Estrogen Metabolites
A woman’s pattern of estrogen metabolism has also been hypothesized to influence her breast cancer risk. Estradiol and estrone can be metabolized through one of two mutually exclusive pathways, the 16a and 2-hydroxy pathways. Products of these two pathways have markedly different biological properties, and opposing hypotheses have been proposed concerning their influence on risk.

The epidemiologic studies that evaluated associations between levels of estrogen metabolites and breast cancer risk have been small (the largest had 42 cases), and results are inconsistent. In the only study of premenopausal women (with 19 cases), the 2-hydroxyestrone to 16a-hydroxyestrone ratio was not associated with breast cancer risk, although in postmenopausal women an inverse relation was observed. In another study of perimenopausal and postmenopausal women, percent oxidation by 16a-hydroxylation was significantly greater and oxidation by 2-hydroxylation nonsignificantly greater in cases than in controls. Similar results were observed in several, but not all, other case control studies of postmenopausal women. These associations have not been evaluated in prospective studies. Overall, limited data exist to address these hypotheses, and no conclusions can yet be drawn.

Androgens
Androgens have been hypothesized to increase breast cancer risk either directly, by increasing the growth and proliferation of breast cancer cells, or indirectly, by their conversion to estrogen. Administration of dehydroepiandrosterone (DHEA) to rodents can decrease the risk of spontaneous and chemically induced cancers. In humans, DHEA may act like an antiestrogen premenopausally but an estrogen postmenopausally in stimulating cell growth, in part because of the estrogenic effect of its metabolite, 5-androstene-3b,17b-diol, which also can bind to the estrogen receptor.

In postmenopausal women, higher testosterone levels have been positively associated with breast cancer in most, but not all, studies. The association has tended to be attenuated, however, after plasma estrogen levels are taken into account. In the largest prospective study, the modest, nonsignificant association with testosterone level was substantially attenuated after the investigators controlled for estrogen levels. Postmenopausal dehydroepiandrosulfate (DHEAS) levels were generally associated with either significant or nonsignificant increases in breast cancer risk in previous prospective studies. In three previous prospective assessments of DHEA, significant positive associations were observed in two,106,107 whereas no association was observed in the third.81 In the only previous study of 5-androstene-3b,17b-diol among postmenopausal women, women in the top quartile of levels had a significant threefold higher risk of breast cancer; women in the highest quartile for both DHEA and 5-androstene-3b,17b-diol (compared with the lowest for both) had a sixfold higher risk.

Overall, higher levels of testosterone may have a modest, but probably indirect, association with postmenopausal breast cancer through its conversion to estradiol. Most studies have noted at least a modest positive association with DHEA and DHEAS; further delineation of the exact nature of these associations is required.

Among premenopausal women, no association was found between testosterone level and breast cancer risk in two prospective studies. Strong positive associations have been noted in several case control studies, with RRs ranging from 3.4 to 10.2 for women in the top category of plasma testosterone. Results from studies addressing androstenedione levels and breast cancer are inconsistent. The only prospective study of DHEA and DHEAS levels and breast cancer in premenopausal women had just 15 cases. Again, the data are too limited to draw any firm conclusions relating androgen levels to breast cancer risk in premenopausal women.