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.

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

References