What is the effect of estrogens on a women's risk for breast cancer?

Updated: Dec 26, 2019
  • Author: Graham A Colditz, MD, DrPH; Chief Editor: Chandandeep Nagi, MD  more...
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Estradiol, considered the most biologically active endogenous estrogen, circulates in blood either unbound ("free") or bound to sex hormone binding globulin (SHBG) or albumin. Free or bioavailable (free plus albumin-bound) estradiol is thought to be readily available to breast tissue and thus may be more strongly related to risk than total estradiol. Postmenopausally, estrone is the source of most circulating estradiol, and estrone sulfate is the most abundant circulating estrogen. Both normal and malignant breast cells have sulfatase and aromatase activity, such that estrone and estrone sulfate could serve as a ready source of intracellular estradiol.

A pooled analysis of all prospective studies of endogenous estrogens and androgens in postmenopausal women combined data from 9 prospective studies that included 663 breast cancer cases and 1765 healthy controls. [33] Mean age of the participants ranged from 58-72 years, and the median time from blood collection to diagnosis ranged from 2-12 years. The risk of breast cancer increased with increasing estrogen levels. For example, the RRs (95% CI) for increasing quintile of estradiol level, all relative to the lowest quintile, were 1.4 (1.0-2.0), 1.2 (0.9-1.7), 1.8 (1.3-2.4), and 2.0 (1.5-2.7).

Other estrogens were similarly related to risk. The RRs for the top quintile, relative to the bottom quintile, were 2 or more for free estradiol, estrone, and estrone sulfate. The variation in RRs between studies was not statistically significant. These data and subsequent prospective studies provide strong evidence for a direct link between plasma estrogens and breast cancer risk in postmenopausal women. Furthermore, consistent with the hormonal origins of breast cancer, plasma levels of estradiol are directly related to risk of ER-positive breast tumors but not ER-negative tumors. [34]

Data on premenopausal estrogen levels and breast cancer risk are more limited, in large part because of the complexities related to sampling during the menstrual cycle. In a prospective analysis of samples from Nurses Health Study II, Eliassen and colleagues evaluated data on 197 cases of breast cancer diagnosed after blood collection and 394 matched controls. Women in the highest (versus the lowest) quartiles of follicular total and free estradiol levels had statistically significantly increased risks of breast cancer; the associations were stronger for invasive breast cancer and for estrogen and progesterone receptor-positive tumors. Luteal estradiol levels were not associated with breast cancer risk.

Higher levels of total and free testosterone and androstenedione in both menstrual cycle phases were associated with modest, non–statistically significant increases in overall risk of breast cancer and with stronger, statistically significant increases in risks of invasive and receptor-positive cancers. [35]

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