Do Estrogen and Progestin Increase Colon Cancer Risk?

Source: Chlebowski RT, et al; Women’s Health Initiative Investigators. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004;350:991-1004.

Abstract: Although the Women’s Health Initiative (WHI) trial of estrogen plus progestin in postmenopausal women identified more overall health risks than benefits among women in the hormone group, the use of estrogen plus progestin was associated with a significant decrease in the risk of colorectal cancer. The researchers analyzed features of the colorectal cancers that developed and their relation to the characteristics of the participants. In the WHI trial, 16,608 postmenopausal women who were 50-79 years of age and had an intact uterus were randomly assigned to a combination of conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo. The main outcome measures were the incidence, stages, and types of colorectal cancer, as determined by blinded central adjudication. There were 43 invasive colorectal cancers in the hormone group and 72 in the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.38-0.81; P = 0.003). The invasive colorectal cancers in the hormone group were similar in histologic features and grade to those in the placebo group but with a greater number of positive lymph nodes (mean ± SD, 3.2 ± 4.1 vs. 0.8 ± 1.7; P = 0.002) and were more advanced (regional or metastatic disease, 76.2% vs. 48.5%; P = 0.004). In exploratory analyses, women in the hormone group with antecedent vaginal bleeding had colorectal cancers with a greater number of positive nodes than women in the hormone group who did not have vaginal bleeding (3.8 ± 4.3 vs. 0.7 ± 1.5 nodes, P = 0.006). Relatively short-term use of estrogen plus progestin was associated with a decreased risk of colorectal cancer. However, colorectal cancers in women who took estrogen plus progestin were diagnosed at a more advanced stage than those in women who took placebo.

Comments by Dónal P. O’Mathúna, PhD

Colorectal cancer is the second leading cause of death from cancer in the United States. Studies have failed to provide evidence of any intervention reducing the risk of colorectal cancer. A variety of interventions have been tested for their efficacy in inhibiting the development or recurrence of colorectal polyps, which can be an early sign of colorectal cancer. Hopes that high-fiber diets would be of benefit here were set back by two studies reported in 2000 that failed to show benefit.1 However, calcium, celecoxib, aspirin, and sulindac have been shown to inhibit the development or recurrence of colorectal polyps.

Observational studies of women taking postmenopausal hormone therapy have suggested a reduced incidence of colorectal cancer. These findings have not been confirmed in a randomized controlled trial. The Women’s Health Initiative (WHI) randomized trial compared the outcomes of postmenopausal women taking estrogen plus progestin to those taking placebo. The highly publicized reports in 2002 noted the higher risk to benefit ratio with hormone therapy.2 However, the trial also found that taking estrogen plus progesterone was associated with a significantly lower risk of colorectal cancer. The present report examines in further detail both this association and the features of the colorectal cancers that occurred during the WHI trial.

As noted in the abstract, significantly fewer cases of colorectal cancer occurred in the hormone group compared to placebo. However, few of these cases were of rectal cancer (eight taking hormones compared to 11 receiving placebo) making the results more clearly applicable to colon cancer (35 cases in the hormone group and 61 with placebo).

Of concern, though, was how the cancers discovered in the hormone group were more advanced and more likely to have lymph-node involvement, despite being similar in histological features and grade. The hormone group also contained more women with metastatic colorectal cancers. The reasons for these differences are unknown. The researchers noted that women in the hormone group more commonly experienced vaginal bleeding than those in the placebo group. This may have led these women to delay seeking medical attention since the early symptoms of colorectal cancer are often attributed to other, less serious causes. This suggests that women taking postmenopausal hormone therapy might benefit from routine bowel screening, despite the fact that their risk of colorectal cancer is reduced by the therapy.

A limitation with this study (as with the whole WHI study) is that 42% of the hormone group stopped their medication for some period during the study and 38% of those taking placebo similarly stopped their tablets. Also, women in both groups reported off-protocol use of postmenopausal hormones: 6% of those taking the study intervention and 10% of the placebo group.

This report reveals the importance of analyzing secondary results carefully and thoroughly before drawing firm conclusions. The initial finding of lower incidence of colorectal cancer in those taking postmenopausal hormone therapy must be balanced against the more advanced nature of the cancers that are discovered. For this reason, current data do not support the use of postmenopausal hormone therapy to reduce the risk of colorectal cancer.

Dr. O’Mathúna, Lecturer , School of Nursing, Dublin City University, Ireland, is on the Editorial Advisory Board of Alternative Therapies in Women’s Health.


1. Byers T. Diet, colorectal adenomas, and colorectal cancer. N Engl J Med 2000;342:1206-1207.

2. Rossouw JE, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333.