0.92 (0.72–1.18) 0.86 (0.66–1.12) 0.60 (0.45–0.81) 0.52 (0.38–0.71) 0.44 (0.30–0.63) 0.37 (0.23–0.60) P‡<.0001 1.00† 1.15 (0.83–1.60) 1.19 (0.85–1.66) 0.85 (0.59–1.23) 0.83 (0.57–1.21) 0.59 (0.37–0.94) 0.55 (0.31–0.97) P‡ ⳱ .0004 1.00† 0.69 (0.47–1.01) 0.53 (0.34–0.81) 0.35 (0.21–0.57) 0.20 (0.11–0.38) 0.28 (0.15–0.53) 0.19 (0.08–0.48) P‡<.0001 1.34 (0.96–1.87) 1.00† 0.94 (0.77–1.14) 0.73 (0.41–1.30) P‡ ⳱ .06 1.52 (1.01–2.28) 1.00† 1.03 (0.82–1.31) 0.63 (0.29–1.35) P‡ ⳱ .18 1.09 (0.61–1.93) 1.00† 0.76 (0.53–1.09) 0.93 (0.38–2.29) P‡ ⳱ .18 1.00† 1.13 (0.86–1.49) 1.14 (0.85–1.51) 1.28 (0.98–1.68) 1.34 (1.02–1.77) P‡ ⳱ .02 1.00† 1.13 (0.80–1.59) 1.16 (0.82–1.65) 1.29 (0.93–1.81) 1.41 (1.01–1.99) P‡ ⳱ .03 1.00† 1.13 (0.71–1.82) 1.09 (0.66–1.78) 1.26 (0.79–1.99) 1.21 (0.75–1.95) P‡ ⳱ .37 *Adjusted for all variables in the table. †Referent category. For age and body mass index, where categories differed substantially in numbers, the category with the highest number of case patients was chosen to maximize statistical stability. For height, where numbers were approximately equal, the lowest category was chosen as reference for readability concerns. ‡P value for trend. androgenic state, although clinical signs of hypogonadism are rare (3). We, therefore, conclude that this study argues in favor of a protective effect of elevated postnatal estrogen levels. These effects may, however, be modified by age, which complicates the interpretation. Another problem is that most studies on the relation between BMI and hormones are done to study obesity, and it is, therefore, not clear whether the increase in risk among the slim can be interpreted in the same way. Although we had low power to do so, we attempted to evaluate effect modification by age by restricting the data to those measured in their 20s. The results gave no indication of heterogeneity of effects; barring the role of chance, this indicates that either the older subjects have been stable in their relative weights or there is no effect modification. Since testicular germ cell cancer is probably initiated in utero, postnatal hormones are likely to function as promoters. These hormones may continue to exert their effect in advanced stages of tumor development, although the time of puberty, when the testicles grow and develop rapidly, may be of particular importance. Previous studies on the association between BMI and testicular cancer report both negative associations (8,9) and null findings (10–12). One of the studies (8) reporting a negative association used a prospective design with objectively measured body size, whereas the others are retrospective investigations with self-reported anthropometric measures. The prevalence of obesity has increased during the study period (13,14) and would, given a true negative association, have counteracted the increasing incidence of testicular cancer. On the basis of descriptive epidemiology, however, it should be noted that it is unlikely that postnatal exposures are strong determinants of the incidence trends. On the other hand, adult obesity may reflect exposures during the fetal period that influence the occurrence of testicular cancer (15). Proxy variables for sex-hormonal activity other than BMI show conflicting results for the association with testicular cancer. Factors thought to reflect increased cumulative exposure to androgens, such as early puberty, have been associated with increased risk (10,12, 16–19), whereas another study (9) has indicated a decrease in risk associated Journal of the National Cancer Institute, Vol. 92, No. 13, July 5, 2000 with factors that appear to be associated with a more androgenic state, such as baldness. Thus, there is yet no clear picture of the relation between postnatal levels of sex hormones and testicular cancer emerging from analytic studies of surrogate measures. As for BMI, previous studies on height in relation to testicular cancer show conflicting results— height has been either positively (10,12) or not associated (8,9,11) with risk. Height may operate as a risk factor through several, not mutually exclusive, mechanisms. First, testicular cancer risk and postpubertal body height may have intrauterine determinants in common (20). Second, adult body height is, in part, determined by age at puberty—late debut of puberty results in shorter height (21). Third, height may be a marker of exposure to growth hormone and insulin-like growth factor-I (IGF-I) (22), which has recently been associated with risk of prostate cancer (23,24) and appears to take part in the control of spermatogenesis (25). 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