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Transdermal estrogen therapy and the risk of breast cancer: a clinical appraisal
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
The metabolism of estrogen follows pathways that result in either estrogenic or non-estrogenic metabolites. Metabolites such as 16α-hydroxyestrone (16a-OHE1) are powerful estrogen agonists; 2-hydroxyestrone (2-OHE1) acts as an estrogen antagonist (Figure 1). It is unclear whether the absolute concentration of these metabolites determines the eventual biological effect on breast tissue, or whether it is the ratio between the two metabolites (2-OHE1/16α-OHE1) that is of greater importance21. A prospective nested case-control study involving 10 786 women concluded that premenopausal women with a ratio favoring 2-over 16α-hydroxylation had a reduced risk of breast cancer. This relationship was not noted for postmenopausal women22. Others showed that urinary estrone, estradiol and estriol excretion in postmenopausal women was more reflective of breast cancer risk than the 2-OHE1 and 16-OHE1 metabolites and their ratio23. Both studies evaluated untreated women.
Sex Hormones in Autoimmunity
Published in Istvan Berczi, Pituitary Function and Immunity, 2019
Elizabeth S. Raveche, Alfred D. Steinberg
In addition, patients with SLE were also found to have alterations in the metabolism of estrogens (see Figure 2),16 namely increased 16-hydroxylation of estrone. The 16-hydroxylated metabolites of estradiol retain substantial peripheral estrogenic activity. Furthermore, 16-hydroxyestrone can form stable covalent adducts with proteins both in vitro and in vivo, which may be recognized in patients with SLE as foreign antigens and trigger autoimmune responses. Pregnancy and phasic estrogen secretion during the menstrual cycle increase the levels of 16-hydroxylated metabolites.17 Thus, further increases in 16-hydroxyestrone may cause a worsening of the disease either because of the formation of antigenic 16-hydroxyestrone-protein adducts or by modulation of the immune response because of the increase in estrogenic activity. 16-Hydroxyestrone is highly estrogenic in vivo and possesses a low binding affinity for the estrogen receptor.18 This suggests that abnormal estrogen metabolism may lead to increased estrogenic activity and secondary abnormalities.
Hormones and Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Heather Spencer Feigelson, Roberta McKean-Cowdin
More consistent data are accumulating to suggest that CYP17 is a modifier of other breast cancer risk factors, such as age at menarche and parity (106,92). At least three studies have shown that the protective effect of later onset of menarche was limited to women with the A1 /A1 genotype (95,97,106). One study has shown that CYP17 genotype was associated with estrogen metabolites measured in urine (107). The ratio between 2-hydroxyestrone (2OHE) and 16α-hydroxyestrone (16αOHE) demonstrated a dose–response relationship by which women with the A1/A1 genotype had the highest urinary ratio of 2OHE to 16αOHE (median = 1.47) and women with the A2/A2 genotype had the lowest ratio (median = 1.21, p = 0.01. Lower 2OHE:16αOHE ratios may be associated with increased risk of breast cancer (108,109). Thus, this observation is compatible with the hypothesis that the CYP17 A2 allele confers a higher risk of breast cancer.
Effectiveness of 3,3′-Diindolylmethane Supplements on Favoring the Benign Estrogen Metabolism Pathway and Decreasing Body Fat in Premenopausal Women
Published in Nutrition and Cancer, 2023
Estela Godínez-Martínez, René Santillán, Reyna Sámano, Gabriela Chico-Barba, Mari Cruz Tolentino, Jessica Hernández-Pineda
Estrogen metabolism itself has been associated with breast cancer (3–7). The major hydroxylation products of estrogen metabolism include 2-hydroxyestrogens and 16α-hydroxyestrone (8). Although both have estrogenic properties, the 16α-hydroxyestrone metabolite is thought to be a more potent estrogen that binds covalently to the estrogen receptor (9). Several studies have reported a negative association between the Estrogen Metabolites (2-hydroxyestrogens:16α-hydroxyestrone) Urine Ratio (EMUR) and breast cancer (3–7). Ho et al. found that women with an EMUR <0.9 have ten times the risk of developing breast cancer than women with an EMUR ≥0.9 (7). Other studies also suggest that the estrogen metabolic pathway that favors 2-hydroxylation over 16α-hydroxylation—which could be translated into a greater EMUR—is associated with reducing the risk of certain types of cancer: prostate (10), proliferative thyroid disease (11), human liver carcinogenesis (12), and endometrial cancer (13). In a recently-published study, Sawicka et al. found that 2-hydroxyestrogens had the most protective effect (or least toxicity) on ovary cancer lines, followed by estradiol, and then lastly, 16α-hydroxyestrone (14). EMURs vary across genetically different populations: Caucasian women have higher EMUR than African American women (2.06 vs. 1.65) (15), and we previously found that Mexican women have lower EMUR than either of those groups (0.9) (16).
Effect of Dietary Flaxseed Intake on Circulating Sex Hormone Levels among Postmenopausal Women: A Randomized Controlled Intervention Trial
Published in Nutrition and Cancer, 2019
Vicky C. Chang, Michelle Cotterchio, Beatrice A. Boucher, David J. A. Jenkins, Lucia Mirea, Susan E. McCann, Lilian U. Thompson
The possible protective effects of flaxseed and lignans on breast cancer risk are thought to be mediated through modulation of sex hormone synthesis, metabolism, and activity (12). It is widely accepted that endogenous sex hormones play a role in breast cancer etiology. In particular, higher circulating levels of estrogens (e.g., estradiol, estrone), androgens (e.g., testosterone), and prolactin have been associated with increased postmenopausal breast cancer risk (18–20). Metabolites formed from the hydroxylation of estrogens, as well as their relative abundance, have also been linked to breast cancer development (21–23). Notably, a high ratio of 2-hydroxylation to 16-hydroxylation pathway estrogen metabolites has been associated with reduced breast cancer risk (22,23). In addition, 2-hydroxyestrone has been shown to exert antiestrogenic activity, which may counteract the estrogen-agonist and cell proliferation effects of 16α-hydroxyestrone (24–27). Although exact mechanisms remain to be elucidated, lignans have been suggested to exert anticancer effects by competing with estrogens for binding to estrogen receptors, resulting in altered estrogen-sensitive gene expression, and subsequently, decreased cell proliferation and increased apoptosis (12). Furthermore, lignans may interact with key enzymes involved in hormone synthesis and metabolism (e.g., aromatase) to modulate relative levels of circulating sex hormones and their metabolites (28,29).
Higher Fruits and Vegetables Consumption Is not Associated with Risk of Breast Cancer in Iranian Women
Published in Nutrition and Cancer, 2022
Maryam Safabakhsh, Sakineh Shab-Bidar, Hossein Imani
Each FV contains its exclusive combination of numerous plausible nutritive and nonnutritive compounds that exert anti-tumor effects (29). Carotenoids (30), β-carotene (31), lycopene (32), folate (33), vitamin C (34), vitamin E (35), B-vitamin pyridoxine (vitamin B6) (36), selenium (37), and quercetin (38) contents of FVs have protective effect through different mechanisms. Also, FVs have the most contribution in raising the dietary total antioxidant capacity (DTAC) (39). Although, in another study in this population, we did not find any significant association between DTAC and BC risk (40). Likewise, our analysis did not indicate any anti-carcinogenic effect of citrus fruits, but vitamin C abundantly found in citrus fruits traps free radicals and reactive oxygen molecules, and regenerates other antioxidant vitamins (41). Also, two citrus flavonoids, hesperetin and naringenin in orange and grapefruit, respectively play a protective role on BC cell proliferation In Vitro (42). It was demonstrated that cruciferous vegetables have been shown to shift production of the estrogen metabolite 16-hydroxyestrone to the less potent estrogen metabolite 2-hydroxyestrone. This change in estrogen metabolite production is protective against estrogen-dependent cancers such as BC, because, higher levels of estradiol, 16-hydroxyestrone has been contributed to increased BC proliferation in murine models (43). The existance of the mentioned negative association between berry consumption and BC risk in our study can be justified by wide range of phytochemicals in berry such as cyanidin, delphinidin, quercetin, kaempferol, ellagic acid, resveratrol, and pterostilbene. Berry elicits anticancer effect via inducing apoptosis and autophagy which resulted in reducing the risk of BC (44). Moreover, the anticancer effects of blueberry were attributed to desirable molecular changes such as down-regulation of cytochrome p450, subfamily i, polypeptide 1 (CYP1A1) and estrogen receptor alpha (ER-α) gene expression, controlling estradiol (E2) metabolism and signaling, respectively (45, 46). Regarding dietary fiber, it has been suggested that in the gut, dietary fiber inhibit reabsorption of estrogen excreted in the biliary system (47). On the other hand, there is evidence that an acidic environment may accelerate cancer cell proliferation (48, 49) while FVs intakes provide a more alkaline environment (50, 51). Nevertheless, a study on this population suggested no significant relationship between dietary acid load (DAL) and BC risk (52).