By the mid-1970s, almost 30 million prescriptions for postmenopausal hormones were being filled annually in the United States. A challenge in studying the relationship between postmenopausal hormone use and breast cancer is the substantial variation in formulations and patterns of use that has occurred over time. By the time sufficient use of one type of hormone has occurred to allow a detailed epidemiologic evaluation, new formulations are already being introduced.

The possible relation between postmenopausal estrogen use and risk of breast cancer has been investigated in more than three dozen epidemiologic studies over the past 20 years. Most of these studies have been summarized in six meta-analyses and a large pooled analysis. A summary of these findings, plus a more detailed discussion of several of the most important and most recent studies, is provided in the following subsections on postmenopausal hormones.

Any Use
All meta-analyses have concluded that, overall, women who have ever used postmenopausal estrogens have little or no increase in risk of breast cancer compared with women who have never used this therapy. Depending on the inclusion criteria for the meta-analyses, the relative risk estimates across studies range from 1.01 to 1.07. The relative risk observed in the pooled analysis was 1.14. As with oral contraceptive use, however, “ever use” is a poor measure of exposure, because it fails to distinguish between short and long duration and recent and past users.

Duration of Use
In the meta-analyses, significant increases in risk of 30% to 45% with more than 5 years of use have been observed. Results of several large case control studies have become available since the publication of the meta-analyses. A significant positive association between postmenopausal hormone use and breast cancer risk was not seen, even among long-term users, but the 95% CIs were broad enough to encompass the elevated RRs observed in the meta-analyses. One potential difficulty in interpreting the results of case control studies is the impact of nonparticipation, particularly among the controls. In the general population, estrogen users tend to have a somewhat higher socioeconomic status on average, and typically, better-educated individuals are more likely to participate as controls in health-related research studies.

In updated results from the Nurses’ Health Study, which included 1,935 breast cancer cases, an excess risk of breast cancer was limited to women with current or very recent use of postmenopausal hormones. The risk increased with increasing duration of use and was statistically significant among current users of 5 or more years duration (e.g., compared with those who never used postmenopausal hormones, relative risk for those with 10 or more years of use was 1.47; 95% confidence interval, 1.22 to 1.76).

Recency of Use
Data on recency of use have been sparse, because many studies did not distinguish current from past users. One meta-analysis calculated a relative risk for current use of 1.63 for women with natural menopause and 1.48 for women with surgical menopause. In a second, the summary relative risk was 1.40 (95% confidence interval, 1.20 to 1.63) for current users compared with those who had never taken menopausal hormones. In the report from the Nurses’ Health Study cohort, an excess risk of breast cancer was limited to women with current or very recent use of postmenopausal hormones. In the Breast Cancer Detection Demonstration Project cohort (BCDDP), a positive association with invasive breast cancer was noted among current users of 5 to 15 or more years’ duration that varied little by duration of use (relative risks ranged from 1.0 to 1.4).

These relationships were evaluated in considerable detail in the pooled analysis that combined results of 51 epidemiologic studies. Importantly, women whose age at menopause was uncertain (e.g., women with simple hysterectomies) were excluded from these analyses, because inadequate accounting for age at menopause in the analysis can lead to substantial attenuation of the observed relationships between postmenopausal hormone use and breast cancer risk. The investigators observed a statistically significant association between current or recent use of postmenopausal hormones and risk of breast cancer; the positive association was strongest among those with the longest duration of use. For example, among women who used postmenopausal hormones within the previous 5 years (compared with those who never used postmenopausal hormones), the relative risks for duration of use were 1.08 for 1 to 4 years of use, 1.31 for 5 to 9 years, 1.24 for 10 to 14 years, and 1.56 for 15 or more years of use. No significant increase in breast cancer risk was noted for women who had quit using postmenopausal hormones 5 or more years in the past, regardless of the duration of use.

Some investigators have suggested that the increased risk observed in many of the studies is an artifact of increased surveillance for breast cancer among women taking hormones. Consistent with such a possibility, a higher relative risk hasbeen found to be associated with in situ disease than with invasive disease. In the studies with this finding, however, a significant positive (although weaker) association was noted when only invasive breast cancer cases were considered. Also, in the Nurses’ Health Study, mammography rates were uniformly high, exceeding 90% even among women who never used hormones. Moreover, past users and current users of short duration were not observed to have an elevated risk, despite higher mammography rates than among those who had never used postmenopausal hormones. Finally, an elevated death rate from breast cancer was observed among current users who had used hormones for 10 or more years at the time of diagnosis. This latter analysis provides further evidence that the association cannot be explained simply as an artifact of screening.