The reason for the probable lack of utility of this method is that, in developed countries, it is unlikely that any influence on breast cancer rates would be large and clear enough to be distinguished from other influences. This indistinguishability is in contrast to the situation of pulmonary embolism in young women, for which the effect of oral contraceptives was detected. In that instance, the risk was fairly large, immediate, and led to sudden death, and the underlying rates were low. Cancer of the endometrium was another such case: there, the widespread use of replacement hormones was age-specific and increased rapidly in a short time.
Opportunities exist to study women who have been heavily exposed to hormones. Some are endogenously exposed (e.g., women with polycystic ovaries), and others are exogenously exposed (e.g., women with Turner 's syndrome who have been treated with steroid hormones, girls given estrogens to stop their long bone growth, or women given diethylstilbestrol (DES) during pregnancy). In the case of DES, both the exposed women and their progeny, male and female, can be followed. Such studies can employ traditional epidemiological designs, comparing exposed subjects with nonexposed subjects for subsequent risk of breast cancer. Controls can be internal (e.g., pregnant women who were not exposed to DES from the same time period and hospital as those who were exposed), or external, which is often a statistical estimate based on the breast cancer experience of a large population. In these heavily exposed populations, investigators can evaluate the direct effects of particular hormones on breast cancer risk, but the issue of inferring that these results pertain to oral contraceptive use remains.
Are there differences in susceptibility among oral contraceptive users who do and do not get breast cancer? Or, alternatively, among women with a high risk for breast cancer, does oral contraceptive use further increase that risk?
These questions arise from an inference that seems logical, given the existing data. Breast cancer occurrence before the age of 40 or even 45 is a rare event. Only 15 percent of all breast cancers occur before age 45. Let us suppose that there is a small increase in the