levels of the 16α-hydroxyestrone metabolite and lower levels of the 2-OH metabolite of estrone. These results need to be replicated in larger studies and the effect of oral contraceptive use on the levels of these metabolites explored. An alternative to the existing radiometric assay is required to evaluate these estrogen metabolites in epidemiological studies using blood or urine samples as the biological medium. Furthermore, it has been stated that the 16α-hydroxyestrone metabolite can form permanent, covalent adducts with the E2 receptor, turning on the receptor indefinitely. This metabolite is also said to form adducts with albumin and hemoglobin. Because a variety of assays for adduct formation are available, additional clarification of these issues would be useful for future epidemiological research. For example, levels of estrogen-metabolite adduct formation in breast tumor and normal tissue from oral contraceptive-using and non-oral contraceptive-using patients could provide suggestive information on the carcinogenic potential of these metabolites.

Progestins

Further studies are needed of the biological effects of the progestin component of oral contraceptives and its interaction with the estrogen component. This effort should be tackled from an interdisciplinary perspective using more combined, in vivo/in vitro studies of endogenous and exogenous hormone effects on human breast epithelial cells. Through use of the thymidine labeling index (TLI), epithelial proliferation of normal breast lobules has been shown to change over the menstrual cycle (Anderson et al., 1990). Proliferation is increased in the second half of the monthly cycle—when progesterone levels are elevated. Furthermore, breast epithelium from young women was shown to be more responsive than that of older women. Nulliparous oral contraceptive users had a significantly greater increase in TLI than their parous counterparts during the last week of their “cycle” (i.e., the equivalent of the late secretory phase of a normal cycle). High-dose estrogen oral contraceptives may cause more proliferation than oral contraceptives with lower estrogen dosages, but there were no significant differences among progestins. This avenue of investigation needs to be extended more broadly in the future to further document the differences between parous and nulliparous women, and to include more data on a variety of oral contraceptive formulations. Such studies should be designed to gather additional data such as blood and tissue levels of endogenous or exogenous hormones (at the time of diagnostic biopsy) that are critical to the interpretation of these findings.



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