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American Journal of Epidemiology Advance Access originally published online on January 10, 2007
American Journal of Epidemiology 2007 165(7):794-801; doi:10.1093/aje/kwk068
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American Journal of Epidemiology Copyright © 2007 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

ORIGINAL CONTRIBUTIONS

Oral Contraceptives, Reproductive Factors, and Risk of Colorectal Cancer among Women in a Prospective Cohort Study

Jennifer Lin1, Shumin M. Zhang1,2, Nancy R. Cook1,2, JoAnn E. Manson1,2,3, Julie E. Buring1,2,4 and I-Min Lee1,2

1 Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA
3 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
4 Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, MA

Correspondence to Dr. Jennifer Lin, Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA 02215 (e-mail: jhlin{at}rics.bwh.harvard.edu).

Received for publication March 31, 2006. Accepted for publication September 18, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Previous findings on the associations between oral contraceptive (OC) use and reproductive factors and risk of colorectal cancer have been inconclusive. The authors evaluated associations of OC use and reproductive factors (including parity, age at first birth, age at menarche, and age at menopause) with risk of colorectal cancer among women in a large-scale prospective cohort study. The analysis included 39,680 participants in the Women's Health Study who had usable information on ever use of OCs and potential risk factors for colorectal cancer. Relative risks and 95% confidence intervals were estimated from Cox proportional hazards regression models. All p values were two-sided. During an average of 11 years of follow-up (1992–2004), 267 incident cases of colorectal cancer were documented. Ever use of OCs was associated with a lower risk of colorectal cancer (relative risk = 0.67, 95% confidence interval: 0.50, 0.89). Women who had used OCs for 6 months–<3 years had a relative risk of 0.61 (95% confidence interval: 0.40, 0.94) relative to never users, with little additional decreased risk being seen with longer duration of use (p for multivariate trend = 0.09). No significant association was observed between reproductive factors and colorectal cancer risk. These findings provide some support for a potential role of OCs in reducing risk of colorectal cancer.

colorectal cancer; contraceptives, oral; hormones; menarche; menopause; parity; women


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Colorectal cancer is one of the most common forms of cancer worldwide and is the second leading cause of cancer-related death in the United States (1). Men tend to have a higher incidence of colorectal cancer than women of similar age (1). In families with hereditary nonpolyposis colorectal cancer, the lifetime risk of developing colon cancer is much lower in females (30 percent) than in males (74 percent) (2). Male rodents with azoxymethane-induced colon carcinogenesis have also been found to have a higher rate of aberrant crypts of tumor formation than their female counterparts (3). The decreased incidence of colorectal cancer in women and female animals has been linked to a role of female hormones. In vitro evidence has demonstrated that estrogen regulates the cell growth of colonic mucosa and inhibits cell proliferation of colonic tumors through binding to estrogen receptors (4–8). The recent Women's Health Initiative estrogen-plus-progestin trial reported a 37 percent lower risk of colorectal cancer among users (9), further suggesting that estrogen and/or progesterone has possible beneficial effects against colorectal cancer risk.

During the past two decades, extensive efforts have been made in epidemiologic studies to investigate the relation of female hormones, including both endogenous and exogenous hormones, to risk of colorectal cancer, but findings have remained inconclusive. Many (10–18) but not all (19–26) studies have observed a lower risk of colorectal cancer in relation to use of oral contraceptives. The association between reproductive characteristics and risk of colorectal cancer also remains unclear (10–14, 19–25, 27–45). With available data from a large cohort of women who reported comprehensive information on reproductive factors and use of oral contraceptives, we aimed to better elucidate the association of exogenous and endogenous hormonal factors with risk of colorectal cancer among female health professionals.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study cohort
The Women's Health Study was a randomized trial, now completed, evaluating aspirin and vitamin E for the primary prevention of cancer and cardiovascular disease (46–48). Beginning in 1992, a total of 39,876 female health professionals aged ≥45 years who were not intending to become pregnant and had no history of heart disease or cancer were randomly entered into the trial. The present analysis included 39,680 women who had usable information on oral contraceptive use as well as potential risk factors for colorectal cancer.

Assessment of exposure factors and other risk factors
We requested information on oral contraceptive use and reproductive factors on the baseline questionnaire. Participants were asked whether they had ever used oral contraceptives (no, yes) and the total number of years of use (categorized as <6, 6–<36, 36–<60, or ≥60 months). We defined parity as the total number of pregnancies lasting 6 months or longer. Age at first pregnancy was assessed as age at the first pregnancy lasting 6 months or longer (not applicable or <15, 15–19, 20–24, 25–29, 30–34, 35–39, or ≥40 years). Number of miscarriages (and abortions) was recorded as the number of pregnancies lasting less than 6 months. Age at menarche and age at menopause were recorded in years.

On the baseline questionnaire, participants provided information on their medical history and potential risk factors for colorectal cancer. Participants also filled out a 131-item food frequency questionnaire which asked about average intake of various foods and beverages during the past year.

Ascertainment of colorectal cancer cases
Every 6 months during the first year of follow-up and annually thereafter, participants were asked whether they had been newly diagnosed with any conditions of interest, including colorectal cancer. For participants who reported a diagnosis of colorectal cancer and for those who died during the trial, we sought permission to retrieve medical records and pathology reports with respect to the diagnosis. An endpoints committee of physicians blind to the outcomes reviewed the records to confirm the diagnosis. During an average of 11 years of follow-up (1992–2004), we documented 267 incident colorectal cancer cases, among which 205 women had primary colon tumors and 55 women had rectal tumors. Seven case women had overlapping lesions of the colorectum.

Statistical analysis
We first compared the baseline distributions of risk factors for colorectal cancer according to duration of oral contraceptive use. We then used Cox proportional hazards regression to model the relative risks and 95 percent confidence intervals for colorectal cancer incidence evaluating the effects of hormonal factors. Results from these analyses were adjusted for age (in years), randomized treatment assignment (aspirin vs. placebo, vitamin E vs. placebo), family history of colorectal cancer in a first-degree relative (yes, no), history of benign colorectal polyps (yes, no), body mass index (weight (kg)/height (m)2; <25, 25–29.9, or ≥30 kg/m2), physical activity (total energy expenditure (kcal/week) in quartiles), smoking status (never, past, or current), multivitamin use (never, past, or current), alcohol consumption (total intake per day; none, <15 g/day, or ≥15 g/day), baseline aspirin use (yes, no), postmenopausal hormone therapy (never, past, or current), and red meat consumption (total intake (g/day) in tertiles). We additionally adjusted for oral contraceptive use in the multivariate models examining the effects of reproductive factors. We repeated the analyses by anatomic site of the malignancy (colon or rectum). Tests for linear trend were performed by fitting a median value within each category for all independent variables. All p values for all tests were two-sided.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Table 1 presents the age-adjusted baseline characteristics of the participants according to duration of oral contraceptive use. Approximately 70 percent of women in this cohort reported having ever used oral contraceptives; more than one third among them had used oral contraceptives for at least 5 years. Women who had ever used oral contraceptives appeared to be younger and leaner and more likely to be current smokers. Women with longer use of oral contraceptives were more likely to take multivitamins, receive postmenopausal hormone therapy, and consume more alcohol. Compared with never users, ever users of oral contraceptives were younger when they first gave birth and underwent menopause at a later age.


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  		TABLE 1. Age-adjusted baseline characteristics of participants according to duration of oral contraceptive use, Women's Health Study, 1992–2004*

 
Women who reported having ever used oral contraceptives were at lower risk of colorectal cancer than never users (table 2). There was a possible L-shaped inverse association between duration of oral contraceptive use and colorectal cancer; women who had used oral contraceptives for 6 months–<3 years had a relative risk of 0.61 (95 percent confidence interval: 0.40, 0.94) relative to never users, with little additional decrease being seen with longer duration of use (p for multivariate trend = 0.09). Additional control for reproductive factors in the multivariate analysis did not appreciably alter the results. When evaluating the effects according to tumor location, we also noted an inverse association between oral contraceptive use and risk of cancers of the colon and rectum (table 2).


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  		TABLE 2. Multivariate-adjusted relative risks* of colorectal cancer and cancers of the colon and rectum, by oral contraceptive use, Women's Health Study, 1992–2004

 
There were no associations of reproductive factors, including age at menarche, number of pregnancies, and number of miscarriages, with colorectal cancer risk (table 3). The null results were not changed when we repeated the analyses according to tumor location (colon or rectum) (table 3). However, later age at menopause was weakly associated with an increase in risk of colorectal cancer. Women who underwent menopause at age 52 years or later had a relative risk of 1.39 (95 percent confidence interval: 0.90, 2.15) compared with those who underwent menopause before age 45 years (p for trend = 0.09). Results for the association between age at menopause and risk of colon cancer alone did not deviate from the original pattern (table 3).


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  		TABLE 3. Multivariate-adjusted relative risks* of colorectal cancer and cancers of the colon and rectum, by reproductive factors, Women's Health Study, 1992–2004

 
Further stratified analyses were performed according to strata of body mass index, menopause, screening tests, and postmenopausal hormone therapy. We found no evidence of significant interactions of oral contraceptive use and reproductive factors with any of these potential confounders (for all interactions, p ≥ 0.20). Similarly, the associations did not differ according to socioeconomic status. In the lower socioeconomic status group (annual household income <$50,000), women who had taken oral contraceptives for <6 months, 6–<36 months, 36–<60 months, and ≥60 months, relative to never users, had relative risks of 0.76, 0.57, 0.65, and 0.72, respectively. In the higher socioeconomic status group (annual household income ≥$50,000), the relative risks for oral contraceptive users who had taken contraceptives for <6 months, 6–<36 months, 36–<60 months, and ≥60 months were 0.46, 0.65, 0.78, and 0.71, respectively. To address the possibility that hormonal effects of oral contraceptive use and reproductive factors may act differently between cancers of the proximal colon and cancers of the distal colon (49), we further conducted analyses according to colon subsite. We found no significant associations with risk of cancers of the proximal and distal colon (data not shown). Finally, analyses carried out according to tumor stage revealed that longer use of oral contraceptives was weakly inversely associated with the tumor stages of Duke's A and Duke's B but not with Duke's C (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In these prospective data, we observed a possible L-shaped inverse association between duration of oral contraceptive use and colorectal cancer risk. However, reproductive factors, including age at menarche, age at first birth, parity, miscarriage, and age at menopause, were not associated with risk of colorectal cancer. The results remained similar for cancers of the colon and rectum.

During the past two decades, at least a dozen studies have evaluated the relation between oral contraceptive use and colorectal cancer risk. Our finding that oral contraceptive use was associated with a lower risk of colorectal cancer was in agreement with many previous studies (10–17). However, several other studies failed to find an association (19–26), possibly because of an insufficient number of ever users; ever users represented less than 20 percent in several study populations. In a recent meta-analysis based on 20 studies, Fernandez et al. (50) obtained a relative risk for colorectal cancer of 0.82 (95 percent confidence interval: 0.74, 0.92) among ever users, suggesting a moderately protective effect of oral contraceptives against incidence of colorectal cancer.

Our finding of an inverse association between colorectal cancer and duration of oral contraceptive use is in line with results from the Nurses' Health Study, in which Martinez et al. (14) observed a relative risk of 0.6 for colorectal cancer in women with use of oral contraceptives for 8 years or longer. Investigators in three other case-control studies also reported a decreased risk with 2 or more years of oral contraceptive use (10, 16, 18). However, in several other studies, researchers did not observe a dose-response trend in relation to colorectal cancer risk (13, 19–21, 23, 24, 26, 34, 43), which may have been attributable in part to the relatively short follow-up. In our study, the possible L-shaped (but not significant dose-response) inverse association with duration of oral contraceptive use may have been attributable to our lack of statistical power. We also had no information on dosage of oral contraceptives to address whether dosage may have confounded the present finding.

An increase in number of childbirths has been hypothesized to reduce colorectal cancer incidence because of the high concentrations of estrogen and progesterone present during pregnancy (51). However, observational data on the association of parity with colorectal cancer risk have remained inconclusive. Although several studies (10, 11, 14, 19, 20, 22, 23, 27–33) observed a lower risk of colorectal cancer with increasing number of births, our study and many others (12, 13, 19, 21, 24, 25, 34–41) found little evidence of an association. In addition, later age at first birth has been suggested to reduce risk of colorectal cancer in some observational studies (11, 14, 29), but not in our study or other studies (19, 21, 22, 37, 39, 41, 42). Furthermore, our finding of no association between number of miscarriages and risk of colorectal cancer is in accord with three other studies (37, 38, 43). To our knowledge, only one case-control study observed an inverse association between number of miscarriages and risk of colorectal cancer (44).

The inconsistent findings from studies on the association with menstrual factors add another layer of complexity to research on the effect of endogenous female hormones on colorectal cancer incidence. Although some investigators have identified an inverse association between increasing age at menarche and risk of colorectal cancer (11, 14, 32, 37), we and several other groups (13, 19, 20, 24, 38, 45) found no such association. Age at menopause was also not related to risk of colorectal cancer in our cohort or in five other study populations (13, 17, 20, 37, 38). Researchers in three studies reported a decreased risk associated with later age at onset of menopause (14, 19, 42), while in two other studies, a positive association was reported (11, 43).

One postulated biologic mechanism by which female hormones may protect against colorectal cancer has been reduced synthesis or secretion of bile acids, which are believed to be carcinogenic and trophic to colonic epithelium (49, 52, 53). Women administered oral conjugated estrogen have been shown to have lower serum concentrations of bile acids (54). Two estrogen receptors, estrogen receptor {alpha} and estrogen receptor ß, which are responsible for most estrogen action, have also been linked to the inhibition of malignant colonic cell proliferation. In vitro studies have shown an abnormal pattern of methylation in the promoter region of estrogen receptor {alpha} in colonic cancer cells (4). Additionally, estrogen receptor ß, activated through 17-estradiol, has been shown in vitro to inhibit colonic tumor development by inducing apoptosis in malignant cells (6–8).

The recent finding from the Women's Health Initiative estrogen-plus-progestin trial that women on the estrogen-and-progestin regimen had an approximately 40 percent lower risk of colorectal cancer than placebo users suggests that progesterone may also play a role in colorectal carcinogenesis (9). This notion is further supported by a null finding from the estrogen-alone arm of the Women's Health Initiative among women who had undergone ovariectomy (55). Given also the inverse association between colorectal cancer risk and oral contraceptives, most likely combined estrogen-plus-progestin or progestin-only contraceptives (56), higher progesterone levels resulting from exogenous hormones and hormone therapy may confer some protection against colorectal cancer. The mechanism by which progesterone may affect colorectal carcinogenesis, however, remains unknown.

In this cohort, exogenous sources of hormones but not endogenous production of sex hormones (e.g., reproductive factors) were associated with a lower risk of colorectal cancer. One possible explanation for the conflicting findings may be the different levels of estrogen produced by the two sources. Our data were collected in the early 1990s from women aged 45 years or older, suggesting that oral contraceptive use in these women probably started before the 1980s. Because higher-dosage formulations were prevalent before 1976 (57), the majority of users in this cohort were likely to have been prescribed preparations containing much higher doses than are currently prescribed. In addition, oral contraceptives are absorbed in the body and undergo a series of metabolic transformations, especially in the liver, which results in a change in circulating levels of several hepatic hormones (58). It has been shown that oral estrogen decreases circulating levels of insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 (59). Both insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 have been shown to elevate risk of colorectal cancer and adenomas (60). Administration of oral estrogen also raises circulating levels of sex hormone-binding globulin, a biomarker which is inversely associated with metabolic syndromes (61). Such metabolic alterations may be associated long-term with an elevated risk of colorectal cancer (62).

There are at least two limitations of the present study. Potentially confounding factors may have affected the association between oral contraceptive use and risk of colorectal cancer. As is shown in table 1, women who reported having used oral contraceptives were more likely to engage in several health-conscious behaviors. We statistically controlled for the effects of these risk factors, although they may not have represented all aspects of health consciousness. We also conducted additional analyses stratified by body mass index, menopausal status, postmenopausal hormone therapy, screening tests, and socioeconomic status, to ensure a homogeneous relation across strata between oral contraceptive use and colorectal cancer risk. In addition, we did not have information on recency of oral contraceptive use and/or age at which use started. Recency of exogenous hormone use may be important in influencing disease risk (63), but we were unable to address this issue in our data. Finally, we were unable to analyze different types of oral contraceptives, which may have different effects on colorectal cancer risk.

In conclusion, the present study provides some support for a protective role of exogenous hormones in the risk of colorectal cancer among women. Additional studies are necessary to examine the biologic roles of estrogen and progesterone in the etiology of colorectal cancer.


   ACKNOWLEDGMENTS
 
This work was supported by grant CA47988 from the National Cancer Institute and grant HL43851 from the National Heart, Lung, and Blood Institute.

The authors thank the entire staff of the Women's Health Study under the leadership of David Gordon, as well as Mary Breen, Susan Burt, Marilyn Chown, Georgina Friedenberg, Inge Judge, Jean Mac-Fadyean, Geneva McNair, David Potter, Claire Ridge, and Harriet Samuelson. They also thank the Endpoints Committee of the Women's Health Study (Dr. Wendy Y. Chen) and Natalya Gomeiskaya for technical assistance with the manuscript.

Dr. Nancy R. Cook has received investigator-initiated research funding and support as a Principal Investigator from the National Institutes of Health (the National Heart, Lung, and Blood Institute and the National Cancer Institute); has received research support from Roche Molecular Systems (Pleasanton, California); and served as a consultant for Bayer HealthCare (Morristown, New Jersey) in 2003.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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C. Bosetti, F. Bravi, E. Negri, and C. La Vecchia
Oral contraceptives and colorectal cancer risk: a systematic review and meta-analysis
Hum. Reprod. Update, September 1, 2009; 15(5): 489 - 498.
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