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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
A simplified scheme for the metabolism of estrogens is presented in Figure 2. Estriol is the most abundant estrogen in the urine and is the product of the metabolism of estrone and estradiol. Estradiol secretion is increased in obesity.10 Estriol has been shown to act as an antiestrogen, perhaps because of its short-term occupancy of estrogen receptor.11 However, if given continuously, it acts as a strong estrogen since the estriol-receptor complexes are continuously translocated to the nucleus where it specifically binds to nonhistone proteins of chromatin eventually leading to messenger RNA production and finally protein formation. 2-Hydroxyestrone, which has a high affinity for the estrogen receptor, behaves as an antiestrogen and is not uterotropic.12 Testostrone and androstenedione are metabolized to 17-ketosteroids, mainly androsterone and eticholanolone.
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.
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).
The WHO claims estrogens are ‘carcinogenic’: is this true?
Published in Climacteric, 2023
Since increased 16-OH-E1 in urine was associated with increased breast cancer risk whereas 2-hydroxylation was not, the use of the urinary ‘2/16 ratio of hydroxy estrogens’ was suggested as a predictive marker for carcinogenesis. However, the results are inconsistent, with some showing a strong association with breast cancer risk with decreasing 2-OH-E1/16-OH-E1 ratio [74] and others not [75]. In our own case–control study including 144 women with breast cancer and 292 controls, respectively, we found lower excretion of 2-hydroxyestrone and higher excretion of 16-OH-E1 in the cases compared to the controls, but only in postmenopausal women [76].
Synthesis, characterization and in vivo evaluation of cadmium telluride quantum dots toxicity in mice by toxicometabolomics approach
Published in Toxicology Mechanisms and Methods, 2018
Maryam Khoshkam, Yasamin Baghdadchi, Roghaye Arezumand, Ali Ramazani
Treatment of mice with different doses of QDs and CdCl2 resulted in alterations in the following pathways: steroid hormone biosynthesis, lysine biosynthesis, steroid biosynthesis, taurine and hypotaurine metabolism, starch, and sucrose metabolism and primary bile acid biosynthesis. Since only the first two of these pathways were considered statistically significant (p < 0.05 and FDR < 1), we will restrict our discussion to them. Our data in Table 2 exhibited that among altered pathways; steroid hormone biosynthesis shows the most significant perturbation in treated groups. Information on Table 2 shows that 72 metabolites are involved in the biosynthesis of steroid hormones, which 22 of them are altered due to treatment with QDs or CdCl2. One study consistent with our data reports that different nanoparticles can alter the endocrine system in different levels including biosynthesis of hormones (Iavicoli et al. 2013). Aldosterone, cortisone, estrogens, and progesterone are main altered metabolites. Also, cholesterol and cholesterol sulfate as the main precursors of steroid hormones are changed. Since the studied mice were female here and metalloestrogenic effects of cadmium have been demonstrated before, the alteration of estrogenic metabolites is more notable. Cadmium activates MAPK/ERK, and Ref-1 and is known as a potent activator/modulator of the mitogenic effects associated with estrogen receptor stimulation (Wallace 2015). In vivo studies have shown that cadmium mimics the effects of estrogen in target organs and induce hormone-regulated genes in ovariectomized animals (Johnson et al. 2003). Specific hormonal conditions and disturbed hormonal homeostasis was reported due to cadmium exposure (Silva et al. 2012). Although there are persuasive in vitro and in vivo studies regarding the metalloestrogenic effect of cadmium, the data are conflicting and not concentrated. Thus, we face a knowledge gap in this area (Nasiadek et al. 2011). Our data exhibited altered levels of several estrogenic metabolites including 16a-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestrone, 2-methoxyestradiol, 2-methoxyestrone, estradiol, and 2-methoxyestradiol. Nevertheless, the mechanism of induced alteration by cadmium remains to be elucidated.