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Epidemiologic Reviews
Copyright © 2001 by the Johns Hopkins University Bloomberg School of Public Health
All rights reserved
Vol. 23, No. 2
Printed in U.S.A.
Height, Leg Length, and Cancer Risk: A Systematic Review
D. Gunnell,1 M. Okasha,1 G. Davey Smith,1 S. E. Oliver,1 J. Sandhu,1 and J. M. P. Holly2
INTRODUCTION
across all cancer sites. In this review, we have aimed to
1) synthesize the evidence linking height to site-specific
cancers and 2) review possible mechanisms underlying the
observed associations. While most studies have focused on
associations between overall height and cancer risk, a few
have also investigated associations of the two main components of height—leg length and trunk length—with cancer
risk. Leg length is a marker for growth before puberty, since
prepubertal increases in stature arise more from increases in
leg length than from increases in trunk length. This is
demonstrated by changes in the ratio of sitting height
(mainly trunk length) to height during growth. At birth, the
ratio is approximately 0.66, but by puberty it has declined to
0.52 (21). Thus, studies examining the relation of cancer
risk to the components of stature—trunk length and leg
length—may indicate periods during childhood growth
when risk factors underlying height-cancer associations
operate (22-24). Therefore, we have included such studies
in this review.
Associations between height and cancer risk have been
reported in a number of prospective studies (1, 2). Taller
individuals appear to be at increased risk. Furthermore, ecologic analyses indicate that geographic patterns of cancer
incidence and mortality are associated with variations in
population height (3-5). The most consistent associations
have been found in relation to breast cancer (6-8), although
associations have also been reported for many other cancer
sites. Therefore, common mechanisms may underlie these
associations, but their precise nature remains unclear.
Models of cancer pathogenesis suggest that cancer arises
as a result of DNA damage at a number of specific loci
important in the regulation of the cell cycle or DNA repair
(9, 10). While specific oncogenes, tumor suppresser genes,
and cancer susceptibility genes have been identified, it has
become increasingly apparent that epigenetic pathways also
underlie the development of some malignancies. Several
mechanisms may be common to many different cancers. For
example, angiogenesis (the formation of new blood vessels)
is an absolute requirement for the growth of all solid tumors
(11). Similarly, apoptosis is a mechanism for eliminating
damaged or dangerous cells from the body, and thus it provides a natural defense against cancer. The most potent cell
survival factor controlling apoptosis is insulin-like growth
factor I (IGF-I). Raised levels of IGF-I and reduced levels of
its main binding protein, insulin-like growth factor (IGF)binding protein 3, may diminish this defense against a range
of cancers. In support of this notion, recent prospective
research has demonstrated that raised levels of IGF-I are
associated with increased risks of prostate (12-14), breast
(15), and colorectal (16, 17) cancers.
While a number of reviews have synthesized results from
studies reporting associations between height and breast
(6-8), colorectal (18), and thyroid (19) cancer, and some
have examined associations across a limited range of cancers (20), none have attempted to describe such associations
SEARCH STRATEGY
We systematically searched MEDLINE databases (US
National Library of Medicine) for all relevant articles published between 1966 and 2000. The search strategy used was
as follows: ["body height" or "height" or "anthropometry"
or "skeletal formation" or "leg length" or "sitting height" or
"body constitution" or "body composition"] AND ["neoplasms" or "cancer" or [the name of any site-specific neoplasm] ]. Terms shown in italic type were used as keywords;
the remainder were mapped to Medical Subject Headings.
Where the title of an article suggested that height-cancer
relations might be presented, the abstract was reviewed by
hand. Both English-language and non-English-language
papers were reviewed. In cases where no results for height
or leg length were mentioned in the abstract of a paper, the
full article was examined to determine whether it should be
included in the review. Relevant papers cited in the retrieved
articles were also obtained.
Received for publication June 2, 2000, and accepted for publication July 26, 2001.
Abbreviations: Cl, confidence interval; IGF, insulin-like growth factor; IGF-I, insulin-like growth factor I.
1
Department of Social Medicine, Faculty of Medicine, University
of Bristol, Bristol BS8 2PR, United Kingdom.
2
Bristol Royal Infirmary, Division of Surgery, Faculty of Medicine,
University of Bristol, Bristol BS2 8HW, United Kingdom.
Correspondence to Dr. David J. Gunnell, Department of Social
Medicine, Canynge Hall, University of Bristol, Whiteladies Road,
Bristol BS8 2PR, United Kingdom (e-mail: [email protected]).
Presentation of findings
Because of the large number of studies identified, we
restricted our tabulations to cohort studies and nested casecontrol studies, since these types of studies are less prone to
bias than case-control studies. We refer to nested casecontrol studies as cohort studies throughout this paper.
Results of case-control studies are summarized; a summary
313
314
Gunnell et al.
of these findings is available from the authors upon request.
Few studies have examined the relation of components of
stature—leg length and sitting height—to cancer risk; we
tabulated the findings for all of these studies.
Smoking may confound height-cancer associations, since
smoking, height, and cancer incidence are all socially patterned. Therefore, we have presented height associations
separately for cancers in which smoking is not thought to
play an important etiologic role and those in which it is. In
these latter studies, failure to adequately control for smoking may lead to biased estimates of height-cancer associations. We did not review studies examining associations of
height with all cancer sites combined.
All imperial units were converted to metric units. Relative
risks are presented for taller groups compared with shorter
(reference) groups. Where risks were presented in relation to
a decrease in stature in the source publication, the inverse of
the relative risk was computed. Relative risks are reported
according to the number of decimal places used in the original paper; we rounded these to two decimal places if more
than two decimal places were given in the data reported.
Height-cancer associations for cancers in which
smoking is not thought to be of etiologic importance
Colorectal cancer. Table 1 summarizes the results of 16
cohort or nested case-control studies that have reported on
associations between height and colorectal cancer (1, 2,
24—37). Seven of the cohort studies reviewed reported that
greater stature was associated with increased cancer risk. A
20-60 percent increased risk among persons in the top
height categories compared with those in the bottom categories was seen in most studies. There were no consistent
differences in the associations according to gender or cancer
site (colon or rectum) or according to whether mortality or
incident disease was examined. In studies that controlled for
socioeconomic position (2, 29), there was no clear evidence
of socioeconomic confounding. In the three studies in which
data were controlled for weight or body mass index, this
adjustment led to a partial attenuation of the height-cancer
associations (1, 27, 33).
We identified 15 case-control studies reporting on heightcolorectal cancer associations. Two of these reported statistically significantly (p < 0.05) increased risks among taller
individuals (38, 39). In one study, associations were seen in
North American patients but not in Chinese patients (39).
Three studies (40—42) found some evidence of increased
risks (odds ratios > 1.2) among taller men or women, but
these effects were not statistically significant at the 5 percent
level. The remaining 10 case-control studies (43-52),
including some with over 200 cases (46, 48-51), showed no
height-cancer associations. In contrast, a meta-analysis of
13 case-control studies with a combined total of 5,287 cases
of colorectal cancer reported weak but consistent heightcancer associations in males and females (18). The odds
ratio in the top quintile of height compared with the bottom
quintile was 1.31 (95 percent confidence interval (CI): 0.94,
1.82) among males (across height quintiles, p M d = 0.006)
and 1.31 (95 percent CI: 0.96,1.79) among females {pmni =
0.19). Surprisingly, only two of the 13 case-control studies
on which this meta-analysis was based (44, 50) had published their findings regarding height-cancer associations
separately.
Prostate cancer. Twenty-two reports on nested casecontrol or cohort studies (1,2, 13, 14, 24-26, 28, 29, 31,
53-64) described associations between height and prostate
cancer (table 2). Some of these reports were based on longer
follow-ups of the same cohort, and in some there may have
been overlap in the populations studied (24-26, 28, 53-55,
58, 64). Where relative risks were specified, with the exception of two studies (61, 64), risks were all greater than 1.0 in
the taller height categories. Most studies reported a 20-40
percent increased risk in the top height groupings compared
with the bottom groups. Controlling for possible socioeconomic confounding attenuated the associations in the two
cohorts reporting positive associations that examined this
issue (29, 60). Height-prostate cancer associations were also
apparent within the relatively socially homogenous US
Physicians and Health Professionals cohorts (1, 56). As was
seen with colorectal cancer, adjustment for measures of adiposity partially attenuated observed associations in two (1,
31) of the three (1, 31, 56) cohorts where its possible confounding effect was assessed. In the Kaiser Permanente
cohort, race and year of birth appeared to strongly confound
height-cancer associations (62). Adjustment for these factors resulted in a reduction in the relative risk in the tall
group (versus the short group) from 1.45 (95 percent CI:
1.26, 1.67) to 1.15 (95 percent CI: 1.00, 1.33). In the one
study where incidence and mortality associations were compared, associations were stronger for cancer mortality than
for cancer incidence (59). This effect may have been due to
the greater preponderance of screen-detected, localized
cases among persons with incident (nonfatal) prostate cancer; many of such cancers may never become invasive.
Inclusion of these cases dilutes the pool of "true" (invasive)
cases and leads to measurement error in effect estimates.
This effect may explain the stronger associations with
advanced disease reported for one cohort (56). However, in
the other two studies that compared height-cancer associations among persons with advanced disease with all cases,
little difference in effect sizes was seen (61, 62).
Of the 24 case-control studies examining height-prostate
cancer associations, two reported associations that were statistically significant at the 5 percent level (65, 66). In one of
these (65), significant associations were seen in US Whites
but not in Blacks. Six papers based on five studies (40,
67-71) reported positive associations with height (odds
ratios > 1.2) that did not reach conventional levels of statistical significance. One study reported a significant protective effect of height, but control patients in this study were
men with prostatic hyperplasia (control selection bias) (72).
The remaining 16 case-control studies, some based on over
1,000 cases, found no clear relation with height (73-88).
Breast cancer. Twenty-four papers describing cohort
and nested case-control studies have reported on associations between height and breast cancer (table 3) (2, 24, 25,
31, 89-108). Some of these papers were based on longer
follow-ups of the same cohort, and in others there was a
Epidemiol Rev Vol. 23, No. 2, 2001
Height, Leg Length, and Cancer Risk
possibility of overlap in the cases studied (24, 89-98). Most
studies examined incident disease, including deaths. Where
reported, relative risks in relation to increasing height were
greater than 1.0 in all but one of the studies (2).
Interestingly, this was the only study in which deaths alone
were included in the analysis (2), and this may indicate that
higher mortality rates among persons from lower socioeconomic (shorter) groups attenuated any association with
height. Increased risks of approximately 10-60 percent were
seen in the top height categories compared with the bottom
categories. Eleven studies distinguished premenopausal
cancers from postmenopausal cancers. Associations were
stronger in relation to postmenopausal cancer risk in seven
of these studies (based on six cohorts), but the differences
were often small. This is in keeping with a pooled analysis
of data from seven prospective studies that reported relative
risks, per 5-cm increase in height, of 1.02 (95 percent CI:
0.96, 1.10) for premenopausal cancer and 1.07 (95 percent
CI: 1.03, 1.12) for postmenopausal cancer (109). In this
pooled analysis, associations with height were stronger
among women whose mothers had had breast cancer (p for
interaction = 0.005), indicating the possible importance of
genetic factors in height-cancer associations (109).
Three papers reported relative risks before and after
adjustment for, among other factors, weight or body mass
index. In one of these, the height association became nonsignificant at the 10 percent level of statistical significance
after adjustment (31); in the other two, no consistent effects
of adjustment were seen (91, 99). In a pooled analysis, there
was weak evidence {p for interaction = 0.12) that height
associations were stronger among persons with low body
mass indexes (109). In the two papers reporting results from
models that controlled for socioeconomic position, there
was little or no evidence of confounding (91, 98).
Seventy-four published case-control studies had investigated height-breast cancer associations. Of these, 22
reported statistically significant positive associations with
increasing height in at least one of the groups examined
(110-131). A further 15 studies found some evidence of
increased risks (odds ratio > 1.2 in the tallest group), but
these increases did not reach conventional levels of statistical significance (132-146). Four studies reported a significantly reduced risk associated with increased height
(147-150). The remaining 33 studies (40, 151-182) showed
no association. A pooled analysis of 12 case-control studies
indicated that height was associated with a greater risk of
premenopausal cancer than of postmenopausal cancer (8).
The relative risk in the top quintile of height versus the bottom quintile was 1.41 {p = 0.004) for premenopausal cancer
and 1.11 (p = 0.20) for postmenopausal cancer. This differential effect was not consistently seen, however, across the
range of studies reviewed and is in the direction opposite of
that reported in the pooled analysis of cohort studies (109).
Endometrial/uterine cancer. Height-endometrial cancer
associations have been assessed in six cohort studies (table
4) (24, 31, 183-186). Positive associations were seen in
three of these (183-185). In one study in which positive
associations were reported, effects were stronger among
persons with raised body mass indexes (184), and in another
Epidemiol Rev Vol. 23, No. 2, 2001
315
the associations were restricted to those with postmenopausal cancer (185).
Seventeen case-control studies described in 18 papers
were identified. In only three of these studies were statistically significant increased risks seen among taller individuals (187-189). In the analysis by Goodman et al. (189), the
increased risk was greatly attenuated after data were controlled for weight (the odds ratio in the top quartile of height
declined from 1.8 to 1.3). A further five studies suggested an
association with increasing height (191-195), but these
findings did not reach the 5 percent level of statistical significance. In one of these studies, there was a suggestion
that height-cancer associations were more marked among
overweight women (192). Ten studies found no evidence of
increased risk among taller women (40, 196-204). One
case-control study found that greater stature was associated
with reduced risk (40, 201).
Other cancers not caused by smoking. Table 5 summarizes results from prospective investigations of other types
of cancers not thought to be caused by smoking. Three (2,
29, 205) of the five cohort studies (2, 25, 29, 31, 205) investigating height associations with hematopoietic cancers suggested that taller individuals are at an increased risk; this
trend persisted after adjustment for socioeconomic position
(2, 29) and body mass index (205). Two case-control studies
of adults have examined height-hematopoietic cancer associations (40, 206). One reported a positive association with
Hodgkin's lymphoma (206); the other found no evidence of
associations with Hodgkin's or non-Hodgkin's lymphoma
and found a nonsignificant inverse association with
myeloma (40). Two case-control studies of childhood
leukemia were also inconclusive (207, 208). A number of
other studies compared the heights of children with
hematopoietic cancer with population norms (209-214), but
these findings are difficult to interpret, because the population data used for comparison were often based on values
for children's heights some years before the study period
and thus took no account of secular increases in stature.
Furthermore, the growth of children with cancer may be
influenced both by cancer itself and by the effects on growth
of the treatment they receive.
Six cohort studies (2, 25, 26, 29, 31, 215) and seven casecontrol studies (40, 46, 216-220) have investigated associations between height and stomach cancer. Results of one of
the six cohort studies suggested that greater stature was
associated with decreased risk (2); the other cohort studies
showed no significant association. Two (217, 220) of the
seven case-control studies showed an inverse association
between height and cancer risk in men and women. By contrast, in a Chinese case-control study, greater stature was
associated with a threefold increased risk in females but not
in males (218). The other four studies showed no clear patterns of association (40, 46, 216, 219).
Associations of height with central nervous system
tumors were examined in four cohort studies (25, 29, 31,
221) and one case-control study (222). One of the cohort
studies indicated an increased risk with increased height
(221), and another suggested a borderline increased risk in
taller individuals (29). The only case-control study we iden-
1. Results of prospective studies reporting on the association between height and colorectai cancer
Cohort
(reference no.)
No. of cases
(incident cases
include deaths)
Estimate of relative risk
Height
comparison
Age-adjusted
risk
(95% Cl*)
aiian Japanese males (28)
101 colon, 63 rectum;
incident cases
>170cm vs. <157cm
Colon 0.8
Rectum 0.8
aiian males (27)
726 colorectum; incident
cases
Top fertile of self-reported
height compared with
bottom fertile
Cecum/ascending colon:
OR* = 1.1
Transverse/descending
colon: OR = 1.3
Sigmoid colon: OR = 1.6
Rectosigmoid junction:
OR = 0.9
Rectum: OR = 0.8
Mean height in cases and
noncases
NES I" (males and females) (24)
62 in males and 67 in
females; incident cases
>178.6 cm vs. <169cm
(males)
>165.5 cm vs. <157 cm
(females)
Males (colorectai): 2.1 (95%
Cl: 1.0,4.5)
Females (colorectai): 1.6
(95% Cl: 0.8, 3.0)
es' Health Study (females) (32)
191 colon, 49 rectum;
incident cases
2168 cm vs. <160 cm
(self-reported height)
Colon: 1.6 (95% Cl: 1.1,
2.5)
Rectum: 1.2 (95% Cl: 0.6,
2.6)
sh male corporate employees (33)
51 colon, 42 rectum;
incident cases
<172cm vs. £178 cm
Colon (mean height of
cases vs. noncases):
175.1 vs. 174.5$
Rectum: 3.7 (95% Cl: 1.4,
9.9)
ehall Study males (29)
P™« = 0.41
NS
NS
309 colon and small intestine, Mean height in cases and
noncases
90 rectum; incident
cases
1,0f (95% Cl: 0.6, 1.7)
P,re* = 0 ° 9
P»nd = 0-58
Colon and small intestine
Rectum
ard and University of Pennsylvania
umni (males) (25)
cohort (females) (34)
P^ = °™
NS*
289 colon, 108 rectum;
incident cases
Statist
significa
P ^ = 0-90
P ^ = 0-94
PM« = 0.90
Colon: 163.0 cm vs.
162.8 cm
Rectum: 163.1 vs 162 8
aiian males (26)
Fully adjusted
risk
(95% Cl)
Statistical
significance
NS
NS
p < 0.01
Rectum: 3.1f (95% Cl: 1.0,
9.0)
212; incident cases
£170 cm vs. <160cm
(self-reported height)
Colon: 1.19
1.23§(95%CI:0.83, 1.84)
No. not specified; deaths
only
Risk per 15-cm increase in
height
Colon: 0.96 (95% Cl: 0.65,
1.43)
Rectum: 1.01 (95% Cl: 0.52,
1.96)
0.93H (95% Cl: 0.63, 1.41)
male health professionals (30)
203 colon; incident cases
2185 cm vs. £173 cm
(self-reported height)
Colon: 1.96 (95% Cl: 1.28,
3.01)
male physicians (1)
341; incident cases
£185 cm vs. <170 cm
(self-reported height)
Colorectai: 1.60 (95% Cl:
1.09,2.34)
javik Study (males and females) (31)
338; incident cases
Risk per 1 -cm increase in
height
No significant associations
in males or females
egian tuberculosis screening cohort
ales and females) (35)
Colon: n = 6,397 in males
and 7,620 in females
Rectum: n = 4,393 in males
and 3,482 in females
Incident cases
Top quintile vs. bottom
quintile
p=0
1.03H (95% Cl: 0.52, 2.08)
^
= 0.002
'end =
0 1 5
p > 0.1
1.76# (95% Cl: 1.13, 2.74)
1 5 3
* * <95%
C l :
1 0 4
'
225
>
No significant associations in
males or femalesft
Male colon: 1.37$$ (95%
Cl: 1.27, 1.49)
Male rectum: 1.17 (95% Cl:
1.06,1.29)
Female colon: 1.35 (95% Cl:
1.26, 1.45)
PL-=
p>0
Height, Leg Length, and Cancer Risk
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Epidemiol Rev Vol. 23, No. 2, 2001
>O2
317
tified that examined the association of height with central
nervous system tumors was based on only 74 cases and indicated that short stature was associated with increased risk
(222); however, it is difficult to interpret studies examining
associations between height and childhood cancers, since
the tumor itself may influence growth. Four cohort studies
(25, 64, 223, 224) and three case-control studies (225, 226,
273) have examined associations with testicular cancer. The
largest of the cohort studies (224) and one of the casecontrol studies (226) showed strong evidence of a greater
risk in taller people. Two (227,228) of the three cohort studies (25, 227, 228) examining malignant melanoma risk factors reported positive associations with height. One (31) of
the two (24, 31) cohort studies and all three case-control
studies (40, 149, 229) of cervical cancer showed inverse
associations with height. These associations remained after
adjustment for an array of possible socioeconomic and
reproductive confounding factors (40, 229). Other prospective studies have suggested that there are no strong height
associations with gallbladder or cystic duct cancers (35).
Four prospective studies (2, 230-232) have grouped
together all cancers not thought to be related to smoking.
Three of these studies indicated an increased risk in taller
individuals that was not attenuated by controlling for possible socioeconomic confounding (2, 230, 232).
Other case-control studies. A meta-analysis of 12 casecontrol studies investigating risk factors for thyroid cancer
(19) reported positive associations between height and cancer
risk in men and women. The pooled estimated of risk per 5cm increase in height was 1.08 (95 percent CI: 1.03, 1.13).
Surprisingly, height-thyroid cancer associations were presented separately in only one (233, 234) of these 12 studies
when findings were originally published. Four studies of
male breast cancer have reported on associations with height
(235-238). All four studies provided some evidence of
increased risk with increasing height, although the evidence
reached conventional levels of statistical significance in only
one (235). Five case-control studies have examined heightovarian cancer associations (40, 239-242); there was probably some overlap in cases and controls in two of them (241,
242). No consistent picture was seen. One study reported a
statistically significant inverse trend (p < 0.01) (40), and
weak (nonsignificant) evidence of increased risk among taller
women was seen in two Japanese reports (241, 242). For
bone tumors, one study of adults suggested that risk increases
with height (243); one (244) of the two studies of children
(244, 245) reported similar effects, but in that study the control population was children with other cancers. The findings
from case series that used population height norms for comparison were unreliable (246-248). One study showed a positive association between height and vaginal cancer (249).
For liver cancer, one study examining this cancer reported
inverse associations with height (40), but another study did
not (250). Inverse associations with height were also reported
in women but not in men in one case-control study of soft tissue sarcoma (251); in the two other case-control studies of
this cancer (252, 253), no clear association was reported,
although trends consistent with increasing risk with height
were seen in the smallest study (252).
2.
Results of prospective studies reporting on the association between height and prostate cancer
Cohort
(reference no.)
No. of cases
(incident cases
include deaths)
Estimate of relative risk
Height
comparison
Age-adjusted
risk
(95% Cl»)
ard University alumni (53)
268; deaths only
Mean height in cases and
noncases
173.6 cm vs. 173.3 cmf
ard and University of Pennsylvania
umni (25)
243; incident cases
Mean height in cases and
noncases
No significant association
aiian Japanese (28)
96; incident cases
>170cm vs. <157 cm
1.93
163.5 cm vs. 162.8 cm
Statistical
significance
Fully adjusted
risk
(95% Cl)
Statis
signific
NS*
P » * = oNS
aiian males (26)
306; incident cases
Mean height in cases and
noncases
aiian Household Survey (54)
198; incident cases
>173 cm vs. <162 cm (selfreported height)
NES I* (24)
NES I (55)
95; incident cases
>178.6 cm vs. <169 cm
1.1 (95% Cl: 0.6, 2.0)
154; incident cases
Mean height in cases and
noncases
Caucasians: 173 cm vs.
174 cm
African Americans: 172 cm
ehall Study (29)
Not specified; deaths only
Risk per 15-cm increase
in height
1.59 (95% Cl: 1.01,2.44)
hysicians (1)
1,047; incident cases
>185cm vs. S170cm
(self-reported height)
1.33H(95%CI:1.06, 1.77)
ealth professionals (56)
1,369; incident cases
>188cm vs. S173 cm
(self-reported height)
All cases: 1.34
= 0.01
Advanced disease: 1.62
= 0.002
1.8* (95% Cl: 1.0, 3.2)
ft-=
vs. 173 cm
1.43§ (95% Cl: 0.90, 2.22)
1.26# (95% Cl: 1.00, 1.59)
All cases: 1.37** (95% Cl:
1.10, 1.70)
Advanced: 1.68** (95% Cl:
1.16,2.43)
Rural Health Study (57)
dish construction workers (59)
71; incident cases
>180cm vs. <173cm
(self-reported height)
1.1 (95% Cl: 0.6, 2.0)
pM = 0.8
n = 2,368—incident cases;
n = 708—deaths only
>180cm vs. <172cm
Incidence: 1.14 (95% Cl:
1.00, 1.29)
Mortality: 1.28 (95% Cl:
1.02, 1.60)
p ^ = 0 04
javik Study (31)
524; incident cases
Risk per 1-cm increase
in height
1.01 (95% Cl: 1.00, 1.03)
egian health screening cohort (60)
n = 642 (entire data set);
n = 378 (subjects with
complete data); incident
cases
Top quintile vs. bottom
quintile
Entire data set: 1.2 (95%
CI:0.9, 1.6)
Subjects with complete
data: 1.4 (95% Cl:
1.0,2.0)
egian cardiovascular disease
reening cohort (64)
220; incident cases
Risk per 10-cm increase
in height
egian cardiovascular disease
reening cohort (58)
70; incident cases
>182cm vs. <170cm
rew and Paisley Survey (2)
59; deaths only
Risk per 10-cm increase
in height
p ^ = 0.04
No significant associationff
p , ^ = 0.16
p , ^ = 0.05
0.99 (95% Cl: 0.82, 1.19)
1.2 (95% Cl: 0.6, 2.4)
1.30 (95% Cl: 0.88, 1.89)
pM = 0.95
1.3#(95%CI:0.9, 1.9)
ft--0-1
rlands cohort study (61)
r Permanente Medical Care
ogram cohort (62)
more Longitudinal Study of Aging
)
n = 681; subgroup analysis
in relation to stage—
n = 239 localized; n =
226 advanced; incident
cases
All cases: 2190 cm vs.
<170cm
Subgroups: risk per 5-cm
increase in height
All cases: 0.97 (95% Cl:
0.53, 1.77)
n = 2,079 cases—1,323
localized, 314 with
regional spread, 264
with distant spread, and
178 unstaged; incident
cases
>181 cm vs. <169cm
All cases: 1.45HH (95% Cl
1.26, 1.67)
72; incident cases
Mean height in cases and
controls
176 cm vs. 176 cm
, = 0.88
All cases: 0.96§§ (95% Cl:
0.52, 1.75)
Subgroups—
Localized: 0.99§§ (95%
CI:0.89, 1.10)
Advanced: 0.98§§ (95%
CI:0.88, 1.10)
All cases: 1.15## (95% Cl:
1 00, 1.33)
Regional/distant cases only:
1.11## (95%CI: 0.85,
1.45)
men (63)
96; incident cases
>180cm vs. <175 cm
1.1 (95%CI:0.7, 1.7)
ern Sweden Health and Disease
hort Study (14)
149; incident cases
Top quartile vs. bottom
quartile
1.48 (95% Cl: 0.87, 2.50)
= 0.7
, confidence interval; NS, not significant; NHANES I, First National Health and Nutrition Examination Survey,
ot adjusted for age.
ontrolled for ethnicity and income.
ontrolled for civil service grade.
so controlled for p-carotene and aspirin use.
ontrolled for p-carotene, aspirin, body mass index, smoking, alcohol, and exercise.
ntrolled for body mass index.
ontrolled for weight, blood pressure, triglycerides, glucose, and creatinine.
ontrolled for smoking, physical activity, education, and marital status.
ontrolled for family history of prostate cancer and socioeconomic position.
ontrolled for race.
ontrolled for race and year of birth (also assessed' marital status, education, smoking, alcohol, and history of venereal disease; data were not controlled for these in the multivariable model).
3.
Results of prospective studies reporting on the association between height and breast cancer
Cohort
(reference no.)
No. of cases
(incident cases
include deaths)
Estimate of relative risk
Height
comparison
Age-adjusted
risk
(95% Cl*)
Fully adjusted
risk
(95% Cl)
70; incident cases
£170 cm vs. <155 cm
reast screening cohort (102)
1,292; incident cases
> 165.1 cm vs. 157.5-160
cm (self-reported
height)
sylvania university alumnae (25)
69; incident cases
Mean height in cases vs.
noncases
NES l« (24)
122; incident cases
>165.5 cm vs. <157 cm
2.1 (95% Cl: 1.2, 3.4)
NES I (90)
131; incident cases
Top quartile vs. bottom
quartile
2.0
NES I (89)
70 premenopausal and
112 postmenopausal;
incident cases
>167 cm vs. <156 cm
1.2* (95% Cl: 1.0, 1.5)
No significant differences
1.9§ (95% Cl: 1.1,3.2)
Premenopausal: 1.6H (95%
Cl: 0.6, 3.8)
Postmenopausal: 2.0H (95%
Cl: 1.0,3.8)
658 premenopausal and
420 postmenopausal;
incident cases
£168 cm vs <160cm;
(self-reported height)
Statist
signific
2.4f
erlands (general practice-based)
00)
es' Health Study (92)
Statistical
significance
Postmenopausal: 1.3
Premenopausal: 1.1# (95%
CI:0.9, 1.3)
Postmenopausal: 1.3# (95%
Premenopausal11.13
Postmenopausal: 1 24
Cl: 1.0, 1.7)
Premenopausal: 1.11**
Postmenopausal: 1.29**
Premenopausal: 1.1
es'Health Study (91)
806 pre- and 1,485 postmen- >170.2 cm vs. <157.5 cm;
opausal; incident cases
(self-reported height)
dish health screening (103)
196 premenopausal,
986 postmenopausal;
incident cases
Per 5-cm increase in height
Premenopausal: 1.11 (95%
CI:0.98, 1.27)
Postmenopausal: 1.10ft
(95% Cl: 1.07, 1.13)
aiian Linkage Study (94)
148 aged 30-44 years,
141 aged 45-49 years,
145 aged 50-54 years,
and 135 aged 55-65
years; incident cases
Top fertile vs. bottom
fertile (self-reported
height), by age at
diagnosis
Age (years) at diagnosis—
30-44: 1.02*4: (0.61, 1.71)
45-49:1.12** (0.65, 1.92)
50-54: 1.554:* (0.92, 2.61)
55-65: 1.28** (0.73, 2.24)
aiian Household Survey (93)
£160.1 cm vs. <154.9 cm;
86 premenopausal (aged
(self-reported height)
<50 years) and 292 postmenopausal (aged >50
years); incident cases
= 0-58
0005
Premenopausal: 1.1 §§
(95%CI:0.6, 1.9)
Postmenopausal: 1.5§§
(95% Cl: 1.1,2.1)
egian tuberculosis screening
hort (105)
3,305 premenopausal and
5,122 postmenopausal
incident cases
789 premenopausal deaths
and 1,594 postmenopausal deaths
Per 15-cm increase in
height
Incidence—
Premenopausal: 1.281111
(95% Cl: 1.13, 1.44)
Postmenopausal: 1.421111
(95% Cl: 1.32, 1.53)
Mortality—
Premenopausal: 1.19ffll
(95% Cl: 0.93, 1.52)
Postmenopausal: 1.381111
(95% Cl: 1.21, 1.58)
women's cohort (106)
229; incident cases
Mean height in cases vs.
controls (self-reported
height)
160 cm vs. 160 cm
p = 0.50
=
P«»x, :
r^rond ~
,=
0
P«« =
PM =
egian health screening cohort (98)
291; incident cases
£167 cm vs. <159 cm
1.43
P,— < ° 0 0 1
egian health screening cohort (97)
137 premenopausal (aged
<51 years) and 99 postmenopausal (aged £51
years); incident cases
£167 cm vs. <159 cm
Premenopausal: 2.63 (95%
Cl: 1.48, 4.68)
Postmenopausal: 1.62 (95%
P _ = 0.001
73 premenopausal (aged
<54 years) and 95 postmenopausal (aged £54
years); incident cases
£166 cm vs. <158cm
Premenopausal: 1.4 (95%
Cl: 0.7, 2.6)
Postmenopausal: 1.9 (95%
Cl: 1.1, 3.2)
79 premenopausal and 101
postmenopausal;
incident cases
£168 cm vs. <158cm
(self-reported
height)
Premenopausal. 0.65
(95% Cl: 0.33, 1.30)
Postmenopausal: 1.90ffi|
(95% Cl: 0.96, 3.78)
Project (Dutch Breast Screening
gramme) (95)
38; incident cases
£166 cm vs. <161 cm
Postmenopausal: 1.51 (95%
Cl: 0.69, 3.42)
Project (Dutch Breast Screening
gramme) (96)
147 premenopausal and 76
postmenopausal;
incident cases
>169 cm vs. <160.8 cm
rlands Cohort Study (101)
626; incident cases
£175 cm vs. S155 cm
(self-reported height)
avik Study (31)
Per 1 -cm increase in
91 premenopausal (aged
height
<55 years) and 343 postmenopausal (aged £55
years); incident cases
sey cohorts (99)
east screening cohort (104)
ho Bernado Study (US Whites)
8)
ew and Paisley Survey (2)
Permanente Medical Care
gram cohort (107)
< 95% Cl: 1-18' 1 - 73 )
Cl: 0.93, 2.81)
Premenopausal: 1.3*** (95%
Cl: 0.7, 2.5)
Postmenopausal: 1.9*** (95%
2.04 (95% Cl: 1.19, 3.49)
161 cm vs. 160 cm
147; deaths only
Per 10-cm increase in
height
0.88 (95% Cl: 0.68, 1.16)
pM = 0
Pi— = ° 0 7
P - = °-18
. < 0.001
2 . 0 6 t t t (95% Cl: 1.17,
3.63)
No significant association§§§
Premenopausal: 1.04 (95%
CIM.00, 1.08)
Postmenopausal: 1.03
(95% Cl: 1.01, 1.05)
Mean height in cases vs.
noncases
Pi— =
Cl: 1.1, 3.3)
Premenopausal: 1.28 (95%
Cl: 0.78, 2.11)
Postmenopausal: 0 . 9 6 t t t
(95% Cl: 0.46, 1.98)
45; incident cases
214; incident cases
143##
pM = 0
Pt— =
P«™i * O
p>0.1
p = 0.90
Height at age 17 years:
1.4 (95% Cl: 1.1, 2.0)
Height at age 10 years:
1.1 (95%CI:0.8, 1.4)
confidence interval; NHANES I, First National Health and Nutrition Examination Survey.
t controlled for age. Calculated by comparing observed cases with expected cases based on national figures.
ntrolled for weight and age at last mammogram.
ntrolled for age at first birth, menopausal status, education, and alcohol consumption.
ontrolled for age at first birth, age at menarche, family history of cancer, and education.
ntrolled for parity, age at first birth, age at menarche, benign breast disease, family history of cancer, and smoking (also time since menopause, in postmenopausal women).
ntrolled for age at baseline, age at menarche, body fatness at ages 5, 10, and 20 years, maternal body fatness, family history of cancer, alcohol (ages 18-22 years), adolescent and maternal sm
ioeconomic position, and adolescent benign breast disease (also age at menopause, in postmenopausal women).
ntrolled for region.
ntrolled for age at first birth, 1972 socioeconomic score, and 1942 Cole (adiposity) index.
ntrolled for education, ethnicity, and alcohol consumption.
ot controlled for age.
ntrolled for age at first birth, parity, occupation, and county of residence.
ntrolled for age at first birth, family history of cancer, and weight.
ntrolled for age at menarche, age at first birth, and number of liveborn children (also age at menopause, in postmenopausal women).
ntrolled for age at menarche, parity, age at first birth, and alcohol consumption.
ntrolled for weight, blood pressure, and levels of triglycerides, glucose, and creatinine.
4. Results of prospective studies reporting on the association between height and endometriai/uterine cancer
Cohort
(reference no.)
breast screening cohort (183)
No. of cases
(incident cases
include deaths)
Estimate of relative risk
Height
comparison
Age-adjusted
risk
(95% Cl*)
43; incident cases
2170 cm vs. <160cm
NES I* (24)
30; deaths only
>165.5 cm vs. <157 cm
1.0 (95% Cl: 0.2, 3.9)
egian tuberculosis screening cohort
4)
2,208—incident cases;
405—deaths only
Above mean vs. below
mean
Incident cases—
Below mean BMI*: 1.2
(95% Cl: 1.1, 1 3)
Above mean BMI: 1.9
(95%CI:1.7, 1.9)
Deaths—
Below mean BMI: 1.3
(95% Cl: 0.9, 1.8)
Above mean BMI: 1.9
(95% Cl: 1.4,3.5)
iian population registration (186)
214; incident cases
Top fertile vs. bottom
fertile (self-reported
height)
Project (Dutch Breast Screening
ogramme) (185)
147; incident cases
2170 cm vs. <160 cm
Premenopausal (n = 49):
0.8
Postmenopausal (n = 98):
2.5f
avik Study (31)
98; incident cases
Risk per 1 -cm increase in
height
No significant association
Statistical
significance
Fully adjusted
risk
(95% Cl)
Statisti
significa
3.2t
1.3* (95% Cl: 0.7, 2.2)
confidence interval; NHANES I, First National Health and Nutrition Examination Survey; BMI, body mass index; NS, not significant.
adjusted for age.
ntrolled for parity, age at first birth, relative weight, and socioeconomic position.
ntrolled for weight, blood pressure, and levels of trigiycendes, glucose, and creatinine.
p>0.1
No significant association§
p>0.1
Height, Leg Length, and Cancer Risk
Height-cancer associations for cancers in which
smoking is thought to be of etiologic importance
Lung cancer. Ten cohort studies (1, 24-26, 28, 29, 31,
254-256) and three case-control studies (257-259) have
reported on associations between height and lung cancer
(table 6). Five of the six cohort studies that presented their
results as relative risks showed that risks were all greater
than 1, although only one of these was statistically significant at conventional levels (254). In several studies (24, 29,
256), the possible confounding effects of smoking were not
controlled for.
One (259) of the three case-control studies (257-259)
indicated that among smokers, shorter stature was associated with increased risk in males and females, with a difference in mean heights of 1 cm. In contrast, in another of these
studies there was a suggestion that greater stature in women
was associated with increased risk (257).
Other cancers caused by smoking. Table 7 summarizes
findings from cohort studies that have examined the associations of height with other smoking-related cancers. Two
(29, 215) of the four cohort studies (25, 29, 31, 215) reporting associations with esophageal cancer demonstrated
reductions in risk with increasing height. Neither of these
analyses controlled for smoking. Similar findings were
reported in the four case-control studies that examined this
issue (40, 219, 220, 260). In two of these studies, each with
approximately 300 cases, strong associations were seen in
models adjusted for smoking (219, 220). In one of these
studies, associations were seen for adenocarcinoma but not
for squamous cell carcinoma (220).
The cohort studies examining pancreatic cancer (25, 29,
31, 35, 261) found no clear pattern of association with
height, although one (262) of the five case-control studies
(40, 190, 262, 263, 335) found evidence of greater risk
among taller women. A pooled analysis of five case-control
studies found some evidence of increasing risk with greater
height: The relative risk in the tallest quintile was 1.35 (95
percent CI: 0.87, 2.09), and the test for linear trend was not
significant at conventional levels (p = 0.12) (336). The four
cohort studies that examined bladder cancer showed no
clear pattern of association with respect to height (24, 25,
29, 31). Neither of the two case-control studies (40, 264)
examining this issue showed strong effects, although in an
Italian case-control study there was some evidence of
increasing risk with height in females (40). An increased
risk of renal carcinoma in taller males was reported in one
(31) of two cohort studies (25, 31) examining this issue. The
five case-control studies that presented data on height-renal
cancer associations (40, 265-268) provided no evidence of
height effects, although in one (40), a twofold increased risk
was seen in the tallest men and the opposite effect was seen
in women. In the two case-control studies that examined
associations between stature and carcinoma of the larynx
(40, 260), one reported no evidence of an influence of height
on cancer risk in men (40). In the other, which examined
risk in men and women combined, risk increased with
decreasing stature, but effects were attenuated and nonsignificant after data were controlled for (among other factors) smoking (260). The same study reported associations
Epidemiol Rev Vol. 23, No. 2, 2001
323
between reduced stature and oropharyngeal cancer risk in
men and women. Again, associations were greatly attenuated but remained significant (p < 0.001) after data were
controlled for smoking differences (260).
In three prospective studies (2, 230, 231) (table 7) and
two case-control studies (269, 270), all smoking-related
cancers were grouped together. None of these studies found
an association between height and smoking-related cancers.
Components of height and cancer risk
Cohort studies. Seven research papers based on three
cohorts (22, 24, 26, 89, 128, 232, 271) have reported results
from prospective investigations of the associations between
components of stature and cancer (table 8). Analyses of data
from the First National Health and Nutrition Examination
Survey (24, 89, 128) indicated either that leg length and sitting height were equally related to risk (prostate, colorectal, bladder, and uterine cancers) or that leg length was
the component of stature associated with increased risks
(lung, breast, and cervical cancers) (24). Neither of the two
analyses of the Honolulu Heart Program cohort showed significant associations with leg length or sitting height (26,
271), although the earlier analysis of prostate cancer risk
suggested that leg length was associated more strongly with
increased risk than was sitting height (26). Two published
articles based on the Boyd Orr cohort assessed associations
between the components of stature, measured in childhood,
and later cancer risk (22, 232). In the first paper, no significant associations were reported, although leg length
appeared to be more strongly associated with risk than did
sitting height (232). More recently, a subgroup analysis based
on persons who were aged <8 years when they were measured in childhood indicated that those with longer legs, but
not those with longer trunks, were at greater risk of death
from cancers not thought to be related to smoking (22).
Case-control studies. Eight case-control studies have
investigated associations between the components of height
and cancer risk (84, 86, 128, 149, 161, 197, 272, 273) (table
9). In all but one (273) of these studies, sitting height was
measured and differences were reported with respect to sitting height or the sitting heightheight ratio. High values for
this ratio indicate a long trunk relative to total height, and
hence relatively short legs. In three studies, the source of
controls is likely to have resulted in selection biases (84, 86,
149). In one of these studies, controls were approximately
15 years younger than cases (149); in the other two (both by
the same group of investigators (84, 86)), urology clinic
patients were used as controls. Two of the remaining five
investigations indicated that leg length was the component
of stature associated with increased risk of breast cancer
(128) and testicular cancer (273). In Swanson et al.'s investigation of endometrial cancer (197), there was no association with overall height but there was a significant decreased
risk with increasing sitting height, which suggests that leg
length was associated with increased risk. A further study
based on postmortem examination of children who died
from leukemia indicated some disproportion in the cases
(272). Reanalysis of the original data tabulated in that paper
5. Results of prospective studies reporting on the associations between height and "other" cancers (cancers other than colorectal, prostate, breast, and
etrlal/uterine cancer) not thought to be caused by smoking
Type of cancer
and cohort
(reference no.)
No. of cases
(incident cases
include deaths)
Estimate of relative risk
Height
comparison
Age-adjusted
risk
(95% Cl*)
atopoietic cancers
arvard and University of Pennsylvania 343; deaths only
alumni (males and females)
(Hodgkin's and non-Hodgkin's
lymphoma and all leukemias) (25)
Mean height in cases and
noncases
No significant association
hitehall Study males (leukemia and
lymphoma) (29)
Risk per 15-cm increase in
height
Leukemia: 1.14 (95% Cl:
0.58, 2.22)
Lymphoma: 1.78 (95% Cl:
0.99, 3.23)
No. not specified: deaths
only
eykjavik Study (males and females)
(leukemia and lymphoma) (31)
137; incident cases
Risk per 1-cm increase in
height
urses' Health Study (females)
(non-Hodgkin's lymphoma) (205)
199; incident cases
enfrew and Paisley Survey (males
and females) (all hematopoietic
cancers) (2)
79; deaths only
2173 cm vs. <157 cm
(self-reported height)
Risk per 10-cm increase in
height
mach cancer
arvard and University of Pennsylvania 64; incident cases
alumni (males and females) (25)
awaiian males (26)
229; incident cases
hitehall Study males (29)
No. not specified; deaths
only
246; incident cases
eykjavik Study (males and females)
(31)
orwegian tuberculosis screening
cohort (males and females) (215)
enfrew and Paisley Survey (males
and females) (2)
6,077 males and 3,737
females; incident cases
103; deaths only
tral nervous system cancers
arvard and University of Pennsylvania 90; incident cases
alumni (males and females) (25)
1,538 males and 1,511
orwegian tuberculosis screening
females; incident cases
cohort (males and females) (221)
hitehall Study males (brain cancer)
(29)
eykjavik Study (males and females)
(31)
Mean height in cases and
noncases
Mean height in cases and
noncases
Risk per 15-cm increase
in height
Risk per 1-cm increase in
height
Top quintile vs. bottom
quintile
Statist
significa
1.10t (95% Cl: 0.55, 2.17)
1.89t(95%CI: 1.04,3.45)
p>0.1
1.89 (95% Cl: 1.33, 2.63)
No significant associations
in males or females^
p>0
ft-=
1.92H (95% Cl: 1.37, 2.78)
No significant association
162.7 cm vs. 162.8 cm#
NS*
0.81 (95% Cl: 0.53, 1.25)
No significant associations
in males or females
O.93f (95% Cl: 0.61, 1.45)
p>0.1
No significant associations
in males or females:}:
p>0
Males: 1.0** (95%CI:0.9,
1.1)
Females: 1.0** (95% Cl:
0.9, 1.1)
0.68 (95% Cl: 0.50, 0.92)
Mean height in cases
and noncases
No significant association
0.75H (95% Cl: 0.56, 1.03)
Per 15-cm increase in
height
Risk per 1-cm increase in
height
Fully adjusted
risk
(95% Cl)
2.4§(95%CI:1.2, 4.7)
Risk per 10-cm increase
in height
No. not specified; deaths only Risk per 15-cm increase
in height
99; incident cases
No significant associations
in males or females
Statistical
significance
1.75 (95% Cl: 0.87, 3.57)
No significant associations
in males or females
p>0.1
Males: 1.2ft (95% Cl:
1.1, 1.4)
Females: 1.2ft (95% Cl:
1.1, 1.4)
1.79f (95% Cl: 0.87, 3.57)
p = 0.
No significant associations
in males or femalesf.
p>0
p = 0.
cular cancer
rvard and University of Pennsylvania 67; incident cases
alumni (25)
Mean height in cases and
noncases
nish military recruits (223)
224 persons aged <19
years at diagnosis and
214 persons aged >19
years at diagnosis;
incident cases
>190 cm vs. <170 cm
rwegian cardiovascular disease
screening cohort (64)
47; incident cases
Risk per 10-cm increase in
height
1.12 (95% Cl: 0.75, 1.67)
rwegian tuberculosis screening
cohort (224)
553; incident cases
£183 cm vs <171 cm
All testicular cancers: 1.60#
(95% Cl: 1.21, 2.10)
noma
rvard and University of Pennsylvania
alumni (males and females) (25)
104; incident cases
Mean height in cases and
noncases
No significant association
rwegian tuberculosis screening
cohort (males and females) (227)
2,144 males and 2,184
females; incident cases
Top quintile vs bottom
quintile
Males: 1.6§§ (95% Cl:
1.4, 1.8)
Females: 1.6§§ (95% Cl:
1.4, 1.8)
rwegian health screening cohort
males and females) (228)
106 men and women;
incident cases
£177 cm vs. <163cm
3.11111 (95% Cl: 1.4,6.7)
cal cancer
ANES I* (24)
20; incident cases
>165.5 cm vs. <157 cm
0.5 (95% Cl: 0.1, 2.2)
40; incident cases
Per 1-cm increase in
height
0.95 (95% Cl: 0.89,
1.00)
rwegian
tuberculosis
screening
ladder/cystic
duct cancers
cohort (males and females) (35)
350 males and 617 females;
incident cases
Top quintile vs. bottom
quintile
ncers not thought to be caused
by smoking
itehall Study males (230)
725; deaths only
>183cm vs. <168 cm
1.29 (95% Cl: 0.96, 1.72)
asgow alumni (males and females)
(231)
190 males and 61 females;
deaths only
Per 10-cm increase in
height
Males: 1.06 (95% Cl: 0.84,
1.33)
Females: 1.04 (95% Cl:
0.67, 1.62)
ykjavik Study (31)
yd Orr cohort (males and females)
(232)
nfrew and Paisley Survey (males
and females) (2)
20 males and 39 females;
deaths only
365 males and 554 females;
deaths only
No significant association
Age <19 years at diagnosis:
1.1«(95%CI:0.4, 2.7)
Age >19 years at diagnosis:
1.0tt (95%CI:0.4, 2.6)
Seminoma: 1.41 (95% Cl:
1.01, 1.99)
Nonseminoma: 1.21 (95% Cl:
0.75, 1.95)
p<0.1
No significant associations in
multivariable analysis!
p>0.
Males: 1.2*» (95% Cl: 0.8,
1.7)
Females: 1.2** (95% Cl: 0.9,
1.5)
Per 1-standard-deviation
increase in childhood
height
Males: 1.21 (95% Cl: 0.78,
1.88)
Females: 1.04 (95% Cl:
0.74, 1.47)
Per 10-cm increase in
height
Males: 1.09 (95% Cl:
0.93, 1.27)
Females: 1.07 (95% Cl:
0.93, 1.23)
P™« < ° 0 1
1
- 3 6 # # < 9 5 % Cl: 1.01, 1.82)
pM
<0
0.92*** (95% Cl: 0.70, 1.20)
0.74*** (95% Cl: 0.45, 1.23)
NS
1.30ttt (95% Cl: 0.80, 2.11)
NS
0.99ttt (95% Cl: 0.69, 1.42)
1.14H(95%CI:0.97, 1.33)
1.12H(95%CI:0.98, 1.30)
Table con
326
Gunnell et al.
(data not shown) indicates that cases had shorter legs relative to their sitting height, although effects of treatment on
growth cannot be ruled out.
DISCUSSION OF MAIN FINDINGS
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Most prospective studies reporting associations between
height and cancer have shown either that risk increases with
stature or that there is no significant relation. Evidence from
case-control studies is considerably weaker, but meta-analysis of their findings in relation to thyroid, breast, pancreatic,
and colorectal cancer suggests a general pattern of increasing risk with greater stature (8, 18, 19, 336). Associations
are similar in men and women and have been reported for a
range of cancer sites—particularly for breast, prostate, colorectal, and hematopoietic cancers—but they are also seen
with central nervous system tumors, malignant melanoma,
endometrial cancer, and thyroid cancer. In the relatively few
studies in which multivariable analyses have been carried
out to control for the possible confounding effects of socioeconomic position and indicators of adiposity, the observed
associations are sometimes but not generally attenuated. For
breast cancer, there is some evidence that height associations are stronger in persons of lower weight (109), whereas
the opposite has been reported for endometrial cancer (184).
Associations are seen in relation to both cancer incidence
and cancer mortality, indicating that survival bias is unlikely
to explain the associations observed. The strength of association in studies with positive effects is relatively weak; there
is usually, at most, a 20-60 percent increased risk in the
tallest groups compared with the shortest. The magnitude of
increased risk is similar for the three most common cancers
not caused by smoking: colorectal cancer, prostate cancer,
and breast cancer. Associations of stature with smokingrelated cancers are more difficult to interpret, since many of
these studies have not controlled for the potentially confounding effects of tobacco smoking.
Few studies have examined associations between the
components of stature and cancer risk. Although the evidence in this area is weak, the component of height more
often associated with increased risk is leg length. Leg length
is a marker for growth before puberty, since prepubertal
increases in stature arise more from increases in leg length
than increases in trunk length. This suggests that the biologic mechanisms underlying the relation between height
and cancer may have their origins in factors which influence
long bone growth in childhood.
The range of studies reporting height-cancer associations
suggests either a common underlying mechanism or bias in
the studies reviewed. Therefore, before we discuss possible
mechanisms for the observed associations, alternative
explanations will be considered.
<D CO
Chance and bias
in
UJ
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_ r O O O O O O O O O O O O 0
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Many large cohort studies and a number of case-control
studies have reported on height-cancer associations, which
indicates that these findings are unlikely to be due to chance
alone. While bias is an important consideration in epidemiEpidemiol Rev Vol. 23, No. 2, 2001
6.
Results of prospective studies reporting on the association between height and lung cancer
Cohort
(reference no.)
No. of cases
(incident cases
include deaths)
Estimate of relative risk
Height
comparison
Age-adjusted
risk
(95% Cl*)
46; deaths only
Mean height in cases and
noncases
iian Japanese males (28)
101; incident cases
£170 cm vs. <160 cm
iian survey of males and females
4)
54 in smokers and 26
in nonsmokers;
incident cases
Males: top fertile vs.
bottom fertile (selfreported height)
Females: above median
vs. below median
(self-reported height)
iian males (26)
236; incident cases
Mean height in cases and
noncases
163.4 vs. 162.8t
rd and University of Pennsylvania
mni (males and females) (25)
335; incident cases
Mean height in cases and
noncases
No significant association
h occupational cohorts of males
5)
NES I* males (24)
hall Study males (29)
women's cohort (256)
ale physicians (1)
avik Study (males and females)
)
168.0 vs. 168.9t
Fully adjusted
risk
(95% Cl)
Statistical
significance
Statisti
significa
NS*
Smokers—
Males: 3.7§ (95% Cl:
1.2, 11.5)
Females: 1.8§ (95% Cl:
0.6, 5.2)
Nonsmokers—
Males: 2.9§ (95% Cl:
0.6, 13.0)
Females: 3.4§ (95% Cl:
0.5, 24.1)
114; incident cases
>178.6 vs. £169 cm
1.1 (95% Cl: 0.6, 2.0)
No. not specified; deaths
only
Risk per 15-cm increase
in height
0.94 (95% Cl: 0.77, 1.16)
233; incident cases
<155cm vs. >165 cm
(self-reported height)
0.81 (95% Cl: 0.57, 1.14)
170; incident cases
£185 cm vs. 5170 cm
(self-reported height)
1.2#(95%CI:0.7, 1.9)
n = 472; incident cases
Risk per 1 -cm increase
in height
No significant associations
in males or females
, confidence interval; NS, not significant; NHANES I, First National Health and Nutrition Examination Survey,
ot adjusted for age.
ontrolled for age and smoking.
ontrolled for socioeconomic position and race.
ontrolled for civil service grade.
so adjusted for p-carotene intake and aspirin use.
ntrolled for p-carotene, aspirin, body mass index, smoking, alcohol, and exercise,
ontrolled for weight, blood pressure, triglycerides, glucose, and creatinine.
NS
1.12H (95%CI: 0.91, 1.37)
Pwnd = ° ' 4 6
p>0.1
1 1
- ** ( 9 5 %
Cl:
°'6'
1 8
)
No significant associations
in males or femalesft
p>0.
7. Results of prospective studies reporting on the associations between height and "other" cancers (cancers other than lung cancer) thought to be caused
g
Type of cancer
and cohort
(reference no.)
No. of cases
(incident cases
include deaths)
hageal cancer
rvard and University of Pennsylvania 48; incident cases
alumni (males and females) (25)
Estimate of relative risk
Height
comparison
Age-adjusted
risk
(95% Cl*)
Mean height in cases and
noncases
No significant association
hitehall Study males (29)
No. not specified; deaths
only
Risk per 15-cm increase in
height
0.43 (95% Cl: 0.22, 0.85)
ykjavik Study (males and females)
(31)
49; incident cases
Risk per 1-cm increase in
height
No significant associations
rwegian tuberculosis screening
cohort (males and females) (215)
742 males and 274 females;
incident cases
Top quintile vs. bottom
quintile
reatic cancer
rvard and University of Pennsylvania
alumni (males and females) (25)
127; incident cases
Mean height in cases and
noncases
Statistical
significance
Fully adjusted
risk
(95% Cl)
0.47f (95% Cl: 0.23, 0.93)
p > 0.1
No significant associations^
No significant association
"Several other anthropometric measurements,
including height, were
not related to subsequent pancreatic
cancer" (261)
450; incident cases
hitehall Study males (29)
No. not specified; deaths
only
Risk per 15-cm increase in
height
0.90 (95% Cl: 0.53, 1.54)
0.93t (95% Cl: 0.54, 1.59)
ykjavik Study (males and females)
(31)
65 males and 36 females;
incident cases
Per 1 -cm increase in
height
Males: 1.0 (95% Cl: 1.0, 1.1)
Females: 1.1 (95%CI:1.0,
1.1)
No significant association^
rwegian tuberculosis screening
cohort (males and females) (35)
4,939; incident cases
Top quintile vs. bottom
quintile
der cancer
rvard and University of Pennsylvania
alumni (males and females) (25)
108; incident cases
Mean height in cases and
noncases
No significant association
HANES I* males (24)
27; deaths only
>178.6 cm vs. <169 cm
0.7 (95% Cl: 0.2, 2.8)
hitehall Study males (29)
No. not specified; deaths
only
Risk per 15-cm increase in
height
1.02 (95% Cl: 0.54, 1.92)
ykjavik Study (males and females)
(31)
215; incident cases
Risk per 1-cm increase in
height
No significant associations
in males or females
77; incident cases
Mean height in cases and
noncases
No significant association
109 males and 58 females;
incident cases
Increase in risk per 1-cm
increase in height
Males: 1.1 (95%CI:1.0, 1.1)
Females
ykjavik Study (males and females)
(31)
p>0.1
Males: 0.6§ (95% Cl: 0.5, 0.8)
Females. 0.7§ (95% Cl:
0.4, 1.0)
iser Permanente Medical Care
Program cohort (males and
females) (261)
ey cancer
rvard and University of Pennsylvania
alumni (males and females) (25)
Statist
significa
p>0.1
No significant association^
1.00t (95% Cl: 0.53, 1.89)
p > 0.1
NS*
No significant associations
in males or females^
Males: 1.0* (95%CI: 1.0, 1.1)
Females
p>0
NS
Height, Leg Length, and Cancer Risk
8
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Epidemiol Rev Vol. 23, No. 2, 2001
329
ologic research, cohort studies—the results of which we
have given the most emphasis to—are less prone to selection and information biases that often beset other observational designs.
Methodological bias in the reported studies. Five possible sources of bias in the conduct of the studies reviewed
here must be considered. First, detection bias would arise if
cancer were more likely to be identified in taller individuals.
This might occur because taller (affluent) individuals are
more likely to undergo health screening. Such an effect
would lead to stronger associations for incident (screendetected) disease compared with fatal disease, under the
assumption that some screen-detected cancers would not
have been fatal or were detected earlier in taller individuals.
The example of prostate cancer provides us with an opportunity to assess this possibility. With the advent of prostate
cancer screening, one might expect height associations to be
stronger for incidence than for mortality, because of the
greater chance of detecting incidental cancers in individuals
who undergo screening and the fact that individuals who
request screening tend to be more affluent (taller). However,
if anything, the opposite effect is seen for prostate cancer
(59). More generally, in the papers reviewed, the associations are similar for incidence and mortality, making detection bias unlikely.
Second, survival bias might arise in studies examining
cancer mortality rather than incidence if stature were a
marker of the chances of surviving once cancer had been
diagnosed, rather than a marker of cancer risk per se. Such
an effect might be expected to diminish rather than increase
height-cancer associations, since higher socioeconomic
position is associated with both greater stature and better
prospects of cancer survival (274). Interestingly, in the
breast cancer cohorts (see table 3), the only study not to
show a positive association with height was the one based
on deaths alone (2).
Third, measurement bias would occur if there were systematic differences in the measurement or reporting of
stature among those who were to go on to become cases. At
the time of measurement in cohort studies, observers are
unlikely to be aware of subjects' likelihood of developing
cancer. While measurement error may arise when height
assessment is based on self-reports rather than on measurements, such errors are likely to be nondifferential with
respect to later cancer occurrence, and this is likely to attenuate associations. Furthermore, since shorter individuals
tend to overreport their height, any height-cancer associations found are likely to be attenuated (275).
Fourth, it has been suggested that height-cancer associations may arise because cancer risk increases with age and
taller individuals are more likely to live longer (276). While
this phenomenon may influence the findings of some studies, it is unlikely to explain associations seen with cancers in
young people (such as premenopausal breast cancer and testicular cancer). In addition, the statistical methods used in
some analyses (Cox's proportional hazards models) ensure
that persons who die of cancer are compared only with persons of the same age who are alive at the time cancer is
detected or cancer death occurs (277).
8.
Results of prospective studies reporting on the associations between components of height (leg length, sitting height, and trunk length) and cancer
Estimate of relative risk
No. of cases
(re.e^nc 'no.)
ANES I • males and femalest
4)
ANES I (89)
olulu Heart Program (271)
olulu Heart Program (26)
Height comparison
and
source of controls
Incident cases—all sites
Top quartile vs. bottom
quartile
Males: 114 lung, 95
prostate, 62 colorectal,
27 bladder, and 170
at all other sites
Females: 122 breast, 67
colorectal, 30 uterus,
20 cervix, and 168
at all other sites
Age-adjusted
risk
(95% Cl*)
Fully adjusted
risk
(95% Cl)
Males:
LungLeg length: 1.6 (95% Cl: 0.9, 2.7)
Sitting height: 0.6 (95% Cl: 0.3, 1.1)
Prostate—
Leg length- 1.2 (95% Cl: 0.7, 2.2)
Sitting height: 1.2 (95% Cl: 0.6, 2.3)
Colon/rectum—
Leg length: 1.5 (95% Cl: 0.7, 3.0)
Sitting height: 1.4 (95% Cl: 0.6, 3.0)
BladderLeg length: 1.1 (95% Cl: 0.4, 3 6)
Sitting height: 1.2 (95% Cl: 0.3, 4.0)
All other sites—
Leg length: 2.0 (95% Cl: 1.2, 3.2)
Sitting height: 1.2 (95% Cl: 0.7, 1.8)
Leg len
Neither
Neither
Neither
Leg len
Females:
Breast—
Leg length: 1.6 (95% Cl- 1.0, 2.6)
Sitting height: 1 3 (95% Cl: 0.7, 2.2)
Colon/rectum—
Leg length: 1.4 (95% Cl: 0.7, 2.8)
Sitting height: 1.4 (95% Cl: 0.7, 3.0)
Uterus—
Leg length: 1.1 (95% Cl: 0.4, 2.8)
Sitting height: 0.9 (95% Cl. 0.3, 3.2)
CervixLeg length: 3.8 (95% Cl: 0.8, 18.3)
Sitting height: 1.0 (95% Cl: 0.3, 3.1)
All other sites—
Leg length: 0.8 (95% Cl: 0.5, 1.2)
Sitting height: 0.8 (95% Cl: 0.5, 1.4)
Incident cases of breast
cancer (n= 182)
Mean height and sitting
height of cases vs.
noncases
Incident cases of prostate
cancer (n= 174)
Leg length >78 cm vs.
<75cm
Sitting height £88 cm vs.
<86cm
Incident cases of prostate
(n = 306), colon (n =
289), rectum (n= 108),
lung (n = 236), and
stomach (n = 229)
cancer
Mean sitting height and
leg length in cases
vs. noncases (cm)
Leg len
Neither
Neither
Leg len
Neither
Height: 161.7 cm vs. 161.2 cmt
(p = 0.28)
Sitting height: 85.4 cm vs 85.1
cm* (p = 0.27)
Leg length: 1.2 (95% Cl- 0.9, 1.8)
Compon
stature as
with incr
cancer
Neither
Leg len
Sitting height: 0 9 (95% Cl: 0.7, 1.3)
Prostate—
Leg length: 76.7 vs. 76.3
Sitting height: 86.7 vs 86.5
Colon—
Leg length: 76.1 vs. 76.3
Sitting height: 86.9 vs. 86.5
Rectum—
Leg length: 76.5 vs. 76 3
Sitting height: 86.7 vs. 86.5
Neither
Height, Leg Length, and Cancer Risk
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331
Lastly, case-control studies may be subject to control
selection biases. In some studies, control subjects were chosen from patients with other cancers (79, 117, 164, 258) or
from persons with other conditions that may themselves be
associated with height (46, 251). This bias could work in
different directions depending on height-disease associations in the control population.
Publication bias. The final type of bias that should be
considered is publication bias. The relatively high proportion of positive findings in the studies reviewed here could
reflect such an effect. Many of the cohort studies reporting
site-specific height-cancer associations have not reported on
cancer at other sites. However, a number of studies carried
out in larger cohorts—the Whitehall (29), Reykjavik (31),
US Physicians (1), and Renfrew and Paisley (2) cohorts, the
Norwegian tuberculosis screening cohort (35, 215, 227),
and the Nurses' Health Study cohort (32, 91, 205)—have
reported associations between height and cancer at a range
of sites, and this increases confidence in such findings' not
being a result of publication bias alone. Publication bias is
more likely to be a concern with cancer sites that have been
examined in only one or two articles. An example of this
phenomenon is seen with the strong positive association
reported in the one case-control study examining the relation between height and vaginal cancer (249). Only one
(233) of 12 case-control studies (19) investigating the etiology of thyroid cancer presented height-cancer associations
when results were published; however, a recent meta-analysis of these studies (19), using data obtained from the investigators, confirmed that height was associated with
increased risk in most of the studies but the association had
not been reported.
Thus, chance and bias appear unlikely to explain reported
height-cancer associations. Below, we outline possible
explanations for the observed relation. The explanations can
be divided into two basic categories: 1) height as a biomarker for other exposures that influence cancer risk and
2) height as a biomarker for biologic mediators of risk.
51 §11
Previously identified confounders
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The roles of several possible confounding factors, particularly body mass index, socioeconomic position, and smoking, have been investigated in the studies included in this
review. Controlling for these factors in multivariable analyses only partially attenuates the height-cancer associations
reported, or even strengthens them (1, 2, 29, 31, 33, 60, 91,
98, 99, 128). While it is possible that residual confounding
remains in some of these analyses as a result of the relatively
crude adjustments made, in most cases the attenuation of
risk is slight (or nonexistent), indicating a residual height
"effect." Socioeconomic position, like height, is a marker
for a range of exposures, some of which may influence
height. Interpretation of the effects of controlling for socioeconomic position in models examining height-cancer associations is therefore not straightforward.
Some of the observed associations may arise as a result of
failure to control for other important confounders, and in
some analyses there is little assessment of possible confound-
9.
Results of case-control studies reporting on the associations between components of height (leg length and sitting height) and cancer
Estimate of relative risk
Case-control study
population
(reference no.)
No. of cases
(incident cases
include deaths)
Height comparison
and
source of controls
Compon
Age-adjusted
risk
(95% Cl»)
mortem study (272)
Children who died of
leukemia compared with
"normal" infants (275
children; not all had
sitting height measured)
Height and sitting height Authors reported
in cases and controls
statistically significant
deviations in the
"distribution of the
group according to
standing and sitting
heights" (272); reanalysis of original
data indicated that
cases had shorter
leg length relative
to sitting height
otherapy center patients
49)
Incident cases of breast
cancer (n= 150),
cervical cancer (n = 60),
and other cancers
(n = 50)
Mean stature in cases
Controls were taller and
and controls (other
had greater sitting
hospitalized patients
heights than cases
(n = 50) and women The relative sitting height
undergoing screening
of breast cancer
cases was less than
for tuberculosis (n =
that of all other
199))
groups}:
Incident cases of prostate
cancer (n= 14)
Cases vs. controls—
Mean stature in cases
and controls (other
Height: 174.9 cm
vs. 177.8 cm
urology clinic patients
Sitting height: 85.9
(n=14))
cm vs. 81.7 cm
Relative sitting
height§: 0.49 vs.
0.46
ogy clinic patients (84)
ogy clinic patients (86)
Incident cases of prostate
cancer (n= 156)
1) Mean stature in cases
and controls
2) Increase in odds of
cancer per 1interquartile- range
increase in stature
Controls: other urology
clinic patients (n 155)
Cases vs. controls—
Height: 175.5 cm
vs. 175.4 cm
Relative sitting
height):: 0.52 vs.
0.52
st screening patients (161)
Incident cases of breast
cancer (n = 67)
Mean stature in cases
and controls (n = 59,
other screening
center patients)
Cases vs. controls—
Height: 159.8 cm vs.
159.1 cm
Head to pubis: 81.5
cm vs. 80.7 cm
Pubis to ground: 78.0
cm vs. 78.4 cm
Statistical
significance
Fully adjusted
,g5"^ c ) .
statistical
significance
s a t u n 3 as
cancer
Sitting
p < 0.01
Breast cancer patients
had lower sitting
heights than controls!
Leg len
p < 0.001
Sitting
p = 0.14
p = 0.06
p = 0.015
Relative sitting height:
0.96H (95% Cl:
0.71, 1.30)
Neither
Neither
NS»
NS
NS
Height, Leg Length, and Cancer Risk 333
ing structures. For example, the increased risk of esophageal
cancer among shorter individuals (29, 215) may be confounded by smoking. Below, we describe other factors that
may confound or explain height-cancer associations.
Height as a biomarker for genotype or environmental
exposures
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Epidemiol Rev Vol. 23, No. 2, 2001
_- o o o o o o
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Height per se clearly does not cause cancer. In the associations reported here, it is simply acting as a biomarker for
some other exposure(s). Thus, strictly speaking, the heightcancer associations could be considered confounded by
these factors; however, since these factors are as yet undetermined and we have ruled out confounding by social class,
smoking, and body mass index (see above), height may be
considered a biomarker for this (these) unknown etiologic
factor(s). To assess possible candidates for these exposures,
it is important to first consider genetic and environmental
influences on growth and hence final adult height and their
relation to the etiology of cancer.
Genetic influences on height. Twin studies highlight
genetic influences on stature. Correlations between the adult
heights of monozygotic twins are approximately 0.90, as
compared with 0.50 for dizygotic twins (278, 279). These
differences probably exaggerate the genetic contribution to
height, since in-utero (environmental) influences on growth
and pregnancy outcome differ for monozygotic twins and
dizygotic twins (280). The particular influence of the
intrauterine environment on later growth is highlighted by
studies demonstrating height differences of over 1 cm
among 6-year-old monozygotic twins who were discordant
for birth weight (278).
The relative contribution of genetic and environmental
factors to adult height depends on the degree of environmental adversity experienced during growth. A twin study
from Finland highlights this by showing that the genetic
contribution to adult height differences increased in the first
half of the 20th century, presumably as a result of environmental improvements' reducing this source of variation
(279). Likewise, parent-child correlations for stature are
higher in well-nourished nations than in poorly nourished
nations; in the latter countries, environmental adversity may
override genetic influences (281).
Growth and final adult height are influenced by a number
of genes. It is likely that prepubertal growth, the timing of
puberty, and peak height velocity are under separate genetic
control. The range of genes involved in growth is highlighted by the number of specific genes involved in growth
disorders. These include the GH-1 (282), SHOX (283),
FMR1 (284), and GHRHR (285) genes. While it is possible
that a gene which is important in growth is closely linked to
one that influences cancer risk, height-cancer associations
have been reported in dizygotic twins who are discordant for
adult height (273). To fully assess this issue, however, studies of cancer risk in relation to height in monozygotic twins
would be required; to date, no such studies seem to have
been conducted.
Environmental influences on height. The three main
environmental factors influencing childhood growth are
334
Gunnell et al.
diet, ill health, and psychological well-being (286). Some of
these factors may have long-term influences on cancer risk.
It has long been recognized that animals on calorierestricted diets are smaller, live longer, and have a reduced
incidence of cancer (287, 288). A recent analysis suggests
that in humans, a lower calorie intake in childhood is also
associated with reduced cancer risk (289). Therefore, it is
possible that stature acts as a biomarker either for diets
which protect against cancer (short stature) or diets which
are associated with an increased risk of cancer (tallness).
The importance of prepubertal diet and growth is supported
by the observation that height-cancer associations appear to
be strongest among birth cohorts exposed to periods of food
shortage during the prepubertal growth period (97, 290).
Likewise, the stronger associations with leg length suggest
that nutritional status before puberty may be most important,
since leg length is the component of stature responsible for
the greatest amount of prepubertal growth and thus may be
a more sensitive marker of nutritional influences at that
time.
A number of pathogens are known to be important in the
etiology of cancer (291), and prolonged illness with such
infections in childhood may lead to stunting (292, 293).
Infection with Helicobacter pylori may underlie the
increased risk of stomach cancer seen among shorter individuals in some studies (2, 217, 220), since it is important
in the etiology of stomach cancer and is associated with
poor childhood growth (294, 295). For most cancers, however, risk increases with stature. Greater height may
reflect a lower infection load in childhood, and this may
have two consequences in relation to cancer risk. First, it
may leave older children susceptible to infections that, if
experienced in later life rather than in early childhood,
carry a greater risk of malignancy. Second, it may lead to
a more generalized underdevelopment of immune function. In support of these notions, it has been shown that
risk of lymphoma is increased among individuals from
small families (2, 296); small family size is, in turn, associated with greater stature.
Psychological stress in childhood may influence growth,
leading to short stature (297, 298). However, it is unlikely
that this could underlie the association between greater
stature and cancer risk, unless childhood stress protects
against later cancer risk.
Height as a biomarker of exposures in utero, childhood
growth, and the timing of puberty
Associations between birth weight and the risks of breast
and prostate cancer have been reported in some studies (299,
300). These associations may reflect the influence of fetal
nutrition, pregnancy steroids, or maternal growth factors on
long-term cancer risk (301). Since birth weight is associated
with height later in life (correlations between birth weight
and adult height of 0.22-0.26 have been reported (302,
303)), it is possible that the relation between height and cancer may simply reflect the long-term effects of prenatal
exposures on cancer risk. While none of the studies reporting height-cancer associations have controlled for birth
weight, the observation that leg length is the component of
height most consistently associated with cancer risk and the
fact that associations of birth weight with leg length and
trunk length are similar (304) suggest that different pathways may underlie birth weight-cancer and height-cancer
associations.
Adult height is also influenced by the timing of puberty,
and this too may affect cancer risk. Early menarche is a recognized risk factor for breast cancer (91), and recently it has
been suggested that early attainment of adult height is independently associated with increased breast cancer risk
(170). These risk factors may indicate either a longer exposure of sensitive tissues to sex hormones or an earlier exposure. Early menarche also signals an earlier cessation of
growth, since the sex hormone surges associated with
puberty result in fusion of the epiphyseal growth plates
(286). Genetic and environmental influences affect the timing of puberty, and while there is some inconsistency in the
evidence, most studies indicate that early puberty is associated with short adult stature (302, 305, 306). On this basis
alone, one would predict that short stature would be associated with increased breast cancer risk, whereas the opposite
is seen (see table 3). Therefore, the height-breast cancer
associations are unlikely to arise as a result of the timing of
puberty. Furthermore, controlling for age at menarche
appears to have little or no effect on height-breast cancer
associations (91, 101, 128).
Height as a biomarker for biologic mediators of risk
The explanations given above are all based on the
assumption that height is simply acting as a marker for
another exposure. In the two possible mechanisms discussed
below, body size is more directly related to cancer risk. Of
course, because they may influence total body size, all of the
mechanisms reviewed above may be relevant to the pathways discussed here.
The first pathway links height to the number of cells in
the body. Larger bodies contain more cells than smaller bodies, and it has been suggested that the more cells one has the
greater the chance that a cell will undergo malignant transformation, escape the body's cancer defense mechanisms,
and progress to cancer (307). Calorie restriction in early life
reduces organ cellularity (308), and it has been proposed
that this mechanism might underlie height-cancer associations. Some support for this notion comes from studies
demonstrating associations between breast size and cancer
risk (128).
The second pathway links body size to circulating levels
of hormones or other substances that influence cancer risk.
Two groups of hormones have been investigated: sex hormones and growth hormones. However, no consistent associations have been observed between sex hormone levels
and height (309-311) or cancer risk (312, 313). More
recently, IGFs have been implicated as having a role in the
development of cancer, and height may act as a marker for
levels of these growth factors. Evidence supporting the role
of IGFs in explaining height-cancer associations is outlined
below.
Epidemiol Rev Vol. 23, No. 2, 2001
Height, Leg Length, and Cancer Risk
IGFs, height, and cancer
IGF biology. IGFs, particularly IGF-I, play a fundamental role in somatic growth. Cross-sectional studies of children (314, 315) demonstrate that IGF-I levels are associated
with stature: Differences of over 20 percent have been
observed between the lowest and highest height quartiles
(314). IGF-I is mainly secreted from the liver in response to
secretion of pituitary growth hormone, although dietary
intake also influences IGF-I levels and some IGF-I synthesis occurs in peripheral tissues. The availability of IGFs to
tissues depends on circulating levels of IGF-binding proteins. The principal binding protein for IGF-I is IGF-binding
protein 3 (316).
Epidemiologic evidence. Recent research based on
prospective studies has demonstrated that raised levels of
IGF-I or low levels of IGF-binding protein 3 are associated
with increased risks of prostate cancer (12-14), premenopausal breast cancer (15), and colorectal cancer (16,
17) over prolonged periods of follow-up. In these studies,
blood samples were collected many years before the onset
of cancer, so it is likely that the raised levels predated the
cancers investigated rather than arose as a result of them. It
is noteworthy that height-cancer associations are found for
these same cancers (tables 1-3). Associations between IGFI and lung cancer risk have also been reported (317).
Because this finding was restricted to a case-control study in
which samples were taken from people with diagnosed lung
cancer, the direction of causality is uncertain.
Studies of cancer risk in acromegaly, a condition characterized by high circulating levels of growth hormone (and
hence IGF-I), provide further support for the role of the
growth hormone-IGF axis in cancer risk (318-320). While
findings were inconsistent, results from two of the largest
prospective studies of people with acromegaly (319, 320)
suggested increased risks of malignant melanoma and of
gastrointestinal, breast, and hematopoietic cancers.
Further evidence that IGFs may underlie height-cancer
associations comes from analyses that have reported on cancer risk in relation to height and its components, leg length
and trunk length. Some studies have indicated that leg
length is the constituent of height most strongly related to
risk of malignancy. In individuals with Laron's syndrome,
an inherited condition characterized by low circulating levels of IGF-I, leg length tends to be low in relation to overall height (321, 322). Thus, it is possible that in the normal
population, relative leg length provides an indication of an
individual's circulating levels of IGF and his or her cancer
risk.
Biologic mechanisms linking IGFs to cancer risk. There
are several plausible biologic mechanisms through which
IGFs may influence cancer risk (323-325). First, IGFs protect damaged cells from apoptosis (cell suicide); hence,
higher levels of IGF may enable damaged cells to survive
and become cancerous. Second, IGFs are potent stimulators
of cell turnover, and the mitotic rate of stem cells is an
important determinant of cancer risk. In primate models,
growth hormone and IGF-I both stimulate glandular and
epithelial cell proliferation, which indicates their potential
to initiate and promote neoplasia (326). Lastly, in vitro studEpidemiol Rev Vol. 23, No. 2, 2001
335
ies show that raised levels of IGF-I may amplify the effects
of DNA-damaging agents (327).
Observational and experimental evidence attests to the
important role of nutrition, including intrauterine nutrition,
in regulating IGF-I (328, 329), with high-energy diets
increasing circulating levels and energy restriction decreasing circulating levels. Thus, IGFs could provide a mechanism explaining associations between nutrition and cancer
in addition to a mechanism underlying the association
between stature and cancer. It is possible that IGF-I levels in
adulthood are "programmed" by nutrition in early life, and
such programming may be responsible for associations
between early life exposures and adult disease.
While there is some attractive evidence in support of a
role for IGFs in explaining height-cancer associations, there
are some inconsistencies in the research record. In studies of
children receiving growth hormone for growth disorders, for
example, neither growth hormone deficiency nor growth
hormone treatment appears to lead to marked disproportion
in leg length relative to height (330). Furthermore, the
strong associations between height and IGF-I reported for
children (314, 315) are weaker in adults (14, 331) or are not
found in adults (12, 332). However, it is possible that adult
IGF levels reflect patterns of childhood and adolescent
growth, such as growth velocity and age at peak height
velocity, that are only weakly related to final adult height.
CONCLUSIONS
A large body of literature supports the existence of a real,
albeit relatively weak, association between height and cancer risk. Taller individuals appear to be at a 20-60 percent
increased risk of a range of cancers. This relation may be
explained by genes or by prenatal or childhood exposures,
including diet and infection. Further research is required to
determine whether the influences of childhood diet on
growth and circulating growth factor levels underlie the
observed associations. Observations that height-cancer
associations differ depending on an individual's weight
require further detailed review, and mechanisms for
observed interactions should be investigated.
The finding in some studies that leg length is the component of height that is generating the height-cancer associations
requires replication. Furthermore, the differential association
of growth factor levels with leg length and trunk length should
be investigated. Such research might provide insight into periods of life that are critical for the development of cancer risk.
From the population perspective, one must remember that
while greater stature is associated with increased cancer
mortality, it has long been recognized that taller individuals
generally have lower overall mortality rates than shorter
people (333, 334). This is largely because associations
between height and cardiorespiratory disease point in a
direction opposite that of associations with cancer (2, 29).
However, understanding the biologic mechanisms through
which height and cancer risk are linked may lead both to
possible interventions and to an appreciation of critical
times in the development of cancer risk in childhood and
adolescence.
336
Gunnell et al.
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