Postmenopausal estrogens--opposed, unopposed, or none of the above.

Abstract

POSTMENOPAUSAL ESTROGENS CAN REDUCE MENOpausal symptoms, risk of osteoporotic fractures, and probably coronary heart disease. Adverse effects include venous thrombosis and cancers of the endometrium and breast. The increased risk of breast cancer is primarily among current or very recent estrogen users and is directly related to duration of use. Addition of progestin to estrogen largely mitigates the increased risk of endometrial cancer, and combination therapy (opposed estrogen) has become the standard hormonal regimen for women with a uterus. The impact of combined estrogen and progestin on risk of breast cancer has been controversial. Although protective effects analogous to those for endometrial cancer have been hypothesized for breast cancer, cyclical use of progestin to simulate normal menstrual cycles increases mitotic activity in the breast. In 2 early reports, addition of progestin to estrogen was reported to reduce breast cancer risk, but these studies were small and did not adequately control for confounding. Reliable data on effects of long-term use of combination therapy have only recently become available. These studies provide firm evidence that addition of progestin to estrogen does not reduce risk of breast cancer and suggest that risk is actually increased. Although data on type of hormone use were limited in the pooled analysis of epidemiological studies, among current or recent hormone users the risk of breast cancer was 53% higher for combination therapy and 34% higher for estrogen alone compared with no hormone use. A preliminary updated report from the prospective Nurses’ Health Study confirmed this trend: for each year of use, the risk of breast cancer increased by 9.0% for combined use and by 3.3% for estrogen alone. Similarly, an updated analysis in a Swedish cohort also found greater risks with combined therapy; for 6 or more years of current or recent use, the risk of breast cancer was increased by 70% for combined therapy but no increase was seen for estrogen alone. In this issue of THE JOURNAL, Schairer and colleagues use data from 46 000 women who participated in the Breast Cancer Detection Demonstration Project to estimate the association between menopausal hormone therapy and breast cancer risk. Based on 2082 incident breast cancer cases, the authors found that the estrogen-progestin regimens were associated with greater increases in breast cancer risk than estrogen alone. Importantly, the findings reinforce evidence that the increased risk is largely limited to current or recent users and is directly related to duration of use. For example, the excess risk increased by 8% (95% confidence interval [CI], 2%-16%) for each year of combined hormone use and by 1% (95% CI, 0.2%-3%) for each year of estrogenonly use. Thus, risk of breast cancer would be predicted to increase by approximately 80% after 10 years of use and by 160% after 20 years. This has major implications for riskbenefit considerations because the risks of hip fracture and coronary heart disease—primary targets of preventive use of hormone therapy—do not become large until a decade or more after menopause. However, the study by Schairer et al has several limitations. Although it is a cohort study, data on hormone replacement therapy were updated retrospectively for subjects with breast cancer who survived to the time of interview and for women who did not develop breast cancer. Thus, reporting bias cannot be excluded. Also, the number of women with longer-term use of combined therapy was modest, resulting in wide CIs. Despite these limitations, the results are in general agreement with previous work and, thus, add to concerns regarding combined therapy. Although the evidence that the addition of progestins to estrogens increases risk of breast cancer is strong, it is not proven. Thus, further data would be extremely valuable, particularly information that would refine precision regarding the magnitude of long-term risk on both incidence and mortality of breast cancer. The Women’s Health Initiative trial may add some information, but the addition of progestin