In this prospective study of 56,733 postmenopausal women, ever-use of menopausal hormone therapy was associated with a reduced risk of colorectal cancer. We observed a statistically significant 17 percent decreased risk of colorectal cancer among ever-users of unopposed estrogen compared with never users. Among these unopposed estrogen users, we observed the largest risk reduction among current users and among users of ten or more years duration. In contrast, we found a nonsignificant 22 percent reduction in colorectal cancer risk among users of estrogen plus progestin, with sequential regimen users having a larger reduction in risk at 36 percent compared to continuous users at 25 percent. Among estrogen plus progestin users, women who had stopped hormone therapy for five or more years and women who had used estrogen plus progestin for medium duration of two to five years had the largest reduction in colorectal cancer risk. An overall dose-response pattern was not evident for duration of use among estrogen plus progestin users. For estrogen with unknown progestin users, a null result was found and it is unclear how this may affect our above findings. Despite the recent decrease in use of all menopausal hormones, these results suggest an important protective effect of all hormone formulations, especially estrogen plus progestin, for the many women who continue to need and use menopausal hormone therapy.
Several biologic mechanisms, via secondary bile acids, insulin-like growth factors, and estrogen and progesterone receptors, have been postulated for the protective effect of menopausal hormone therapy on risk of colorectal cancer. A comprehensive overview of the biological aspects of hormones on colorectal cancer was recently published by Newcomb and colleagues (43
). In brief, the original biologic mechanism was proposed in 1980 when McMichael and Potter suggested that increased concentrations of bile acids within the colon may enhance colon carcinogenesis and that exogenous estrogens and progestins may reduce bile acid production (1
). More recently, epidemiologic research, although inconsistent, suggests a relation between serum insulin-like growth factor (IGF) and IGF binding protein-3 ( IGFBP-3) levels and colorectal cancer risk. Studies suggest that use of menopausal hormone therapy decreases both IGF and IGFBP-3 levels (44
). In addition, estrogen receptors, including ERα and ERβ, and progesterone receptors have been identified in colon epithelial cells (46
). Research indicates that decreasing levels of ERβ coincide with the loss of differentiation of malignant colon calls, supporting a protective mechanism of ERβ (49
). Age-associated CpG island methylation of the ER gene is also evident in colorectal tumors, further suggesting a protective effect of estrogen receptors (51
Menopausal hormone therapy was introduced nearly 70 years ago, with widespread use of unopposed estrogens. The 1970s showed a marked decreased in prescriptions due to an observed increase in endometrial cancer among hormone users, an outcome that could be mitigated by the addition of progestin (52
). As such, estrogen plus progestin use became common for women with an intact uterus, but it was not until 1995 when estrogen and progestin were introduced in the same pill. Therefore, only a limited number of observational studies exist with the ability to investigate colorectal cancer risk with specific menopausal hormone formulations.
Our findings of a general protective effect of hormones, regardless of formulation, on the risk of colorectal cancer are consistent with results of the three previous case-control studies in which separate risk estimates by type of hormone formulation and duration and/or recency were provided. These studies each found a statistically significant 15 to 46 percent reduction in the risk of colon or colorectal cancer among unopposed estrogen users and a 25 to 46 percent reduction in the risk of colon or colorectal cancer among estrogen plus progestin users (15
). The greatest reduction in colorectal cancer risk varied according to formulation between two studies, while the third study found a 46 percent reduction in colon cancer risk among both estrogen and estrogen plus progestin users. One of the two studies that investigated duration found the most pronounced risk reduction among five years or more of estrogen use (OR, 0.74; 95% CI, 0.59-0.92), similar to our results, and the other found users of unopposed estrogen of less than five years duration (OR, 0.58; 95% CI, 0.41-0.82) had the greatest risk reduction (30
). These two studies also reported the greatest reduction in risk of colorectal cancer among estrogen plus progestin users of shorter duration, defined as less than five years, at 28 to 40 percent. The only study in which recency of hormone use by formulation was assessed found the greatest reduction in risk among current users of estrogen at 45 percent and among former users of estrogen plus progestin at 44 percent (30
). None of these studies examined regimen of estrogen plus progestin use against which to compare our results.
Randomized clinical trial data from the Women's Health Initiative (WHI) indicated a decreased risk of colorectal cancer among estrogen plus progestin users, and no difference in the rates of colorectal cancer among estrogen alone users (37
). The WHI trial of estrogen plus progestin enrolled 16,608 postmenopausal women and had a mean follow-up time of 5.6 years. This trial found a 39 percent decreased risk of colorectal cancer among women taking continuous combined estrogen plus progestin (0.625 mg/day conjugated equine estrogen plus 2.5 mg/day medroxyprogesterone acetate) versus placebo (HR, 0.61; 95% CI, 0.42-0.87) (37
). The WHI trial of unopposed estrogen enrolled 10,739 postmenopausal women with a hysterectomy and had a mean follow-up time of 6.8 years. This trial concluded there was no significant difference in the rates of colorectal cancer among women taking estrogen (0.625 mg/day conjugated equine estrogen) versus placebo (HR, 1.08; 95% CI, 0.63-1.86) (38
). Two observational studies also found a nonsignificant increased risk of colorectal cancer associated with unopposed estrogen menopausal hormone therapy use (22
). While our findings are similar to those of the WHI for estrogen plus progestin users, direct comparison of clinical trial data with that of observational data in this context is limited.
Although it is tempting to focus primarily on the WHI results since they originate in a randomized trial, it is important to note that the WHI was designed as a prevention study in older women, meaning it has unique design features that distinguish it from observational studies such as the BCDDP. For example, in the WHI estrogen plus progestin trial, two-thirds of the women were age 60 or older at randomization and roughly 75 percent had never used hormone therapy before being randomly assigned to placebo or estrogen plus progestin (37
). In contrast, in the BCDDP, nearly two-thirds of participants had already used hormone therapy by age 60 and most of that use would have been in response to menopausal symptoms. Timing and indication for exposure was distinctly different in the BCDDP which, in turn, means the two studies were designed to investigate different aspects of potential risks of hormone therapy use. Despite these differences in study population characteristics, we saw somewhat similar results for estrogen plus progestin in the BCDDP as WHI investigators observed in their study, but the null finding for unopposed estrogen in WHI was contrary to our finding of a reduced risk of recent long term use of unopposed estrogen. Perhaps a major difference between WHI and BCDDP that could help explain this discrepancy is the relatively short duration of hormone therapy in WHI, making it impossible to observe effects of long term use in the way we could in BCDDP.
Several limitations are present in our study. The risk estimates generated for estrogen plus progestin users, and most notably among sequential and continuous regimen users, are based on relatively small numbers of women who developed colorectal cancer. As a result, our relative risk estimates may be unreliable or imprecise for assessing the effects of estrogen plus progestin regimens. Hormone therapy exposure was a self-reported measure in our study and, therefore, may be subject to error. While hormone therapy use was not validated in our study, others have reported good reliability for self report of hormone therapy exposures (53
). We adjusted for several potential confounders, however the possibility remains for residual confounding by imperfectly measured covariates and for confounding by variables not considered or measured.
In summary, our study found that ever use of any menopausal hormone therapy was associated with a reduced risk of colorectal cancer. In this study, estrogen plus progestin use, especially sequential regimen use, was associated with the overall largest reduction of colorectal cancer risk. These findings expand upon estrogen plus progestin regimens that are inversely associated with colorectal cancer risk.