In this large prospective investigation of postmenopausal women, we observed statistically significant positive associations between age at menopause and age at birth of first child with risk of incident colorectal cancer after controlling for multiple other colorectal cancer risk factors. In addition, among women with no history of hormone therapy use, age at menarche and parity were inversely associated with risk of colorectal cancer, although the latter association was not statistically significant. It is notable that these associations are similar to reported relationships between reproductive factors and risks of breast and endometrial cancers. For example, early age at menarche, late age at menopause, nulliparity, and later age at birth of first child are all established risk factors for breast and uterine cancers (16
); these factors are believed to influence the risks of these malignancies by increasing lifetime exposure to endogenous sex hormones such as estrogen (14
). Our finding that these same risk factors are also associated with the risk of colorectal cancer suggests that similar endocrinologic mechanisms may play a role in colorectal tumorigenesis.
Evidence that endogenous estrogen levels are positively associated with colorectal cancer development has recently emerged from two prospective studies conducted among postmenopausal women (6
). Both investigations reported statistically significant positive associations between circulating estrogen levels and the risk of colorectal cancer, and one study (6
) also controlled for circulating insulin and free insulin-like growth factor I (IGF-I) levels and obesity, which suggests that the relationship between estrogen and risk of colorectal cancer may be independent of obesity-related pathways. In vitro data also support a role for estrogen in colorectal tumorigenesis (8
). For example, in human colorectal cancer cell lines, estradiol has been shown to activate the mitogen-activated protein kinase cascade, a pathway that plays a key role in the stimulation of DNA and protein synthesis, which induces cell growth and proliferation (10
). In addition, colorectal cancer tissue was found to have higher levels of estradiol activity compared with nonmalignant colorectal tissue (34
), and a cross-sectional study of colon cancer patients reported that colon carcinoma tissue had a statistically significant twofold higher level of total estrogen compared with normal colon mucosa (36
). Low concentrations of intratumoral estrogen were also statistically significantly associated with better prognosis (36
), and higher levels of estrogen receptor beta expression were reported in colorectal carcinomas compared with normal colonic mucosa (37
Later age at menopause is an established risk factor for breast cancer (32
); the higher number of ovulatory cycles and increased estrogen exposure associated with later menopause has been hypothesized to drive this relationship (14
). Most previous studies of the association between reproductive history and the risk of colorectal cancer have generally reported a null association for age at menopause and risk of colorectal cancer. However, all of these investigations included premenopausal women and, thus, their statistical power to evaluate the association between age at menopause and risk of colorectal cancer was limited. In this study, we observed an inverse relationship between age at menarche and the risk of colorectal cancer. Like age at menopause, age at menarche is an indicator of the duration of exposure to cyclic ovarian function, and some (39
), but not all (41
), studies have demonstrated an inverse relationship between age at menarche and circulating estrogen level. The Nurses’ Health Study (19
) and the Japan Collaborative Cohort Study (21
) reported statistically significant inverse trends for the association between age at menarche and risk of colorectal cancer, which is consistent with our data. However, other investigations that evaluated the association between age at menarche and risk of colorectal cancer reported null associations (17
). It is interesting that in this study, the inverse relationship between age at menarche and risk of colorectal cancer was only observed among women with no history of hormone therapy use. One potential explanation for this observation is that among women using hormone therapy, the association of earlier age at menarche and colorectal cancer incidence is masked by the strong protective effect of hormone therapy use on risk of colorectal cancer.
In this study, later age at birth of first child was positively associated with the risk of colorectal cancer. This finding is also consistent with data from the Nurses’ Health Study, which reported a statistically significant positive association between age at first pregnancy and risk of colorectal cancer (relative risk for women age ≥30 years at first pregnancy vs <24 years = 1.57, 95% CI = 1.15 to 2.14) (19
). Two other cohort studies also reported positive, albeit non-statistically significant associations between age at birth of first child and risk of colorectal cancer (18
). Although later age at birth of first child has also been found to be positively associated with the risk of breast cancer (14
the mechanism underlying the positive association with colorectal cancer is less apparent than it is for breast cancer. For example, in the case of breast cancer, in the period between the onset of menarche and the first pregnancy, the breast tissue is undifferentiated and is particularly susceptible to carcinogenic insults (42
). Therefore, the longer this period of susceptibility, the greater is the risk of breast tumorigenesis. It is unknown whether endocrinologic changes that occur during pregnancy also confer a similar type of protection against colorectal carcinogenesis or whether the colonic mucosa is particularly susceptible to mutagenic events before pregnancy. Further investigation into the mechanism underlying the association between age at birth of first child and the risk of colorectal cancer is warranted.
It is interesting that although parity was inversely associated with the risk of colorectal cancer in this study, as with the association between age at menarche and risk of colorectal cancer, this relationship was only apparent among women who had never used hormone therapy. Although most of the prior studies did not find statistically significant associations between parity and the risk of colorectal cancer, one cohort study (23
) demonstrated that compared with nulliparous women, women who had given birth to two or more children had a decreased risk of malignancy in the cecum or ascending colon. Pregnancy leads to substantial changes in the hormonal milieu, which may be protective against colorectal cancer. For example, during gestation, production of ovarian estradiol ceases and the predominant estrogen in circulation is estrone (26
). Whereas estradiol has been demonstrated to have proliferative properties in colorectal cancer cell lines (10
), estrone has been shown to exert antiproliferative effects in these tissues (35
). Therefore, it is possible that a hormonal profile in which estrone predominates confers protection against colorectal tumorigenesis. We note, however, that the New York University Women’s Health Study reported a weak positive association between circulating estrone levels and the risk of colorectal cancer (7
). Pregnancy is also characterized by continuous production of progesterone from the early gestation period until delivery (26
). Progesterone opposes the mitogenic effects of estrogen in reproductive tract tissues (eg, the endometrium) (26
), and it is conceivable that progestagens may exert similar effects on other tissues, such as the colonic epithelium. Both normal and malignant colon cells express progesterone receptors (44
); however, the direct biological effects of progesterone on colonic tissue are not understood.
In contrast to our results, a recent study conducted in the European Prospective Investigation into Cancer (EPIC), which evaluated a similar number of colorectal cancer case subjects as in this study, found no association between reproductive history and the risk of colorectal cancer (25
). We note, however, that the women enrolled in the EPIC cohort were considerably younger than the NIH-AARP participants and that 25% of the case subjects in the EPIC study were premenopausal or perimenopausal women, in whom the association between reproductive history and risk of colorectal cancer may differ from that in postmenopausal women due to substantial differences in the endocrinologic profile. In addition, a comparison of the baseline characteristics of the EPIC and NIH-AARP populations reveals some notable differences that may also influence the relationship between reproductive history and risk of colorectal cancer. For example, oral contraceptive use was much more prevalent among EPIC participants compared with NIH-AARP study subjects; the profound changes that oral contraceptive use has on the hormonal milieu (eg, reduced number of ovulation cycles and potentially lower endogenous estrogen levels) may influence the association of reproductive history with colorectal cancer risk.
The associations between reproductive history and incident colorectal cancer observed in this study suggest that increased exposure to endogenous estrogen increases risk of colorectal cancer, a finding that is consistent with the results of two prospective cohort studies of circulating estrogen levels and colorectal cancer (6
). However, these findings stand in direct contrast to the results from the WHI Clinical Trial (4
) and from a large number of observational investigations that indicate that use of hormone therapy (ie, exogenous estrogen) protects against colorectal cancer development. Several hypotheses have been advanced to explain the disparate results (6
). First, oral hormone therapy may expose the liver to a large bolus of estrogen (the so-called first-pass effect), which could alter hepatic protein synthesis. It is known that oral estrogens result in decreased synthesis of insulin–IGF-I axis components (47
), which are positively associated with the risk of colorectal cancer (6
). Conversely, expression of sex hormone–binding globulin, the main estrogen-binding protein in circulation, is increased in hormone therapy users, leading to reduced levels of bioavailable estrogen (49
). In addition, oral estrogens may also induce or suppress other as-yet uncharacterized pathways that play an important role in colorectal cancer pathogenesis. Second, the protective effect of hormone therapy use against colorectal cancer may not lie in the estrogen components of oral hormone therapy. In the WHI Clinical Trial, estrogen plus progestin therapy was shown to protect against colorectal cancer, whereas estrogen alone had no effect (4
). It is possible, therefore, that progestin is the protective component in hormone therapy and that progesterone may be etiologically relevant to colorectal cancer (5
). Finally, it is also important to consider that other hormonal and physiological mechanisms related to colorectal tumorigenesis, including alterations in the insulin–IGF-I axis (6
), may also underlie the association between reproductive history and colorectal cancer.
The strengths of this study include the large, well-characterized prospective cohort of more than 200 000 postmenopausal women with more than 2000 colorectal cancer cases verified by tumor registry data and the relatively long follow-up of the study participants. The age-specific colorectal cancer incidence rates in this study were highly consistent with those reported by the Surveillance, Epidemiology, and End Results Program (51
), indicating the completeness of the colorectal cancer incidence data and suggesting that there was no substantial bias in cohort selection relating to voluntary response to the NIH-AARP dietary questionnaire. The large sample size enabled us to perform stratified analyses with adequate statistical power, which allowed the assessment of women according to BMI or hormone therapy use, two factors that could have a confounding effect on the association between reproductive history and colorectal cancer.
This study has several possible limitations. In particular, all of the primary variables of interest were based on self-reported reproductive history and thus we cannot exclude the possibility of bias related to inaccurate recall. However, self-reported reproductive history has shown good agreement with medical records in validation studies (12
). In addition, we could not further stratify the analyses by hormone therapy subtypes, and we lacked more detailed data on other reproductive factors, such as age at birth of last child, breastfeeding history, and history of induced or spontaneous abortion, which have been linked with breast cancer (52
) and which could help further elucidate the role of sex hormones in colorectal cancer development.
In conclusion, the findings of this investigation support a role for sex hormones in colorectal tumorigenesis and suggest that greater endogenous estrogen exposure may increase the risk of colorectal cancer in postmenopausal women. Further prospective studies that directly assess levels of circulating estrogens and other sex hormones in postmenopausal women in relation to colorectal cancer risk would be highly informative.