We found that obesity (BMI ≥30 kg/m2) was associated with a nearly twofold increased risk of colorectal cancer among women who were premenopausal at baseline. In postmenopausal women, there was essentially no association, or a small reduction in risk at most. Due to the greater number of cases among women who were postmenopausal at baseline, there was only a weak positive association in the entire cohort.
Results similar to ours were observed in a large cohort of Swedish women10
that found a twofold increased risk among obese women less than 55 years of age compared with their normal weight counterparts, but found no association among older women. In agreement with those results, although no association was observed overall in a large cohort of female Seventh Day Adventists,3
the investigators reported a clear association among “younger women” without specifying the age range. Similarly, a twofold increased risk of colon cancer was observed among women who were obese at enrolment into the Nurses' Health Study,4
a large prospective cohort study of female American nurses who were between the ages of 34 and 59 at enrolment, while no association between BMI and risk was observed among women in the Leisure World cohort of retired people5
who were mostly over 65 years of age at baseline (the exact age range was not reported). In addition, four case control studies examined the association by age and all observed stronger associations among younger compared with older women.6–9
Two of these studies6,8
compared obesity at stages of life that included very youthful ages, ages 15, 25, and 35 years,8
and ages 12 and 30 years,6
respectively. In both studies, obesity at very young ages (12 and 15 years) was associated with an increased risk of colorectal cancer at magnitudes similar to those associated with obesity among older women who were still premenopausal (25, 30, and 35 years). Overall, these studies suggest that among premenopausal women the positive association between obesity and colorectal cancer risk may be as strong and consistent as that which has been observed previously among men.17,18
The results of previous studies also suggest that a positive association among premenopausal women might be stronger in the distal colon and rectum than in the proximal colon.10
Our results offer some support for this hypothesis in that the greatest increased risk was observed among obese women for cancers of the distal colon although statistically non-significant positive associations were also observed for cancers of the proximal colon and rectum.
Among the strengths of our study was the large sample size of our cohort of women and the relatively long term follow up. The completeness of follow up of the cohort13,14
reduces the likelihood that our results reflect bias due to differential follow up of obese compared with non-obese women. Moreover, the large number of cases in our study allowed us to examine associations according to menopausal status with reasonable statistical power. On the other hand, although we adjusted our estimates for a wide range of potentially confounding variables, we cannot exclude the possibility of residual confounding by other factors.
We can only speculate on the biological mechanisms underlying our observations. Adiposity is positively related to blood insulin levels.1
An increase in blood insulin levels lowers insulin-like growth factor (IGF) binding protein 1 and may subsequently lead to increased levels of free IGF-1.19
IGF-1 has been positively associated with the risk of colorectal cancer in men20
Oestrogen on the other hand appears to be associated with a lower risk of colorectal cancer. For example, hormone replacement therapy has been associated with a reduced risk of colorectal cancer22
and such benefits have been found to be stronger in the distal colon and rectum.23,24
In addition, the observation that hormone replacement therapy may confer greater benefits regarding both colorectal cancer25,26
and colorectal adenomas27
among lean women than among obese women suggests that hormone replacement therapy offers no additional benefit over and above that from oestrogen derived from adipose tissue in postmenopausal obese women, which is the main source of endogenous oestrogen after the menopause.28
Moreover, early age at menopause was associated with an increased risk of colorectal cancer in a cohort of Dutch women29
but only among lean women. Thus in postmenopausal women, the potentially deleterious effects of obesity through increased insulin and IGF-1 levels might be offset by the ameliorative effect of obesity on endogenous oestrogen levels. In contrast, in premenopausal women, oestrogen derived from adipose tissue is a relatively unimportant source of this hormone compared with that derived from the ovaries28
and, therefore, would not significantly offset the deleterious effects of obesity on colorectal cancer risk.
In conclusion, our data suggest that obesity is associated with a twofold increase in the risk of colorectal cancer in premenopausal women, and that at most it is associated with a small reduction in risk in postmenopausal women. Effect modification by menopausal status may therefore better explain the inconsistent or weak findings in previous studies of women than the presumed lack of an association among women.17,18
Given the relatively high incidence of colorectal cancer in Western populations,30
and the rising prevalence of obesity, especially in younger age groups,31
the possible benefits with respect to this disease should be added to the list of potential advantages of weight control.32