Local release of biologically active estrogens from conjugates and their further metabolism prolong the effect of estrogen on peripheral tissues. Some active estrogens are also formed from circulating estrone sulfate or 17β-estradiol sulfate as the result of de-conjugation by sulfatase. The aromatization of androgens into estrogens is the most important source of estrogens in the breast tissue. However, only a few studies evaluated breast tissue estrogen levels and their involvement in breast carcinogenesis.Įstrogen synthesis takes place primarily in the ovary (especially membrana granulose and luteinized granulosa cells) in premenopausal women and primarily in peripheral tissues in postmenopausal women. Breast tissue acting as an intracrine organ with local estrogen production highlights the potential importance of this intracrine function. Moreover, the ratios of the major estrogen metabolites also differ between the circulation and the breast tissue. Studies in postmenopausal women show that levels of estradiol in uterine endometrium and breast cancer tissues can be 10- to 50-fold higher than those levels in blood. Active estrogens in the breast are formed as the result of the local estrogen synthesis (aromatization) and the uptake of estrogen sulfates from circulation and their subsequent desulfation. The blood estrogen levels might not reflect the actual levels of estrogens and their metabolites in peripheral tissues, including the breast, due to the local metabolism of estrogens. However, tissue levels of endogenous hormones might be a more relevant measure of exposure of the breast tissue to their hormonal influences. Studies relating endogenous hormones to breast health-related outcomes measured hormone levels in urine and/or serum. The hormonal microenvironment surrounding the breast tissue may play an important role in the breast carcinogenesis. In addition, estrogen stimulates prolactin secretion and production of local growth promoters (growth factors), implicated in cancer promotion. In contrast, the products of 2-hydroxylation inhibit tumorigenesis. Some metabolites formed as the result of 4- and 16-hydroxylation of estrogens have genotoxic properties. Importance of accumulated exposure to hormones is supported by the increase in breast cancer risk with early menarche, late first full-term pregnancy, and late menopause. Those effects accumulate with increasing cumulative exposure to estrogens. Estradiol and, to lesser degree, other estrogens, increase proliferation of breast epithelium and stroma and, consequently, increase the chances of mutation in rapidly proliferating epithelium. Both direct and indirect mechanisms support estrogen’s contribution to the initiation and promotion of breast cancer. Numerous studies have linked the use of exogenous hormones to the risk of breast, ovarian, and, possibly, prostate cancer. The role of estrogens in hormonal carcinogenesis has been investigated over the last few decades in cell culture, animal models, and humans.
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