Andrey Nailor, M.D.·Published 6 June 2008·8 min read
Key points
By the mid-1970s, almost 30 million prescriptions for postmenopausal hormones were being filled annually in the United States.
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.
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.
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.
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).
Written and revised by
Andrey Nailor, M.D.
Our doctors write and review articles for accuracy and keep them up to date.
health.am provides general information, not medical advice. Always consult a qualified health professional about your own health.
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.{pagebreak}
Type, Dosage, and Mode of Delivery of Estrogen Limited data are available regarding the effects of dosage or type of estrogen on breast cancer risk. Again, the best data come from the pooled analysis. No significant differences in relative risks were observed according to either the type of estrogen used (conjugated estrogen versus other) or estrogen dose (less than 0.625 mg versus 1.25 mg or more), although some modest differences in estimates suggested that further evaluation is warranted.
Although the effect of estrogen use on breast cancer risk could be reasonably hypothesized to vary by mode of estrogen delivery (e.g., patch estrogen, by avoiding the first-pass effect in the liver, does not increase sex hormone-binding globulin to the extent that oral preparations do), insufficient data are available to evaluate these potential differences.
Risk According to Breast Cancer Risk Factor Profile The risk associated with postmenopausal hormone use was assessed in a number of specific subgroups in the pooled analysis. Risk did not appear to vary according to reproductive history, alcohol or smoking history, or family history of breast cancer. However, the relative risks associated with 5 or more years of postmenopausal hormone use were highest among the leanest women (p for heterogeneity = .001); this interaction has been consistently observed.
Use of Estrogen Plus Progestin The addition of a progestin to estrogen regimens has become increasingly common, because it minimizes or eliminates the increased risk of endometrial hyperplasia and cancer associated with the use of unopposed estrogens. Inthe United States, by the mid-1980s, almost 30% of postmenopausal hormone prescriptions included a prescription for progestin. The impact, if any, of an added progestin on the risk of breast cancer was first evaluated in 1983 and remains controversial.
{embed="ref/stat-menu-br-cancer"}
Two of the first studies to assess this relationship suggested that the addition of a progestin could decrease breast cancer risk. These studies were small, however, and potentially important confounders (e.g., age, parity) were not accounted for in the analyses. Since that time, several additional studies have assessed this relationship, and together these studies indicate that a protective effect of the dosages typically used in postmenopausal hormone therapy can be ruled out. Only two prospective studies have reported on this relationship, and their findings were similar. Bergkvist et al. observed a relative risk of 4.4 (95% confidence interval, 0.9 to 22.4) among women who used estrogen plus progestin for 6 or more years compared with those who had never used progestin.
Women using hormones for shorter duration did not appear at an increased risk, but CIs again were wide and did not exclude either a modest increase or decrease in risk. In findings from the Nurses' Health Study in which, among women using progestins, approximately two-thirds used 10 mg of medroxyprogesterone for 14 or fewer days per month, the relative risk associated with current use of estrogen plus progestin versus no previous use was 1.4 (95% confidence interval, 1.2 to 1.7). In the pooled analysis, data on postmenopausal hormone formulation were available from only 39% of women, and only 12% of these reported using estrogen plus a progestin. The relative risk associated with 5 or more years of recent use, relative to no previous use, was 1.53. The comparable relative risk for estrogen use alone was 1.34. Data from the Nurses' Health Study indicate that the addition of a progestin appears to increase risk beyond that for estrogen use alone. Because widespread use of estrogen plus progestin is so recent, few data are available to evaluate the effect of different formulations, dosages, or schedules of use on risk of breast cancer.
Summary of Postmenopausal Hormone Use and Breast Cancer Risk Although some aspects of the relationship between postmenopausal hormone use and breast cancer risk remain unresolved, several areas of agreement have emerged. The finding of no increase in risk of users compared with those who never used postmenopausal hormones is consistent and reassuring. Much of that observation, however, reflects the experience among short-term users and hormone use in the past. Among these groups, most studies are in agreement that little if any excess risk is present.
Overall, the findings also indicate an increased risk in two important subgroups of users: users of long duration and current users. In general, users of long duration are more likely to be current users, so in many studies these two groups overlap substantially. From a biological perspective, these are the groups one would most expect to demonstrate a relation with breast cancer risk, because exogenous estrogens appear to act at a very late stage, perhaps stimulating growth of tumors that are already present but undiagnosed. Although limited data exist, the increase in breast cancer risk associated with the use of estrogen plus progestin may be greater than that for use of estrogen alone; this is an important issue that needs further evaluation.
Walter C. Willett, Beverly Rockhill, Susan E. Hankinson, David J. Hunter and Graham A. Colditz
W. C. Willett: Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts B. Rockhill: Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts S. E. Hankinson: Departments of Medicine and Epidemiology, Harvard Medical School and Harvard School of Public Health, Boston Massachusetts D. J. Hunter: Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachussetts G. A. Colditz: Department of Medicine, Harvard Medical School, Boston, Massachussetts
News
News
News
