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The Estrogen Metabolites (2-hydroxyestrogens: 16α-hydroxyestrone) Urine Ratio (EMUR) has been negatively associated with breast cancer; Mexican women have a lower EMUR than other populations. We evaluated the effectiveness of 3,3′-diindolylmethane (DIM) supplementation on increasing EMUR in premenopausal women. A randomized, double-blind clinical trial (NCT02525159 at ClinicalTrial.gov) was carried out on 60 women with an EMUR below 0.9. Patients were assigned randomly to receive a placebo or 75 mg of DIM a day (administered as 300 mg of DIM-BR®) for 30 day. Urine samples were obtained at baseline, at 30 day of supplementation, and 30 day after finishing supplementation. A Mann-Whitney U test was used to compare the EMUR; an ANOVA was used to analyze differences in body composition. EMUR was analyzed using ESTRAMET™ kits. While DIM-treated subjects did not increase their EMUR at 30 day of supplementation (p > 0.05), there was a non-significant positive trend 30 day once supplementation ended (p = 0.06). The DIM group saw a more significant decrease in body fat percentage than the placebo group (p = 0.04). In premenopausal Mexican women, 75 mg of the daily DIM supplement was ineffective in increasing EMUR; further studies are needed to evaluate the effective dosage, time frames, and effect on body fat. [ABSTRACT FROM AUTHOR]

Endogenous estrogens have been associated with overall breast cancer risk, particularly for postmenopausal women, and ways to reduce these estrogens have served as a primary means to decrease overall risk. This narrative review of clinical studies details how various nutritional and exercise lifestyle interventions have been used to modify estrogen levels and metabolism to provide a protective impact against breast cancer incidence. We also summarized the evidence supporting the efficacy of interventions, outcomes of interest and identified emerging research themes. A systematic PubMed MEDLINE search identified scholarly articles or reviews published between 2000-2020 that contained either a cohort, cross-sectional, or interventional study design and focused on the relationships between diet and/or exercise and overall levels of different forms of estrogen and breast cancer risk and occurrence. Screening and data extraction was undertaken by two researchers. Data synthesis was narrative due to the heterogeneous nature of studies. A total of 1625 titles/abstracts were screened, 198 full texts reviewed; and 43 met eligibility criteria. Of the 43 studies, 28 were randomized controlled trials, and 15 were observational studies. Overall, studies that incorporated both diet and exercise interventions demonstrated better control of detrimental estrogen forms and levels and thus likely represent the best strategies for preventing breast cancer development for postmenopausal women. Some of the strongest associations included weight loss via diet and diet + exercise interventions, reducing alcohol consumption, and consuming a varied dietary pattern, similar to the Mediterranean diet. More research should be done on the effects of specific nutritional components on endogenous estrogen levels to understand the effect that the components have on their own and in combination within the diet. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is more frequently observed and aggressive in men compared with women. Increasing evidence demonstrates that the sex disparity appears to be mediated by the stimulatory effects of androgens and the protective effects of estrogen in the development and progression of HCC. In the past few decades, studies on the sex difference of HCC mainly focused on the effect of sex hormones on the transactivation of hepatitis B virus X protein and the release of inflammatory cytokines, and these studies have further intensified in recent years. Sex hormones are also involved in genetic alterations and DNA damage repair in hepatocytes through binding to their specific cellular receptors and affecting the corresponding signaling pathways. Furthermore, the theory of sex chromosomes participating in HCC has been considered. The present review discussed the recent advances in the molecular mechanisms of sex disparity in HCC, with the aim of improving the understanding of the underlying critical factors and exploring more effective methods for the prevention and treatment of HCC. [ABSTRACT FROM AUTHOR]

Lignan intake, and its richest food source, flaxseed, have been associated with reduced breast cancer risk. Endogenous sex hormones, such as estrogens, play a role in breast cancer development, and lignans may alter these sex hormone levels. To assess the effect of flaxseed on circulating sex hormones, a randomized controlled trial was conducted among 99 postmenopausal women in Toronto, Canada. The intervention arm consumed 2 tablespoons (15 g) of ground flaxseed daily for 7 weeks; the control arm maintained usual diet. Baseline and week 7 concentrations of 14 serum sex hormones were measured using liquid chromatography–tandem mass spectrometry (LC-MS/MS) and immunoassay, and serum enterolignans (lignan biomarker) using LC-MS/MS. Intervention effects on sex hormone levels were assessed using analysis of covariance. Serum enterolignans increased among the flaxseed arm (+516%). Women consuming flaxseed (vs. controls) had increased serum 2-hydroxyestrone [treatment effect ratio (TER) = 1.54; 95% CI: 1.18–2.00] and 2:16α-hydroxyestrone ratio (TER =1.54; 95% CI: 1.15–2.06); effects on other hormones were not statistically significant. Within the flaxseed arm, change in enterolignan level was positively correlated with changes in 2-hydroxyestrone and 2:16α-hydroxyestrone ratio, and negatively with prolactin. Findings suggest flaxseed affects certain circulating sex hormone levels with possible implications for future breast cancer prevention research. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and accounts for the third-leading cause of cancer-related deaths. Over the past decades, advances have been made in the field of surgery, but effective treatment of HCC is lacking. Due to a marked male predominance in morbidity and mortality in HCC patients, it has long been considered that sex hormones play a role in HCC development. Recently estrogen has been proven to exert protective effects against HCC through IL-6 restrictions, STAT3 inactivation and tumour-associated macrophage inhibition. While IL-6-dependent STAT3 activation is considered a key event in inflammation-induced liver cancer, the anti-inflammation effect of estrogen is well documented. The roles of the estrogen receptor and aromatase and interactions between microRNAs and estrogen in HCC have been investigated. In this review, we present a novel model to elucidate the mechanism of estrogen-mediated inhibition of HCC development through an anti-inflammation effect and provide new insights into the roles of estrogen in liver disease. [ABSTRACT FROM AUTHOR]

Accumulating data suggest arsenic may be an endocrine disruptor and tentatively linked to breast cancer by some studies. Therefore, we tested the effects of chronic inorganic arsenic exposure on the normal estrogen receptor (ER)-negative breast epithelial cell line, MCF-10A. Cells were chronically exposed to a low-level arsenite (500 nM) for up to 24 weeks. Markers of cancer cell phenotype and the expression of critical genes relevant to breast cancer or stem cells (SCs) were examined. After 24 weeks, chronic arsenic-exposed breast epithelial (CABE) cells showed increases in secreted MMP activity, colony formation, invasion, and proliferation rate, indicating an acquired cancer cell phenotype. These CABE cells presented with basal-like breast cancer characteristics, including ER-α, HER-2, and progesterone receptor negativity, and overexpression of K5 and p63. Putative CD44/CD24 breast SCs were increased to 80 % over control in CABE cells. CABE cells also formed multilayer cell mounds, indicative of loss of contact inhibition. These mounds showed high levels of K5 and p63, indicating the potential presence of cancer stem cells (CSCs). Epithelial-to-mesenchymal transition occurred during arsenic exposure. Overexpression of aromatase, a key rate-limiting enzyme in estrogen synthesis, occurred with arsenic starting early on in exposure. Levels of 17β-estradiol increased in CABE cells and their conditioned medium. The aromatase inhibitor letrozole abolished arsenic-induced increases in 17β-estradiol production and reversed cancer cell phenotype. Thus, chronic arsenic exposure drives human breast epithelia into a cancer cell phenotype with an apparent overabundance of putative CSCs. Arsenic appears to transform breast epithelia through overexpression of aromatase, thereby activating oncogenic processes independent of ER. [ABSTRACT FROM AUTHOR]

Purpose: No population-based study has investigated breast cancer (BC) subtypes defined by including Ki67. The aim of this study was to evaluate the relative proportions of immunohistochemical subtypes and differences in relative and disease-free survival between subtypes, in relation to patient and other cancer characteristics in Italian BC patient. Methods: Information on estrogen, progesterone, human epidermal growth factor (HER2), Ki67, and relapses was obtained for 3,381 cases, sampled randomly and anonymously from cases diagnosed in 2003-2005 in nine Italian cancer registries. Relative excess risks (RERs) of death and risks of relapse 5 years after diagnosis were estimated. Results: Luminal A cancers were 42 % of the total, luminal B 27 %, luminal-HER2 14 %, triple-negative 11 %, and HER2-enriched 7 %. For non-metastatic (3,302) cases, 4 and 7 % developed locoregional and distant metastases, respectively. RERs of death and risks of relapse were significantly greater for all cancer subtypes than luminal A, particularly for triple-negative and HER2-enriched cancers, which were more frequent in women <40 years. Conclusions: Our population-based findings confirm that subtype is an independent prognostic factor for BC. Triple-negative and HER2-enriched subtypes would benefit from the development and wide application, respectively, of targeted treatments, which would also improve survival for younger patients. [ABSTRACT FROM AUTHOR]

Circulating estrogens are an established risk factor for breast cancer and some data suggest that diet may influence estrogen levels. Therefore, using a subsample ( n = 550) of women from a large cohort, we applied reduced rank regression to identify a dietary pattern that was correlated with estradiol and estrone sulfate. We then adapted the pattern to be used with the full cohort ( n = 67,802) and prospectively assessed its association with postmenopausal breast cancer. The estrogen food pattern, characterized by higher intakes of red meat, legumes, and pizza, but lower intakes of coffee and whole grains, was modestly but significantly correlated with estradiol ( r = 0.14) and estrone sulfate ( r = 0.20). During 22 years of follow-up, we ascertained 4,596 incident breast cancer, with 2,938 estrogen receptor-positive tumors and 689 estrogen receptor-negative tumors. However, after adjusting for potential confounders, we did not observe any association with overall estrogen receptor-positive or estrogen receptor-negative breast cancer. In conclusion, diet pattern appeared to only have modest association with estrogens, and was not associated with postmenopausal breast cancer risk. Although these results were null, it should be repeated in other populations as differences in food intake may yield a dietary pattern with stronger association with estrogens. [ABSTRACT FROM AUTHOR]

BACKGROUND: [ABSTRACT FROM AUTHOR]

Cell death processes have been widely investigated in recent years in order to elucidate the different pathways involved in the complex machinery implicated in determining cell fate. Different forms of cell death have been described: Apart from the classical form of death known as necrosis, a well-characterized traumatic injury of the cell, several additional forms of cell death have been identified. Of these, apoptosis has been characterized in the greatest detail. Defects in the mechanisms of cell demise (that is, an excess of or decrease in apoptosis) have been associated with the pathogenesis of a number of human diseases. Here we review some new aspects derived from recent insights into this field, particularly the hypothesis that cells of males and females could display several different features, including those determining their fate. [ABSTRACT FROM AUTHOR]

Evaluates the application of sex hormone adjuvanting therapy in rheumatoid arthritis. Circulating plasma concentrations of sex hormones; Ratio of androgens to estrogens; Influence of different types of psychosocial stressors on neuroendocrine and immune mechanisms.

Simple Summary: Today, we know that estrogen hormones are required for the development and function of many organs, such as the liver, in both males and females. However, in some circumstances, estrogen excess may be implicated in the appearance of various chronic diseases, including cancer. This review will inspect the results of several studies to better understand the mechanisms responsible for estrogens to change from protective into harmful hormones in human liver. Estrogens are recognized as key players in physiological regulation of various, classical and non-classical, target organs, and tissues, including liver development, homeostasis, and function. On the other hand, multiple, though dispersed, experimental evidence is highly suggestive for the implication of estrogen in development and progression of hepatocellular carcinoma. In this paper, data from our own studies and the current literature are reviewed to help understanding this apparent discrepancy. [ABSTRACT FROM AUTHOR]

Estrogen evidently involves critically in the pathogenesis of gynaecological-cancers. Reports reveal that interference in estrogen-signalling can influence cell-cycle associated regulatory-processes in female reproductive-organs. The major determinants that influence E2-signallings are estrogen-receptor (ER), estrogen-sulfotransferase (SULT1E1), sulfatase (STS), and a formylglycine-generating-enzyme (FGE) which regulates STS activity. The purpose of this mini review was to critically analyze the correlation between oxidative-threats and redox-regulation in the process of estrogen signalling. It is extensively investigated and reported that oxidative-stress is linked to cancer. But no definite mechanism has been explored till date. The adverse effects of oxidative-threat/free-radicals (like genotoxic-effects, gene-regulation, and mitochondrial impairment) have been linked to several diseases like diabetes/cardiovascular-syndrome/stroke and cancer. However, a significant correlation between oxidative-stress and gynaecological-cancers are repeatedly reported without pointing a definite mechanism. For the first time in our study we have investigated the relationship between oxidative stress and the regulation of estrogen via estrogen metabolizing proteins. Reports reveal that ER, SULT1E1, STS and FGE are target-molecules of oxidative-stress and may function differently in oxidizing and reducing environment. In addition, estrogen itself can induce oxidative-stress. This fact necessitates identifying the critical connecting events between oxidative-stress and regulation of estrogen-associated-molecules (ER, SULT1E1, STS, and FGE) that favors tumorigenesis/carcinogenesis. The current review focus is on unique redox-regulation of estrogen and its regulatory-molecules via oxidative-stress. This mechanistic-layout may identify new therapeutic-targets and open further scopes to treat gynecological-cancers more effectively. [ABSTRACT FROM AUTHOR]