Since oral contraceptives were first introduced in the 1960s, they have been used by many millions of women. In 1988, more than 10.7 million U.S. women were current oral contraceptive users.133 Most combined oral contraceptives contain ethinyl estradiol (or mestranol, which is metabolized to ethinyl estradiol) and a progestin. The estrogen dose in oral contraceptives has ranged from 100 or more µg in 1960 to 20 to 30 µg, the doses most commonly used today; during this same time period, at least nine different progestins have been used. Patterns of use also have changed considerably over time, with both increasing durations of use and a trend toward earlier age at first use. More than 50 epidemiologic studies have evaluated the relationship between oral contraceptive use and breast cancer risk.
Any Use of Oral Contraceptives
In several meta-analyses, reviews, and a large pooled analysis studying women who had “ever used” oral contraceptives, use of oral contraceptives was not found to be associated with breast cancer risk. Although this finding is reassuring, defining oral contraceptive use this way is misleading, because women in the “ever use” category are a mixture of women with long-term and short-term use, so any true relationship with one particular aspect of oral contraceptive use may be missed.
Duration of Use
Most studies have observed no significant increase in breast cancer risk with long durations of use of oral contraceptives. Individual data from 54 epidemiologic studies were collected and analyzed centrally. In this large pooled analysis, data from 53,297 women with breast cancer and 100,239 women without breast cancer were evaluated, and no overall relationship was observed between duration of use and risk of breast cancer. These analyses, in which women of all ages were combined, provide considerable evidence against any material adverse effect of long-term oral contraceptive use overall.
Similar results were generally observed when long-term use was evaluated among either postmenopausal women or women older than 45 years of age. Findings have not been quite as consistent or reassuring, however, in analyses of long-term use in young women. Summary relative risks for long duration of use in young women were 1.5 in one meta-analysis and 1.4 in another. The greatest increase tended to be observed in the youngest women, generally women younger than 35 years of age.
Several cohort studies also have evaluated these relationships. In the Oxford Family Planning Association study, no association was observed with increasing duration of use among women 25 to 44 years, although only 14 cases were younger than 35 years. In the Royal College of General Practitioners cohort, a substantial increased risk was observed among women aged 30 to 34 years. These results must be interpreted cautiously, however, because few cases of breast cancer occurred among women aged 30 to 34 years, the follow-up rate in this cohort was low, and the incidence among the youngest women who did not use oral contraceptives was considerably lower than the age-specific national breast cancer rates. In the Nurses’ Health Study cohort, no positive association was noted among women older than 35 years of age. Both the Oxford study and the Nurses’ Health Study have provided considerable reassurance that no substantial increase in risk occurs among women older than 35 years who used oral contraceptives for extended durations. However, neither of these cohorts included a sufficient number of women younger than 35 years to evaluate the risk in this specific group, and thus further study is needed.
In the large pooled analysis, current and recent users of oral contraceptives were found to have an increased risk of breast cancer (relative risk for current users versus those who never used oral contraceptives was 1.24; 95% confidence interval, 1.15 to 1.33). This increased risk subsided within 10 years of stopping oral contraceptive use (relative risk by years since stopping use versus no use: 1 to 4 years, 1.16; 5 to 9 years, 1.07; 10 to 14 years, 0.98; more than 15 years, 1.03). Importantly, the authors observed a modestlyincreased risk of breast cancer only among current and recent oral contraceptive users, and did not observe any independent effect of long duration of use on risk of breast cancer, even among very young women. Thus, the increased risk of breast cancer observed among young, long-term oral contraceptive users in past individual studies appears to be due primarily to recency of oral contraceptive use rather than to duration of use. These data suggest that oral contraceptives may act as late-stage promoters.
Use before a First Full-Term Pregnancy or at an Early Age
Because any influence of oral contraceptives on the breast has been hypothesized to be greatest before the cellular differentiation that occurs with a full-term pregnancy, a number of investigators have evaluated the effect of oral contraceptive use before a first full-term pregnancy. In both meta-analyses, the summary relative risk indicated a modest increase in risk with long-term use. In several studies not included in these meta-analyses, no increase in risk was observed. In the pooled analysis, a significant trend of increasing risk with first use before age 20 years was observed. Among women diagnosed at ages 30 to 34 years, the relative risk associated with recent oral contraceptive use was 1.54 if use began before age 20 years and 1.13 if use began at age 20 years or older.