Download Body Size and Testicular Cancer

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). It appears that there is
no clear mechanism by which both the
findings on BMI and height may be explained, and it is conceivable that they
reflect distinct exposures. It could be
speculated, however, that the common
denominator is growth hormone and
IGF-I, since both of these hormones promote growth and increase the use of fat
as energy supply (26).
In summary, we have found a lower
risk of testicular cancer among men with
high BMI. Furthermore, body height
was positively associated with risk. The
biologic mechanism proposed is the promotion of this cancer by sex hormones
and/or growth hormones, such as growth
hormone and/or IGF-I. The increasing
trend in body height (27) approximates
an increasing trend in testicular cancer
incidence, whereas the rising prevalence
of obesity could not explain the increasing incidence of testicular cancer. On
the contrary, it displays an inverse effect.
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NOTES
We thank The National Health Screening Service in Norway for making the data available and
Dr. Matthew Zack for his valuable advice.
Manuscript received June 21, 1999; revised
March 28, 2000; accepted April 27, 2000.
Journal of the National Cancer Institute, Vol. 92, No. 13, July 5, 2000