We found that current use of oral contraceptives was associated with breast cancer risk among women using the formulations commonly prescribed in the 1990’s. Our findings also suggest that current use of triphasic preparations containing levonorgestrel as the progestin is associated with higher risk than use of other formulations. Although we found no overall increase in risk with past use of oral contraceptives, an increased risk due to long-term past use of triphasic EE/LNG preparations cannot be excluded and requires further evaluation.
The Collaborative Group on Hormonal Factors in Breast Cancer (4
) has provided the most comprehensive summary of data on the association of oral contraceptives and breast cancer risk. This analysis pooled primary data from 53,297 cases and 100,239 controls, mainly from case-control studies conducted in the 1970’s and 1980’s. A modest increase in risk was observed among women who were currently using oral contraceptives, or who had stopped using them in the preceding 10 years (odds ratio = 1.24, 95 percent confidence interval 1.15–1.33). Consistent with prior meta-analyses (10
), there was no overall increase in risk of breast cancer 10 years or more after stopping use. A recent prospective study also observed an increased risk among current users at young age (12
), and a recent large case-control study confirmed the absence of an association with past use a decade or more after use has ceased (6
). Despite the massive data on earlier oral contraceptives preparations, the relation of newer oral contraceptives formulations to risk of breast cancer has not been established. Most oral contraceptive use in the Collaborative analysis was of older formulations (only 11% of cases first used oral contraceptives in 1975 or later); the Collaborative Group concluded “there is still insufficient evidence to comment reliably about the effects of specific types of estrogen or of progestogen.” (5
) A more recent case-control study conducted between 1990 and 1992, reported an elevation in risk associated with recent oral contraceptive use among women younger than 45 years of age(13
). A case-control study conducted on Long Island reported an elevation in risk of premenopausal breast cancer associated with ever use of hormonal birth control(14
Two recent large case-control studies have provided data on specific oral contraceptive formulations and breast cancer risk. In a population-based case-control study with 4,575 cases aged 35–64 years (the Women’s Contraceptive and Reproductive Experiences study) (6
), there was no apparent difference in risk between users of low and high estrogen dose preparations. The only type of progestin associated with an elevation in risk among current users was ethynodiol diacetate (odds ratio, 3.5; 95 percent confidence interval 1.1–10.7) based on 15 exposed case subjects; past use of this preparation was not associated with an elevation in risk. No increase in risk was observed for preparations containing levonorgestrel (odds ratio for current use, 0.9; 95 percent confidence interval 0.5–1.5). In an earlier population-based case-control study of 1,640 case subjects aged 20–44 years, Althuius et al. (15
) observed significant trends in risk associated with recent use of pills with higher estrogen doses. Recent use of levonorgestrel-containing formulations (odds ratio, 1.7; 95 percent confidence interval, 1.0–2.9) and norethindrone-containing formulations (odds ratio, 1.4; 95 percent confidence interval, 1.0–1.8) were marginally significantly associated with increased breast cancer risk. Odds ratios observed for the less commonly used preparations containing ethynodiol diacetate (odds ratio 1.9; 95 percent confidence interval, 0.9–4.2) and norethindrone acetate (odds ratio 1.9; 95 percent confidence interval, 0.9–3.8) were higher, but not statistically significant. In our study, a striking elevation in risk was present for triphasic levonorgestrel-containing preparations, and the two major brands with this formulation had equivalent relative risks. Neither monophasic preparations with levonorgestrel as the progestin, nor triphasic preparations with norethindrone as the progestin were associated with increased risk. This suggests that the dosage schedule associated with triphasic levonorgestrel use may confer risk, but that use of triphasic preparations with other progestins may not convey this risk. Interestingly, in a study of breast cancer survival among younger women, risk of death was increased if the most recent oral contraceptive used prior to diagnosis included levonorgestrel, but no association was seen for other progestin types (16
Concern regarding progestins in oral contraceptives has been strengthened by findings in postmenopausal women that the addition of progestin to estrogen greatly increases risk of breast cancer (17
). Breast cell proliferation assessed by thymidine labeling index is higher in the second half of the menstrual cycle, when progesterone levels are highest (20
). Analyses of proliferation markers in fine needle aspirate biopsies from healthy women confirm a positive correlation of proliferation with serum progesterone levels on the day of aspiration (22
). Among 26 women who underwent fine needle aspirate biopsies before and after 2 months of oral contraceptive use, proliferation was increased during oral contraceptive use (23
). In a randomized trial of 42 women who received one cycle of an oral contraceptive containing 30ug ethinyl estradiol and 150ug levonorgestrel, breast tissue proliferative activity in the first week was increased compared with 40 women undergoing a normal menstrual cycle (24
). Among 37 women using oral contraceptives containing levonorgestrel, breast epithelial cell proliferation was significantly positively correlated (Spearman r = 0.43) with serum concentrations of levonorgestrel (23
). In animal assays of progestin activity, levonorgestrel is substantially more potent than the other commonly used progestins (25
); however, the doses used in oral contraceptives are lower in an attempt to make the progestin action equipotent (26
). Levonorgestrel is also the most androgenic of the currently used progestins (27
); a positive relation between serum androgens and breast cancer risk was observed in a pooled analysis of data from nested case-control studies (28
). In addition to the type and dose of progestin, the pattern or temporal component, whether cyclical or continuous, may also influence breast cancer risk.
Our study has several advantages compared with previous investigations of this issue. Its prospective design, with a high follow-up rate, limits the potential for recall bias or selection bias to influence the relative risks observed. In addition, we documented the validity of our assessment in this population of lifetime oral contraceptive use at baseline in 1989 (29
). Furthermore, it seems reasonable to expect that contemporary reporting of the current oral contraceptive brand during follow-up will be even more accurate than the report of past brand use at baseline, as assessed in our validation study.
We also had extensive, prospectively collected, information on other breast cancer risk factors that could confound the relation between oral contraceptive use and breast cancer. Current oral contraceptive users had an increased prevalence of several breast cancer risk factors (nulliparity, limited breast feeding, alcohol consumption, and low BMI) that might modestly confound associations with current use. However, control of these and other factors in multivariate models resulted in very little change between the age-adjusted and multivariate point estimates, suggesting little potential for residual confounding by the covariates we measured.
The major limitation of our study is the relatively small number of cases that occurred among women currently using oral contraceptives because breast cancer incidence rates are low at the ages that most women typically use oral contraceptives. The attributable risk associated with current use was less than two percent, emphasizing that current oral contraceptive use is not a major cause of breast cancer. Even larger prospective studies than ours may be needed to determine precisely the relation between different oral contraceptive formulations and health risks and benefits occurring during actual use of these preparations. Because an association specifically with triphasic preparations containing levonorgestrel was not a prior hypothesis, replication of our findings is desirable.
In summary, we confirmed that the modest increase in risk associated with current use of the oral contraceptives also applies to the formulations in contemporary use. In our study, use of triphasic preparations with levonorgestrel as the progestin was associated with particularly high risk, and these formulations accounted for nearly all of the excess risk.